Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C([O-])([O-])=O.[K+].[K+].I[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:33](=[O:34])[CH:32]2[CH:27]([CH:28]=[CH:29][CH:30]=[CH:31]2)[C:26]1=[O:35]>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[C:33](=[O:34])[CH:32]3[CH:27]([CH:28]=[CH:29][CH:30]=[CH:31]3)[C:26]2=[O:35])[CH2:9][CH2:8]1
Reactant: COC(=O)CCCC1CCNCC1
Reactant: O=C1C2C=CC=CC2C(=O)N1CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CCCC1CCN(CCCCN2C(=O)C3C=CC=CC3C2=O)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 18.3 %

Procedure:
To a suspension of 2 (1.96 g, 8.86 mmol), K2CO3 (2.82 g, 17.72 mmol) and acetone (100 mL) was added 2-(4-iodobutyl)-3a,7a-dihydroisoindole-1,3-dione (2.93 g, 8.86 mmol). The newly formed suspension was stirred at ambient temperature for 48 hours. The solid was vacuum filtered and the filtrate was concentrated under vacuum. The resulting residue was subjected to column chromatography eluting with 0-100% ethyl acetate in hexanes to afford the desired product 3 (0.63 g, 40%) as a white solid: 1H NMR (500 MHz; CDCl3) δ 1.16-1.28 (m, 3H), 1.65 (m, 2H), 1.60-1.72 (m, 4H), 1.86 (m, 2H), 2.26 (t, 2H), 2.32 (t, 2H), 2.88 (d, 2H) 3.64 (s, 3H), 3.70 (t, 2H), 7.68 (d, 2H), 7.72 (d, 2H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[C:23]5[CH2:31][CH2:30][NH:29][CH2:28][C:24]=5[N:25]=[CH:26][N:27]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.C([CH2:38][C:39]([O:41]Br)=[O:40])(C)(C)C>C(#N)C>[C:3]([O:41][C:39](=[O:40])[CH2:38][N:29]1[CH2:30][CH2:31][C:23]2[C:22]([O:21][C:17]3[CH:16]=[C:15]4[C:20](=[CH:19][CH:18]=3)[N:12]([C:10](=[O:11])[NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:4]=3)[CH:13]=[CH:14]4)=[N:27][CH:26]=[N:25][C:24]=2[CH2:28]1)([CH3:4])([CH3:8])[CH3:2]
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ncnc4c3CCNC4)ccc21
Reactant: CC(C)(C)CC(=O)OBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)C1

Procedure:
A solution of 5-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, Example 33-C, (250 mg, 0.55 mmol), bromo tert-butylacetate (204 μL, 1.38 mmol), TEA (384 μL, 2.76 mmol) and ACN (5 mL) is stirred at room temperature. Following completion of the reaction the contents of the flask are partitioned between DCM and brine. Organic layer is dried over anhydrous Na2SO4, concentrated, and the residue is separated via FCC (50-100% EtOAc/heptane) to give the title compound. MS (ESI) m/z 568.1 (M+1).
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:15]1[CH:16]=[C:17]([C:23](=[O:25])[CH3:24])[CH:18]=[N:19][C:20]=1[O:21][CH3:22].[CH2:26]([NH:29][C:30](=[O:33])[O:31][CH3:32])[C:27]#[CH:28]>CCCCCC.C(NC(C)C)(C)C.O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:23]([C:17]1[CH:16]=[C:15]([C:28]#[C:27][CH2:26][NH:29][C:30](=[O:33])[O:31][CH3:32])[C:20]([O:21][CH3:22])=[N:19][CH:18]=1)(=[O:25])[CH3:24]
Reactant: C#CCNC(=O)OC
Reactant: COc1ncc(C(C)=O)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CC(C)NC(C)C
Solvent: C1COCCO1
Solvent: CCCCCC
Product: COC(=O)NCC#Cc1cc(C(C)=O)cnc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.7 %

Procedure:
Bis(benzonitrile)dichloropalladium (II) (12 mg) and copper (I) iodide (3.8 mg) were added to 1,4-dioxane (1 mL) under argon, and then thereto were added a solution of 10% tri-t-butylphosphine in hexane (179 μL), diisopropylamine (168 μL), 1-(5-bromo-6-methoxypyridin-3-yl)ethanone (230 mg) and a solution of methyl prop-2-yn-1-ylcarbamate (149 mg) in 1,4-dioxane (1 mL). The mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1→1/3) to give methyl [3-(5-acetyl-2-methoxypyridin-3-yl)prop-2-yn-1-yl]carbamate [Ex(296-2)] (188 mg) as a pale yellow powder.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH3:15])=[C:11]([NH2:14])[CH:12]=2)[C:7]([CH3:17])([CH3:16])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CC([O-])(C)C.[Na+].I[C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:30]([O:29][C:27](=[O:28])[C:26]1[CH:32]=[CH:33][C:34]([NH:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([CH3:17])([CH3:16])[CH2:6][CH2:5][N:4]3[CH:1]([CH3:3])[CH3:2])=[CH:9][C:10]=2[CH3:15])=[CH:35][CH:25]=1)[CH3:31]
Reactant: Cc1cc2c(cc1N)N(C(C)C)CCC2(C)C
Reactant: CCOC(=O)c1ccccc1I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)(C)CCN3C(C)C)cc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 78.5 %

Procedure:
1-Isopropyl-4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-7-ylamine (Compound 45, 500 mg, 2.152 mmol) was placed into the round bottom flask charged with argon. Pd2 (dab)3 (4.926 mg, 0.25 mol %), and BINAP (10.05 mg, 0.75 mol %) were added, followed by NaOtBu (405.27 mg, 3.012 mmol), ethyl iodobenzoate (831.7 mg, 3.012 mmol) and toluene (8 mL). The resulting mixture was stirred at 80° C. for 3 days, cooled to room temperature, and filtered through Celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (10% ethyl acetate in hexane, Rf=0.26) to give the title compound (642.76 mg, 79%) as a pale yellow solid:
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1.COCC(O)C.S1C=CC=C1>[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: COCC(C)O
Product: O=C(O)c1ccccc1Cc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
In a hydrogenation flask was added 2-(4-fluoro-benzoyl)-benzoic acid, propylene glycol monomethyl ether (1 L/mol) and Pd/C 10% wet (15 g/mol). Hydrogenation was performed at 50° C. over 18 hours. Thiophene (0.3 kg/mol) was added and the catalyst was filtered off. The filtrate was heated up to 80° C. and water (1.12 L/mol) was added at that temperature. The mixture was heated up to reflux, then cooled down to 25° C. and stirred at that temperature during 1 hour. The precipitate was filtered off, washed with water (1 L/mol) and dried at 50° C. during 18 hours. Active yield: 83%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH3:8][O:9][C:10](=O)[O:11]C.CC(C)([O-])C.[K+]>>[CH3:8][O:9][C:10]([CH:3]1[C:4](=[O:7])[CH2:5][CH2:6][O:1][CH2:2]1)=[O:11]
Reactant: O=C1CCOCC1
Reactant: COC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COC(=O)C1COCCC1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 26.5 %

Procedure:
To a solution of tetrahydro-pyran-4-one (1.3 kg, 12.98 mol) and carbonic acid dimethyl ester (11.69 kg, 129.8 mol) was added solid potassium tert-butoxide (1.89 kg, 16.08 mol) in portions at −10° C. over 2 h under nitrogen protection. The suspension was stirred at room temperature 10 h after the addition. LCMS (215 nm) indicated that tetrahydro-pyran-4-one had been completely consumed. The reaction was acidified by HCl (2 N) to pH 6˜7 and then the phases were separated. The organic phase was washed with water (3 L×2) and the combined aqueous phases were extracted with MTBE (2.5 L×2). The combined organic phase was concentrated under reduced pressure at 25° C. to remove most of MTBE. The residue was distilled out by oil pump (˜200 Pa) at 74° C. to give the title compound as colorless oil (545 g, 26.3%). CHN analysis: calculated (results). C, 53.16; (53.10), H, 6.37; (6.245), N, 0.00; (0.00).
Reaction SMILES: [C:1]1([CH:7]([OH:14])[CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:17][C:18]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:19]=1[CH2:20][O:21][C@@H:22]1[O:27][C@@H:26]([CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][CH2:24][CH2:23]1.O>CN(C)C=O>[Cl:17][C:18]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:19]=1[CH2:20][O:21][C@@H:22]1[O:27][C@@H:26]([CH2:28][O:14][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH2:25][CH2:24][CH2:23]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OCc3ccc(Cl)cc3Cl)O2)cc1
Reactant: OC(Cn1ccnc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(CO[C@H]2CCC[C@H](COC(Cn3ccnc3)c3ccccc3)O2)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.2 %

Procedure:
A solution of 106 mg of 1-phenyl-2-(1-imidazolyl)ethanol in 1 ml of dimethylformamide was stirred with 5 mg of 55% sodium hydride at 50° C. for 30 minutes and the mixture was then left to cool at room temperature. To the resulting mixture were added 3 ml of a dimethylformamide solution containing 300 mg of trans-6-(2,4-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran, prepared as described in Example 2(a); the mixture was then stirred at 80° C. for 4 hours and then at 90° C. for 1 hour. At the end of this time, the reaction mixture was cooled, poured into water and extracted with diethyl ether. The ethereal extract was washed with water, dried over anhydrous sodium sulphate and then concentrated to evaporation under reduced pressure. The residue was purified by column chromatography through silica gel eluted with a 30:1 by volume mixture of ethyl acetate and triethylamine, to give 107 mg of the title compound as a liquid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][NH:10][CH2:9][CH2:8]2.[C:13]([O-])(=[O:15])[CH3:14].[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:13]([N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[C:3]([Cl:2])[CH:4]=[CH:5][CH:6]=2)[CH2:11]1)(=[O:15])[CH3:14]
Reactant: Clc1cccc2c1CNCC2
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N1CCc2cccc(Cl)c2C1

Procedure:
A mixture of 20.4 g. (0.1 mole) 8-chloro-1,2,3,4-tetrahydroisoquinoline, hydrochloride, 9.85 g. (0.12 mole) sodium acetate 40 ml. acetic anhydride and 100 ml. acetic acid was heated for 3 hours on a steambath with stirring. After the solvent was removed under reduced pressure, the residue was dissolved in water which was then made basic with concentrated ammonium hydroxide. The crude product was extracted into methylene chloride and the organic solution was washed with water, 10% hydrochloric acid, water and 5% aqueous sodium bicarbonate. The organic solution was then dried over anhydrous magnesium sulfate and then concentrated to dryness under vacuum to afford 2-acetyl-8-chloro-1,2,3,4-tetrahydroisoquinoline as a yellow oil.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:20][CH:21]([O:25][C:26](ON1C(=O)CCC1=O)=[O:27])[CH:22]([CH3:24])[CH3:23])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:20][CH:21]([O:25][C:26]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:27])[CH:22]([CH3:24])[CH3:23])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)C(OC(=O)ON1C(=O)CCC1=O)OC(=O)c1ccccc1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Solvent: O
Product: CC(C)C(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)c1ccccc1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (630 mg, 4.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]-2-methylpropyl benzoate (500 mg, 1.5 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 49 (200 mg, 35% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.84-0.91 (br. m, 2H), 0.99 (d, J=6.8 Hz, 6H), 1.16-1.31 (br. m, 3H), 1.66-1.68 (br. m, 2H), 1.82-1.85 (m, 2H), 2.03-2.12 (br. m, 2H), 2.80 (t, J=6.4 Hz, 2H), 6.11 (d, J=4.4 Hz, 1H), 7.51 (t, J=6.0 Hz, 1H), 7.57 (t, J=6.0 Hz, 2H), 7.71 (t, J=7.2 Hz, 1H), 7.96 (dd, J=8.4, 1.6 Hz, 2H), 11.97 (br. s, 1H). MS (ESI) m/z 400.08 (M+Na)+; 376.10 (M−H)−.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:51])[N:5](C)[C@H:6]([C:10]([N:12]1[CH2:16][C@@H:15]([CH3:17])[CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]5[N:40]=[C:41]([C@@H:44]6[CH2:48][C@H:47]([CH3:49])[CH2:46][NH:45]6)[NH:42][CH:43]=5)=[CH:35][CH:34]=4)=[CH:29][CH:28]=3)=[CH:26][C:20]=2[N:19]=1)=[O:11])[CH:7]([CH3:9])[CH3:8].[CH3:52][O:53][C:54]([N:56]([CH3:64])[C@@H:57]([CH:61]([CH3:63])[CH3:62])[C:58]([OH:60])=O)=[O:55].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:2][O:3][C:4]([NH:5][C@@H:6]([CH:7]([CH3:9])[CH3:8])[C:10]([N:12]1[CH2:16][C@@H:15]([CH3:17])[CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([C:27]3[CH:28]=[CH:29][C:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]5[N:40]=[C:41]([C@@H:44]6[CH2:48][C@H:47]([CH3:49])[CH2:46][N:45]6[C:58](=[O:60])[C@@H:57]([N:56]([CH3:64])[C:54](=[O:55])[O:53][CH3:52])[CH:61]([CH3:63])[CH3:62])[NH:42][CH:43]=5)=[CH:35][CH:34]=4)=[CH:31][CH:32]=3)=[CH:26][C:20]=2[N:19]=1)=[O:11])=[O:51]
Reactant: COC(=O)N(C)[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6C[C@H](C)CN6)n5)cc4)cc3)ccc2[nH]1)C(C)C
Reactant: COC(=O)N(C)[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6C[C@H](C)CN6C(=O)[C@H](C(C)C)N(C)C(=O)OC)n5)cc4)cc3)ccc2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 43.9 %

Procedure:
To a solution of methyl {(S)-2-methyl-1-[(2S,4S)-4-methyl-2-(5-{4′-[2-((2S,4S)-4-methyl-pyrrolidin-2-yl)-1H-imidazol-4-yl]-biphenyl-4-yl}-1H-benzoimidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester hydrochloride (68.7 mg, 0.0987 mmol) and (2S)-2-[methoxycarbonyl(methyl)amino]-3-methyl-butanoic acid (18.67 mg, 0.09867 mmol) in DMF (2 mL), cooled in an ice bath is sequentially added HATU (41.25 mg, 0.1085 mmol) and DIPEA (38.26 mg, 51.56 μL, 0.2960 mmol) under nitrogen atmosphere. The reaction mixture is stirred at room temperature for 5 hours, and diluted with water (6 mL). The mixture is extracted with EtOAc (5×6 mL), and the combined organic layers are washed with H2O (3×3 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (0 to 10% methanol in CH2Cl2) and is further purified by reverse phase preparative HPLC to give methyl ((S)-1-((2S,4S)-2-(4-(4′-(2-((2S,4S)-1-((S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-4-methylpyrrolidin-2-yl)-3H-benzo[d]imidazol-6-yl)-[1,1′-biphenyl]-4-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate (36 mg, 41%).
Reaction SMILES: C(O[C@@H:5]1[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[Cl:38]CCl>[Ti](Cl)(Cl)(Cl)Cl>[C:8]([O:7][C@@H:6]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:27][CH:5]1[Cl:38])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Product: O=C(OC[C@H]1OC(Cl)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (3.02 g, 5.98 mmol) in dry dichloromethane (100 ml) was added via cannula a dichloromethane solution of titanium tetrachloride (1.13 g, 5.98 mmol, 5.98 ml of a 1M solution). The solution was stirred at room temperature for 1.5 hours under argon, then washed with water (3×100 ml), dried over anhydrous magnesium sulfate and evaporated in vacuo to give the title compounds as a colourless oil (2.9 g, 100%). 1H nmr indicated it to be an approximately 1:1 mixture of α:β-anomers.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[CH3:2].[Cl:12][CH:13]=[CH:14][CH2:15]Cl.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Cl:12]/[CH:13]=[CH:14]/[CH2:15][N:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[CH2:1][CH3:2]
Reactant: ClC=CCCl
Reactant: CCNCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCN(C/C=C/Cl)Cc1cccc(Br)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 4.28 g (20 mmol) of N-ethyl-3-bromobenzylamine in 30 ml of N,N-dimethylfcrmamide were added 2.44 g (22 mmol) of 1,3-dichloropropene and 1.70 g (12 mmol) of ground potassium carbonate under ice cooling. The mixture was stirred for 8 hours at 60° C., poured into 40 ml of ethyl acetate, washed with 40 ml ×2 of water and 40 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate =9/1). The desired fractions were put together and concentrated under reduced pressure to obtain 3.70 g (yield: 64%) of the above identified compound as an oil.
Reaction SMILES: Cl.Cl.C[CH:4]1[CH2:8][CH2:7][CH2:6][C:5]1([NH:12][CH2:13][CH2:14][C@H:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([OH:11])=[O:10].[O:23]=[C:24]1[NH:32][C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[C@:25]21[CH2:46][C:35]1[CH:36]=[C:37]3[C:42](=[CH:43][C:34]=1[CH2:33]2)[N:41]=[CH:40][C:39]([CH:44]=O)=[CH:38]3.[CH3:47]CN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl>[O:23]=[C:24]1[NH:32][C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[C@:25]21[CH2:46][C:35]1[CH:36]=[C:37]3[C:42](=[CH:43][C:34]=1[CH2:33]2)[N:41]=[CH:40][C:39]([CH2:44][NH:22][C@H:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:14][CH2:13][NH:12][C:5]1([C:9]([O:11][CH3:47])=[O:10])[CH2:4][CH2:8][CH2:7][CH2:6]1)=[CH:38]3
Reactant: O=Cc1cnc2cc3c(cc2c1)C[C@@]1(C3)C(=O)Nc2ncccc21
Reactant: CC1CCCC1(NCC[C@H](N)c1ccccc1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(NCC[C@H](NCc2cnc3cc4c(cc3c2)C[C@@]2(C4)C(=O)Nc3ncccc32)c2ccccc2)CCCC1
Reaction time: 0.5 h

Procedure:
To a stirred suspension of methyl-{[(3S)-3-amino-3-phenylpropyl]amino}cyclopentanecarboxylate dihydrochloride (222 mg, 0.634 mmol, prepared according to U.S. Patent Application Publication No. US 2007/0265225) and (7S)-2′-oxo-1′,2′, 6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-3-carbaldehyde (200 mg, 0.634 mmol, Intermediate 1) in chloroform (16 mL) was added Hunig's base (0.222 mL, 1.27 mmol). One hour later, sodium triacetoxyborohydride (403 mg, 1.90 mmol) was added. Two hours later, the reaction was quenched by the addition of saturated sodium bicarbonate (3 mL) and the reaction was allowed to stir for an additional 30 minutes. This mixture was further diluted with water (10 mL) and chloroform (40 mL). The aqueous layer was separated and extracted once with chloroform (30 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue. This residue was applied to a silica gel column for purification, eluting with a gradient of CH2Cl2:MeOH (10% conc. NH4OH)—99:1 to 90:10. Clean product-containing fractions were pooled and concentrated in vacuo to give the title compound. MS: m/z=576 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2C(=O)C.Cl>CO>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: CC(=O)n1ncc2c(Br)cccc21
Agent: Cl
Solvent: CO
Product: Brc1cccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.9 %

Procedure:
To a solution of the 1-(4-bromo-indazol-1-yl)-ethanone (3.09 g, 12.9 mmol) in MeOH (50 mL) was added 6N aqueous HCl (30 mL) and the mixture was stirred at room temperature for 7 h. The MeOH was evaporated and the mixture partitioned between EtOAc (2×50 mL) and water (50 mL). The combined organic layers were washed with brine (50 mL), separated and dried (MgSO4). The solvent was removed by evaporation under reduced pressure to give 4-bromo-1H-indazole (2.36 g, 93%).
Reaction SMILES: Cl.[F:2][C:3]([F:12])([F:11])[C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[N:13]([O-])=O.[Na+].[CH3:17][C:18](=[O:23])[CH2:19][C:20](=[O:22])[CH3:21].[OH-].[Na+]>O>[F:2][C:3]([F:11])([F:12])[C:4]1[CH:10]=[CH:9][CH:8]=[C:6]([NH:7][N:13]=[C:19]([C:18](=[O:23])[CH3:17])[C:20](=[O:22])[CH3:21])[CH:5]=1
Reactant: O=N[O-]
Reactant: CC(=O)CC(C)=O
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C(=NNc1cccc(C(F)(F)F)c1)C(C)=O
Yield: 92 %

Procedure:
To a cold (0° C.) solution of 80 ml. of concentrated hydrochloric acid and 300 ml. of water, there is added a solution of 49.2 g. (0.305 mole) of m-trifluoromethylaniline and then a solution of 22.1 g. (0.32 mole) of sodium nitrite in 100 ml. of water. The resulting benzenediazonium chloride solution is filtered to remove a small amount of insoluble material. To this solution is added 100 g. of sodium acetate followed by a solution of 30.5 g. (0.305 mole) of 2,4-pentanedione and 12.2 g. (0.305 mole) of sodium hydroxide in 150 ml. of water. After about 0.5 hour the solids that form are filtered, washed with water, partly dried on the filter funnel and recrystallized from 450 ml. of ethanol to yield 76.6 g. (92% yield) of product (III), melting at 107.5° to 109° C. An analytical sample is obtained by recrystallization from ethanol to give pure 2,3,4-pentanetrione 3 -[(α,α,α-trifluoro-m-tolyl)hydrazone] (III), melting at 108 to 109.5°C. with slight softening at 102° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)O)=[CH:4][CH:3]=1.Cl.C(O)(=O)C.O>CC1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[C:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Fc1ccc(C(=C2CCN(Cc3ccccc3)CC2)c2ccc(F)cc2)cc1

Procedure:
A mixture of 40 parts of α,α-bis(4-fluorophenyl)-1-(phenylmethyl)-4-piperidinemethanol, 120 parts of a hydrochloric acid solution and 50 parts of acetic acid was stirred and refluxed for 2 hours. The reaction mixture was cooled and water and methylbenzene were added: three layers were obtained. The two supernatant phases were separated and treated with ammonium hydroxide. The organic phase was separated, dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 26 parts of 4-[bis(4-fluorophenyl)methylene]-1-(phenylmethyl)piperidine (intermediate 13).