Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:31]=[CH:30][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH:58]2[CH2:60][O:59]2)=[CH:52][CH:51]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:29][C:23]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=1[CH2:21][O:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:60][C@H:58]([OH:59])[CH2:57][O:56][C:53]3[CH:54]=[CH:55][C:50]([OH:49])=[CH:51][CH:52]=3)=[CH:31][CH:30]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(NC2CCN(C(=O)OCc3cc(F)ccc3F)CC2)cc1
Solvent: O=CO
Product: O=C(OCc1cc(F)ccc1F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1

Procedure:
2,5-Difluorobenzyl 4-[4-(2-aminoethyl)anilino]-1-piperidinecarboxylate formate (0.609 g, 1.4 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane according to Procedure G to yield the title compound (0.260 g, 0.3 mmol).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C:16]1[CH:15]=[CH:14][C:13]([O:20]C)=[CH:12][C:11]=1[CH2:10][C@H:9]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C@H:31]([CH2:35][CH2:36][C:37]([F:49])([F:48])[C:38]([F:47])([F:46])[C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41])[C:32]([OH:34])=[O:33].B(Br)(Br)Br>ClCCl>[OH:20][C:13]1[CH:14]=[CH:15][C:16]2[C@@H:17]3[C@H:8]([C@H:5]4[C@@:3]([CH2:19][CH2:18]3)([CH3:4])[C@@H:2]([OH:1])[CH2:7][CH2:6]4)[C@H:9]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C@H:31]([CH2:35][CH2:36][C:37]([F:48])([F:49])[C:38]([F:46])([F:47])[C:39]([F:44])([F:45])[C:40]([F:41])([F:42])[F:43])[C:32]([OH:34])=[O:33])[CH2:10][C:11]=2[CH:12]=1
Reactant: COc1ccc2c(c1)C[C@@H](CCCCCCCCC[C@H](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCCC[C@H](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O)[C@H]3[C@@H]1CC[C@@H]2O
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 65.7 %

Procedure:
Anhydrous dichloromethane (10 ml) was added to (2R)-11-(17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoic acid (358 mg, 0.50 mmol) under nitrogen atmosphere and the resulting mixture was cooled to −78° C. Boron tribromide (1.0 M in tetrahydrofuran, 3.0 ml, 3.0 mmol) was added dropwise to the mixture, which was then stirred on ice for 2.5 hours. The reaction mixture was cooled again to −78° C. and quenched with saturated aqueous sodium bicarbonate over 1 hour. After the reaction mixture was extracted with ethyl acetate, the organic layer was washed sequentially with saturated aqueous potassium bisulfate, saturated aqueous sodium chloride, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure using an evaporator and the resulting residue was purified by silica gel column chromatography (Wako gel C-200, eluent: ethyl acetate/n-hexane=4/6) to give (2R)-11-(3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoic acid (231 mg, Yield 60%) as a yellow amorphous mass.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH:36]1([CH:39]=O)[CH2:38][CH2:37]1.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:39][CH:36]3[CH2:38][CH2:37]3)[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: O=CC1CC1
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 90 °C
Yield: 54.7 %

Procedure:
To a solution of 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (2173. mg, 4.61 mmol) in ethanol (36 mL) was added cyclopropanecarbaldehyde (0.53 mL, 6.91 mmol) and piperidine (0.23 mL, 2.3 mmol). The reaction was heated to 90° C. for 75 minutes, then cooled and concentrated. The residue was dissolved in ethyl acetate (200 mL) and washed with water and then brine. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by Isolera (100 g column, 1%-7% MeOH/DCM) to provided 1.32 g (55% yield) of the title compound. LCMS m/z 524 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[S:38][C:39]([C:42]([NH:44][CH:45]2[CH2:47][CH2:46]2)=[O:43])=[CH:40][N:41]=1>>[CH:45]1([NH:44][C:42]([C:39]2[S:38][C:37]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[N:41][CH:40]=2)=[O:43])[CH2:47][CH2:46]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=C(NC1CC1)c1cnc(Br)s1
Product: C[C@@H](c1ccc(-c2ncc(C(=O)NC3CC3)s2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromo-N-cyclopropylthiazole-5-carboxamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.219 min, m/z=462.1; 1H NMR (CDCl3) 0.51 (m, 2H), 0.81 (m, 2H), 1.04 (s, 3H), 1.12 (s, 3H), 1.47 (d, 3H), 2.06-2.24 (m, 5H), 2.29-2.40 (m, 1H), 2.71-2.89 (m, 2H), 5.62 (m, 1H), 6.09 (s, 1H), 6.94 (m, 2H), 7.21-7.39 (m, 5H), 7.61 (m, 2H), 8.01 (s, 1H)
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.Br[C:18]1[CH:19]=[CH:20][C:21]2[NH:27][C:26](=[O:28])[CH:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24][CH2:23][C:22]=2[CH:37]=1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[C:1]1([C:18]2[CH:19]=[CH:20][C:21]3[NH:27][C:26](=[O:28])[CH:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:24][CH2:23][C:22]=3[CH:37]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(Br)ccc2NC1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCc2cc(-c3ccccc3)ccc2NC1=O
Temperature: 100 °C

Procedure:
371 mg of phenylboronic acid (3.04 mmol), 62 mg of 1,1′-bis(diphenylphosphino)ferrocene palladium chloride (C35H30Cl4FeP2Pd, Mw 816.65, 0.025 mmol) and 3.96 g of caesium carbonate (12.16 mmol) are introduced into a 100 ml round-bottomed flask, with stirring and under an argon atmosphere, containing 22 ml of water, 6.5 ml of dioxane and 1.08 g of 10 (3.04 mmol). The medium is heated at 100° C., with stirring, for 1 h. The medium is filtered over celite and washed with 10 ml of dioxane, 10 ml of CH2Cl2 and 10 ml of MeOH. The filtrate is concentrated under vacuum. 25 ml of EtOAc are then added and the mixture is washed with 2 times 25 ml of water. The organic phase is dried over MgSO4, filtered and evaporated to dryness. The crude is chromatographed on a silica cartridge (50 g), elution being carried out with CH2Cl2/MeOH (as an MeOH gradient: 1 to 10%). 350 mg of expected product 13 (white solid) are recovered.
Reaction SMILES: Br[CH:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[CH:8][CH:9]=2)[O:4][CH2:3]1.BrC1(Br)C(=O)C2C(=CC(O[Si](C(C)C)(C(C)C)C(C)C)=CC=2)OC1.[OH:48][C:49]1([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(N(CC)CC)C>C(O)C>[OH:48][C:49]1([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:54][CH2:53][N:52]([CH:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][C:7]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[CH:8][CH:9]=3)[O:4][CH2:3]2)[CH2:51][CH2:50]1
Reactant: CC(C)[Si](Oc1ccc2c(c1)OCC(Br)C2=O)(C(C)C)C(C)C
Reactant: OC1(c2ccccc2)CCNCC1
Agent: CC(C)[Si](Oc1ccc2c(c1)OCC(Br)(Br)C2=O)(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)[Si](Oc1ccc2c(c1)OCC(N1CCC(O)(c3ccccc3)CC1)C2=O)(C(C)C)C(C)C
Yield: 3 %

Procedure:
7-(Triisopropylsilyloxy)-4-chromanone (2.0 g, 6.2 mmol) was dissolved in CCl4 (45 ml). Bromine (0.3 ml, 6.4 mmol) in CCl4 (5 ml) was added dropwise at ambient temperature over 10 minutes. The reaction initially turned dark red but after stirring for 10 minutes the color changed to light yellow. This yellow solution was washed with dilute NaHSO3, saturated NaHCO3 and brine, dried by filtering through phase separatory paper, and concentrated to yield a brown oil (2.3 g, 93%) which NMR showed was a 2.5:1:1 mixture of 3-bromo-7-(triisopropylsilyloxy)-4-chromanone, 3,3-dibromo-7-(triisopropylsilyloxy)-4-chromanone and starting material. This crude mixture (2.3 g, 5.6 mmol) was combined with 4-hydroxy-4-phenyl piperidine (1.0 g, 5.8 mmol), triethylamine (0.9 ml, 6.5 mmol) and ethanol (50 ml). The reaction was refluxed for 3 hours, then cooled and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over CaSO4, concentrated and the residue chromatographed on silica gel using gradient elution with ethyl acetate/hexanes to give 80 mg (3%) of present title product as a yellow solid, mp 132°-132.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C(N(CC)CC)C.BrBr.[OH-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: Oc1cc(F)c(F)c(F)c1
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1cccc(F)c1F
Temperature: -78 °C

Procedure:
1.27 g of 3,4,5-trifluorophenol and 870 mg of triethylamine were dissolved in 10 ml of methylene chloride, and the solution was stirred at −78° C. To the solution was added dropwise 5 ml of a methylene chloride solution of 2-(2-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)ethyl)-1,3-dithianilium triflate obtained above (3.8 g), and the to solution was further stirred for one hour. 6.24 ml of Et3N.3HF was then -added, and a methylene chloride solution of bromine (6.24 g) was further added dropwise. After stirring at −70° C. for one hour, the reaction solution was allowed to gradually warm up. It was poured into 100 ml of a cold 3N sodium hydroxide solution at 0° C. and extracted with methylene chloride (30 ml×3). The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting yellow oily substance was isolated and purified by a silica gel column chromatography with heptane as a developing solvent to obtain 1.0 g of 1-(3-(trans-4-propylcyclohexyl)cyclohexyl)-1,1-difluoropropyleneoxy)-3,4,5-trifluorobenzene as colorless crystals. A transition point thereof is shown below.
Reaction SMILES: [CH:1]([NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([NH:13][C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][C:15]=2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)=[O:24])=[O:12])[CH2:7][CH2:6]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:40]([N:4]([C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]([NH:13][C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][C:15]=2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)=[O:24])=[O:12])[CH2:9][CH2:10]1)[CH:1]([CH3:3])[CH3:2])(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: CC(C)N[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N(C(C)C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trans-3-[4-(isopropylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (100 mg) obtained in Example 310 and triethylamine (61 μl) is dissolved in chloroform (5 ml), and thereto is added acetyl chloride (24 μl). The mixture is stirred at room temperature for one hour, and thereto is poured a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is washed successively with water and a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1, then ethyl acetate). The resulting residue is suspended in n-hexane, and collected by filtration to give the title compound (60 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:57][CH:58]([CH3:60])[CH3:59])[C:7]([F:56])=[C:8]([CH:10]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]3[N:54]=[C:53]([CH3:55])[O:52][N:51]=3)=[CH:46][CH:45]=2)[C:11]2[N:12]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:13]=[C:14]([C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[CH:18]=[O:19])[N:15]=2)[CH:9]=1)[CH3:2].[CH3:61][CH2:62][Mg+].[Br-].CCOC(C)=O.[Na+].[Cl-]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:57][CH:58]([CH3:59])[CH3:60])[C:7]([F:56])=[C:8]([CH:10]([NH:43][C:44]2[CH:45]=[CH:46][C:47]([C:50]3[N:54]=[C:53]([CH3:55])[O:52][N:51]=3)=[CH:48][CH:49]=2)[C:11]2[N:12]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:13]=[C:14]([C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[CH:18]([OH:19])[CH2:61][CH3:62])[N:15]=2)[CH:9]=1)[CH3:2]
Reactant: CC[Mg+]
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C=O)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C(O)CC)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of Intermediate 122.1 (50 mg, 0.06 mmol) in THF (1 mL) was added EtMgBr dropwise at 0° C. under N2 atmosphere, the reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was then partionated between EtOAc and sat. NaCl, the organic layer was collected and dried over (Na2SO4), filtered and concentrated. The crude material Intermediate 122.2 was used as is in the following step. LCMS (2 min gradient) RT=2.23 min, 828.4 (M+H).
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7](OC)=[O:8])[C:2]=1[C:11](OC)=[O:12].O.[NH2:22][NH2:23].Cl>>[C:15]1([C:1]2[CH:6]=[CH:5][CH:4]=[C:3]3[C:2]=2[C:11]([OH:12])=[N:22][N:23]=[C:7]3[OH:8])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cccc(-c2ccccc2)c1C(=O)OC
Reactant: NN
Agent: Cl
Solvent: O
Product: Oc1nnc(O)c2c(-c3ccccc3)cccc12
Yield: 85.1 %

Procedure:
A solution of dimethyl [1,1′-biphenyl]-2,3-dicarboxylate (0.600 g, 2.22 mmol) in hydrazine hydrate (5.00 mL, 159 mmol) was heated in a sealed tube at 100° C. for 16 h. The reaction mixture was acidified to pH˜3 with 1.5N HCl. The resulting precipitate was filtered, washed with water (3×50 mL) and hexanes (2×50 mL). The precipitate was dried under vacuum to yield 5-phenylphthalazine-1,4-diol (0.450 g, 85.0%) as an off-white solid. LCMS (Condition 11): retention time 0.76 min, [M+1]=239.4. 1H NMR (400 MHz, DMSO-d6) δ 7.29-7.34 (m, 5 H), 7.60 (d, J=7.6 Hz, 1 H), 7.89 (t, J=7.6 Hz, 1 H), 8.13 (br s, 1 H), 11.40 (br s, 2 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(N(CC)CC)C.Cl[S:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>C(Cl)Cl>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][NH:1][S:21]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:31][CH:32]=2)(=[O:23])=[O:22])=[CH:5]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1ccc(S(=O)(=O)NCCc2c[nH]c3ccccc23)cc1
Reaction time: 2 h

Procedure:
To 3.0 g (18.7 mmol) of tryptamine in 20 ml of CH2Cl2 was added, 2.5 ml (18.7 mmol) of triethylamine followed by 2.06 g (9.4 mmol) of 4-(chlorosulphonyl) benzoic acid. After stirring for 2 h, the mixture was extracted with CH2Cl2 (3×50 ml) and the combined organic extracts were washed with water and dried and evaporated. The residue was chromatographed on silica gel using 2:98:0.5 MeOH/CH2Cl2/AcOH to afford the title compound as a solid. MS m/e 345; HPLC retention time 2.52 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.C(Cl)Cl.O>CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][CH:13]2[CH2:15][CH2:14]2)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: NC1CC1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1cnc(Cl)nc1NC1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.2 %

Procedure:
To 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.25 g, 5.8 mmol) in methanol (4 mL) at 0° C. was added cyclopropylamine (0.69 mL, 10 mmol). The mixture was allowed to stir at RT for 4 h. and then DCM (20 mL) and water (20 mL) were added. The mixture was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-100% DCM in iso-hexane) gave 2-chloro-N-cyclopropyl-5-(trifluoromethyl)pyrimidin-4-amine (472 mg, 34%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=238 at 3.64 min. 1H NMR (400 MHz, CDCl3): δ 8.27 (d, J=1.1 Hz, 1H), 5.56 (br s, 1H), 3.03-2.93 (m, 1H), 0.99-0.89 (m, 2H), 0.65-0.60 (m, 2H).
Reaction SMILES: C(=O)(OC(C)(C)C)N.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2([NH:22][C:23]([C@H:25]3[CH2:31][CH2:30][CH:29]4[CH:27]([CH2:28]4)[N:26]3C(OC(C)(C)C)=O)=[O:24])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)=[O:12]>>[CH:27]12[CH2:28][CH:29]1[CH2:30][CH2:31][C@H:25]([C:23]([NH:22][C:19]1([C:16]3[CH:15]=[CH:14][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:18][CH:17]=3)[CH2:20][CH2:21]1)=[O:24])[NH:26]2
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCC4CC4N3C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)(C)OC(N)=O
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCC4CC4N3)CC2)cc1
Yield: 94.2 %

Procedure:
The title compound (D101) (20 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (3R)-tert-butyl 3-((1-(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-2-azabicyclo[4.1.0]heptane-2-carboxylate (D70) (28 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[C:16](=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:2].O.O.[Sn](Cl)Cl>C(O)C>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:26][CH3:27])[CH2:1][CH3:2])=[C:8]([C:16](=[O:25])[CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=1
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1C(=O)C=Cc1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CCN(CC)CCOc1ccc(N)cc1C(=O)C=Cc1ccccc1
Reaction time: 2 h

Procedure:
To 5.00 g (13.6 mmol) of 1-[2-[2-(diethylamino)ethoxy]-5-nitrophenyl]-3-phenyl-2-propen-1-one in 50 mL of ethanol add 9.20 g (40.8 mmol) of tin(II) chloride dihydrate and heat the mixture to reflux with stirring for two hours. After cooling remove the solvent in vacuo. Add water and adjust the pH to 12 with potassium hydroxide. Add ethyl acetate and filter the mixture through celite. Separate the layers of the filtrate and extract the aqueous layer twice with ethyl acetate. Wash the combined organic layers with water, saturated sodium chloride solution, and dry over anhydrous sodium sulfate. Remove the solvent in vacuD to provide the title compound.
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]3[N:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[CH:14]=2)[CH2:9]1)(C)(C)C.Cl.O1CCOCC1>CCOC(C)=O>[CH3:24][C:21]1[N:20]=[N:19][C:18]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][N:8]([CH2:7][C:6]([OH:25])=[O:5])[CH2:17][CH2:16]3)=[CH:23][CH:22]=1
Reactant: Cc1ccc(-c2ccc3c(c2)CCN(CC(=O)OC(C)(C)C)C3)nn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc3c(c2)CCN(CC(=O)O)C3)nn1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a stirred solution of [6-(6-methyl-pyridazin-3-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-acetic acid tert-butyl ester (957 mg, 2.82 mmol) in EtOAc (30 ml), is added the solution of hydrochloride in dioxane (4.0M, 10 ml, 40 mmol). The mixture is stirred at 50° C. overnight. The organic solvents are evaporated to give the title compound as dihydrochloric acid salt. MS (+VE) m/z 284.1 (M++1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:18][C:19]([NH:21][C@@H:22]([C:33]([OH:35])=[O:34])[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>O1CCCC1>[C:41]([O:40][C:38]([CH2:37][N:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([CH2:23][C@H:22]([C:33]([OH:35])=[O:34])[NH:21][C:19]([O:18][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:20])=[CH:25]1)=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(N[C@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1cc(C[C@@H](NC(=O)OCc2ccccc2)C(=O)O)c2ccccc21
Reaction time: 1 h
Yield: 101.7 %

Procedure:
600 ml of a solution of NaHMDS (sodium salt of 1,1,1,3,3,3-hexamethyldisilazane) (1M) in tetrahydrofuran are added dropwise, at -78° C. under an inert atmosphere, to a solution of 100 g of Nα-benzyloxycarbonyl-D-tryptophan in a liter of anhydrous tetrahydrofuran. After one hour, the temperature is brought to 0° C. and a solution of 64 g of tert-butyl bromoacetate in 50 ml of anhydrous tetrahydrofuran is added dropwise. The reaction mixture is then brought to ambient temperature and the solvent is subsequently evaporated off in vacuo. The residue is diluted with dichloromethane and the solution is acidified by adding an aqueous 4N hydrochloric acid solution. After extraction with dichloromethane, the organic phases are dried over sodium sulphate and then concentrated in vacuo. 136 g of the expected product are obtained.
Reaction SMILES: Cl.[I:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.C[O:21][C:22](=[O:31])[C:23]([CH3:30])([CH3:29])[CH2:24][C:25](=O)[CH2:26][CH3:27]>C(O)(C)(C)C>[I:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:26]([CH3:27])=[C:25]2[CH2:24][C:23]([CH3:30])([CH3:29])[C:22]([OH:31])=[O:21])=[CH:5][CH:4]=1
Reactant: CCC(=O)CC(C)(C)C(=O)OC
Reactant: COc1ccc(N(N)Cc2ccc(I)cc2)cc1
Agent: Cl
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)c(C)c(CC(C)(C)C(=O)O)n2Cc1ccc(I)cc1

Procedure:
Following the method of Example 2, but using 1-[4-iodobenzyl]-1-(4-methoxyphenyl)hydrazine hydrochloride and methyl-2,2-dimethyl-4-oxo-hexanoate as starting materials, using t-butanol as solvent, the title compound was prepared.