Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([N:15]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][C:22]([N:24]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25]3)=[O:23])[CH2:16]2)[S:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)#[N:2].[O:33]1CCCC1.O>>[C:1]([C:3]1[N:4]=[C:5]([N:15]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][C:22]([N:24]3[CH2:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:32]3)=[O:23])[CH2:16]2)[S:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)(=[O:33])[NH2:2]
Reactant: N#Cc1nc(N2CCC[C@@H](NC(=O)N3Cc4ccccc4C3)C2)sc1Nc1ccccn1
Reactant: C1CCOC1
Solvent: O
Product: NC(=O)c1nc(N2CCC[C@@H](NC(=O)N3Cc4ccccc4C3)C2)sc1Nc1ccccn1
Reaction time: 8 h

Procedure:
To a solution of give 1,3-dihydro-isoindole-2-carboxylic acid {(R)-1-[4-cyano-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-amide (11.3 mg, 25.4 μmol) in 10:1 v/v tetrahydrofuran/water (2.75 mL total volume) was added hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphnito-kP]platinum (II) (CAS number 173416-05-2) (1.1 mg, 2.5 μmol) and the mixture was heated to reflux under argon. After 8 hours LC/MS indicated approximately ˜30% conversion to a single main product which exhibited the molecular ion for the expected product. The reaction mixture was transferred to a resealable tube, an additional aliquot of hydrido(dimethylphosphinous acid-kP)[hydrogen bis-(dimethylphosphnito-kP]platinum (II) (1 mg, 2.3 μmol) was added and the tube heated to 80° C. overnight. LC-MS indicated the expected product as the major component present in the reaction mixture but with some starting material still present. An additional aliquot of hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphnito-kP]platinum (II) (1 mg, 2.3 μmol) was added and the reaction vessel heated at 100° C. for 3.5 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by reverse phase chromatography using a C-18 column gradient eluted from 10% up to 100% acetonitrile in water. The product containing fractions were combined and concentrated in vacuo to give partially purified 1,3-dihydro-isoindole-2-carboxylic acid {(R)-1-[4-carbamoyl-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-amide as a yellow solid. Purified further by reverse phase HPLC using a C-18 column gradient eluted from 30% to 100% acetonitrile in water to remove a close running impurity. The product containing fractions were combined and concentrated in vacuo and the residue lyophilized from acetonitrile/water to obtain 1,3-dihydro-isoindole-2-carboxylic acid {(R)-1-[4-carbamoyl-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-amide as a pale yellow solid (2.1 mg, 18%).
Reaction SMILES: C(Cl)(=O)C.[CH3:5][C:6]1[N:10]([CH2:11][C:12]2[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=2)[O:15][CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)[N:9]=[C:8]([C:29]2[O:33][N:32]=[C:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=3)[N:30]=2)[N:7]=1>CO>[NH2:18][CH2:17][CH2:16][O:15][C:14]1[CH:13]=[C:12]([CH2:11][N:10]2[C:6]([CH3:5])=[N:7][C:8]([C:29]3[O:33][N:32]=[C:31]([C:34]4[CH:39]=[CH:38][C:37]([O:40][C:41]([F:42])([F:43])[F:44])=[CH:36][CH:35]=4)[N:30]=3)=[N:9]2)[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(OCCNC(=O)OC(C)(C)C)c1
Solvent: CO
Solvent: CC(=O)Cl
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(OCCN)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (229 uL, 3.21 mmol) was added dropwise to MeOH (1.1 mL) at 0° C., and the resulting mixture was stirred at 0° C. for 1 hr. Tert-butyl (2-(3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)phenoxy)ethyl)carbamate (Example 67; 60.0 mg, 0.107 mmol) was the added in one portion, and the reaction mixture was stirred at RT for 16 h and then concentrated under reduced pressure; the residue was purified using Prep-HPLC to furnish the title compound; MS (ES+) C2iH19F3N6O3 requires: 460. found 461 [M+H]+; 1H-NMR (600 MHz, CD3OD) δ ppm 8.17 (d, J=8.6 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 7.17 (m, 1H), 6.78 (d, J=7.9 Hz, 1H), 6.73 (d, J=8.2 Hz, 1H), 6.67 (s, 1H), 5.32 (s, 2H), 4.06 (m, 2H), 3.21 (m, 2H), 2.47 (s, 3H).
Reaction SMILES: ClCCl.[NH:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:8])[C:5]1=[O:6].[S:15]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16]1.C(N(CC)CC)C>C(OC(=O)C)(=O)C.C(N(CC)CC)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[S:15]1[CH:19]=[CH:18][C:17]([N:4]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:7](=[O:8])[C:5]2=[O:6])=[CH:16]1
Reactant: OB(O)c1ccsc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=C1C(=O)N(c2ccsc2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.4 %

Procedure:
Copper(II) acetate monohydrate (4.25 g, 23.4 mmol) was heated at reflux in acetic anhydride (30 mL) for 2 h. The mixture was filtered and washed with anhydrous ether (500 mL). The solid was dried in vacuo at 55° C. for 16 h. Dichloromethane (1 mL) was added to a mixture of copper(II) acetate (62 mg, 0.34 mmol), isatin (50 mg, 0.34 mmol), and thiophene-3-boronic acid (87 mg, 0.68 mmol), followed by triethylamine (0.10 mL, 0.68 mmol) under argon. The resulting solution was stirred for 16 h at room temperature. The reaction mixture was then recharged with 0.10 mmol copper(II) acetate, 0.10 mmol of 3-thiophene boronic acid, and 1 drop of triethylamine, and the mixture was heated at 50° C. for 6 h. The crude material was purified by preparative TLC using 3:97 methanol in chloroform as the eluent, giving the desired product as a yellow solid (25 mg, 0.11 mmol, 33%). 1H NMR (400 MHz): δ 7.70 (d, J=7.5, 1H), 7.58 (t, J=7.8, 1H), 7.50 (d, J 5.1, 1H), 7.48 (s, 1H), 7.24 (d, J=5.1, 1H), 7.18 (t, J=7.51, 1H), 7.05 (d, J=8.0, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:32]1[N:37]=[CH:36][C:35]([O:38][CH2:39][CH3:40])=[CH:34][N:33]=1>CS(C)=O.CCOC(C)=O>[CH2:39]([O:38][C:35]1[CH:34]=[N:33][C:32]([N:15]2[CH2:14][CH2:13][CH:12]([C@H:10]3[CH2:11][C@H:9]3[CH2:8][O:7][CH2:6][C:5]3[CH:18]=[CH:19][C:20]([S:21]([CH3:24])(=[O:22])=[O:23])=[C:3]([F:2])[CH:4]=3)[CH2:17][CH2:16]2)=[N:37][CH:36]=1)[CH3:40]
Reactant: CCOc1cnc(Cl)nc1
Reactant: CS(=O)(=O)c1ccc(COC[C@@H]2C[C@@H]2C2CCNCC2)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(S(C)(=O)=O)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.8 %

Procedure:
4-((1R,2R)-2-(((3-fluoro-4-(methylsulfonyl)benzyl)oxy)methyl)cyclopropyl)piperidine hydrochloride (Step D product, 200 mg, 0.53 mmol) was dissolved in DMSO (5 ml) at RT under N2 and Cs2CO3 (517 mg, 1.588 mmol) was added. The mixture was stirred at RT for 5 min and 2-chloro-5-ethoxypyrimidine (101 mg, 0.635 mmol) in DMSO (0.5 mL) was added. The mixture was stirred at 100° C. overnight. The mixture was diluted with EtOAc, washed with sat. NH4Cl, dried over MgSO4, evaporated. The crude material was purified by flash column (25 g SNAP, 15˜50% EtOAc in hexane) to afford 56 mg (23%) of the title compound. 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 2H), 7.90 (m, 1H), 7.30 (m, 2H), 4.60 (m, 4H), 4.00 (t, 2H), 3.60 (m, 2H), 3.20 (s, 3H), 2.93-2.80 (m, 2H), 1.96 (d, 1H), 1.85 (d, 1H), 1.43 (m, 5H), 1.25 (m, 1H), 1.15 (m, 1H), 0.80-0.71 (m, 2H), 0.12-0.08 (m, 1H). MS (ESI) m/z 464 [M+H]+. GPR119 Human EC50: 1.65 nM.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:19](=[C:20]([C:22]([NH2:24])=[O:23])[CH:21]=2)[NH:18][C:17]2[CH2:16][CH2:15][CH:14]([C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:26])[CH2:13][C:12]3=2)=[CH:5][CH:4]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:21]=[C:20]([C:22]([NH2:24])=[O:23])[C:19]3[NH:18][C:17]4[C:12]([C:11]=3[CH:10]=2)=[CH:13][C:14]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])=[CH:15][CH:16]=4)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(C(N)=O)c3[nH]c4c(c3c2)CC(C(=O)N2CCOCC2)CC4)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4ccc(C(=O)N5CCOCC5)cc4c3c2)cc1
Yield: 49.9 %

Procedure:
A stirred suspension of 6-(4-methoxyphenyl)-3-(morpholine-4-carbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (6 mg, 0.014 mmol, Example 1) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (9.43 mg, 0.042 mmol) in toluene (2 mL) was heated at reflux for 2 h. The reaction mixture was concentrated, and the crude was purified by prep. HPLC to afford 3 mg of 3-(4-methoxyphenyl)-6-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide. MS (ESI) m/z 430.2 (M+H). 1H NMR (DMSO-d6) δ ppm 11.50 (s, 1H) 8.63 (s, 1H) 8.30 (s, 2H) 8.16-8.24 (m, 1H) 7.77 (d, J=8.79 Hz, 2H) 7.69 (d, J=8.35 Hz, 1H) 7.49 (br. s., 1H) 7.38-7.44 (m, 1H) 7.01 (d, J=8.79 Hz, 2H) 3.76 (s, 3H) 3.55-3.61 (m, 4H) 3.48-3.55 (m, 4H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1.C1OCCOCCOCCOCCOC1.[Na+].[I-].Cl[CH2:31][CH2:32][N:33]([CH2:41][CH2:42]Cl)[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2([C:11]#[N:12])[CH2:42][CH2:41][N:33]([C:34]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:40])[CH2:32][CH2:31]2)[CH:7]=[CH:8][CH:9]=1
Reactant: N#CCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 79.7 %

Procedure:
60% NaH (2.31 g, 57.7 mmol) was added in 2 portions to a 0° C. solution of 2-(3-chlorophenyl)acetonitrile (3.50 g, 23.1 mmol) and 15-crown-5 (0.509 g, 2.31 mmol) in DMF (80 mL). The reaction mixture was warmed to room temperature while stirring for 35 minutes and then cooled back to 0° C. NaI (3.46 g, 23.1 mmol) was added, followed by the addition of a solution of freshly prepared tert-butyl bis(2-chloroethyl)carbamate (5.59 g, 23.1 mmol) in DMF (10 mL) by syringe. The reaction mixture warmed back to room temperature and stirred overnight (16 hours). The reaction mixture was poured into iced saturated NH4Cl and extracted with EtOAc. The extracts were dried (Na2SO4), filtered, and concentrated. The crude was flashed on silica (Biotage 40L, 9:1 hex:EA until prod, then gradient to 4:1 hexane:EtOAc) to give tert-butyl 4-(3-chlorophenyl)-4-cyanopiperidine-1-carboxylate (5.91 g, 79.8% yield) as a yellow foam. LC/MS (APCI+) m/z 221 [M-Boc+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]([CH2:22][C:23](=[O:49])[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([CH:33]1[CH2:38][CH2:37][N:36](C(OCC2C=CC=CC=2)=O)[CH2:35][CH2:34]1)=[O:32])[C:10](=[O:21])[NH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCCCC=1>C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([CH2:8][N:9]([CH2:22][C:23](=[O:49])[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32])[C:10](=[O:21])[NH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)Nc1ccccc1C(=O)C1CCN(C(=O)OCc2ccccc2)CC1)C(=O)Nc1cccc(C(=O)O)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC(C)(C)OC(=O)CN(CC(=O)Nc1ccccc1C(=O)C1CCNCC1)C(=O)Nc1cccc(C(=O)O)c1
Reaction time: 0.5 h
Yield: 1495.3 %

Procedure:
To a solution of 3-(3-(tert-butoxycarbonylmethyl(2-(N-(benzyloxycarbonyl)piperidine-4-carbonyl)phenylcarbamoylmethyl)ureido)benzoic acid (compound 53) (19 mg, 1.49 μmol) in ethanol (1.0 ml) are added cyclohexene (144 μl) and 10% palladium-carbon (15 mg), and the mixture is refluxed with stirring for 30 minutes. The reaction solution is filtered and the filtrate is concentrated under reduced pressure to obtain the titled compound 54 (12 mg). Yield 79%.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35].O>C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[S:34]([O:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:9])([CH3:10])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1)(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COS(=O)(=O)c2cc(Cl)ccc2Cl)OC(C)(C)O1
Reaction time: 3.5 h
Yield: 137.9 %

Procedure:
To a stirring 0°-5° C. solution of the (4R-cis)-1,1-dimethylethyl 6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (European Patent Application 0319,847) (10 g, 38 mmol) in methylene chloride (250 mL) containing triethylamine (10 mL, 72 mmol) is added 2,5-dichlorobenzenesulfonyl chloride (14.7 g, 57.5 mmol). Stirring is continued at 0°-5° C. for 3.5 hours, the solution is poured onto 200 mL of water, and the layers separated. The upper aqueous layer is extracted with 200 mL of methylene chloride and the combined organic layers are washed with 200 mL each of saturated sodium bicarbonate solution to ensure complete removal of 2,5-dichlorobenzenesulfonyl chloride and then saturated sodium chloride solution. Drying the solution with magnesium sulfate and concentration in vacuo gives 24.6 g of the product as a yellow-orange oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].[CH2:46]1[O:54][C:53]2[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][C:48]=2[O:47]1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:51]2[CH:50]=[CH:49][C:48]3[O:47][CH2:46][O:54][C:53]=3[CH:52]=2)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(Br)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2ccc3c(c2)OCO3)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C

Procedure:
The title compound was prepared according to Method B, using compound 19 (91.9 mg, 0.135 mmol), 3,4-methylenedioxyphenylboronic acid (112 mg, 0.676 mmol), Pd(PPh)3Cl2 (4.70 mg, 0.0067 mmol), 2 M Na2CO3 (aq., 0.203 mL, 0.405 mmol), EtOH (0.4 mL) and DME (1.6 mL). Purification by RP-LC-MS (35 min gradient of 30-100% CH3CN in 0.05% aqueous formic acid) afforded the product (47.7 mg, 49%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7](Cl)[N:6]=[N:5][C:4]=1[NH:10][NH2:11].[OH-].[Na+].[H][H]>CO.[Pd]>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[N:5][C:4]=1[NH:10][NH2:11]
Reactant: CNc1cc(Cl)nnc1NN
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNc1ccnnc1NN
Reaction time: 6.5 h

Procedure:
A solution of 10 g. of 4-methylamino-6-chloro-3-hydrazinopyridazine in 450 ml. of methanol and 150 ml. of 0.5 N sodium hydroxide in methanol are charged into a Paar shaker. To this solution, 2 g. of 10% palladium on carbon is added. The Paar shaker is charged with hydrogen at room temperature to an initial pressure of 50 psi and shaken. After about 6.5 hours, the reaction mixture is filtered, the solvent evaporated and the residue extracted with chloroform. The chloroform solution is evaporated to dryness and the 4-methylamino-3-hydrazinopyridazine obtained is dissolved in methanol. Hydrogen chloride gas is bubbled in, and the 4-methylamino-3-hydrazinopyridazine dihydrochloride (m.p. 247°-251°C.) which precipitates is collected by filtration.
Reaction SMILES: C([O:8][C:9]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:10]=1)C1C=CC=CC=1>[Pd].O1CCCC1>[OH:8][C:9]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:10]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)nn1-c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cc(O)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A mixture of methyl 3-benzyloxy-1-phenyl-1H-pyrazole-5-carboxylate (15.00 g), 5% palladium on carbon (10.92 g) and tetrahydrofuran (200 mL) was stirred under a hydrogen atmosphere at room temperature for 1 hr. After removing palladium on carbon by filtration, the mother liquid was concentrated. The residue was subjected to silica gel column chromatography to give methyl 3-hydroxy-1-phenyl-1H-pyrazole-5-carboxylate (10.30 g, yield 97%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, v/v). The crystals were recrystallized from tetrahydrofuran-isopropyl ether. melting point: 227-228° C.
Reaction SMILES: B.C(C[C:5]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=O.C(O)(=O)C[C:40](CC(O)=O)(C(O)=O)[OH:41]>O1CCCC1>[OH:41][CH2:40][C:5]([C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])([C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])[C@H:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(CC=O)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: B
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(CO)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 0.08 h

Procedure:
8.2 ml of a 1M solution of borane in tetrahydrofuran was added to a solution of 4.055 g of 1,2-dibenzyl 1-tert.butyl 1-(formylmethyl)-4-methyl-1,1,2(R)-pentanetricarboxylate in 40 ml of dry tetrahydrofuran. After stirring for 5 minutes, the mixture was acidified with 5% aqueous citric acid solution and was extracted twice with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporate. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate for the elution. There was obtained 2.518 g of 1,2-dibenzyl 1-tert.butyl 1-(hydroxymethyl)-4-methyl-1,1,2(R)-pentanetricarboxylate in the form of a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.ClCCCl.[Cl:12][C:13]1[C:14]2[N:15]([C:19]([CH:23]3[CH2:26][C:25](=O)[CH2:24]3)=[N:20][C:21]=2[I:22])[CH:16]=[CH:17][N:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:12][C:13]1[C:14]2[N:15]([C:19]([CH:23]3[CH2:26][CH:25]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH2:24]3)=[N:20][C:21]=2[I:22])[CH:16]=[CH:17][N:18]=1
Reactant: CN1CCNCC1
Reactant: O=C1CC(c2nc(I)c3c(Cl)nccn23)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCN(C2CC(c3nc(I)c4c(Cl)nccn34)C2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-Methyl piperazine (5.75 mL, 0.0514 mol) in 1,2-dichloroethane (1096.7 mL, 13.892 mol) was added to 3-(8-chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanone (17.00 g, 0.04892 mol) and sodium triacetoxyborohydride (21.8 g, 0.0978 mol). The reaction stirred at rt for 3 h. The reaction was concentrated, dissolved in CH2Cl2, and then washed with saturated NaHCO3 solution and brine. The product was dried over sodium sulfate, filtered, and concentrated in vacuo. The product was flushed through a quick silica gel plug (wetted with 100% CHCl3, eluted with 8% (7N NH3) MeOH in CHCl3), to afford the title compound; 1H NMR (CDCl3, 400 MHz) δ 7.63 (1H, d), 7.30 (1H, d), 3.42 (1H, m), 2.94 (1H, m), 2.65 (4H, m), 2.44 (8H, m), 2.32 (3H, s); MS (ES+): m/z 431.85/433.87 (100/45) [MH+]; HPLC: tR=1.82 min. (OpenLynx, polar—5 min.).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)[C:11]([NH2:13])=[O:12])[N:6]=[N:5][N:4]=1.Cl.[C@H:22]12[CH2:28][C@H:25]([NH:26][CH2:27]1)[CH2:24][O:23]2>C(#N)C>[C@H:22]12[CH2:28][C@H:25]([N:26]([CH2:2][C:3]3[N:7]([C:8]4[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=4)[C:11]([NH2:13])=[O:12])[N:6]=[N:5][N:4]=3)[CH2:27]1)[CH2:24][O:23]2
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: NC(=O)c1cc(-n2nnnc2CCl)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CC#N
Product: NC(=O)c1cc(-n2nnnc2CN2C[C@@H]3C[C@H]2CO3)cc(C(F)(F)F)c1
Temperature: 140 °C

Procedure:
To a solution of 3-[5-(chloromethyl)-1H-tetrazol-1-yl]-5-(trifluoromethyl)benzamide (Intermediate 31, 300 mg, 0.982 mmol) in acetonitrile (0.5 mL) was added (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (160 mg, 1.18 mmol) and di-idopropylethylamine (0.377 mL, 2.16 mmol). The reaction was heated to 140° C. for 20 minutes in a microwave reactor.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:10][C@H:11]([OH:38])[C@@H:12]([NH:20][C:21]([O:23][CH2:24][CH:25]1[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)(C)(C)C.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>>[OH:50][C:48]([C:47]([F:52])([F:51])[F:46])=[O:49].[NH2:8][C@@H:9]([CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:10][C@H:11]([OH:38])[C@@H:12]([NH:20][C:21]([O:23][CH2:24][CH:25]1[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Compound (2S,3S,5S)-5-amino-2-[N-((9-fluorenylmethoxy)carbonyl)amino]-1,6-diphenyl-3-hydroxy hexane TFA salt (LL-96) was prepared. Compound (2S,3S,5S)-5-[N-(tert-butyloxy carbonyl)amino]-2-[N-((9-fluorenylmethoxy)carbonyl)amino]-1,6-diphenyl-3-hydroxy hexane (LL-87, 787 mg, 1.3 mmol) was dissolved in trifluoroacetic acid (10 mL), and stirred at room temperature for 10 min. after which solvents were evaporated. The evaporation was repeated 3 times with ethyl ether (10 mL) and finally dried under vacuum. This compound (LL-96) was used in next step with out further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([Br:8])[Br:7])[C@H:3]1[C:9]([OH:11])=[O:10].S(Cl)(Cl)=O.[O:17]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1.C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([Br:8])[Br:7])[C@H:3]1[C:9]([O:11][CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:25]=1)=[O:10]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C=C(Br)Br
Reactant: OCc1cccc(Oc2ccccc2)c1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC1(C)[C@H](C(=O)OCc2cccc(Oc3ccccc3)c2)[C@@H]1C=C(Br)Br

Procedure:
The carboxylic acid described above was converted to its acid chloride by reaction with thionylchloride in pyridine as described in Example 17 and the resulting acid chloride reacted with 3-phenoxybenzyl alcohol in dry benzene in the presence of pyridine as described in Example 17 to give 3-phenoxy-benzyl [1R-cis-]-2,2-dimethyl-3-(2,2-dibromovinyl)cyclopropane carboxylate, m.p. 93°, nD 1.5848 (Compound P29A).