Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.C(COC1C=CC2NC(=O)CCCC=2C=1)(O)=O.Cl[N:25]1[C:31]2[CH:32]=[CH:33][C:34]([C:36]([O:38][CH3:39])=[O:37])=[CH:35][C:30]=2[CH2:29][CH2:28][C:27]([Cl:41])([Cl:40])[C:26]1=[O:42]>C1(C)C(C)=CC=CC=1>[Cl:41][C:27]1([Cl:40])[CH2:28][CH2:29][C:30]2[CH:35]=[C:34]([C:36]([O:38][CH3:39])=[O:37])[CH:33]=[CH:32][C:31]=2[NH:25][C:26]1=[O:42]
Reactant: COC(=O)c1ccc2c(c1)CCC(Cl)(Cl)C(=O)N2Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C(O)COc1ccc2c(c1)CCCC(=O)N2
Solvent: Cc1ccccc1C
Product: COC(=O)c1ccc2c(c1)CCC(Cl)(Cl)C(=O)N2
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
Phosphorus pentachloride (40.55 g, 194.7 mmol) was added to a mixture of 7-carbomethoxy-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one 2 (14.23 g, 64.91 mmol) and xylene (200 mL) and was heated to 90° C. over a period of 15 min. After an additional 35 min at 90° C. the resulting solution was cooled to RT, filtered, concentrated, and saturated Na2CO3 (200 mL, aqueous) was added to the resulting oil. After stirring the mixture for 1.5 h the solid material was filtered and washed with EtOH (×2) then ether (×2) to give a mixture of 3. (LRMS (ES), [M+H] m/z=288) and a small amount of 1,3,3-trichloro-7-carbomethoxy-2,3,4,5-tetrahydro-1-benzazepin-2-one (13.60 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]>C(OCC)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH2:13]
Reactant: COc1cccc(C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1cccc(CN)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Add lithium aluminum hydride (3.795 g, 100 mmol) portion wise to a solution of 3-methoxybenzonitrile (5.326 g, 40 mmol) in anhydrous ethyl ether (200 mL) at 0° C. Stir for 1 h, warm to ambient temperature and continue to stir for 12 h. Quench the reaction with 0.1N aqueous NaOH, filter the solid, dry the filtrate over Na2SO4 and concentrate to give the title compound as a colorless oil (5.107 g, 93%). MS (ES+) m/z: 138 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6]CC)=O.[CH3:15][C:16]1[N:17]=[C:18]2[C:23](=O)[CH2:22][CH2:21][CH2:20][N:19]2[C:25]=1[CH3:26].CC(C)([O-])C.[K+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:15][C:16]1[N:17]=[C:18]2[C:23]3[NH:1][C@H:2]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:3][C:4](=[O:6])[C:22]=3[CH2:21][CH2:20][N:19]2[C:25]=1[CH3:26]
Reactant: CCOC(=O)C[C@H](N)c1ccccc1
Reactant: Cc1nc2n(c1C)CCCC2=O
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc2n(c1C)CCC1=C2N[C@H](c2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
9.7 g (51.6 mmol) of ethyl (S)-3-amino-3-phenylpropionate, 8.5 g (51.6 mmol) of 2,3-dimethyl-6,7-dihydro-5H-imidazo[1,2-a]pyridin-8-one and 0.26 g (1.3 mmol) of p-toluenesulphonic acid monohydrate are heated to reflux in 50 ml of toluene using a water separator. After no more water separates, the reaction mixture is cooled to 0° C. and diluted with 100 ml of tetrahydrofuran. 7.24 g (64.5 mmol) of potassium tert-butoxide are then introduced and the mixture is stirred at room temperature for 16 h. 150 ml of saturated ammonium chloride are added to the reaction mixture, the organic phase is removed and the aqueous phase is extracted with 300 ml of ethyl acetate. The combined organic phases are washed with 250 ml of water, dried over sodium sulphate and evaporated. 13.27 g (88%) of the title compound are isolated as a red-brown oil. An analytical sample is obtained by crystallizing with diethyl ether (red solid, m.p. 134° C.).
Reaction SMILES: [C:1]1([C:7]2([C:11]#[N:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[N+:18]([O-])([O-:20])=[O:19].[K+]>C(O)(=O)C>[N+:18]([C:4]1[CH:5]=[CH:6][C:1]([C:7]2([C:11]#[N:12])[CH2:10][CH2:9][CH2:8]2)=[CH:2][CH:3]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])[O-]
Reactant: N#CC1(c2ccccc2)CCC1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Product: N#CC1(c2ccc([N+](=O)[O-])cc2)CCC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of 1-phenylcyclobutanecarbonitrile (5 g) and acetic acid (15 ml) and H2SO4 (10 ml) and KNO3 (1.1 eq) was stirred at 0° C. for 20 min. The mixture was warmed to RT and stirred for two hours. The mixture was poured on ice and stirred until all ice melted. The precipitate was filtered and recrystalized from EtOH to give 1-(4-nitrophenyl)-cyclobutanecarbonitrile. The above product (2 g) was mixed with Pd—C (10%, 800 mg) in EtOH (100 ml) and hydrogenated under H2 atmosphere for 1 hour. The reaction was filtered through Celite and evaporated to give 1-(4-aminophenyl)-cyclobutanecarbonitrile, Mass: (M+1) 172, which was used for next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]#[N:16])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=[O:19].[OH-].[Na+].OO>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15](=[O:19])[NH2:16])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C)(C(N)=O)CC1
Temperature: 50 °C

Procedure:
To a solution of 4-cyano-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (2.24 g, 10 mmol) in methanol (25 mL) was added DMSO (1 mL), aqueous 1N NaOH (12 mL, 12 mmol) and H2O2 (4 mL) at room temperature. The mixture was heated at 50° C. for 3 hours. After cooling to room temperature, the mixture was partitioned between EtOAc and H2O. The organic layer was washed successively with H2O and brine. After drying (Na2SO4), the solvent was removed to afford the desired product.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]1>CCOCC.[Cu](I)I>[CH2:2]([C:12]1[CH2:13][CH2:14][CH2:15][C:10](=[O:16])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: O=C1C=CCCC1
Agent: I[Cu]I
Agent: [Mg]
Solvent: CCOCC
Product: O=C1C=C(Cc2ccccc2)CCC1
Temperature: -20 °C
Reaction time: 24 h
Yield: 57.6 %

Procedure:
A 500-ml four-necked flask equipped with a thermometer and a condenser was charged with 2.4 g of a piece of magnesium and 120 ml of absolute ether, to which a part of 17 g of benzyl bromide was added with heating. After a reaction started, the remaining amount of benzyl bromide was added dropwise to such a degree that reflux continued. After completion of the drop addition, the resultant mixture was stirred further for 1 hour at room temperature to obtain a liquid reaction mixture. A 500-ml four-necked flask equipped with a thermometer was charged with a suspension of 1 g of copper iodide in 60 ml of absolute ether, to which the liquid reaction mixture was added dropwise at -5° C. After stirring the resultant mixture for 1 hour at the same temperature, it was cooled to -20° C. A solution of 8.6 g of 2-cyclohexen-1-one in 10 ml of absolute ether was added dropwise to the mixture, and the temperature of the resulting liquid reaction mixture was then raised to room temperature while stirring for 24 hours. The liquid reaction mixture was washed with water, dried, filtered and concentrated, and 21 g of the resulting crude product were purified by column chromatography, thereby obtaining 9.6 g (yield: 57%) of 3-benzylcyclohexenone.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[NH:7][CH2:6][CH2:5]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>ClCCl>[C:15]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([OH:1])=[C:10]([C:11]([F:14])([F:12])[F:13])[CH:9]=2)[CH2:5][CH2:6]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cc2c(cc1C(F)(F)F)NCC2
Solvent: ClCCl
Product: CC(=O)N1CCc2cc(O)c(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
A mixture of indoline (D10, 2.84 g, 14 mmol) and acetic anhydride (1.32 ml, 14 mmol) in dry dichloromethane (50 ml) was stirred at room temperature for 3 h, then evaporated. The residue was treated cautiously with saturated sodium bicarbonate solution, then the solid product was filtered off, washed with water and dried to give the title compound (3.28 g, 96%), m.p. 244-7° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:34]=[C:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([F:45])[CH:38]=1)[CH3:36]>CN(C=O)C.[Cu]I>[F:45][C:39]1[CH:38]=[C:37](/[C:35](/[CH3:36])=[CH:34]/[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]3[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2=3)[CH:42]=[CH:41][C:40]=1[O:43][CH3:44]
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: COc1ccc(C(C)=CBr)cc1F
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(/C(C)=C/n2c3c(c4cc(C)ccc42)CCN(C)CC3)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (73 mg, 0.34 mmol) was dissolved in DMF (6 mL). Copper (I) iodide (6 mg, 0.034 mmol), L-proline (8 mg, 0.068 mmol) and K3PO4 (145 mg, 0.68 mmol) were added and the reaction mixture was stirred for 10 min at RT. 4-(1-Bromoprop-1-en-2-yl)-2-fluoro-1-methoxybenzene (100 mg, 0.34 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 70 mg. 1HNMR (CD3OD, Oxalate salt) δ (ppm): 7.42 (s, 1H), 7.40 (d, 1H), 7.30 (s, 1H), 7.15 (t, 1H), 7.02 (m, 2H), 6.96 (s, 1H), 3.90 (s, 3H), 3.60 (m, 4H), 3.22 (m, 4H), 3.05 (s, 3H), 2.40 (s, 3H), 1.82 (s, 3H).
Reaction SMILES: [C:1]1(=[O:14])[C:6]2[CH:7]=[C:8]3[N:13]([C:5]=2[CH:4]=[N:3][NH:2]1)[CH2:12][CH2:11][CH2:10][CH2:9]3.[Br:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20](Br)[C:17]=1[CH:18]=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1>[Cu]I.O1CCOCC1>[Br:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([N:2]2[C:1](=[O:14])[C:6]3[CH:7]=[C:8]4[N:13]([C:5]=3[CH:4]=[N:3]2)[CH2:12][CH2:11][CH2:10][CH2:9]4)[C:17]=1[CH:18]=[O:19]
Reactant: O=c1[nH]ncc2c1cc1n2CCCC1
Reactant: O=Cc1c(Br)cc(F)cc1Br
Agent: [Cu]I
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=Cc1c(Br)cc(F)cc1-n1ncc2c(cc3n2CCCC3)c1=O
Temperature: 90 °C
Yield: 26.8 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 127e (450 mg, 2.4 mmol), 2,6-dibromo-4-fluorobenzaldehyde (2.0 g, 7.2 mmol), cesium carbonate (1.6 g, 4.8 mmol), and 1,4-dioxane (50 mL). After bubbling nitrogen through the resulting mixture for 10 minutes, copper(I) iodide (450 mg, 2.4 mmol) and 4,7-dimethoxy-1,10-phenanthroline (571 mg, 2.4 mmol) were added, and the reaction mixture was heated at 90° C. for 12 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was partitioned between methylene chloride (40 mL) and water (40 mL). The aqueous layer was separated and extracted with methylene chloride (3×30 mL). The combined organic layer was washed with brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:2 ethyl acetate/petroleum ether to afford 127f as a brown solid (251 mg, 31%). MS-ESI: (M+H)+ 390.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:36])[O:32][CH:33]([CH3:35])[CH3:34])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[C:26]([NH:30][C:31](=[O:36])[O:32][CH:33]([CH3:34])[CH3:35])[CH:27]=[CH:28][CH:29]=3)[CH2:20][CH2:19]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: CC(C)OC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)OC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(C)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 142 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and isopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.29–7.22 (m, 3H), 7.20–7.11 (m, 3H), 7.09–7.06 (m, 1H), 6.79 (d, 1H, J=7.6 Hz), 6.61 (s, 1H), 6.60–6.50 (m, 1H), 4.94 (septet, 1H, J=6.7 Hz), 4.05 (q, 1H, J=6.8 Hz), 3.24 (q, 2H, J=5.9 Hz), 2.86–2.79 (m, 2H), 2.36 (tt, 1H, J=11.9, 3.2 Hz), 2.27 (t, 2H, J=6.3 Hz), 1.85 (t, 2H, J=11.9 Hz), 1.72–1.66 (m, 2H), 1.60–1.52 (m, 3H), 1.48 (s, 6H), 1.23 (d, 6H, J=6.7 Hz); ESMS m/e: 500.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[N:17][C:5]2[NH:6][C:7]([N:12]3[CH:16]=[CH:15]N=C3)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH2:19](N)C=C>>[CH2:16]([NH:12][C:7]1[NH:6][C:5]2[N:17]=[CH:18][C:2]([Cl:1])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1)[CH:15]=[CH2:19]
Reactant: C=CCN
Reactant: O=S1(=O)N=C(n2ccnc2)Nc2ncc(Cl)cc21
Product: C=CCNC1=NS(=O)(=O)c2cc(Cl)cnc2N1

Procedure:
m.p. 224°-227° C. from 7-chloro-3-(imidazol-1-yl)-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1,1-dioxide and allylamine. (Compound 16).
Reaction SMILES: C([Li])(CC)C.CN(C)CCN(C)C.Br[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=1.S(=O)=O.[OH-].[Na+].[NH:27]([S:29](O)(=[O:31])=[O:30])O>O>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([S:29]([NH2:27])(=[O:31])=[O:30])=[N:16][CH:17]=1
Reactant: O=S(=O)(O)NO
Reactant: Cc1ccc(Br)nc1
Agent: CN(C)CCN(C)C
Agent: O=S=O
Agent: [Li]C(C)CC
Solvent: O
Product: Cc1ccc(S(N)(=O)=O)nc1
Temperature: 25 °C
Yield: 12.5 %

Procedure:
Sec-butyllithium (9.8 ml of 1.3M in cyclohexane) and N,N,N',N'-tetramethylethylenediamine (1.8 ml, 12.2 mmol) were added to a stirred solution of 2-bromo-5-methylpyridine (2 g, 11.6 mmol) at -78° C. under a nitrogen atmosphere. After 90 min sulphur dioxide (approximately 30 ml) was condensed into the reaction mixture using a cold finger and the reaction mixture was slowly warmed to room temperature over 12 h. The reaction mixture was concentrated to dryness and the residue dissolved in ice-water. To this was added a mixture of sodium hydroxide (1.39 g, 35 mmol) and hydroxylamine sulphonic acid (3.9 g, 35 mmol) in water (20 ml). After 24 h the solution was extracted with ethyl acetate, dried (MgSO4) and concentrated. Flash column chromatography (95% dichloromethane/5% methanol) gave the product (250 mg) as a clear oil which crystallised on standing.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([S:18][CH3:19])[N:3]=1.[K].[CH2:21]([NH:28][S:29](=[O:32])(=[O:31])[NH2:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:17][C:6]1[N:5]=[C:4]([S:18][CH3:19])[N:3]=[C:2]([NH:30][S:29](=[O:31])(=[O:32])[NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: NS(=O)(=O)NCc1ccccc1
Reactant: COc1ccccc1Oc1c(Cl)nc(SC)nc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K]
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(SC)nc1NS(=O)(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 79.2 %

Procedure:
4,6-Dichloro-5-(2-methoxy-phenoxy)-2-methylsulfanyl-pyrimidine (1.5 g) was dissolved in DMSO (30 ml) and benzylsulfamic acid amide potassium salt (2.12 g, Referential Example 22) was added. Stirring was continued for 18 h. The reaction mixture was poured onto water, acidified by solid citric acid (1.9 g), cooled to 0° C. and the precipitate was filtered off and purified by column chromatography over silica gel with hexane/EtOAc=2/1 to give benzylsulfamic acid [6-chloro-5-(2-methoxy-phenoxy)-2-methylsulfanyl-pyrimidin-4-yl]-amide (1.75 g) as a white powder. LC-MS: tR=5.27; [M+H]+=467.04.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][NH:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:11]([O:13][CH3:14])=[O:12].[CH2:22]=O>C(Cl)Cl>[S:2]1[C:3]2[CH2:7][CH2:8][N:9]([CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:11]([O:13][CH3:14])=[O:12])[CH2:22][C:4]=2[CH:5]=[CH:6]1
Reactant: COC(=O)C(NCCc1cccs1)c1ccccc1Cl
Reactant: C=O
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Reaction time: 2 h

Procedure:
35 g of the hydrochloride of racemic methyl alpha-(2-thienylethylamino)(2-chlorophenyl)acetate are suspended in 150 ml of a 30% (w/w) aqueous solution of formaldehyde. The mixture is kept at 50° C. for 2 hours and then poured, at about 20° C., into 200 ml of methylene chloride. The organic phase is concentrated and the residual oil is dissolved in 120 ml of isopropyl ether in which the hydrochloride is prepared as before; 29.5 g are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][CH2:17]3)=[CH:12][N:11]=2)=[CH:5][C:4]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([N:32]3[C:44](=[O:45])[C:43]4[S:42][C:41]5[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=5[C:35]=4[CH2:34][CH2:33]3)[C:27]=2[CH:46]=[O:47])=[CH:3]1.[BH4-].[Na+]>CO>[OH:47][CH2:46][C:27]1[C:28]([N:32]2[CH2:33][CH2:34][C:35]3[C:36]4[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=4[S:42][C:43]=3[C:44]2=[O:45])=[N:29][CH:30]=[CH:31][C:26]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:20][CH2:21]3)=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1cc(-c2ccnc(N3CCc4c(sc5c4CCCC5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(N3CCc4c(sc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
A mixture of 169b (45 mg, 0.070 mmol), NaBH4 (8 mg, 0.21) and methanol (5 mL) was stirred at room temperature for 1 h. The reaction mixture was quenched with water (5 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (2×10 mL). The combined dichloromethane extract was concentrated under reduced pressure. The residue was purified with reverse-phase prep-HPLC to afford 169 (14 mg, 30%). LCMS-ESI: [M+H]+ 654. 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.43 (s, 1H), 7.86 (d, J=4.5 Hz, 1H), 7.45 (d, J=2.5 Hz, 1H), 7.39-7.34 (m, 2H), 7.25-7.22 (m, 1H), 4.95-4.93 (m, 1H), 4.57-4.55 (m, 2H), 4.47-4.41 (m, 4H), 4.19-4.17 (m, 1H), 3.82-3.80 (m, 1H), 3.60 (s, 3H), 3.45-3.43 (m, 1H), 3.32-3.30 (m, 1H), 3.09-3.07 (m, 4H), 3.01-2.90 (m, 1H), 2.89-2.88 (m, 1H), 2.80-2.79 (m, 2H), 2.51-2.50 (m, 1H), 2.40-2.38 (m, 4H), 1.83-1.80 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([N:6]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])[CH2:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:4]([CH:24]=O)[CH:3]=1.CC(C)([O-])C.[K+].O>C1(C)C=CC=CC=1.CC(O)(C)C>[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])[CH2:7][CH2:8][C:9]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:24][C:4]=2[CH:3]=1
Reactant: CCOCCN(CCCC(=O)OC(C)(C)C)c1ccc(Br)cc1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOCCN1CCC(C(=O)OC(C)(C)C)=Cc2cc(Br)ccc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 6.5 %

Procedure:
In toluene (4.8 ml)/2-methyl-2-propanol (0.48 ml) was dissolved tert-butyl 4-[4-bromo(2-ethoxyethyl)-2-formylanilino]butyrate (2.4 g). To the solution was added potassium tert-butoxide. (72 mg), the mixture was stirred at 100° C. for 1 hour and cooled to room temperature. The reaction solution was added to water, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=6/1) to give tert-butyl 7-bromo-1-(2-ethoxyethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.15 g).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[H-].[Na+].Cl[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl-].[NH4+]>O1CCCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:11]=1[O:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Clc1ncccn1
Reactant: CCOC(=O)CO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ncccn1
Temperature: 0 °C
Yield: 77.2 %

Procedure:
Ethyl glycolate (1.04 g) was dissolved in tetrahydrofuran (10 ml) and the solution was cooled to 0° C. Sodium hydride (60% suspension in oil, 0.43 g) was added and the suspension was stirred and then sonicated in an ultrasonic bath. 2-Chloropyrimidine (1.14 g) was added and the mixture was sonicated for a further 110 min. Ammonium chloride solution was added and the mixture was extracted thrice with ethyl acetate, the organic phases were washed with brine and dried, filtered and evaporated. The residue was purified by chromatography eluting with iso-hexane:ethyl acetate (13:7) to give the subtitle compound (1.40 g) as an oil.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[Cl:9][C:10]1[CH:11]=[C:12]([N+:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=[CH:14][C:15]=1[C:16]([O:18]C)=[O:17].FC(F)(F)C(O)=O>O>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[C:16]([C:15]1[CH:14]=[CH:13][C:12]([N+:20]([CH3:22])([CH3:21])[CH3:23])=[CH:11][C:10]=1[Cl:9])([OH:18])=[O:17]
Reactant: COC(=O)c1ccc([N+](C)(C)C)cc1Cl
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[N+](C)(C)c1ccc(C(=O)O)c(Cl)c1

Procedure:
A solution of 0.5 g (1.32 mmol) 1b, 12 ml dest. water and 12 ml trifluoroacetic acid was refluxed for 2 days. The reaction mixture was evaporated, dried by use of oil pump vacuum over night and treated with diethyl ether. The resulting solid was filtered, washed extensively with diethyl ether and dried by oil pump vacuum. The solid crude 1c was obtained in 98% yield (471 mg, 1.3 mmol) and crude compound 1c was used for the next step without purification.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:30][C:31]1[CH:35]=[CH:34][O:33][C:32]=1[CH3:36]>O>[CH3:36][C:32]1[O:33][CH:34]=[CH:35][C:31]=1[CH2:30][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: Cc1occc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccoc2C)CC1
Reaction time: 0.5 h
Yield: 19 %

Procedure:
To a stirred mixture of 4.6 parts of a sodium hydride dispersion 50% and 450 parts of N,N-dimethylformamide were added portionwise 57.6 parts of ethyl 4-(1H-benzimidazol-2-ylamino)-1-piperidinecarboxylate under nitrogen atmosphere. Upon complete addition, stirring was continued for 30 minutes at room temperature. 27.0 Parts of 3-(chloromethyl)-2-methylfuran were added dropwise while cooling. Upon completion, stirring was continued for 1 hour. Water was added dropwise to the mixture and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was stirred in 1,1'-oxybisethane. The solid product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 1,1'-oxybisethane. The product was filtered off and dried, yielding 37.5 parts (19.0%) of ethyl 4-[[1-[(2-methyl-3-furanyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate; mp. 150.4° C. (int. 23).