Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18](C)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.C(Cl)Cl.CN(C)C=O.N1C=CC(N)=N1.N1C(C)=CC=CC=1C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][NH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: Nc1cc[nH]n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cc[nH]n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
The 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) was dissolved in chloroform (1 mL). To this solution was added a 2.0 M solution of oxalylchloride in methylene chloride (151 μL, 0.30 mmol) and N,N-dimethylformamide (23 μL, 0.30 mmol). The solution was allowed to stir for 1 h at 25° C., after which 1H-pyrazol-3-ylamine (25 mg, 0.30 mmol) was added along with 2,6-lutidine (70 μL, 0.60 mmol). The reaction was allowed to proceed for 40 h. The solvent was removed in vacuo and the crude material was purified by reverse phase preparative HPLC (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1H-pyrazol-3-yl)-propionamide (52 mg, 43%) as a white solid: ESI-LRMS m/e calcd for C18H22ClN3O3S [M+] 395.1, found 396.1 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.00-1.19 (m, 2H, CH2), 1.34-1.91 (m, 8H, 4×CH2), 2.08-2.29 (m, 1H, CH), 3.24 (s, 3H, SO2CH3), 3.65 (t, J=7.6 Hz, 1H, CH), 6.54 (d, 1H, J=1.7, Ar), 7.39 (m, 2H, Ar), 7.54 (d, Jm=1.3 Hz, 1H, Ar), 7.94 (d, Jo=8.2 Hz, 1H, Ar), 9.26 (s, 1H, NH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:17]=[C:18](O)[C:19](=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:20]([O:22][CH3:23])=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][C:25]([N+:26]([O-:28])=[O:27])=[C:16]([CH3:15])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc([N+](=O)[O-])c(C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 9 h
Yield: 93.7 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (5.4 g), methyl 4-methyl-5-nitrosalicylate (2.8 g) and triphenylphosphine (9.0 g) in dichloromethane (100 ml) was added diethyl azodicarboxylate (5.4 ml) and the mixture was stirred at room temperature for 9 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=4/1 as an eluant to give the desired compound (4.9 g, yield 93%) as a yellow oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][C:15]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16]1>ClCCl.O>[CH3:8][S:9]([O:13][CH2:14][C:15]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16]1)(=[O:11])=[O:10]
Reactant: CCOC(=O)C1(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(COS(C)(=O)=O)CC1
Temperature: 23 °C
Reaction time: 20 h
Yield: 86.8 %

Procedure:
Triethylamine (990 μL, 7.1 mmol, 1.2 equiv) and methanesulfonyl chloride (500 μL, 6.5 mmol, 1.1 equiv) were sequentially added to a stirred solution of ethyl 1-(hydroxymethyl)cyclopropanecarboxylate (840 mg, 5.7 mmol, 1.0 equiv) in dichloromethane (15 mL) at 23° C. The resulting bright yellow solution was stirred at 23° C. for 20 h. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were dried (MgSO4), gravity-filtered, and concentrated by rotary evaporation to afford the title compound as a brown oil (1.1 g, 85%): 1H NMR (300 MHz, CDCl3) δ 4.33 (s, 2H), 4.16 (q, J=7 Hz, 2H), 3.08 (s, 3H), 1.43 (dd, J=7, 4 Hz, 2H), 1.26 (t, J=7 Hz, 3H), 1.04 (dd, J=7, 4 Hz, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[N:6]3[C:7](=[CH:12][CH:13]=[C:5]3[C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=1)[CH:8]=[CH:9][CH:10]=2)[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].C(S)C.Cl>ClCCl.C1(C)C=CC=CC=1.C(OCC)(=O)C.C(OCC)(=O)C.O.O1CCCC1>[CH2:1]([C:3]1[C:11]2[N:6]3[C:7](=[CH:12][CH:13]=[C:5]3[C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH:8]=[CH:9][CH:10]=2)[CH3:2]
Reactant: CCc1c(-c2ccc(OC)cc2)c2ccc3cccc1n32
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCS
Product: CCc1c(-c2ccc(O)cc2)c2ccc3cccc1n32
Yield: 43.9 %

Procedure:
A solution of 1-ethyl-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine (Compound 34) (0.77 g, 2.79 mmol) in 25 ml of dry dichloromethane was stirred under a nitrogen atmosphere and aluminium chloride (2.23 g, 16.7 mmol) was added in portions. When the addition was complete, ethanethiol (1.25 ml, 16.7 mmol) was added, and stirring was continued for half an hour. The mixture was cooled in an ice bath followed by the addition of tetrahydrofuran (15 ml), 6M hydrochloric acid (3 ml), water (50 ml) and ethyl acetate (100 ml). The organic phase was separated and evaporated to leave a residue which was chromatograped over silica gel with toluene/ethyl acetate (4:1) as eluent. The proper fractions were collected and evaporated, and the residue was triturated with a mixture of ether (2 ml) and petroleum ether (5 ml) to afford 0.32 g (44%) of the title compound. M.p. 104-05° C. 1H-NMR (DMSO-d6, 200 MHz) δ: 1.41 (t, 3H), 3.22 (q, 2H), 6.98 (d, 2H), 7.29 (d, 1H), 7.67 (d, 2H), 7.69(d, 1H), 7.72(t, 1H), 8.05 (d, 1H), 8.10 (d, 1H), 9.68 (s, 1H). (Compound 52).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([S:14][C:15]([CH3:23])([CH2:19][N+:20]([O-])=O)[CH2:16][CH2:17][OH:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)C.O>O1CCCC1>[NH2:20][CH2:19][C:15]([S:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:23])[CH2:16][CH2:17][OH:18]
Reactant: CC(CCO)(C[N+](=O)[O-])SCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(CN)(CCO)SCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a mixture of lithium aluminum hydride (1.67 g) and tetrahydrofuran (30 ml) was added a solution of 3-(benzylthio)-3-methyl-4-nitrobutan-1-ol (3.00 g) in tetrahydrofuran (10 ml) over 1 hr at room temperature. The reaction mixture was stirred at room temperature for 1 hr, ethanol (10 ml) and water (6.4 ml) were added in this order, and the resulting inorganic salt was removed by filtration. The filtrate was concentrated, and the residue was dissolved in ethyl acetate, dried (MgSO4), and concentrated to give the title compound (2.62 g, yield 99%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[N-:16]=[N+]=[N-].[Na+]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[NH:16][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCCCC1Cc1ccc(Cl)cc1
Agent: [Na+]
Product: O=C1CCCCC(Cc2ccc(Cl)cc2)N1
Temperature: 0 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To an ice-cold solution of 4.47 g of 2-(4-chlorobenzyl)cyclohexanone in 100g of polyphosphoric acid add 2.6 g of sodium azide while stirring. Stir the mixture for another 1.5 hours at 0° and for a further 8 hours at room temperature, pour it into ice water and then extract it with methylene chloride. After drying the organic phase over sodium sulfate distill off the solvent to obtain 2.85 g of the title compound as a light brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11](Cl)(=[O:13])=[O:12].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19]>CCOCC>[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][S:11]([C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])(=[O:13])=[O:12]
Reactant: NCc1ccccc1Cl
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Solvent: CCOCC
Product: COc1ccc(OC)c(S(=O)(=O)NCc2ccccc2Cl)c1

Procedure:
2,5-dimethoxyphenyl-sulfonyl chloride is reacted with 2-chlorobenzylamine in ether at about 25° C. to provide N-(2-chlorobenzyl)-2,5-dimethoxy-phenylsulfonamide.
Reaction SMILES: BrC1C=CC(O)=C(C2(O)C3C(=CC=CC=3)N(CCCCC)C2=O)C=1.O[C:26]1([C:41]2[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[CH:43][C:42]=2[OH:51])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:27]1=[O:40]>>[OH:51][C:42]1[CH:43]=[CH:44][C:45]([C:47]([F:48])([F:49])[F:50])=[CH:46][C:41]=1[CH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:27]1=[O:40]
Reactant: CCCCCN1C(=O)C(O)(c2cc(C(F)(F)F)ccc2O)c2ccccc21
Agent: CCCCCN1C(=O)C(O)(c2cc(Br)ccc2O)c2ccccc21
Product: CCCCCN1C(=O)C(c2cc(C(F)(F)F)ccc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 15B, and making non-critical variations to replace 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-hydroxy-3-[2-hydroxy-5-(trifluoromethyl)phenyl]-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (78%): 1H NMR (300 MHz, CDCl3) δ 8.20-8.00 (br, 1H), 7.43-7.14 (m, 5H), 7.02 (d, 1H), 6.95 (d, 1H), 5.11(s, 1H), 3.82-3.72 (m, 2H), 1.79-1.66 (m, 2H), 1.40-1.27 (m, 4H), 0.88 (t, 3H); MS (ES+) m/z 364 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=O.Cl.[CH3:15][O:16][C:17](=[O:27])[CH:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:19].C(N(C(C)C)C(C)C)C.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[B-](F)(F)F>O1CCCC1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([NH:19][CH:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17]([O:16][CH3:15])=[O:27])=[O:6]
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Reactant: COC(=O)C(N)Cc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Cc1ccccc1)NC(=O)c1c(N)cccc1[N+](=O)[O-]

Procedure:
1.18 g (6.5 mmol) 2-amino-6-nitrobenzoic acid, 1.0 g (4.6 mmol) D,L-phenylalanine-methylester hydrochloride, 4.05 ml (23.2 mmol) N-ethyldiisopropylamine are combined with 2.5 ml of tetrahydrofuran. 1.71 g (5.1 mmol) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate are added to this reaction mixture and it is heated for 12 h to 50° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (50:50).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:15]([O-])=O>[Pd].CO>[NH2:15][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[N:7][C:2]=1[NH2:1]
Reactant: Nc1nc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCC(O)CC2)nc1N
Reaction time: 12 h
Yield: 94.5 %

Procedure:
To a parr flask was added 6′-Amino-5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol (10.0 g, 42.0 mmol) (Step 1), 10% Pd/C (2.5 g) and MeOH (100 mL). The flask was pressurized to 50 psi with H2 for 12 hr with shaking. The contents of the flask were filtered through Celite and the filtrate (dark green) was concentrated to afford 5′,6′-Diamino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol as a dark purple solid (8.90 g, 39.7 mmol, 95%). MS ESI m/z 209.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH:24][CH2:25][C:26]([NH2:29])([CH3:28])[CH3:27]>>[OH:24][CH2:25][C:26]([NH:29][C:20]([C:17]1[NH:18][N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:23])[CH:16]=1)=[O:22])([CH3:28])[CH3:27]
Reactant: CC(C)(N)CO
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)[nH]n1
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)NC(C)(C)CO)[nH]n1
Yield: 36 %

Procedure:
As described for example 132, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2H-pyrazole-3-carboxylic acid was converted, using 2-hydroxy-1,1-dimethylethylamine instead of morpholine, to the title compound (11 mg, 36%) which was obtained as an off white solid. MS: m/e=385.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][S:4][C:3]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:14].[C:24](OCC)(OCC)(OCC)[CH3:25].C(O)(=O)C.C(OCC)C>CCOC(C)=O>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([N:15]2[C:13](=[O:14])[C:3]3[S:4][CH:5]=[C:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:2]=3[N:1]=[C:24]2[CH3:25])=[CH:21][CH:20]=1
Reactant: COc1ccc(NC(=O)c2scc(-c3ccccc3)c2N)cc1
Reactant: CCOC(C)(OCC)OCC
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(-n2c(C)nc3c(-c4ccccc4)csc3c2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
3-Amino-N-(4-methoxyphenyl)-4-phenylthiophene-2-carboxamide (57 mg, 0.18 mmol), triethyl orthoacetate (1 ml), and acetic acid (0.1 ml) were placed in a pressure bottle. The mixture was heated with stiffing at 160° C. for 18 hr. After the completion of the reaction was confirmed by TLC, the reaction mixture was cooled to room temperature and solidified with diethyl ether and EtOAc to give 13 mg (0.037 mmol, 21% yield) of the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][C:6](=[O:10])[O:7]2)[C@H:3]1/[CH:11]=[CH:12]/[C@@H:13]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[OH:10][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][C@@H:2]([OH:1])[C@@H:3]2/[CH:11]=[CH:12]/[C@@H:13]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[O:7]1
Reactant: CCCCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1O)OC1CCCCO1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CCCCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(O)O[C@H]2C[C@H]1O)OC1CCCCO1

Procedure:
Alcohol (6) (2.00 g) was reduced in dry toluene (40 ml) using DIBAL-H at −70° C. The lactol (7) was obtained by a usual work up.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][C:7]=1I.[CH3:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(Cl)Cl>[F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][C:7]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:12]=1[CH3:11]
Reactant: N#Cc1nccc(I)c1F
Reactant: Cc1ccncc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccncc1-c1ccnc(C#N)c1F
Temperature: 85 °C
Yield: 18.3 %

Procedure:
A vial containing a mixture of 3-fluoro-4-iodopicolinonitrile (0.150 g, 0.605 mmol), 4-methylpyridin-3-ylboronic acid (0.174 g, 1.270 mmol), and cesium carbonate (0.414 g, 1.270 mmol) in dioxane (Ratio: 2.0, Volume: 1.222 ml) and water (Ratio: 1.000, Volume: 0.611 ml) was degassed with N2 for 5 min, then PdCl2(dppf)-CH2Cl2Adduct (0.026 g, 0.032 mmol) was added. The solution was heated at 85° C. for 14 hr, then allowed to cool to room temperature. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (40 g column, 40 mL/min, 70-100% EtOAc in hexanes over 19 min, tr=14 min) gave the title compound (24 mg, 0.111 mmol, 18.42% yield) as a purple residue. ESI MS (M+H)+=214.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:21](O)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][C@H:9]1[CH2:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(2S,4R)-4-Benzyloxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (960 mg, 3 mmol) in THF (5 mL) was cooled to 0° C. using ice-water bath. Then 1M solution of BH3 (6 mL, 6 mmol) in THF was added under nitrogen over period of 30 min. Reaction was stirred at 0° C. for 2 h and at rt for another 1 h. Reaction mixture was poured over ice water and product was extracted with EtOAc. Organic layers were combined, washed with water, brine, saturated sodium bicarbonate, dried over anhydrous MgSO4 and concentrated to give the crude product. It was used in next step without purification (900 mg, 97%).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]2[C:7]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=3)([CH2:8]2)[C:6]1=[O:21])[CH:2]([CH3:4])[CH3:3]>C(O)C.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]23[CH2:8][CH:9]2[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:6]3=[O:21])=[CH:17][CH:16]=1
Reactant: CC(C)CN1C(=O)C2CC2(c2ccc([N+](=O)[O-])cc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)CN1C(=O)C2CC2(c2ccc(N)cc2)C1=O

Procedure:
Following the procedure of Example 3, a solution of 0.55 g of 3-isobutyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione in 25 ml of ethanol is hydrogenated in the presence of 0.1 g of 5% palladium on carbon and worked up, affording the title compound which melts at 115°-117° C. after recrystallisation from ether/petroleum ether.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[O:13]1[C:17]2([CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>O1CCCC1>[O:13]1[C:17]2([CH2:22][CH2:21][C:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(C(=O)OCC)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 500 mL round-bottomed flask was charged with diisopropylamine (16 mL) and tetrahydrofuran (311 mL). The solution was cooled to −78° C. under N2 and n-BuLi (2.5 M in hexanes, 44.8 mL)) was added. The reaction was stirred for 30 minutes at −78° C. and ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (20 g) was added as a tetrahydrofuran solution (ca. 10 mL). The solution was stirred at −78° C. for 1 hour and ethyl chloroformate (9 mL) was added neat. After stirring at −78° C. for 10 minutes, the reaction was warmed to room temperature over 2 hours. The reaction was quenched with saturated aqueous NH4Cl and was diluted with diethyl ether. The layers were separated, the aqueous layer was extracted with diethyl ether and the combined organics were dried (Na2SO4), filtered and concentrated by rotary evaporation. The residue was purified by regular phase flash column chromatography (Analogix, 0-65% hexanes/ethyl acetate).
Reaction SMILES: CS(O[CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)(=O)=O.[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>CN(C=O)C>[CH2:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH2:15][CH:6]1[N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OC1CCc2ccccc2C1
Solvent: CN(C)C=O
Product: c1ccc2c(c1)CCC(n1ccnc1)C2
Yield: 37500 %

Procedure:
A mixture of 1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate (15.74 g, 69.6 mmol), prepared as in Example 7, and imidazole (23.68 g, 349 mmol) in 100 mL of DMF was heated at 80° to 90° C. under argon for 24 hours. The solvent was removed under vacuum by rotary evaporation. The residue was dissolved in 500 mL of ethyl acetate and the solution was washed with water (5×250 mL). The combined aqueous layer was extracted with 500 mL of ethyl acetate and the extract was then washed with water (5×250 mL). The combined ethyl acetate extract was washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by rotary evaporation. Purification of the residue by column chromatography on silica gel (elution: 5% methanol/methylene chloride) gave 1-(1,2,3,4-tetrahydronaphthalen-2-yl)imidazole (5.18 g, 26.1 mol), m.p. 93°-95° C.
Reaction SMILES: [CH3:1][C:2](=[CH:8][CH:9]=[C:10]([CH3:24])[CH:11]=[CH:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([O:20][CH3:21])=[C:15]([CH3:22])[C:14]=1[CH3:23])[C:3]([O:5]CC)=[O:4]>CCOCC>[CH3:1][C:2](=[CH:8][CH:9]=[C:10]([CH3:24])[CH:11]=[CH:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([O:20][CH3:21])=[C:15]([CH3:22])[C:14]=1[CH3:23])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)=CC=C(C)C=Cc1c(C)cc(OC)c(C)c1C
Solvent: CCOCC
Product: COc1cc(C)c(C=CC(C)=CC=C(C)C(=O)O)c(C)c1C

Procedure:
In a manner similar to Example 6, alkaline hydrolysis of ethyl 2,5-dimethyl-7-(4-methoxy-2,3,6-trimethylphenyl)-hepta-2,4,6-trienoate afforded, after trituration from ether, the corresponding acid as yellow powder, m.p. 188°-190° C.
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@H:20]2[CH3:25])[N:15](CC2C=CC=CC=2)[CH2:14][C@H:13]1[CH3:33])=[O:11])([CH3:8])([CH3:7])[CH3:6]>CCO.[Pd]>[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@H:20]2[CH3:25])[NH:15][CH2:14][C@H:13]1[CH3:33])=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
Pd/C (33 g) and acetic acid (220 mL) were added to a solution of (2R,5S)-4-benzyl-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (41.3 g, 102 mmol) in EtOH (300 mL). The mixture was stirred under H2 (1 atmosphere) at room temperature for 18 h. The reaction mixture was then filtered through a pad of Celilte to remove the catalyst and the solvent was removed in vacuo. The crude material was partitioned between saturated aqueous NaHCO3 and DCM and the product extracted with DCM (3×). The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give the title compound (30.5 g) as a pale yellow oil. 1H NMR (CDCl3): 4.43-3.87 (1H, m), 3.78 (1H, d), 3.73-3.55 (3H, m), 3.32 (1H, dd), 3.22 (1H, dd), 3.16-2.93 (3H, m), 2.93-2.72 (1H, m), 2.55-2.35 (2H, m), 2.35-2.15 (2H, m), 1.89 (1H, dd), 1.45 (9H, s), 1.26 (3H, d), 0.96 (3H, d).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([OH:34])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@@H:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][C@H:37]1[OH:49]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][C@@H:36]4[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])[CH2:38][C@H:37]4[OH:49])=[O:34])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: Cc1cc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Product: Cc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C[C@H]4O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c11) and tert-butyl (3R*,4R*)-4-amino-3-hydroxy-piperidine-1-carboxylate (example C2) the title compound is obtained as pale yellow foam.