Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26](=[O:45])[CH2:27][C@@H:28]([O:43][CH3:44])[C@@H:29]([N:34]([CH3:42])[C:35](=[O:41])[C@H:36]([CH:38]([CH3:40])[CH3:39])[NH2:37])[C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@@H:4]([CH3:20])[C:5]([NH:7][C@H:8]([C:16]([O:18]C)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].[CH3:46][N:47]1[CH2:54][CH2:53][CH2:52][C@:48]1([CH3:55])[C:49](O)=[O:50].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.[Li+].[OH-]>ClCCl.O>[CH3:46][N:47]1[CH2:54][CH2:53][CH2:52][C@:48]1([CH3:55])[C:49]([NH:37][C@H:36]([C:35]([N:34]([C@@H:29]([C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@H:28]([O:43][CH3:44])[CH2:27][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:21]1[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:20])[C:5]([NH:7][C@H:8]([C:16]([OH:18])=[O:17])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:6])=[O:45])[CH3:42])=[O:41])[CH:38]([CH3:39])[CH3:40])=[O:50]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CN1CCC[C@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCN1C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring mixture of #114 (240 mg, 0.379 mmol, 1.0 eq.), #152 (71 mg, 0.49 mmol, 1.3 eq.), and HATU (188 mg, 0.49 mmol, 1.3 eq.) in 10 mL of dichloromethane, Hunig's base (0.27 mL, 4.1 mM, 4.1 eq.) was added. The reaction was allowed to stir at room temperature for 1 hour. Reaction was concentrated in vacuo. THF (6 mL) was added to crude material. To this stirring mixture LiOH (36 mg, 1.5 mmol, 4 eq.) dissolved in 2 mL of water was added. Reaction was allowed to stir at room temperature for 1 hour. Reaction was concentrated in vacuo and residue was purified by medium pressure reverse phase C18 chromatography (Gradient: 5% to 40% acetonitrile in water with 0.02% TFA in each phase) #153 (220 mg, 78%) as a white solid. LC-MS (Protocol Q): m/z 744.8 [M+H+], retention time=1.16 minutes; HPLC (Protocol A at 45° C.): /z 744.4 [M+H+], retention time=6.713 minutes (purity >98%). 1H NMR (400 MHz, DMSO-d6), δ 9.72-9.85 (m), 8.65 (t), 8.41 (d), 8.14 (d), 7.14-7.28 (m), 4.69-4.79 (m), 4.38-4.53 (m), 3.95-4.04 (m), 3.73-3.79 (m), 3.37-3.62 (m), 3.13-3.33 (m), 2.95-3.10 (m), 2.79-2.89 (m), 2.67-2.75 (m), 2.00-2.46 (m), 1.61-1.90 (m), 1.22-1.54 (m), 1.02-1.09 (m), 0.95-1.01 (m), 0.85-0.94 (m), 0.75-0.83 (m)
Reaction SMILES: [CH2:1]([N:8]1[C:14](=O)[C:13]2[CH:16]=[CH:17][CH:18]=[C:19]([Br:20])[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.CO.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:19]([Br:20])[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2cccc(Br)c2OCCN1Cc1ccccc1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Brc1cccc2c1OCCN(Cc1ccccc1)C2
Temperature: 60 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To a solution of 4-benzyl-9-bromo-3,4-dihydro-1,4-benzoxazepine-5 (2H)-one (8.00 g, 24.1 mmol) in tetrahydrofuran (80 ml) was added 1M borane-tetrahydrofuran solution (96.4 ml, 96.4 mmol), and the mixture was stirred at 60° C. for 2 hr. Under ice-cooling, methanol (240 ml) and sodium hydroxide (20.8 g, 519 mmol) were added, and the mixture was stirred at room temperature for 2 hr, and the solvent was evaporated under reduced pressure. The residue was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the desired product (6.20 g, 80.8%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:9]=1[NH:10][CH3:11])[C:7]#[N:8].[H-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].CO>CN(C=O)C>[CH2:19]([O:18][C:16]([C:15]1[N:10]([CH3:11])[C:9]2[C:2]([F:1])=[CH:3][N:4]=[CH:5][C:6]=2[C:7]=1[NH2:8])=[O:17])[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: CNc1c(F)cncc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(=O)c1c(N)c2cncc(F)c2n1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
5-Fluoro-4-methylamino-nicotinonitrile (2.35 g, 15 mmol) was dissolved in DMF (50 mL) and the solution cooled in an ice-bath. This solution was treated portionwise with sodium hydride (900 mg, 60% in oil, 22.5 mmol). The mixture was allowed to warm to room temperature and stirring continued for 15 minutes at room temperature. Ethyl bromoacetate (2.49 ml, 22.5 mmol) was added and the mixture stirred for 30 minutes at room temperature The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was isolated, dried (Na2SO4) and evaporated to give a solid. Trituration of the resultant solid with methanol gave the title compound (1.85 g, 52%) as a yellow solid. LCMS (method B): RT=2.09 min, M+H+ 238.
Reaction SMILES: C([N:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[C@H:10]([OH:15])[CH2:9]1)C1C=CC=CC=1.[ClH:16]>C(O)C.[Pd]>[ClH:16].[CH3:13][C:11]1([CH3:14])[CH2:12][NH:8][CH2:9][C@H:10]1[OH:15]
Reactant: CC1(C)CN(Cc2ccccc2)C[C@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1(C)CNC[C@H]1O

Procedure:
A solution of 6.34 g (41.7 mmol) of (3S)-1-benzyl-4,4-dimethyl-3-pyrrolidinol in 250 mL of ethanol and 50 mL of 1N hydrochloric acid was stirred under hydrogen (40 psi) for 18 h in the presence of 300 mg of 10% Pd/C, after which the amount of 10% Pd/C was doubled and 2 mL of concentrated hydrochloric acid were added. The mixture was stirred for an additional 72 h under hydrogen (40 psi), before the 10% Pd/C was filtered off over celite. The filtrate was concentrated and several portions of toluene were distilled from the residue, which was then dried under high vacuum to afford 4.74 g (quantitative yield) of (3S)-4,4-dimethyl-3-pyrrolidinol hydrochloride. 1H NMR (300 MHz, DMSO-d6) δ 9.46 (m, 2H), 5.43 (br s, 1H), 3.75 (m, 1H), 3.36 (m, 1H), 2.88 (m, 3H), 0.98 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:13][C:12]=3[CH:11]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:35][NH2:36]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH:36][CH3:35])[CH2:13][C:12]=3[CH:11]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cc(-c3ccccc3)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)cc1
Reactant: CN
Product: CNCC1Cc2cc(-c3ccccc3)cc(-c3ccc(C)cc3)c2O1

Procedure:
The title compound was prepared (0.051 g, 65%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(4-methylphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.10 g, 0.213 mmol) and methylamine (0.30 g, 9.8 mmol). mp >250° C.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:14][C:15](=[O:29])[NH:16][C@H:17]([C:22]([N:24]1[CH2:27][CH:26](O)[CH2:25]1)=[O:23])[C@@H:18]([CH3:21])[CH2:19][CH3:20])([CH3:13])([CH3:12])[CH3:11]>ClCCl.C(OCC)(=O)C>[C:10]([O:14][C:15](=[O:29])[NH:16][C@H:17]([C:22]([N:24]1[CH2:27][CH:26]([F:7])[CH2:25]1)=[O:23])[C@@H:18]([CH3:21])[CH2:19][CH3:20])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(O)C1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To a cooled (−78° C.) solution of diethylaminosulfur trifluoride (0.46 mL, 3.5 mmol) in dichloromethane (6 mL), was added dropwise a solution of [(1S,2S)-1-(3-hydroxy-azetidine-1-carbonyl)-2-methyl-butyl]-carbamic acid tert-butyl ester (1.0 g, 3.5 mmol) in dichloromethane (4 mL). The mixture was warmed to room temperature, stirred overnight, then diluted with ethyl acetate and poured into ice/water. The layers were separated, and the organic phase washed with water and brine, dried over magnesium sulfate and concentrated. The product was purified by flash-chromatography (ethyl acetate) and isolated as an oil (250 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17]([I:19])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:30]([CH3:32])[CH3:31]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:20])[C:12]3[CH:18]=[C:17]([I:19])[S:16][C:13]=3[N:14]([CH:30]([CH3:32])[CH3:31])[CH:15]=2)=[O:9])=[CH:21][CH:22]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(I)cc2c1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)sc21
Temperature: 90 °C
Reaction time: 18 h
Yield: 39 %

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-2-iodothieno-[2,3-b]pyridine-5-carboxamide (Example No. 2) (2.00 g) in DMF (14 mL) are added K2CO3 (1.76 g) and 2-bromopropane (1.19 mL). The reaction is heated to 90° C. and stirred for 18 h. The reaction mixture is concentrated in vacuo. The resulting residue is partitioned between H2O (100 mL) and CH2Cl2 (200 mL). The aqueous layer is extracted with CH2Cl2 (3×150 mL). The combined organic layers are dried with MgSO4, filtered and concentrated in vacuo. The resulting yellow solid is purified via column chromatography (CH2Cl2, CH2Cl2:CH3OH; 99:1). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a yellow solid. This material is recrystallized from ethanol then methanol to yield 0.808 g (39%) of the title compound as an off-white solid.
Reaction SMILES: [O:1]=[C:2]1[CH:15]([C:16](O)=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([C:19]([OH:21])=[O:20])[NH:3]1.N1CCCCC1.C=O.Cl>N1C=CC=CC=1>[CH2:16]=[C:15]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([C:19]([OH:21])=[O:20])[NH:3][C:2]1=[O:1]
Reactant: O=C(O)C1CCCCCCCCCCC(C(=O)O)C(=O)N1
Agent: C=O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: C=C1CCCCCCCCCCC(C(=O)O)NC1=O
Temperature: 65 °C

Procedure:
2-oxo-1-azacyclotetradecane-3,14-dicarboxylic acid (0.868 g, 2.9 mmol) is dissolved in pyridine (15.0 mL). Piperidine (0.060 mL, 0.59 mmol) is added, followed by paraformaldehyde (0.133 g, 4.43 mmol), and the reaction is heated to 65° C. for 4 hours. The reaction is then cooled to 0° C., and concentrated hydrochloric acid is added to bring the pH to approximately 2. The reaction is partitioned between ethyl acetate and water, and the aqueous phase is extracted several times with ethyl acetate. The combined organic layers are dried (Na2SO4), and the solvent is evaporated to give 3-methylidene-2-oxo-1-azacyclotetradecane-14-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15][CH:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[C:17]([F:20])([F:19])[F:18])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([N+:12]([O-])=O)=[CH:7][CH:6]=2.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[C:3]([O:15][CH:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[C:17]([F:19])([F:20])[F:18])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([NH2:12])=[CH:7][CH:6]=2
Reactant: O=[N+]([O-])c1ccc2nc(OC(c3cccnc3)C(F)(F)F)c(Cl)nc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2nc(OC(c3cccnc3)C(F)(F)F)c(Cl)nc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
In a mixed solvent of ethanol (19.5 mL) and water (9.75 mL) was dissolved 3-chloro-6-nitro-2-(2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy)quinoxaline (975 mg, 2.53 mmol) obtained in Step 2. To the solution were added iron (0) (425 mg, 7.60 mmol) and ammonium chloride (68.0 mg, 1.27 mmol) and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was filtered through Celite and the filtrate was extracted with ethyl acetate. Washing with saturated brine and drying over anhydrous magnesium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 0/1) to give 3-chloro-2-(2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy) quinoxaline-6-amine (555 mg, 62% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:15][C@H:16]1[O:21][C@@H:20]([CH2:22]I)[CH2:19][CH2:18][CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:5])[CH3:2].[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.[K].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]([CH2:15][C@H:16]1[O:21][C@@H:20]([CH2:22][N:28]2[C:27](=[O:29])[C:26]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]3[C:24]2=[O:34])[CH2:19][CH2:18][CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:5])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)N(Cc1ccc(F)cc1)C[C@@H]1CCC[C@H](CI)O1
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N(Cc1ccc(F)cc1)C[C@@H]1CCC[C@H](CN2C(=O)c3ccccc3C2=O)O1
Temperature: 100 °C
Reaction time: 10 h
Yield: 202.3 %

Procedure:
To a solution of cis-6-[N-ethoxycarbonyl-N-(p-fluorobenzyl)aminomethyl]-2-iodomethyltetrahydropyrane (2.71 g, 5.10 mmol) in dimethylformamide (30 ml) was added potassium phthalimide (1.04 g, 5.61 mmol) and the mixture was stirred at 100° C. for 10 hours. To the reaction mixture was added ethyl acetate (200 ml), washed successively with purified water (50 ml) and saturated aqueous sodium chloride (50 ml), dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give crude cis-6-[N-ethoxycarbonyl-N-(p-fluorobenzyl)aminomethyl]-2-phthalimidomethyltetrahydropyrane (4.69 g). This compound was used for the subsequent reaction without purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:18][CH2:17]2)[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:44])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[C:34]([CH2:35][O:36]C3CCCCO3)=[CH:33][N:32]=[N:31]2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH:16]2[CH2:18][CH2:17]2)[CH3:15])=[CH:13][C:8]2[N:7]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]4[C:34]([CH2:35][OH:36])=[CH:33][N:32]=[N:31]4)[CH:25]=3)[CH2:22][C:21](=[O:44])[NH:20][C:9]=2[CH:10]=1
Reactant: CN(c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2)C1CC1

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-(cyclopropyl-methyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert.-butyl ester (Example M33) (200 mg, 0.313 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (54 mg).
Reaction SMILES: [CH3:1][C:2]1OC([Si](C)(C)C)=[CH:4][C:3]=1C=O.CI.[CH2:15]([Si:17]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:18]1[O:19][CH:20]=[C:21]([CH:23]=[O:24])[CH:22]=1)[CH3:16].ICCCC>>[CH2:1]([C:20]1[O:19][C:18]([Si:17]([CH2:25][CH3:26])([CH2:15][CH3:16])[CH2:27][CH3:28])=[CH:22][C:21]=1[CH:23]=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Reactant: Cc1oc([Si](C)(C)C)cc1C=O
Solvent: CCCCI
Solvent: CI
Product: CCCCc1oc([Si](CC)(CC)CC)cc1C=O

Procedure:
Using the same procedure as for 5-methyl-2-trimethylsilyl-4-furaldehyde but substituting 2-trimethylsilyl-4-furaldehyde and methyl iodide with 2-triethylsilyl-4-furaldehyde and 1-iodobutane, respectively, gives 5-butyl-2-triethylsilyl-4-furaldehyde. IR (neat) 1690 cm-1; 'HNMR (CDCl3) 0.73 (q, 6H, J=8.4 Hz), 0.95 (m, 12H), 1.36 (p, 2H, J=7.5 Hz), 1.69 (p, 2H, J=7.5 Hz), 2.94 (t, 2H, J=7.5 Hz), 6.89 (s, 1H) and 9.91 (s, 1H) 13CNMR (CDCl3): 3.03, 7.17, 13.6, 22.2, 26.8, 30.4, 118.6, 122.5 158.4, 170.2 and 184.8. LRMS m/e (% abundance) 266 (M+, 20) 238 (20) 237 (100), 87 (10) and 75 (20); HRMS exact mass calculated for C15H26O2Si 266.1702, found 266.1690.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.ClCCCl.[Cl-].[Al+3].[Cl-].[Cl-].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]12[CH2:37][CH2:36][CH2:35][C:33]3[C:34]1=[C:29]([CH:30]=[CH:31][CH:32]=3)[NH:28][C:27]2=[O:38]>CO>[CH3:7][O:6][C:5]([C:32]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=[O:38])[C:26]3([CH2:25][CH2:24][CH2:23][CH2:22][Br:21])[CH2:37][CH2:36][CH2:35][C:33]=1[C:34]=23)=[O:11]
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CO
Product: COC(=O)c1ccc2c3c1CCCC3(CCCCBr)C(=O)N2
Temperature: 0 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A 1.44 g (4.87 mmol) portion of triphosgene was added to 1,2-dichloroethane suspension (30 ml) of aluminum chloride (1.95 g, 14.61 mmol) and the mixture was cooled to 0° C. Thereto was added 30 ml of 1,2-dichloroethane solution containing 1.50 g (1.64 mmol) of 2a-(4-bromobutyl)-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one, subsequently carrying out 2 hours of stirring at 0° C. The reaction solution was mixed with 50 ml of methanol, stirred at a room temperature for 1 hour, extracted with chloroform and then washed with 1 N hydrochloric acid. After drying (Na2SO4), the solvent was evaporated under a reduced pressure, and the thus obtained oily substance was purified by a silica gel column chromatography (300 cc; elution with ethyl acetate-hexane=1:1) and then recrystallized from ethyl acetate-hexane to obtain 0.63 g of the title compound (35% in yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.[C:13]([C:15]1[CH:16]=[C:17]([S:22](Cl)(=[O:24])=[O:23])[CH:18]=[CH:19][C:20]=1[F:21])#[N:14].Cl>ClCCl>[C:13]([C:15]1[CH:16]=[C:17]([S:22]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:24])=[O:23])[CH:18]=[CH:19][C:20]=1[F:21])#[N:14]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: Nc1nccs1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1F
Yield: 66.6 %

Procedure:
To 2-aminothiazole (12.55 g, 125.3 mmol) was added pyridine (46 ml) and dichloromethane (75 mL) and the mixture stirred to give a solution. A solution of 3-cyano-4-fluorobenzenesulfonyl chloride (25 g, 114 mmol) in dichloromethane (50 ml) was added over approx 20 minutes at room temperature. The reaction was stirred at this temperature for 2 days before decanting the supernatant and concentrating in vacuo to furnish a dark oil. 2M HCl (200 ml) was added and the mixture triturated until solidification occurred. A brick red solid was filtered off, washed with water and dried to furnish 21.5 g of the title product. 1HNMR (d6-DMSO): δ 6.9(d, 1H), 7.3 (m, 1H), 7.6 (m, 1H), 8.15 (m, 1H), 8.3 (d, 1H), 12.9 (br s 1H). LCMS Rt=2.34 min MS m/z 284 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[C:8]([C:27]#[N:28])=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23]C(=O)C)[CH:18]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1>[NH2:23][C:19]1[CH:18]=[C:17]([C:9]2[S:10][C:11]([C:12]3[NH:16][CH:15]=[N:14][N:13]=3)=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:30][CH:29]=3)[C:8]=2[C:27]#[N:28])[CH:22]=[CH:21][N:20]=1
Reactant: CC(=O)Nc1cc(-c2sc(-c3nnc[nH]3)c(Cc3ccc(Cl)cc3)c2C#N)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1c(-c2ccnc(N)c2)sc(-c2nnc[nH]2)c1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.7 %

Procedure:
To a solution of N-{4-[4-(4-chlorobenzyl)-3-cyano-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide (0.020 g, 0.046 mmol) in tetrahydrofuran (5.0 mL) was added sodium hydroxide (1.0M solution in water, 2.0 mL, 2.0 mmol). The solution was stirred at room temperature for 48 hours. The mixture was extracted with ethyl acetate three times, and the combined organic extracts were then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (0.007 g, 30%). LCMS: (FA) ES+, 393. 1H NMR (400 MHz, d6-DMSO) δ: 8.75 (s, 1H), 8.07-8.03 (m, 1H), 7.36-7.26 (m, 4H), 6.83-6.79 (m, 1H), 6.78-6.76 (m, 1H), 6.34-6.29 (m, 1H), 4.61 (s, 2H), 4.04 (s, 2H).
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:17][C:16](=O)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH2:1]=[C:16]1[CH2:17][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH2:15]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: C=C1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (1.56 g, 4.37 mmol) in 30 mL of Et2O stirred at 0° C. was added potassium tert-butylate (0.459 g, 4.09 mmol). After 0.5 h the cold bath was removed and the mixture was stirred for 1 h at r.t. Afterwards, it was cooled off in water-ice bath, and 3-oxo-azetidine-1-carboxylic acid tert-butyl ester (500 mg, 2.92 mmol) was added. The cold bath was removed. After overnight resting, the reaction mixture was quenched with a saturated solution of NH4Cl in water, extracted with Et2O, dried on Na2SO4, evaporated to dryness in vacuo, dissolvent. The residual crude was purified by automated flash chromatography (SP1®TM-Biotage; gradient Petroleum Ether-Acetone from 10:0 to 7:3) to give the title compound (426 mg) as a dense colourless oil. Yield: 86.2%
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]>CN(C)C=O>[F:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1F
Yield: 52.4 %

Procedure:
A finely ground mixture of potassium fluoride (11.62 g, 0.2 mole) and CsF-silica (5 g, ca. 5 mmole equiv. F) is dried at 150° C. and then immediately transferred to a three-necked flask containing 2-chloronitrobenzene (7.88 g, 0.05 mole) and dimethylformamide. The flask is connected to a water-condenser and a mechanical stirrer and the reaction mixture is brought to reflux with vigorous stirring. After 24 h. the reaction mixture is cooled and separated into its ether- and water-soluble components. Chloride analysis of the aqueous extracts (AgNO3 titration, K2CrO4 indicator) shows better than 60% conversion of the 2-chloronitrobenzene. The ethereal extracts are washed with water (to remove the D.M.F.), dried over anhydrous Na2SO4, evaporated to dryness on a rotary evaporator and distilled under reduced pressure to give 3.7 g (52%) of 2-fluoronitrobenzene, b.p. 68°-70° C. (4 Torr). When the same reaction is carried out using (i) a dried mixture of KF (11.62 g) and CsF (0.75 g) and (ii) dried KF (11.62 g) alone in place of the KF-CsF-silica mix, chloride analysis of the aqueous extracts shows ca. 60% and ca. 20% conversion of 2-chloronitrobenzene respectively.