Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([I:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH:18]([CH3:20])[CH3:19])=[CH:6][N:5]=[C:4]([NH:21][C:22](=[O:25])[CH2:23]Cl)[N:3]=1.[CH3:26][CH:27]1[O:32][CH:31]([CH3:33])[CH2:30][NH:29][CH2:28]1.[I-].[Na+]>CC(C)=O>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([I:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH:18]([CH3:20])[CH3:19])=[CH:6][N:5]=[C:4]([NH:21][C:22](=[O:25])[CH2:23][N:29]2[CH2:28][CH:27]([CH3:26])[O:32][CH:31]([CH3:33])[CH2:30]2)[N:3]=1
Reactant: CC1CNCC(C)O1
Reactant: COc1cc(C(C)C)c(Oc2cnc(NC(=O)CCl)nc2N)cc1I
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(C(C)C)c(Oc2cnc(NC(=O)CN3CC(C)OC(C)C3)nc2N)cc1I
Temperature: 55 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
N-[4-Amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-2-chloro-acetamide (477 mg, 1 mmol), 2,6-dimethyl morpholine (0.62 mL, 5 mmol) and sodium iodide (25 mg) were added to 20 mL acetone. The reaction mixture was stirred under nitrogen at 55° C. for 18 hours, then cooled and concentrated under reduced pressure. The residue was diluted with water and extracted with methylene chloride. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting oil was purified by flash chromatography (0%-20% “Magic Base”/methylene chloride) to give 311 mg of N-[4-amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-2-(2,6-dimethyl-morpholin-4-yl)-acetamide as an amorphous solid, MS (M+H)=556.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH2:21])[CH2:19][NH2:20]>>[C:2]1([C:1]2[CH:16]=[CH:15][CH:14]=[C:10]3[C:9]=2[CH:17]2[NH:21][CH2:18][CH2:19][N:20]2[C:11]3=[O:13])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Product: O=C1c2cccc(-c3ccccc3)c2C2NCCN12
Temperature: 0 °C

Procedure:
Reflux 45 g. of o-benzoylbenzoic acid and 120 ml. of ethylenediamine for 3 hours. Pour the mixture into ice water, allow to stand until the mixture is at room temperature and separate the product by filtration. Recrystallize from ethanol to obtain 9-phenyl-1,2,3,9b-tetrahydro-5H-imidazo-[2,1-a]isoindol-5-one, m.p. 155°-7° C. Elemental analysis confirms the empirical formula C16H14N2O.
Reaction SMILES: [H-].[Na+].[O:3]([C:5]1[CH:13]=[CH:12][C:11]([Br:14])=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2)[CH3:4].[CH3:15]I>CN(C=O)C>[CH3:15][N:9]1[C:10]2[C:6](=[C:5]([O:3][CH3:4])[CH:13]=[CH:12][C:11]=2[Br:14])[CH:7]=[CH:8]1
Reactant: COc1ccc(Br)c2[nH]ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Br)c2c1ccn2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60%, 0.23 g, 5.75 mmol) in DMF (18 mL) was added a solution of 4-methoxyl-7-bromoindole (1.1 g, 4.87 mmol) in DMF (2 mL). After 1 h at room temperature, the mixture was treated with methyl iodide (0.45 mL, 7.23 mmol) with cooling in an ice-water bath. The reaction mixture was allowed to warm up room temperature and stirred overnight. The reaction was quenched with water, extracted with ethyl acetate and the extract washed with water and brine, and dried (sodium sulfate). Evaporation of solvent gave a crude product, which was used without further purification. 1H NMR (400 MHz, CDCl3) 3.92(σ,3H), 4.13 (s, 3H), 6.35 (d, J=8.21 Hz, 1H), 6.55 (d, J=3.13 Hz, 1H), 6.89 (d, J=3.52 Hz, 1H), 7.22 (d, J=8.21 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16]
Reactant: OB(O)c1ccccc1
Reactant: CCCNC(=O)c1nnc2c(I)c(OC)ccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccccc3)c(OC)ccc2c1N
Yield: 51.4 %

Procedure:
Using Method F, 4-amino-7-methoxy-8-iodo-N-propyl-cinnoline-3-carboxamide (311 mg, 0.81 mmol) and phenylboronic acid (394 mg, 3.24 mmol) were reacted (refluxed overnight) to afford the title compound (140 mg, 52% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.51 (bm, 1H), 7.90 (d, J=9.2 Hz, 1H), 7.52 (d, J=9.2 Hz, 1H), 7.36-7.50 (m, 5H), 3.92 (s, 3H), 3.43 (apparent q, J=6.4 Hz, 2H), 1.63 (apparent sextet, J=7.2 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H). MS APCI, m/z=337 (M+H) HPLC 1.76 min.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([CH2:11][CH2:12][C:13]([OH:15])=O)[C:3]1=2.[C:16](N1C=CN=C1)([N:18]1C=CN=[CH:19]1)=O.CNC>ClCCl.O1CCCC1>[CH3:16][N:18]([CH3:19])[C:13](=[O:15])[CH2:12][CH2:11][C:4]1[C:3]2[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=2[NH:6][CH:5]=1
Reactant: O=C(O)CCc1c[nH]c2c1C(=O)CCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)CCc1c[nH]c2c1C(=O)CCC2
Reaction time: 1 h
Yield: 56.9 %

Procedure:
3-(4-Oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (12 g, 0.06 mol) was suspended in 80 ml of dichloromethane and carbonyldiimidazole (11.3 g, 0.07 mol) was added with stirring. After 30 minutes 58 ml of 2.0 M dimethylamine in tetrahydrofuran was added. After one hour the solvent was rotary evaporated. The residue was redissolved in dichloromethane, washed with 1 N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and rotary evaporated. The solid residue was washed with ethyl acetate and dried under vacuum to give N, N-dimethyl-3-(4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionamide (8 g, 60% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:62])([CH3:61])[C@H:3]([N:45]1[CH2:49][CH2:48][N:47]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[N+:57]([O-])=O)[C:46]1=[O:60])[C:4]([NH:6][C@@H:7]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@@H:8]([OH:37])[CH2:9][C@@H:10]([NH:24][C:25]([C@@H:27]([NH:32][C:33](=[O:36])[O:34][CH3:35])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1)=[O:5]>C(O)C.[Pd]>[NH2:57][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=1[CH2:50][N:47]1[CH2:48][CH2:49][N:45]([C@@H:3]([C:2]([CH3:1])([CH3:61])[CH3:62])[C:4]([NH:6][C@@H:7]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@@H:8]([OH:37])[CH2:9][C@@H:10]([NH:24][C:25]([C@@H:27]([NH:32][C:33](=[O:36])[O:34][CH3:35])[C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:16][CH:17]=2)=[O:5])[C:46]1=[O:60]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2[N+](=O)[O-])C1=O)C(C)(C)C)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2N)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55.1 %

Procedure:
A solution containing the product from Example 123B (0.027 g, 0.031 mmol) in ethanol (1 mL) was treated with 10% Pd on carbon (0.010 g), stirred under an atmosphere of hydrogen (balloon pressure) at 25° C. for 2.5 hours, filtered and concentrated under reduced pressure. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (0.014 g, 55% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.84(s, 9H), 0.86(s, 9H), 1.63-1.46(m, 2H), 2.16-2.07(m, 1H), 2.65-2.54(m, 3H), 3.00-2.74(m, 3H), 3.18-3.08(m, 1H), 3.50(s, 3H), 3.71-3.62(m, 1H), 3.87-3.83(d, J=9.56 Hz, 1H), 4.05(s, 1H), 4.28-4.10(m, 4H), 4.53-4.51(d, J=7.72 Hz, 1H), 5.20(s, 2H), 6.56-6.51(t, J=7.35 Hz, 1H), 6.68-6.64(m, 2H), 7.08-6.92(m, 7H), 7.24-7.21(d, J=8.09 Hz, 2H), 7.33-7.29(m, 1H), 7.43-7.40(d, J=9.93 Hz, 1H), 7.91-7.82(m, 5H), 8.64-8.63(d, J=4.41 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[C@@H:15]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=O)[CH3:16].C(=O)([O-])[O-].[K+].[K+].[OH2:35]>CN(C)C=O>[F:14][C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=1[N:17]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)(=[O:20])=[O:35])[C@H:15]2[CH3:16]
Reactant: COc1ccc(S(=O)(=O)N[C@@H](C)c2cc(F)ccc2-c2ccccc2F)cc1
Reactant: O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3[C@@H]2C)cc1
Temperature: 100 °C
Reaction time: 96 h

Procedure:
A stirred suspension of N-[(1S)-1-(2′,4-difluoro-1,1′-biphenyl-2-yl)ethyl]-4-methoxybenzenesulfonamide (1.7 g, 4.2 mmol) and potassium carbonate (1.16 g, 8.4 mmol) in N,N-dimethylformamide (25 mL) was heated at 100° C., and the reaction progress was monitored by LCMS. After 96 hours, water (300 mL) was added with stirring. A precipitate was filtered and washed with copious amounts of water. The product was purified by preparative liquid chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butylether in hexane, to afford a purified solid. Recrystallization of the solid afforded (6S)-8-fluoro-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine* (1.4 g, 87%, >99.9% ee), m.p. 196.8-198° C.;
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1COCC1.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>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: OB(O)c1cccs1
Reactant: O=Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2cccs2)cc1
Temperature: 85 °C
Yield: 77.8 %

Procedure:
To a stirred degassed solution of 4-bromobenzaldehyde (371 mg, 2.00 mmol) and thiophene-2-boronic acid (287 mg, 2.24 mmol) in DME/THF (5 mL, 4:1) were added a 2 M Na2CO3 solution (3.0 mL) and Pd(PPh3)4 (110 mg, 0.095 mmol). The reaction mixture was flushed with argon and maintained under argon while being heated at 85° C. over 2 days. The mixture was then cooled and diluted with EtOAc (35 mL) and water (30 mL). The aqueous layer was washed with EtOAc (2×10 mL) and the combined organic extracts dried (Na2SO4), filtered and concentrated. Purification of the resultant oil by column chromatography on silica gel (Hexanes/EtOAc, 4:1) afforded the title compound (293 mg, 78%) as a yellow solid. 1H NMR (CDCl3) δ 7.14 (dd, 1H, J=5.1, 3.6 Hz), 7.40 (dd, 1H, J=5.1, 0.9 Hz), 7.46 (dd, 1H, J=3.6, 0.9 Hz), 7.76 (d, 2H, J=8.4 Hz), 7.88 (d, 2H, J=8.4 Hz), 10.00 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([C:13]3[N:17]4[N:18]=[C:19]([C:22](=O)[CH3:23])[CH:20]=[CH:21][C:16]4=[N:15][CH:14]=3)[CH3:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Cl.[NH2:26][O:27][CH2:28][CH2:29][OH:30]>>[OH:30][CH2:29][CH2:28][O:27]/[N:26]=[C:22](/[C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([CH:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[N:3]=[CH:4]4)[CH3:12])=[CH:14][N:15]=2)[N:18]=1)\[CH3:23]
Reactant: CC(=O)c1ccc2ncc(C(C)c3ccc4c(cnn4C)c3)n2n1
Reactant: NOCCO
Agent: Cl
Product: C/C(=N\OCCO)c1ccc2ncc(C(C)c3ccc4c(cnn4C)c3)n2n1
Yield: 18.3 %

Procedure:
The title compound (9.0 mg, 17%, 88% purity) was synthesized from 1-(3-(1-(1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (40.0 mg, 0.13 mmol) and 2-(aminooxy)ethanol hydrochloride (19.31 mg, 0.25 mmol) using the same procedure as described in the synthesis of example 13. 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.94 (d, 1H), 7.85 (s, 1H), 7.79 (s, 1H), 7.66 (s, 1H), 7.85 (d, 1H), 7.52 (d, 1H), 7.37 (dd, 1H), 4.72 (t, 2H), 4.21 (t, 2H), 3.97 (s, 3H), 3.66 (q, 1H), 2.20 (s, 3H), 1.78 (d, 3H). LCMS (method A): [MH]+=379, tR=5.25 min.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[C:14]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][C:12]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:11][N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:27]O>CCOC(C)=O>[CH3:27][O:17][C:16](=[O:18])[CH2:15][C:14]1[C:9]([NH:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[N:10][CH:11]=[C:12]([NH:19][C:20](=[O:25])[C:21]([CH3:22])([CH3:24])[CH3:23])[CH:13]=1
Reactant: CC(C)(C)C(=O)Nc1cnc(NCC2CCCCC2)c(CC(=O)O)c1
Reactant: CO
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc(NC(=O)C(C)(C)C)cnc1NCC1CCCCC1
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of the product 2-[(cyclohexylmethyl)amino]-5-[(2,2-dimethyl-1-oxopropyl)amino]-3-pyridineacetic acid in dry MeOH (7.5 mL) was added 4N HCl solution (in dioxane, 2.5 mL) at 0° C. The reaction mixture was stirred overnight at r.t, and then condensed under vacuum, diluted with AcOEt (50 mL), washed with 1N NH4OH (100 mL), brine (50 mL), and dried over MgSO4. Removal of solvent afforded desired title product (325 mg, 90%). 1H-NMR (CDCl3): δ 0.98 (m, 2H), 1.19 (m, 3H), 1.24 (s, 9H), 1.58 (m, 1H), 1.67 (m, 3H), 1.76 (m, 2H), 3.20 (d, J=6.8 Hz, 2H), 3.39 (s, 2H), 3.63 (s, 3H), 4.98 (brs, 1H), 7.24 (brs, 1H), 7.680 (s, 1H), 7.92 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.O[CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:30][C:31]([F:34])([F:33])[F:32])[CH:29]=1)[C:25]#[N:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[C:25]([C:24]1[CH:23]=[C:22]([CH:29]=[C:28]([O:30][C:31]([F:32])([F:34])[F:33])[CH:27]=1)[CH2:21][O:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1)#[N:26]
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Reactant: N#Cc1cc(CO)cc(OC(F)(F)F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3cc(C#N)cc(OC(F)(F)F)c3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.7 %

Procedure:
Ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (100 mg, 0.386 mmol) and 3-(hydroxymethyl)-5-(trifluoromethoxy)benzonitrile (84 mg, 0.386 mmol) were dissolved in THF (3.0 mL) and cooled to 0° C. Triphenylphosphine (202 mg, 0.771 mmol) and diisopropylazodicarboxylate (DIAD) (0.15 mL, 0.771 mmol) were added. The mixture was warmed to room temperature and stirred for 1 h. Additional DIAD (0.15 mL, 0.771 mmol) and triphenylphosphine (202 mg, 0.771 mmol) were added and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 50.8 mg of impure ethyl 2-(7-(3-cyano-5-(trifluoromethoxy)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate. The material was dissolved in dioxane (1.3 mL) and 1.0 M aqueous LiOH (0.33 mL, 0.33 mmol) was added. The reaction was monitored by HPLC until judged complete and then acidified to pH 2 with 1.0 M HCL. The aqueous mixture was extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography followed by HPLC to give the title compound (1.1 mg). LCMS m/z=431.2 [M+H]+; 1H NMR (400 MHz, CD3OD) δ ppm 2.11-2.20 (m, 1H), 2.50 (dd, J=15.8, 8.0 Hz, 1H), 2.66-2.84 (m, 4H), 3.51-3.60 (m, 1H), 5.18 (s, 2H), 6.78 (dd, J=8.8, 2.5 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 7.20 (d, J=8.9 Hz, 1H), 7.64 (s, 1H), 7.73 (s, 1H), 7.84 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:16]=[CH:15][C:10](NCC#C)=CC=2)[CH2:2]1.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[O:42]1C=C[CH2:44][CH2:43]1.[O-2].[Al+3].[O-2].[O-2].[Al+3]>C1C=CC=CC=1.CO.C(Cl)Cl>[O:42]1[C:4]2[C:3]3[CH:7]=[CH:16][CH:15]=[CH:10][C:2]=3[N:1]=[CH:6][C:5]=2[CH:44]=[CH:43]1
Reactant: C#CCNc1ccc(C2CCCNC2)cc1
Reactant: C1=COCC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Solvent: CO
Solvent: c1ccccc1
Product: c1ccc2c(c1)ncc1ccoc12

Procedure:
Using a Dean-Stark apparatus, 4-(3-piperidinyl)-propargyl-aniline (300 mg, 1.40 mmol) and Teoc-protected 5-bromoindole aldehyde (555 mg, 1.50 mmol) were heated at reflux for 8 h with a catalytic amount of p-tolunensulfonic acid monohydrate (15 mg, 0.078 mmol) in 15 mL benzene. The solvent was then removed in vacuo. The reaction mixture was then redissolved in 45 mL acetonitrile (HPLC grade, Aldrich #27071-7). Under nitrogen gas, 540 mg molecular sieves (Aldrich #23,366-8, 4A, activated), 540 mg ytterbium triflate (0.87 mmol) and 405 μL 2,3-dihydrofuran (5.4 mmol) were added sequentially and the resulting mixture was stirred at room temperature for an additional 14 h, at which point TLC (aluminum oxide, basic, J. T. Baker #4467-02, CH2Cl2:MeOH=50:1) indicated completion of the reaction. The reaction mixture was concentrated under vacuum. The mixture was redissolved in CH2Cl2 and 357 mg of 8-[3-(piperidinyl)-propargyl]-2,3,3a,4,5,9b-hexahydro-4-(3- cis- and trans-N-indolyl)-furo[3,2-c]quinoline were obtained in a 3:1 ratio after purification by flash column chromatography using aluminum oxide (Brockmann I, basic, Aldrich #19,944-3, CH2Cl2:MeOH=50:1, 45% yield).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>O1CCCC1.CCCCCC>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:32])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1ccccc1)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexane solution, 0.701 ml, 1.10 mmol) was added to a tetrahydrofuran (5 ml) solution of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (303 mg, 1.00 mmol) obtained in Example 5. The temperature of the resulting mixture was raised to room temperature and then stirred for 10 minutes. After cooling the reaction mixture to −78° C., benzoyl chloride (0.140 ml, 1.20 mmol) was added thereto dropwise. The reaction mixture was stirred at −78° C. for 30 minutes. The temperature of the mixture was then raised to OC over 3 hours. After addition of 1N hydrochloric acid (2.0 ml), the mixture was extracted with ethyl acetate. The extracts were combined, washed successively with water, a saturated aqueous solution of sodium bicarbonate, and brine, dried over MgSO4, and then concentrated. The residue was purified by medium-pressure chromatography on a silica gel column (10% ethyl acetate-hexane). The solid thus obtained was washed with hexane, whereby the title compound (200 mg, 49%) was obtained as a colorless solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][N:16]=1)[CH3:14].[C:21]([O:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[F:35])=[O:27])(=[O:23])[CH3:22]>O1CCCC1.CCCCCC.CCOCC.O.C(O)(=O)C>[C:21]([O:24][CH2:25][C@:26]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[F:35])([OH:27])[C@@H:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][N:16]=1)[CH3:14])(=[O:23])[CH3:22]
Reactant: CCc1ccncn1
Reactant: CC(=O)OCC(=O)c1ccc(F)cc1F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)OC[C@@](O)(c1ccc(F)cc1F)[C@H](C)c1ccncn1
Reaction time: 0.58 h

Procedure:
A solution of diisopropylamine (30.3 g) in dry tetrahydrofuran (400 ml) was treated successively with n-butyllithium (188 ml of a 1.6M solution in hexane) followed by 4-ethylpyrimidine (32.4 g) according to the method of Example 3. A solution of the product of part (i) (64.0 g) in dry tetrahydrofuran (400 ml) was added with stirring over 0.58 hour at -40° to -50°. Acetic acid (30 ml) was then added and the solution was allowed to reach room temperature. Ether (1000 ml) and water (1000 ml) were added and the mixture was shaken. The organic layer was separated, washed with brine and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel. Elution with ether/hexane (1:4) gave starting ketone initially. Further elution with ether/hexane (1:1), gradually decreasing the proportion of hexane until neat ether was being used, gave a semi-solid consisting of a (±)-enantiomeric mixture of the title compounds together with the (2R,3R)- and (2S,3S)-diastereoisomeric pair of enantiomers. Ether was added until a clear solution was obtained and then hexane (20% by volume) was added. The mixture was cooled and the resulting solid was filtered off, washed with hexane and dried to give the (±)-enantiomeric mixture of the title compounds, (23.3 g), m.p. 102°-103.5°.
Reaction SMILES: O[C:2]1([C:22]([F:25])([F:24])[F:23])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][S:13]([C:10]1[CH:9]=[CH:8][C:7]([N:5]2[CH:6]=[C:2]([C:22]([F:25])([F:24])[F:23])[N:3]=[C:4]2[C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)(=[O:14])=[O:15]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2cccs2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cccs2)cc1
Yield: 82 %

Procedure:
A mixture of the 4,5-dihydro-imidazole of step 2 (0.60 g, 1.54 mmol) and p-toluenesulfonic acid monohydrate (0.12 g, 0.63 mmol) in toluene (100 ml) was heated to reflux for 4.5 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude mixture (1.2 g) was purified by chromatography on silica gel using ethyl acetate/hexane 50/50 to give pure 2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]thiophene (0.47 g, 82%) as a white solid: mp (DSC) 182° C. Anal. Calced. for C15H11N2S2O2F3 C, 48.38, H, 2.98, N, 7.52, S, 17.22. Found: C, 48.36, H, 3.02, N, 7.42, S, 17.47.
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]([CH3:10])[CH2:5][CH2:6][CH2:7][NH:8][CH3:9].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.Cl>CS(C)=O.O>[CH3:3][N:4]([CH3:10])[CH2:5][CH2:6][CH2:7][N:8]([CH3:9])[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CNCCCN(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CCCN(C)c1ccc([N+](=O)[O-])cc1
Temperature: 65 °C

Procedure:
To a suspension of potassium hydroxide (1.4 g, 25 mmol) in dimethylsulfoxide (13 mL) is added N,N,N′-trimethyl-1,3-propanediamine (1.8 mL, 12 mmol). While stirring vigorously and while heating to 65° C., 4-fluoronitrobenzene (1.1 mL, 10 mmol) is added dropwise. After stirring at this temperature for 6 hours, the mixture is allowed to cool to room temperature. Water is added and the mixture is acidified to pH 1 with concentrated hydrochloric acid and then extracted thrice with chloroform (3×30 mL). The acidic phase is then basified to pH 11 with 2.5 M sodium hydroxide solution. The basic phase is extracted thrice with chloroform (3×30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an orange-red oil, which is purified by reverse phase high performance liquid chromatography to give N,N,N′-trimethyl-N′-(4-nitrophenyl)propane-1,3-diamine as its ditrifluoroacetate salt.