Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1I.C(NC(C)C)(C)C>C(Cl)Cl.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>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: Clc1ccc(I)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: Clc1ccc(C#Cc2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.4 %

Procedure:
A mixture of 1-chloro-4-ethynyl-benzene (2.71 g, 0.020 mol), 2,4-dichloro-1-iodo-benzene (3.23 mL, 0.024 mol), PdCl2(PPh3)2 (0.10 g, 1.4 mmol), CuI (1.44 g, 7.6 mmol), and diisopropylamine (7 mL) in DCM (i.e., dichloromethane) (100 mL) was stirred at room temperature for 16 h. The mixture was filtered through CELITE. The filtrate was concentrated in vacuo. The residue was chromatographed (SiO2, hexane) to afford 2,4-dichloro-1-(4-chloro-phenylethynyl)-benzene as a white solid (3.23 g, 87%).
Reaction SMILES: [CH2:1]([C:3](=[CH2:6])[CH:4]=O)[CH3:2].[NH2:7][C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(O)(=O)C>[CH2:1]([C:3]1[CH:4]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:7][CH:6]=1)[CH3:2]
Reactant: C=C(C=O)CC
Reactant: CCOC(=O)C=C(N)C(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC)cnc1C(=O)OCC
Reaction time: 4 h
Yield: 44.9 %

Procedure:
Glacial acetic acid 100 g and 2-ethyl-2-propenal 30 g (0.357 mol) were placed in a 200 ml four neck distillation flask: with a reflux condenser and heated on an oil bath. When the inside temperature reached 90° C., ethyl β-amino-β-ethoxycarbonylacrylate 60 g (0.321 mol) was added dropwise thereto at 90° to 95° C. over a period of 4 hours. After completion of the dropping, the mixture was reacted at 90° to 95° C. for 3 hours. After completion of the reaction, the reaction mixture was distilled to give 36.2 g of 5-ethyl-2,3-diethoxycarbonylpyridine (bp2 : 151° to 152° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8](Br)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[C:14]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)#[CH:15]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([C:15]#[C:14][C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Reactant: C#Cc1ccc(N)cc1
Product: CCOC(=O)c1c(C)nc(C#Cc2ccc(N)cc2)n1C

Procedure:
The title compound, MS: m/e=284.4 (M+H+) was prepared in accordance with the general method of example 1b from 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and 4-ethynylaniline.
Reaction SMILES: C(OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].Cl.C([O-])=O.[NH4+].[F:16][C:17]([F:30])([F:29])[C:18]1[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH2:26][CH:27]=[O:28])=[CH:20][CH:19]=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:28][CH:27]([CH2:26][CH2:25][S:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]([F:29])([F:16])[F:30])=[CH:19][CH:20]=1)[CH2:2][C:3](=[O:4])[CH3:5]
Reactant: O=CCCSc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)CC(O)CCSc1ccc(C(F)(F)F)cc1
Reaction time: 3 h
Yield: 77.5 %

Procedure:
7.55 Grams of methyl acetoacetate were dissolved in 10 ml of water, and 9.1 g of a 30% aqueous sodium hydroxide solution were added thereto by drops while cooling the mixture to 35° C. or less. After having been stirred at 30°-35° C. for 3 hours, the mixture was adjusted to pH 7.5 with a concentrated aqueous hydrochloric acid solution. Thereafter, 0.32 g of ammonium formate and 1.61 g of tetrabutylammonium bromide were added thereto and then 54.0 g of a toluene solution containing 17.4% of 3-(4-trifluoromethylphenylthio)propanal were added thereto. The mixture was stirred at from 45°-50° C. for 10 hours and then at room temperature for 12 hours. After the mixture had been neutralized with a concentrated aqueous hydrochloric acid solution, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Removing the solvent from the layer under reduced pressure gave 13.90 g of crude 4-hydroxy-6-(4-trifluoromethylphenylthio)-2-hexanone (purity: 81.4%, yield: 77.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.[Li][CH:22]([CH2:24]C)[CH3:23].[Cu]C#N.C(Br)C=C.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH2:24]([C:7]1[C:2]([Cl:1])=[C:3]2[CH:10]=[CH:9][N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[C:4]2=[N:5][CH:6]=1)[CH:22]=[CH2:23]
Reactant: [Li]C(C)CC
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Agent: N#C[Cu]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C=CCBr
Product: C=CCc1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1Cl
Temperature: -75 °C
Reaction time: 0.75 h
Yield: 91.7 %

Procedure:
The 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.10 g, 10.0 mmol, Preparation #1, Step A) in THF (40 mL) was cooled to about −75° C. then sec-BuLi (1.4 M in hexane, 14.3 mL, 20.0 mmol) was added slowly keeping the temperature below −65° C. The mixture was stirred at about −75° C. for about 45 min then copper(I) cyanide (0.090 g, 1.00 mmol) was added. The mixture was stirred for about 5 min then allyl bromide (2.61 mL, 30.1 mmol) was added drop-wise. After about 10 min saturated aqueous NaHCO3 (20 mL) and EtOAc (50 mL) were added to the mixture. The mixture was partitioned between water (20 mL) and EtOAc (50 mL). The layers were separated then the aqueous layer was extracted with EtOAc (25 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (40 mL) then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The material was purified by flash chromatography on 120 g silica gel with 98:2 heptane/EtOAc as an eluent to give 5-allyl-4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.2 g, 91%): LC/MS (Table 2, Method g) Rt=2.63 min; MS m/z 349 (M+H)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][N:13]1[C:17]([CH3:18])=[C:16]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26]3[C:31]([N:32]4[CH2:37][CH2:36][CH:35]([CH2:38][OH:39])[CH2:34][CH2:33]4)=[N:30][CH:29]=[CH:28][N:27]=3)[CH2:22][CH2:21]2)[CH:15]=[N:14]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:12][N:13]1[C:17]([CH3:18])=[C:16]([CH2:19][N:20]2[CH2:21][CH2:22][N:23]([C:26]3[C:31]([N:32]4[CH2:37][CH2:36][CH:35]([CH2:38][O:39][S:7]([C:4]5[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=5)(=[O:9])=[O:8])[CH2:34][CH2:33]4)=[N:30][CH:29]=[CH:28][N:27]=3)[CH2:24][CH2:25]2)[CH:15]=[N:14]1
Reactant: Cc1c(CN2CCN(c3nccnc3N3CCC(CO)CC3)CC2)cnn1C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCN(c3nccnc3N3CCN(Cc4cnn(C)c4C)CC3)CC2)cc1
Reaction time: 20.5 h
Yield: 51 %

Procedure:
Add p-toluenesulfonyl chloride (272 mg, 1.43 mmol, 1.1 eq) to a solution of {1-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-piperidin-4-yl}-methanol (0.5 g, 1.30 mmol, 1 eq, free base and triethylamine (1.43 mL, 10.24 mmol, 1.1 eq) in DCM (3 mL) at 0° C. Stir the mixture under nitrogen for 20.5 hr. Add a further portion of p-toluenesulfonyl chloride (0.13 g, 0.682 mmol, 0.5 eq) to the reaction mixture and continue stirring for a further 4.5 hr. Quench the reaction with saturated aqueous sodium bicarbonate solution (20 mL), and then pass through a hydrophobic frit to separate. Wash the aqueous layer twice with DCM (20 mL), combine the organic extracts and concentrate. Purify by flash chromatography on 40 g silica gel column, eluting with 0-10% methanol in DCM to give toluene-4-sulfonic acid 1-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-piperidin-4-ylmethyl ester (0.36 g, 51%). MS (m/z): 540.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)N.N([O-])=[O:15].[Na+].O>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(O)cc(C(F)(F)F)c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
3-Methoxy-5-(trifluoromethyl)aniline (5 g) was suspended in 20% HCl (200 mL), stirred for 30 min, cooled to 0-5° C. and diazotized with NaNO2 (2.17 g) added in small portions. The mixture was stirred for 30 min at that temperature and added dropwise to boiling water (200 mL). The mixture was refluxed for 15 min, allowed to cool to room temperature and extracted with AcOEt, dried (MgSO4), filtered and evaporated. The residue was then purified by column chromatography (silica gel; eluent: hexane and AcOEt) to give 3-methoxy-5-(trifluoromethyl)phenol (3.6 g)
Reaction SMILES: [OH:1][C:2]([CH3:18])([CH3:17])[C@H:3]([NH:10][C:11](=[O:16])C(Cl)(Cl)Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:4]1([C@@H:3]2[C:2]([CH3:18])([CH3:17])[O:1][C:11](=[O:16])[NH:10]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(O)[C@H](NC(=O)C(Cl)(Cl)Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC1(C)OC(=O)N[C@@H]1c1ccccc1
Yield: 92.1 %

Procedure:
To a solution of (14) (1.655 g, 5.33 mmol) in ethanol (140 ml) was added potassium carbonate (0.369 g. 2.67 mmol) and the solution was refluxed for 30 minutes. After concentration in vacuo, dichloromethane was added and the mixture was washed with saturated aqueous sodium chloride solution. Concentration in vacuo gave crude crystalline solid which was purified by recrystallisation in ethyl acetate/pentane to give the title compound (15) (0.939 g, 92%); mp 149° C.; νmax (CHCl3) 1753 cm-1 ; [α]D25 (c 0.5 in CHCl3)=-77.6; (Found: C, 69.32; H, 7.05; N, 7.38. C11H13NO2 requires C, 69.09; H, 6.85; N, 7.33%); δH (200 MHz; CDCl3) 0.93 (3H, s, C(CH3)2), 1.61 (3H, s, C(CH3)2), 4.66 (1H, s, CHPh), 6.25 (1H, s, NH), 7.25-7.44 (5H, m, ArCH); δC (125 MHz; CDCl3 23.53 (CH3), 28.04 (CH3), 65.93 (CH), 84.63 (C), 126.67 (ArCH), 128.72 (ArCH), 128.93 (ArCH), 137.16 (C), 159.75 (CO) ; m/z (CI+, NH3) 192 (M+ +1).
Reaction SMILES: C1COCC1.[Li+].[BH4-].[CH3:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][N:10]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>CO>[CH2:19]([O:18][C:16]([N:10]1[CH2:11][CH:12]([OH:15])[CH2:13][CH2:14][CH:9]1[CH3:8])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1CCC(=O)CN1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1CCC(O)CN1C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of THF (200 mL) and MeOH (11 mL) was added LiBH4 (2 M, 89 mL, 0.18 mol). Some gas evolution and a small exotherm were observed. The reaction was aged at room temperature for 30 min before being cooled to −10° C.±benzyl 2-methyl-5-oxopiperidine-1-carboxylate (22.0 g, 0.089 mol) was then added dropwise, keeping the temperature below −5° C. The reaction was then aged at −10° C. for 30 min. The reaction was quenched by adding half-saturated, aqueous NaHCO3, then extracted with EtOAc. The layers were separated and the organics dried with MgSO4. The organics were concentrated to give crude ±benzyl-5-hydroxy-2-methylpiperidine-1-carboxylate as a crude, colorless oil.
Reaction SMILES: [C:1]([N:4]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8][CH2:7][C:6]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:5]1=2)(=[O:3])[CH3:2].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1>>[C:1]([N:4]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8][CH2:7][C:6]2[CH:13]=[C:14]([NH:17][C:19]3[N:24]=[C:23]([NH:25][C:26]4[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=4[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=3)[CH:15]=[CH:16][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)N1CCC(=O)NCc2cc(N)ccc21
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CNC(=O)CCN3C(C)=O)ncc1Cl

Procedure:
2-[2-(1-Acetyl-4-oxo-1,2,3,4,5,6-hexahydro-benzo[b][1,5]diazocin-8-ylamino)-5-chloro-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide was prepared from 1-Acetyl-8-amino-2,3,5,6-tetrahydro-1H-benzo[b][1,5]diazocin-4-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1221d. Isolated as a beige solid. MP: 97-103. HPLC purity: 95%, LCMS: 512.28 (M+H) HNMR: CD3OD: 8.16 (s, 1H), 7.51-7.41 (m, 5H), 7.12 (d, J=8.6 Hz, 1H), 4.79-4.75 (m, 1H), 4.37-4.33 (m, 1H), 3.86-3.79 (m, 1H), 3.20-3.12 (m, 1H), 2.86 (s, 3H), 2.73-2.71 (m, 1H), 2.49-2.44 (m, 1H), 1.78 (s, 3H).
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:17])[C@H:3]2[CH2:18][CH2:19][CH2:20][CH2:21][C@@H:2]12.C(N1C=CN=C1)([N:25]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1>[C:1]1(=[O:22])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][C:8]([NH2:25])=[O:9])[C:4](=[O:17])[C@H:3]2[CH2:18][CH2:19][CH2:20][CH2:21][C@@H:2]12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(c1ccccc1)N1C(=O)[C@H]2CCCC[C@H]2C1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)CC(c1ccccc1)N1C(=O)[C@H]2CCCC[C@H]2C1=O
Reaction time: 1 h
Yield: 23.3 %

Procedure:
A mixture of 3-(cis-hexahydrophthalimido)-3-phenylpropionic acid (0.903 g, 3.00 mmol) and carbonyldiimidazole (0.525 g, 3.75 mmol) in 13 mL of anhydrous tetrahydrofuran under nitrogen was stirred for 1 hour, then 0.25 mL of concentrated ammonium hydroxide was added to the reaction solution. After 20 minutes, the reaction mixture was concentrated in vacuo to an oil. The oil was diluted with 20 mL of water and the mixture extracted with ethyl acetate (20 mL). The organic layer was dried (sodium sulfate) and concentrated to afford an oil. The oil was then purified by flash chromatography (silica gel, 5/95 methanol/methylene chloride, Rf =0.3) to afford 210 mg of 3-(cis-hexahydrophthalimido)-3-phenylpropionarnide as an oil which slowly crystallized to an ivory solid: 1H NMR (DMSO-d6) d7.49 (s, 1 H, NH), 7.4-7.2 (m, 5 H, Ar), 6.90 (s, 1 H, NH), 5.54 (t, 1 H, J=7.8 Hz, CH), 3.09 (d, 2 H, J=7.8 Hz, CH2), 2.95-2.80 (m, 2 H, CH2), 1.8-1.1 (m, 8 H); 13C NMR (DMSO-d6) δ 179.6, 179.5, 171.5, 139.5, 128.6, 127.7, 127.2, 55.2, 50.6, 38.8, 36.5, 23.4, 23.3,21.5.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]3[N:32]4[CH2:33][CH2:34][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][C:31]4=[N:30][C:25]=3[CH:26]=[N:27]2)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[NH4+:45].[Cl-]>C(Cl)(Cl)Cl>[NH2:45][C:26]1[C:25]2[N:30]=[C:31]3[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34][CH2:33][N:32]3[C:24]=2[C:23]2[C:28](=[CH:29][C:20]([O:19][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:21][CH:22]=2)[N:27]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCn2c(nc3cnc4cc(OCc5ccccc5)ccc4c32)C1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Cl-]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCn2c(nc3c(N)nc4cc(OCc5ccccc5)ccc4c32)C1
Reaction time: 0.5 h

Procedure:
mCPBA (0.782 g of 77% purity, 3.49 mmol) was added to a solution of tert-butyl 3-benzyloxy-10,11-dihydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate (1.0 g, 2.3 mmol) in chloroform (15 mL), and the reaction was stirred for 30 minutes. Ammonium hydroxide (5 mL), and the reaction was stirred for five minutes before the rapid addition of p-toluenesulfnyl chloride (0.4865 g, 2.55 mmol). The reaction was stirred overnight at ambient temperature. The organic layer was separated and concentrated under reduced pressure. The residue was purified by normal phase prep HPLC on silica gel (eluting with 2 N ammonia in methanol/chloroform in a 42-minute gradient from 0:100 to 5:95) to provide 550 mg of tert-butyl 6-amino-3-benzyloxy-10,11-dihydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)=[O:28])=[CH:23][CH:22]=1.[CH:36]1([N:39]([CH2:41][CH:42]2[CH2:44][CH:43]2[CH2:45]O)[CH3:40])[CH2:38][CH2:37]1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:45][CH:43]3[CH2:44][CH:42]3[CH2:41][N:39]([CH:36]3[CH2:38][CH2:37]3)[CH3:40])=[CH:31][CH:30]=2)=[O:28])=[CH:23][CH:22]=1
Reactant: CN(CC1CC1CO)C1CC1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(CC1CC1COc1ccc(C(=O)c2ccc(Br)cc2)cc1)C1CC1
Reaction time: 3 h
Yield: 42.2 %

Procedure:
A solution of 6.2 g of triphenylphosphine, 6.5 g of (4-bromo-phenyl)-(4-hydroxy-phenyl)-methanone and 3.64 g of (1RS,2RS)-[2-[(cyclopropyl-methyl-amino)-methyl]-cyclopropyl]-methanol (Ex. 31.1.A.d) in 190 ml of THF is treated at room temperature during 1 hr. with 4.03 ml of diethyl azodicarboxylate in 18 ml of THF. After stirring for 3 hrs. the mixture is concentrated, taken up in ether and washed with saturated sodium bicarbonate solution and 10% sodium chloride solution, dried and concentrated. The residue is dissolved in ether and precipitated with hexane. The mother liquor is concentrated and the crude (1RS,2RS)-(4-bromo-phenyl)-[4-[2-[(cyclopropyl-methyl-amino)-methyl]-cyclopropylmethoxy]-phenyl]-methanone is dissolved in ethanol, treated with 2.7 g of fumaric acid and crystallized out. There are obtained 4.1 g of (1RS,2RS)-(4-bromo-phenyl)-[4-[2-[(cyclopropyl-methyl-amino)-methyl]-cyclopropylmethoxy]-phenyl]-methanone.fumarate (1:1), m.p. 136-137° C.
Reaction SMILES: N1C=CC=CC=1.O[C:8]([CH:11]1[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH2:12]1)([CH3:10])[CH3:9].P(Cl)(Cl)(Cl)=O.Cl>CCOCC>[C:8](=[C:11]1[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH2:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)(O)C1Cc2ccccc21
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)=C1Cc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.8 %

Procedure:
Into 30 ml of dried pyridine, was dissolved 1.78 g of 1-(1-hydroxy-1-methylethyl)benzocyclobutene. To the solution, was added dropwise 3.37 g of phosphorus oxychloride over a period of 5 minutes at room temperature. The mixture was stirred for 24 hours at room temperature, then poured into 3% aqueous cold hydrochloric acid solution and admixed with ether. After the ether layer was separated, the aqueous layer was extracted twice with ether. The ether layers were combined, washed with saturated aqueous sodium hydrogencarbonate solution, then with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain as the residue 1.5 g of a mixture of the intended product and 1-isopropenylbenzocyclobutene. This mixture was used without further purification as the starting material in the next step of preparation.
Reaction SMILES: O.C([O:9][C:10](=[O:23])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])C1C=CC=CC=1>[Pd].CO>[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:10]([OH:23])=[O:9])(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCCCCC(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.8 %

Procedure:
10% Pd-C (3.00 g) was added to a 1% water-containing methanol solution (200 ml) of N-hexanoyl-L-proline benzyl ester (25.61 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 1.5 hours. After the catalyst was filtered off, the filtrate was concentrated to obtain 17.61 g of N-hexanoyl-L-proline.
Reaction SMILES: I[C:2]1[C:3]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[C:23]1(B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26][CH2:25][CH:24]=1>>[C:23]1([C:2]2[C:3]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([CH:16]=2)[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Reactant: O=C(Nc1cccnc1)c1cnc(OCC(F)(F)F)c(I)c1
Product: O=C(Nc1cccnc1)c1cnc(OCC(F)(F)F)c(C2=CCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1c using 5-iodo-N-(pyridin-3-yl)-6-(2,2,2-trifluoroethoxy)nicotinamide (Example 1b) and 2-(1-cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAN 287944-10-9) as starting materials; MS (ESI) 364.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]=1.C=O.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16](S(O)(=O)=O)=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]=1[CH2:1][C:2]1[CH2:23][C:13]2[C:18]([C:3]=1[CH3:4])=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CC1=CCc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: Cc1ccccc1
Product: CC1=C(CC2=C(C)c3ccccc3C2)Cc2ccccc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 247.4 %

Procedure:
In a 500 mL flask equipped with magnetic stirring bar were introduced 14.8 g (0.114 moles) of 3-methyl-indene, 2.3 g (0.077 moles) of para-formaldehyde and 4.37 g (0.023 moles) of para-toluenesulphonic acid in 200 ml of toluene; the mixture was heated to 80° C. and was maintained under stirring for 1 hour at 80° C. Then the reaction was quenched with water/NaHCO3; the conversion, measured by gas chromatographic analysis, was 85.9%. The organic layer was separated, washed with water and brought to dryness under reduced pressure. The crude product was crystallized upon standing at room temperature, and then was further purified by washing with pentane or MeOH, thus isolating 15.5 g of bis(3-methyl-2-indenyl)methane (purity of 89.8% by G.C.; yield=89.8%).
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.O.[OH-].[Li+].Cl>C1COCC1.O>[NH2:4][C:5]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CC(=O)Nc1ccc(C(C)C)cc1C(=O)O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc(N)c(C(=O)O)c1

Procedure:
A mixture of Example 2B (0.621 g, 2.81 mmol) and lithium hydroxide monohydrate (0.38 g, 9.0 mmol) in THF (6 mL) and water (6 mL) was stirred at 60° C. for 72 hours, acidified to pH 3.5 with 1M HCl, and extracted twice with ethyl acetate. The combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by C18 reverse-phase HPLC with acetonitrile/water/0.1% TFA to provide the desired product. MS (ESI(+)) m/e 180 (M+H)+; (ESI(−)) m/e 178 (M−H)−.