Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][N:8]([CH3:34])[C:9](=[O:33])[CH2:10][CH:11]([C:13]1[C:14]([CH:30]2[CH2:32][CH2:31]2)=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)O.C(N(CC)CC)C>ClCCl>[CH3:6][O:7][N:8]([CH3:34])[C:9](=[O:33])/[CH:10]=[CH:11]/[C:13]1[C:14]([CH:30]2[CH2:31][CH2:32]2)=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: CON(C)C(=O)CC(O)c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Yield: 79.9 %

Procedure:
A dichloromethane (10 ml) solution of methanesulfonyl chloride (1.44 g, 12.6 mmol) was added to a dichloromethane (40 ml) solution of N-methoxy-N-methyl-3-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}-3-hydroxypropanamide (3.30 g, 8.38 mmol) and triethylamine (1.27 g, 12.6 mmol). The resulting mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 3 hours before treatment with triethylamine (1.27 g, 12.6 mmol). The mixture was heated to reflux for 3 hours, quenched with saturated NaHCO3 aq solution, and extracted with dichloromethane. The organic layer was washed with saturated NaCl aq solution, dried over magnesium sulfate, and then concentrated. The residue was purified by column chromatography (hexane:ethyl acetate=3:1) to give N-methoxy-N-methyl-(E)-3-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}propenamide (2.52 g, 80% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:23])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20]Cl)[CH:7]=1.CO>C1COCC1>[CH3:3][O:4][C:5](=[O:23])[C:6]1[CH:7]=[C:8]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]2=[O:22])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1
Reactant: COC(=O)c1cc(NC(=O)CCCCCl)cc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(N2CCCCC2=O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
NaH (60% w/w in mineral oil, 680 mg, 17 mmol, 0.9 equiv) was added portionwise to a solution of 3-(5-chloro-pentanoylamino)-5-nitro-benzoic acid methyl ester (D3) (6 g, 19 mmol, 1 equiv) in THF (40 ml) under nitrogen. The resulting mixture was stirred at room temperature for 1 h and then MeOH was added dropwise. The solution was concentrated in vacuo and the residue diluted with AcOEt. The organic phase was washed with H2O, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (AcOEt/iso-hexane: 1/2) gave 3-nitro-5-(2-oxo-piperidin-1-yl)-benzoic acid methyl ester (B82) (2.8 g, 53%) as a pale orange oil.
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.CCN(CC)CC>C(Cl)Cl.[Cl-].[Na+].O.[Cu]I>[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:2]2=[O:1])=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCNC1=O
Agent: [Cu]I
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCCN(c2ccc(F)cc2)C1=O
Yield: 39.1 %

Procedure:
The mixture of [(3R)-hexahydro-2-oxo-1H-azepin-3-yl]-carbamic acid, 1,1-dimethylethyl ester 400 mg), 4-fluorophenylboronic acid (200 mg), Et3N (0.3 mL), and CuI (150 mg) in CH2Cl2 (5 mL) are mixture at rt for 4 days. The reaction mixture was diluted with brine, extracted with EtOAc, and dried. Concentration followed by flash chromatograph afforded the product (180 mg).
Reaction SMILES: [CH2:1]([C:5]12[CH2:20][C:19](=[O:21])[CH:18]=[C:6]1[C:7]1[CH:8]=[CH:9][C:10]([O:14][CH2:15][O:16][CH3:17])=[CH:11][C:12]=1[CH2:13]2)[CH2:2][CH2:3][CH3:4].[CH:22]([N-]C(C)C)([CH3:24])[CH3:23].[Li+].C(I)CC>O1CCCC1.CCOC(C)=O>[CH2:1]([C@@:5]12[C@H:20]([CH2:23][CH2:22][CH3:24])[C:19](=[O:21])[CH:18]=[C:6]1[C:7]1[CH:8]=[CH:9][C:10]([O:14][CH2:15][O:16][CH3:17])=[CH:11][C:12]=1[CH2:13]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CC(=O)C=C1c1ccc(OCOC)cc1C2
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[C@]12Cc3cc(OCOC)ccc3C1=CC(=O)[C@H]2CCC
Temperature: 2.5 °C
Reaction time: 0.42 h

Procedure:
A solution of 8a-butyl-6-(methoxymethoxy)-8,8a-dihydrocyclopenta[a]inden-2(1H)-one (109 mg, 0.38 mmol) in anhydrous tetrahydrofuran (THF, 2 mL) was placed under a N2 atmosphere and cooled in an ice bath. Freshly prepared lithium diisopropylamide in THF (1.2 mL of a 0.4M solution, 0.48 mmol) was added and the resulting solution was stirred at 0-5° C. for 25 minutes. Propyl iodide (0.185 in L, 1.9 mmol) was then added and the mixture was stirred overnight with gradual warming to room temperature. The mixture was diluted with EtOAc, washed with 1N HCl, 5% NaHCO3, and brine, dried over MgSO4, filtered, and evaporated under vacuum. The residue (125 mg) was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 12S (1.2×7.5 cm) silica gel column, eluting with 19:1 hexane-EtOAc, to afford (rac)-(1S,8aR)-8a-butyl-6-(methoxymethoxy)-1-propyl-8,8a-dihydrocyclopenta[a]inden-2(1H)-one as an oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[Br:12][C:13]([CH2:15]Br)=[CH2:14]>CN(P(N(C)C)(N(C)C)=O)C>[Br:12][C:13](=[CH2:14])[CH2:15][CH:4]([C:3]([O:10][CH3:11])=[O:9])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=C(Br)CBr
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=C(Br)CC(C(=O)OC)C(=O)OC
Temperature: 50 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a suspension of sodium hydride (5.0 g, 125 mmol) in HMPA (50 ml, distilled from calcium hydride) was added a solution of dimethyl malonate (11.7 ml, 100 mmol) in HMPA (5 ml) at 0° C. under argon. The mixture was heated to 50° C. and stirred 1 hour. Following this the solution was again cooled to 0° C., and a solution of 2,3-dibromopropene (12.2 ml, 100 mmol) in HMPA (5 ml) was added to the reaction mixture. Next, the solution was warmed to 40° C. and stirred for 1 hour. The reaction mixture was quenched with aq. HCl (10%, 88 ml) and extracted with ether (3×45 ml). The organic fractions were collected, dried over MgSO-4, and the solvent was removed in vacuo. The crude oil was purified via silica gel chromatography (eluants: chloroform/hexane) to obtain the titled product as a colorless oil (16.3 g, 65%). 1H-NMR (300 MHz, CDCl3) δ 5.70 (d, J=1.8 Hz, 1H), 5.48 (d, J=1.8 Hz, 1H), 3.63 (t, J=7.5 Hz, 1H), 3.76 (s, 6H), 3.04 (d, J=7.5 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=2)[CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)#[CH:13]>>[CH3:11][C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:13]#[C:12][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:7][N:6]2[N:8]=1
Reactant: C#Cc1ccncc1
Reactant: Cc1cc2ncc(Br)cn2n1
Product: Cc1cc2ncc(C#Cc3ccncc3)cn2n1

Procedure:
The title compound, light brown solid, MS: m/e=235.1 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 4-ethynylpyridine.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@H:15]([C:17](=[O:39])[N:18]([C@H:25]([CH2:36][O:37][CH3:38])[CH2:26][CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:19][CH:20](OC)OC)[CH3:16])(C)(C)C.C([SiH](CC)CC)C.C(N(CC)CC)C>ClCCl>[CH2:29]([O:28][CH2:27][CH2:26][C@H:25]([N:18]1[CH2:19][CH2:20][NH:14][C@@H:15]([CH3:16])[C:17]1=[O:39])[CH2:36][O:37][CH3:38])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC[C@H](CCOCc1ccccc1)N(CC(OC)OC)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H](CCOCc1ccccc1)N1CCN[C@@H](C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
Trifluoroacetic acid (8.03 g, 70.4 mmol) was added at 0° C. to a solution of {(S)-1-[((S)-3-benzyloxy-1-methoxymethyl-propyl)-(2,2-dimethoxy-ethyl)-carbamoyl]-ethyl}-carbamic acid tert-butyl ester (2.20 g, 4.69 mmol) in dichloromethane (40 mL). The reaction mixture was allowed to reach room temperature over 2 h, then triethylsilane (2.73 g, 70.4 mmol) was added. The reaction mixture was stirred for 16 h at room temperature, then cooled to 0° C. and treated with triethylamine (7.24 g, 70.4 mmol). After 10 min the ice bath was removed and the reaction mixture evaporated. The residue was taken up in ethyl acetate/water and neutralized with 2 M aq. sodium carbonate solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chomatography (SiO2; dichloromethane-methanol gradient) afforded the title compound (735 mg, 51%). Light yellow oil, MS (ISP)=307.3 (M+H)+.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].C#C.[CH3:7][C@:8]12[CH2:24][CH2:23][C@H:22]3[C@@H:13]([CH2:14][CH2:15][C@@H:16]4[C@@H:21]3[CH2:20][CH:19]=[CH:18][CH2:17]4)[C@@H:12]1[CH2:11][CH2:10][C:9]2=[O:25].[Cl-].[NH4+]>O1CCCC1.CCOCC.O>[OH:25][C@@:9]1([C:1]#[CH:2])[CH2:10][CH2:11][C@H:12]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:8]12[CH3:7])[C@@H:21]1[C@H:16]([CH2:17][CH:18]=[CH:19][CH2:20]1)[CH2:15][CH2:14]3
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC=CC[C@@H]43)[C@@H]1CCC2=O
Reactant: CC[Mg]Br
Agent: C#C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@@H]4[C@H]3CC[C@@]21C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 20 ml of dry tetrahydrofuran at 0° C. is added 0.75 ml of ethylmagnesium bromide (3 molar in ethyl ether) and through this solution is passed a stream of acetylene gas. After 30 min, 0.50 of ethylmagnesium bromide was added, followed after 30 min by another 0.50 ml of ethylmagnesium bromide. Acetylene gas is passed through the mixture all the time, and is continued for another 2 hr after the last addition. To the Grignard reagent is added dropwise 0.160 g of 5α-estr-2-en-17-one, Compound 6, dissolved in 5 ml of dry tetrahydrofuran. The combined reaction mixture is stirred at 0° C. for 2 hr, and then at room temperature for 16 hr. To the reaction mixture is added dropwise saturated ammonium chloride solution, water (30 ml) and ether (30 ml). The organic phase is separated, and the water phase is extracted once more with 12 ml of ether. The combined organic phase is washed twice with sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent gave a brownish oil, which was purified on a silica gel column to give 0.087 g of Compound Ia, mp 107.5°-109° C.
Reaction SMILES: CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:30][C:31]1[CH:32]=[C:33]2[C:37](=[C:38]([C:41]([OH:43])=O)[C:39]=1[F:40])[NH:36][CH:35]=[CH:34]2.[F:44][C:45]([F:68])([F:67])[C:46]1[CH:47]=[C:48]([CH2:52][CH2:53][NH:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([C:62]3([C:65]#[N:66])[CH2:64][CH2:63]3)=[CH:58][CH:57]=2)[CH:49]=[CH:50][CH:51]=1>CN(C=O)C.O>[C:65]([C:62]1([C:59]2[CH:58]=[CH:57][C:56]([CH2:55][N:54]([CH2:53][CH2:52][C:48]3[CH:49]=[CH:50][CH:51]=[C:46]([C:45]([F:67])([F:68])[F:44])[CH:47]=3)[C:41]([C:38]3[C:39]([F:40])=[C:31]([Cl:30])[CH:32]=[C:33]4[C:37]=3[NH:36][CH:35]=[CH:34]4)=[O:43])=[CH:61][CH:60]=2)[CH2:64][CH2:63]1)#[N:66]
Reactant: N#CC1(c2ccc(CNCCc3cccc(C(F)(F)F)c3)cc2)CC1
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(CN(CCc3cccc(C(F)(F)F)c3)C(=O)c3c(F)c(Cl)cc4cc[nH]c34)cc2)CC1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
69 mg (0.7 mmol) of N-methyl morpholine and then 129 mg (0.34 mmol) of TBTU were added to 48 mg (0.23 mol) of 5-chloro-6-fluoro-1H-indol-7-carboxylic acid and 78 mg (0.27 mmol) of 1-(4-{[2-(3-trifluoromethyl-phenyl)-ethylamino]-methyl}-phenyl)-cyclo-propanecarbonitrile dissolved in 2.3 ml DMF at rt under nitrogen. The reaction mixture was stirred at rt over night. Water was added and the reaction mixture was extracted twice with EtOAc. The combined organic layers were washed once with 1N aqueous HCl solution, once with saturated aqueous NaHCO3 solution and once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (20 g silica gel; methylene chloride/methanol 19:1) to yield 107 mg (87%) product as a yellow viscous oil. MS (ISP) 540.3 (100), 541.3 (30), 542.3 (32) (M+H)+, 562.3 (39), 563.4 (11), 564.4 (12) (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)[CH:9]=2)[NH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[I:26]CCI.S([O-])([O-])(=O)=S.[Na+].[Na+]>CCOCC.C1COCC1>[I:26][C:14]1[O:15][C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])=[CH:12][N:13]=1
Reactant: ICCI
Reactant: Cc1n[nH]c2ccc(-c3cnco3)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S([O-])([O-])=S
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1n[nH]c2ccc(-c3cnc(I)o3)cc12
Temperature: -78 °C
Yield: 68.7 %

Procedure:
To a 150 mL round-bottomed flask was added 3-methyl-5-(oxazol-5-yl)-1H-indazole (0.90 g, 4.52 mmol), and THF (20 mL). The resulting reaction mixture was stirred at −78° C. The solution was then treated dropwise via syringe with lithium bis(trimethylsilyl)amide (1.0 M solution in THF (13.6 mL, 13.6 mmol)), and the reaction was stirred for 1 hour at −78° C. A THF solution of 1,2-diiodoethane (5.20 mmol) was then added dropwise and the reaction was allowed to warm to room temperature for 1 hour. The reaction was then poured into a 1:1 mixture of ether and saturated sodium thiosulfate. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 10 to 50% EtOAc in Hexanes to give the desired product as a tan powder (1.01 g, 69% yield). LCMS (API-ES) m/z (%): 325 (100%, M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.O.O.[Sn](Cl)Cl.Cl>C(O)C>[NH2:12][C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1
Reactant: O=[N+]([O-])c1cc(Cl)c2cccnc2c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)c2cccnc2c1
Temperature: 25 °C
Yield: 42 %

Procedure:
5-Chloro-7-nitroquinoline (D82) (50 mg, 0.24 mmol) was treated with tin dichloride dihydrate (216 mg, 0.96 mmol) and conc. hydrochloric acid (2 ml) in ethanol (5 ml) at 70° C. for 4 h. After cooling to room temperature and the ethanol removed in vacuo then the residue was dissolved in water and neutralised with potassium carbonate. This was then extracted with EtOAc which was dried over MgSO4 and concentrated in vacuo to give the title compound as a brown solid (18 mg). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.78 (d, 1H), 8.39 (d, 1H), 7.25 (dd, 1H), 7.18 (d, 1H), 7.11 (d, 1H).
Reaction SMILES: C([NH:8][C:9]1[C:14]([F:15])=[C:13]([O:16][CH3:17])[CH:12]=[C:11]([O:18][CH3:19])[C:10]=1[F:20])C1C=CC=CC=1.[H][H]>C1COCC1.[OH-].[OH-].[Pd+2]>[F:15][C:14]1[C:13]([O:16][CH3:17])=[CH:12][C:11]([O:18][CH3:19])=[C:10]([F:20])[C:9]=1[NH2:8]
Reactant: [H][H]
Reactant: COc1cc(OC)c(F)c(NCc2ccccc2)c1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(OC)c(F)c(N)c1F
Temperature: -10 °C
Yield: 94.9 %

Procedure:
N-Benzyl-2,6-difluoro-3,5-dimethoxyaniline (6.0 g, 21.5 mmol) was dissolved in THF (40 mL) and the solution hydrogenated over 20% palladium hydroxide on carbon catalyst (0.6 g) at 20° C.–25° C. 48–50 psi hydrogen pressure for 16 hours. The mixture was filtered, the catalyst washed with THF (2×15 mL) and the combined filtrates concentrated to a solid. This was recrystallized from heptane (10 mL) and toluene (4.5 mL). The mixture was cooled to −10° C. before filtering. The crystals were washed with heptane (2×10 ML) and vacuum dried at 35° C. to give 2,6-difluoro-3,5-dimethoxyaniline as off-white needles (3.85 g, 20.4 mmol). mp: 78° C.–79° C.
Reaction SMILES: COC(=O)NC(C(N1CCCC1C1NC(C2C=CC(Br)=CC=2)=CN=1)=O)C(C)C.C(OC([N:36]1[CH2:40][CH2:39][CH2:38][CH:37]1[C:41]1[NH:45][C:44]2[CH:46]=[C:47]([Br:50])[CH:48]=[CH:49][C:43]=2[N:42]=1)=O)(C)(C)C>>[Br:50][C:47]1[CH:48]=[CH:49][C:43]2[N:42]=[C:41]([CH:37]3[CH2:38][CH2:39][CH2:40][NH:36]3)[NH:45][C:44]=2[CH:46]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(Br)cc2[nH]1
Agent: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Product: Brc1ccc2nc(C3CCCN3)[nH]c2c1
Yield: 66 %

Procedure:
Prepared by the same method as (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester, except that 2-(6-Bromo-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester was used as the substrate. 120 mg light yellow solid (66% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:20]1[CH2:26][C:25]2[CH:27]=[C:28]([O:31][CH2:32][C:33](O)=[O:34])[CH:29]=[CH:30][C:24]=2[CH2:23][CH2:22][CH2:21]1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH:37][CH2:38][CH2:39][CH2:40][CH3:41].Cl.CN(C)CCCN=C=NCC.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH2:38]([N:37]([CH3:36])[C:33]([CH2:32][O:31][C:28]1[CH:29]=[CH:30][C:24]2[CH2:23][CH2:22][CH2:21][CH:20]([N:8]([CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:26][C:25]=2[CH:27]=1)=[O:34])[CH2:39][CH2:40][CH3:41]
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)C1CCCc2ccc(OCC(=O)O)cc2C1
Reactant: CCCCNC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCN(C)C(=O)COc1ccc2c(c1)CC(N(C[C@H](O)COc1ccccc1)C(=O)OC(C)(C)C)CCC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under nitrogen, a solution of 2-[8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid (100 mg) in dichloromethane (3 ml) were added N-methylbutylamine (29 μl) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (47 mg) in the presence of catalytic amounts of 4-dimethylaminopyridine at 5° C., and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give N-[3-[(butylmethylcarbamoyl)methoxy]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-N-tert-butoxycarbonyl-[(2S)-2-hydroxy-3-phenoxypropyl]amine (96 mg).
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:33]C(=O)OC(C)(C)C)([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([C:18]4[N:22]=[C:21]([C:23]5[CH:24]=[CH:25][C:26]6[O:30][C:29]([CH3:31])=[CH:28][C:27]=6[CH:32]=5)[O:20][N:19]=4)[CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH2:4][O:3]1.C(OC1C=C(C2ON=C(C3C=CC=C4C=3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)N=2)C=CC=1OCC)C>>[NH2:33][C:5]([CH2:8][N:9]1[C:17]2[C:12](=[C:13]([C:18]3[N:22]=[C:21]([C:23]4[CH:24]=[CH:25][C:26]5[O:30][C:29]([CH3:31])=[CH:28][C:27]=5[CH:32]=4)[O:20][N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)([CH2:4][OH:3])[CH2:6][OH:7]
Reactant: Cc1cc2cc(-c3nc(-c4cccc5c4CCN5CC4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)no3)ccc2o1
Agent: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Product: Cc1cc2cc(-c3nc(-c4cccc5c4CCN5CC(N)(CO)CO)no3)ccc2o1
Yield: 67 %

Procedure:
When the product of Step F was substituted for tert-butyl 5-((4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)methyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 34, Step E, the identical process afforded the title compound in 67% yield., as a colourless foam. 1H-NMR (DMSO-d6) 1.36 (broad s, 3H); 2.91 (s, 2H); 3.29 (m, 2H+H2O); 3.55 (tr, 2H, J=8.02 Hz); 4.55 (m, 2H); 6.75-6.79 (m, 2H); 7.14 (tr, 1H, J=7.9 Hz); 7.26 (d, 1H, 7.8 Hz); 7.72 (d, 1H, J=8.5 Hz); 8.02 (d, 1H, J=9.17 Hz); 8.36 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]3[CH2:15][CH2:14][CH2:13][CH:7]3[C:8](=O)[NH:9][C:10]=2[CH:11]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]3[CH2:15][CH2:14][CH2:13][CH:7]3[C:8](=[S:25])[NH:9][C:10]=2[CH:11]=1
Reactant: Cc1ccc2c(c1)NC(=O)C1CCCC21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: Cc1ccc2c(c1)NC(=S)C1CCCC21
Yield: 105.8 %

Procedure:
Analogously to Example 4, 7-methyl-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (200 mg, 1.0 mmol) is reacted with Lawesson's reagent (425 mg, 1.1 mmol) to form 230 mg of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19]C2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: CCOC(=O)C1(N2CCN(S(=O)(=O)c3ccccc3Cl)CC2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(N2CCN(S(=O)(=O)c3ccccc3Cl)CC2)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 41.3 %

Procedure:
Ethyl 1-(4-(2-chlorophenylsulfonyl)piperazin-1-yl)cyclobutanecarboxylate (47 mg, 0.13 mmol) was dissolved in THF (3 ml). Lithium aluminum hydride (0.32 ml, 1.0 M in THF) was added at 0° C. The reaction mixture was stirred at 0° C. for 45 minutes. It was quenched by careful addition of EtOAc at 0° C. The mixture was stirred for another 30 minutes before 1N NaOH and equal volume of brine were added. The mixture was extracted with EtOAc three times. Combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 70% EtOAc/hexanes) to give the title compound (20 mg, 8% 3 steps) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm: 0.51-0.54 (m, 2 H), 0.60-0.63 (m, 2 H), 1.74 (bs, 1 H), 2.80-2.84 (m, 4 H), 3.17-3.24 (m, 4 H), 3.56 (s, 2 H), 7.38 (td, J=7.4, 1.6 Hz, 1 H), 7.45-7.52 (m, 2 H), 8.00 (dd, J=7.7, 1.6 Hz, 1 H); 13C NMR (100 MHz, CHLOROFORM-D) δ ppm 12.2, 46.5, 46.6, 49.7, 64.7, 127.0, 132.1, 132.3, 132.4, 133.6, 135.9; ESI-MS: m/z 331.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:5][C:6](=[O:21])[C:7]([CH2:19][OH:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([NH:10][CH2:11][CH3:12])=[O:9])[CH3:4].Br[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:28][O:27][C:25](=[O:26])[CH2:24][CH2:23][O:20][CH2:19][C:7]([C:6](=[O:21])[NH:5][CH2:3][CH3:4])([C:8](=[O:9])[NH:10][CH2:11][CH3:12])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)CCBr
Reactant: CCNC(=O)C(CO)(C(=O)NCC)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCNC(=O)C(COCCC(=O)OC)(C(=O)NCC)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
Sodium hydride (89 mg) was dissolved in THF (5 ml), and the solution was cooled to 0° C. and thereto were added a THF solution (1 ml) of N,N′-diethyl-2-hydroxymethyl-2-phenylmalonamide (400 mg) and tetrabutyl ammonium iodide (10 mg). After addition of a THF solution (2 mL) of methyl 3-bromopropionate (314 mg), the resulting mixture was stirred overnight at room temperature, and further at 60° C. for 0.5 hour. The reaction solution was filtered through a Celite, and the filtrate was concentrated and purified by column chromatography on silica gel (ethyl acetate:hexane=1:1) to give 3-(2,2′-bisethylcarbamoyl-2-phenylethoxy)propionic acid methyl ester (175 mg).