Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[I:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.Cl.[CH3:21][NH:22][C:23](=[O:31])[C@H:24]([C:27](=[O:30])[O:28][CH3:29])[NH:25][CH3:26]>C(Cl)(Cl)Cl>[I:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](=[O:16])[N:25]([CH:24]([C:23]([NH:22][CH3:21])=[O:31])[C:27]([O:28][CH3:29])=[O:30])[CH3:26])=[CH:13][CH:12]=1
Reactant: CNC(=O)[C@@H](NC)C(=O)OC
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.5 %

Procedure:
DIPEA (27 mL) was added to a chloroform (0.20 L) suspension of 4-iodobenzoyl chloride (13 g) and N,N2,O-trimethyl-3-oxoserinamide hydrochloride (Intermediate 5-2, 10 g) under ice cooling, and the mixture was stirred for 4 hours at room temperature, whereafter the reaction mixture was concentrated. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with hexane/ethyl acetate=70/30→0/100) to obtain 1-iodo-4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}benzene (Intermediate 6-2, white solid) (14 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1Cl.[NH2:13][C@H:14]([C:18]([O-:20])=[O:19])[CH:15]([CH3:17])[CH3:16].[K+].S1(CCCC1)(=O)=O.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[NH:13][CH:14]([CH:15]([CH3:17])[CH3:16])[C:18]([OH:20])=[O:19]
Reactant: CC(C)[C@H](N)C(=O)[O-]
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Temperature: 160 °C
Yield: 85 %

Procedure:
A mixture of 10 parts of 3,4-dichlorobenzotrifluoride, 23 parts of potassium valinate and 60 parts of sulfolane was heated and maintained at about 160° C. for about 48 hours, with mixing. The mixture was then cooled to room temperature, diluted with water, acidified with hydrochloric acid to a pH of 1.0. The aqueous layer was extracted with diethyl ether. The ether layers were washed with water, then dried and concentrated by evaporation to yield 10.4 parts of 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid (85% purity); a yield of about 75% based on the dichlorobenzotrifluoride starting material.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][O:11][C:12]([C:14]1([CH:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][O:15]1)=[O:13]>C(Cl)Cl>[CH3:10][O:11][C:12]([C:14]1([CH:17]([F:7])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][O:15]1)=[O:13]
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)C1(C(O)CCCCc2ccccc2)CO1
Solvent: ClCCl
Product: COC(=O)C1(C(F)CCCCc2ccccc2)CO1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2.44 g (15 mmol; 2.01 ml) of diethylaminosulfur trifluoride in 50 ml of methylene chloride cooled to -78° C. under a nitrogen atmosphere is added dropwise a solution of 2.00 (7.6 mmol) of 2-[1-hydroxy-5-phenylpentyl]-2-oxiranecarboxylic acid methyl ester (isomer A) in 50 ml of methylene chloride over 30 minutes. The mixture is stirred at -78° C. for 90 minutes and then is allowed to come to room temperature. The mixture is stirred at room temperature for 1.5 hours, is quenched with a saturated aqueous solution of sodium bicarbonate and is extracted with ethyl ether. The combined ethereal extracts are dried over magnesium sulfate, filtered and rotoevaporated. The resulting oil is purified chromatographically (silica gel; hexane:ethyl acetate (9:1)) to give 1.19 g of the title compound (Rf 0.54 in hexane:ethyl ether (3:2)): IR (neat) γ1750 cm-1 ; NMR (CDCl3) δ1.40-1.96 (6H, m), 2.64 (2H, t, J=8 Hz), 3.07 (1H, dd, J=4, 6 Hz), 3.15 (1H, d, J=6 Hz), 3.79 (3H, s), 5.14 (1H, ddd, JHF =49 Hz, J=10, 3 Hz), 7.21 (2H, d, J=8 Hz) and 7.31 (2H, d, J=8 Hz).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][CH:13]=[O:14])[CH:2]=1.[BH4-].[Na+].C(OC(C)C)(=O)C.[Cl-].[NH4+]>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][CH2:13][OH:14])[CH:2]=1
Reactant: O=CC=Cc1cnc2ccccc2c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)OC(C)C
Solvent: CO
Product: OCC=Cc1cnc2ccccc2c1
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 65.3 %

Procedure:
A mixture of 3-(3-quinolyl)propenal (10 g, 54.6 mmol) in methanol (50 mL) was cooled to 0° C. and to this mixture, sodium borohydride (1.03 g, 27 mmol) was charged in small portions keeping the temperature below 10° C. After the addition was complete, the mixture was stirred at 23° C. for 90 min. until the reaction was complete as monitored by TLC (isopropyl acetate, visualize under uv). To the mixture, saturated ammonium chloride solution (20 mL) was added and the mixture was stirred for one hour. The mixture was then concentrated under vacuum at 45° C. to remove methanol. The product was extracted in isopropyl acetate (150 mL), and the solvent was evaporated under vacuum to dryness. The product was triturated with MTBE (40 mL), filtered, washed with MTBE (10 mL) and dried to give 3-(3-quinolyl)-2-propen-1-ol (6.6 g, 65.4%) as a light yellow solid. The NMR of the product was consistent with the proposed structure.
Reaction SMILES: ClCCl.ClC(Cl)(Cl)[C:6]([N:8]=C=O)=[O:7].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1/[C:18](=[N:36]/[O:37][CH3:38])/[C:19]([NH:21][C@@H:22]1[C:34](=[O:35])[N:24]2[C:25]([C:31]([OH:33])=[O:32])=[C:26]([CH2:29][OH:30])[CH2:27][S:28][C@H:23]12)=[O:20].C(C(CCCC)C([O-])=O)C.[Na+:49]>C1COCC1.C(O)CO>[CH3:38][O:37]/[N:36]=[C:18](\[C:19]([NH:21][C@@H:22]1[C:34](=[O:35])[N:24]2[C:25]([C:31]([O-:33])=[O:32])=[C:26]([CH2:29][O:30][C:6]([NH2:8])=[O:7])[CH2:27][S:28][C@H:23]12)=[O:20])/[C:14]1[O:13][CH:17]=[CH:16][CH:15]=1.[Na+:49]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.17 h

Procedure:
A mixture of THF (60 ml), dichloromethane (25 ml), and trichloroacetyl isocyanate (6.2 ml) was protected from moisture and cooled to -10°.To the stirred mixture was added (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (10 g) in one charge followed by THF (20 ml). The temperature was controlled in the range 0° to +5° and the mixture stirred for 10 minutes. Ethane-1,2-diol (15 ml) was added followedby a solution of sodium 2-ethylhexanoate (10 g) in THF (20 ml) to raise thepH to 7.3. The mixture was warmed to 25° and left undisturbed for 1 hour. The mixture was then stirred briefly and left undisturbed for a further hour. The crystalline material which had separated from the mixture was collected by filtration, washed with THF (2×50 ml), and dried in vacuo at 35° to yield sodium cefuroxime (10.76 g) THF solvate. The isolated product was shown by G.L.C. to contain 8.8% w/w of THF and 0.56% w/w of ethane-1,2-diol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:7]3[CH2:16][CH2:15][CH2:14][CH:8]3[C:9](=O)[NH:10][C:11]=2[CH:12]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:7]3[CH2:16][CH2:15][CH2:14][CH:8]3[C:9](=[S:26])[NH:10][C:11]=2[CH:12]=1
Reactant: COc1ccc2c(c1)NC(=O)C1CCCC21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COc1ccc2c(c1)NC(=S)C1CCCC21
Yield: 77.5 %

Procedure:
Analogously to Example 4, 7-methoxy-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (180 mg, 0.83 mmol) is reacted with Lawesson's reagent (370 mg, 0.91 mmol) to form 150 mg (78%) of product.
Reaction SMILES: Cl[CH2:2][CH:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.[F:9][C:10]([F:24])([F:23])[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1>>[F:24][C:10]([F:9])([F:23])[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][N:20]([CH2:2][CH:3]3[O:7][C:6](=[O:8])[NH:5][CH2:4]3)[CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=C1NCC(CCl)O1
Product: O=C1NCC(CN2CCN(c3cccc(C(F)(F)F)c3)CC2)O1

Procedure:
Following the procedure of Example 35, the title compound was prepared from 5-chloromethyl-2-oxazolidinone and 1-(3-trifluoromethylphenyl)piperazine, mp 122°-124° C.
Reaction SMILES: [CH2:1]([C:3]1[C@@H:4]2[C@@H:20]([C@:21]3([CH3:29])[C:26]([CH:27]=1)=[CH:25][C:24](=[O:28])[CH2:23][CH2:22]3)[CH2:19][CH2:18][C@@:17]1([CH3:30])[C@H:5]2[CH2:6][CH2:7][C@@H:8]1[C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH3:2].[Li].BrCCBr.[Cl-].[NH4+]>N.C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([C@H:3]1[CH:27]=[C:26]2[C@:21]([CH3:29])([CH2:22][CH2:23][C:24](=[O:28])[CH2:25]2)[C@@H:20]2[C@@H:4]1[C@H:5]1[C@:17]([CH3:30])([CH2:18][CH2:19]2)[C@@H:8]([C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:7][CH2:6]1)[CH3:2]
Reactant: CCC1=CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@H]12
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: Cc1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC[C@H]1C=C2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@H]12
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 3.1 g of 3, from Example 3, in 46 ml ammonia, 10 ml THF, 10 milliliters toluene, was added 449 mg of metallic lithium in small pieces. After stirring the blue solution for 2 hours at -78° C., a solution of 1,2-dibromethane in 2 ml THF was added. After stirring the solution at -78° C. for 10 minutes, 2.1 g of ammonium chloride was added and the mixture stirred for 10 minutes. The excess ammonia was removed by evaporation under a nitrogen stream. The reaction mixture was diluted with brine, extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to yield crude brown viscous liquid 4 which was used as such in Example 5. Rf=0.70 (20% EtOAc/hexane). Mass Spec. 412 (EI); calculated MW 412.70.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[S:7]1[CH:11]=[CH:10][C:9]2[C:12]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24](OCC)=[O:25])[CH2:18][CH2:17]3)=[CH:13][CH:14]=[CH:15][C:8]1=2.O.[OH-].[Na+]>O1CCCC1>[S:7]1[CH:11]=[CH:10][C:9]2[C:12]([N:16]3[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][OH:25])[CH2:20][CH2:21]3)=[CH:13][CH:14]=[CH:15][C:8]1=2
Reactant: CCOC(=O)CCN1CCN(c2cccc3sccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCN1CCN(c2cccc3sccc23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 5 %

Procedure:
Lithium aluminum hydride (1.18 g, 24.8 mmol) was added to a solution of 5.26 g (16.5 mmol) of ethyl 3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propionate in tetrahydrofuran (55 ml) with cooling in an ice-bath, followed by stirring at room temperature for 4 hours. Water (1.2 ml), 15% sodium hydroxide aqueous solution (1.2 ml), and water (3.6 ml) were added to the reaction mixture in this order with stirring at room temperature. Insoluble matters were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:2→ethyl acetate), then concentrated and dried under reduced pressure to obtain 3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propane-1-ol (0.23 g) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])[CH2:16][CH2:15][CH:14]([NH:17][S:18]([N:21]3[CH2:25][CH2:24][C@@H:23]([OH:26])[CH2:22]3)(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])[CH2:12][CH2:13][CH:14]([NH:17][S:18]([N:21]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]3)(=[O:20])=[O:19])[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(NC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)N1CC[C@@H](O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CCN(S(=O)(=O)NC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
The product from Example 181 (89 mg, 0.17 mmol) in dichloromethane (5 ml) was treated with Dess Martin periodinane (212 mg, 0.5 mmol) and stirred at room temperature for 2 hours. The resulting mixture was filtered through celite and evaporated to an oil which was purified by chromatography (50% ethyl acetate/hexane) to yield a white solid (69 mg). 1H NMR (360 MHz, CDCl3) δ 7.39–7.29 (4H, m), 7.08–7.04 (2H, m) 6.88–6.82 (1H, m), 5.00 (1H, d, J=6.8 Hz), 3.70–3.60 (5H, m), 2.65–2.56 (4H, m), 2.46–2.38 (2H, m), 2.04–2.00 (2H, m), 1.58–1.50 (2H, m). m/z=533, 535[MH]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[N:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([OH:20])=[C:12]([C:21]3[NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[S:23](=[O:32])(=[O:31])[N:22]=3)[C:11]2=[O:33])=[CH:4][CH:3]=1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([OH:20])=[C:12]([C:21]3[NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[S:23](=[O:31])(=[O:32])[N:22]=3)[C:11]2=[O:33])=[CH:6][CH:7]=1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=Cc1ccc(Br)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 264A (0.049 g, 0.094 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.008 mL, 0.188 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.134 mL, 0.268 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (6.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with dichloromethane/diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.92 (brs, 2 H) 7.09 (t, J=6.99 Hz, 1 H) 7.28 (m, 3 H) 7.54 (m, 5 H) 7.68 (d, J=8.09 Hz, 2 H) 8.09 (dd, J=8.09, 1.47 Hz, 1 H) 16.25 (brs, 1 H). MS (ESI−) m/z 524 (M−H)−.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=[CH:11][CH:12]=1)(=O)=O.[C:29]([C:31]1([OH:39])[CH:36]2[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]2)[CH2:32]1)#[CH:30].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.CN(C)C=O>[CH2:20]([C:8]1[C:7]([C:30]#[C:29][C:31]2([OH:39])[CH:36]3[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]3)[CH2:32]2)=[CH:12][CH:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:9]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(Oc1ccc(-c2ccccc2O)nc1Cc1ccccc1)C(F)(F)F
Reactant: C#CC1(O)CN2CCC1CC2
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: Oc1ccccc1-c1ccc(C#CC2(O)CN3CCC2CC3)c(Cc2ccccc2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A mixture of 67.0 mg of 2-benzyl-6-(2-hydroxyphenyl)-3-pyridyl trifluoromethane sulfonate, 24.7 mg of 3-ethynyl-3-quinuclidinol, 19.0 mg of tetrakis(triphenylphosphine)palladium(0), 0.1 mg of cuprous iodide, 68.6 μl of triethylamine and 1.5 ml of N,N-dimethylformamide was heated under stirring at 100° C. for 2 hours in a nitrogen atmosphere. NH-silica gel was added to the reaction solution, and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 3% methanol/ethyl acetate, to give 56.8 mg of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[N:13]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:16]1[CH2:17][CH2:18][CH2:19][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:15]1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccnc3ccc(Br)cc23)CC1

Procedure:
6-Bromo-4-chloroquinoline (3.5 g, 14.5 mmol) was reacted with tert-butyl 1,4-diazepane-1-carboxylate (3.7 g, 18.8 mmol) and K2CO3 (4 g, 29 mmol) in DMSO at 100° C. overnight. After cooling the mixture was poured into water and extracted with DCM. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue was purified by flash chromatography using a gradient of EtOAc:hexane 1:1 to 2:1 giving 2.1 g (36%) of yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (d, J=5.5 Hz, 9H) 2.08-2.16 (m, 2H) 3.35-3.44 (m, 4H) 3.60-3-73 (m, 4H) 6.87 (d, J=5.5 Hz, 1H) 7.69 (dd, J=9.0, 2.0 Hz, 1H) 7.88 (d, J=8.5 Hz, 1H) 8.16 (s, 1H) 8.65 (d, J=5.0 Hz, 1H). MS (ESI+) for C19H24BrN3O2 m/z 406.4 (M+H)+. HRMS (EI) calcd for C19H24BrN3: 405.1052, found 405.1045.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[CH:32]=[CH:31][C:26]([C:27](OC)=[O:28])=[CH:25][CH:24]=3)[CH2:17][CH2:16]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li].C(=O)(O)[O-].[Na+]>O1CCCC1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([CH2:27][OH:28])=[CH:31][CH:32]=3)[CH2:17][CH2:16]2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CN2CCCN(Cc3ccc(Oc4ccccc4)cc3)CC2)cc1
Agent: O=C([O-])O
Agent: [Li]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1ccc(CN2CCCN(Cc3ccc(Oc4ccccc4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A solution of methyl 4-[[hexahydro-4-[(4-phenoxyphenyl)methyl]-1H-1,4-diazepin-1-yl]methyl]benzoate (260 mg, 0.60 mmol) in tetrahydrofuran (6 mL) was cautiously added to lithium alanate (45.5 mg, 1.2 mmol) in tetrahydrofuran (12 mL) at 0° C. The reaction was stirred overnight at ambient temperature. The mixture was treated with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 190 mg of [4-[[hexahydro-4-[(4-phenoxyphenyl)methyl]-1H-1,4-diazepin-1-yl]methyl]phenyl]methanol; 1H NMR (300 MHz, CDCl3) δ 7.33 (m, 4H), 7.33 (dd, 2H), 7.29 (d, 2H), 7.09 (dd, 1H), 7.00 (d, 2H), 6.95 (d, 2H), 4.68 (s, 2H), 3.64 (s, 2H), 3.61 (s, 2H), 2.73 (m, 4H), 2.67 (s, 4H), 1.80 (m, 2H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([NH:9][C:10](=O)[C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([C:16]#[N:17])=[C:4]([CH3:18])[C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Br:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)=[C:4]([CH3:18])[C:5]([C:16]#[N:17])=[C:6]2[C:7]=1[O:8][C:10]([C:11]([CH3:12])([CH3:14])[CH3:13])=[N:9]2
Reactant: Cc1c(C#N)c(NC(=O)C(C)(C)C)c(O)c(Br)c1-c1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(-c2cccc([N+](=O)[O-])c2)c(Br)c2oc(C(C)(C)C)nc2c1C#N
Yield: 92.5 %

Procedure:
A mixture of N-(2-bromo-5-cyano-3-hydroxy-6-methyl-3′-nitrobiphenyl-4-yl)-2,2-dimethylpropionamide (I-15) (490 mg, 1.13 mmol), p-toluenesulfonic acid monohydrate (22 mg, 4.23 mmol) and toluene (50 ml) was heated under reflux for 3 hours. After cooling, the reaction liquid was diluted with ethyl acetate, successively washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine, dried on anhydrous magnesium sulfate, the solvent was evaporated away under reduced pressure to obtain a pale brown residue. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the entitled compound (433 mg, 93%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:15][CH3:16])[CH2:3][O:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH2:17]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>>[CH2:17]([O:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([O:14][C:11]2[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][CH2:5][O:4][CH2:3][C@@H:2]([CH3:1])[CH2:15][CH3:16])=[CH:13][CH:12]=2)=[O:33])=[CH:35][CH:36]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CC[C@H](C)COCCCc1ccc(O)cc1
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Product: CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(CCCOC[C@@H](C)CC)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.3 %

Procedure:
Into a four-necked flask equipped with a stirrer and a thermometer were charged 1.11 g (5 millimole) of (+)-4-[3-{2(S)-methylbutoxy}propyl]phenol, 1.67 g (6 millimole) of 4-decyloxybenzoic acid and 30 ml of anhydrous dichlomethane, and then 1.22 g (6 millimole) of N,N'-dicyclohexylcarbodiimide and 0.1 g of 4-pyrrolidinopyridine were added thereto, followed by stirring at room temperature for one day. After completion of the reaction, precipitates formed were filtered off and diluted with 200 ml of toluene. The organic phase was washed with water, 5% aqueous acetic acid solution, water, 5% aqueus sodium hydrogen carbonate solution and water in this order and then dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The obtained residue was purified by silica gel column chromttography (eluent: toluene-ethyl acetate) to obtain 2.18 g (yield: 90.4%) of (+)-4-[3-{2(S)-methylbutoxy}propyl]phenyl 4-decyloxybenzoate.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9](OS(C(F)(F)F)(=O)=O)=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=1)=[CH:15][C:14]([Cl:27])=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[C:1]([O:5][C:6]([C:8]1[C:9]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:25])[CH3:26])[CH:19]=1)=[CH:15][C:14]([Cl:27])=[CH:13][CH:12]=2)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C1CCNCC1
Reactant: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(OS(=O)(=O)C(F)(F)F)nc3ccc(Cl)cc23)c1
Product: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(N3CCCCC3)nc3ccc(Cl)cc23)c1

Procedure:
The title compound was prepared in analogy to example 79 step A from 6-chloro-4-(3-isopropyl-phenyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid tert-butyl ester (prepared as described in example 78 step C, 250 mg, 0.47 mmol) and piperidine (0.093 ml, 0.94 mmol). Yellow solid (140 mg, 64%). LC-MS (ESI): 465 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=2[N+:26]([O-])=O)(=[O:15])=[O:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl[Sn]Cl.CCO>C(Cl)Cl>[NH2:26][C:17]1[CH:18]=[C:19]([S:22]([CH3:25])(=[O:23])=[O:24])[CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)c3cccnc23)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: ClCCl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)c3cccnc23)c(N)c1
Yield: 63 %

Procedure:
In the similar fashion using route 15 general procedure 29, N-(5-chloro-quinolin-8-yl)-4-methanesulfonyl-2-nitro-benzenesulfonamide (Intermediate 262 (350 mg, 0.79 mmol), SnCl2 (399 mg, 4.76 mmol) and EtOH (12 ml) gave the title compound (205 mg, 63%) after trituration from DCM: pentane