Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([CH3:29])([CH3:28])/[CH:10]=[CH:11]/[CH2:12][C@:13]1([C:18]([O:20]CC2C=CC=CC=2)=[O:19])[CH2:16][C:15](=[O:17])[O:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]([CH3:29])([CH3:28])/[CH:10]=[CH:11]/[CH2:12][C@:13]1([C:18]([OH:20])=[O:19])[CH2:16][C:15](=[O:17])[O:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(/C=C/C[C@]1(C(=O)OCc2ccccc2)CC(=O)O1)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Product: CC(C)(/C=C/C[C@]1(C(=O)O)CC(=O)O1)OCc1ccccc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of benzyl ester 85 (52.8 mg, 0.134 mmol, 1.00 equiv.) were added TEA (3.0 μL, 0.0214 mmol, 0.16 equiv.), triethylsilane (32.1 μL, 0.201 mmol, 1.50 equiv.), and Pd(OAc)2 (1.6 mg, 0.0071 mmol, 0.053 equiv.). The resulting black solution was stirred at 23° C. for 1 h then partitioned between 10 mL sat'd NH4Cl solution and 10 mL CH2Cl2. The phases were separated and the aqueous phase was extracted with 2×10 mL CH2Cl2. The combined aqueous phases were dried over MgSO4 and solvent removal by rotary evaporation left a brown oil that upon purification by silica gel column chromatography (4% HOAc in 1:1 hex:EtOAc) yielded acid 86 (34.4 mg, 85%) as a clear, colorless oil. Rf=0.17 (4% HOAc in 1:1 hex:EtOAc); 1H NMR (500 MHz, CDCl3) δ 10.09 (br s, 1H, CO2H), 7.33-7.23 (m, 5H, aryl H), 5.81 (d, 1H, J=15.9 Hz, (CH3)2CCH), 5.62 (m, 1H, CH2CH), 4.35 (s, 2H, PhCH2), 3.57 (d, 1H, J=16.6 Hz, C(O)CH2), 3.36 (d, 1H, J=16.6, Hz, C(O)CH2), 2.87 (dd, 1H, J=14.6, 7.1 Hz), 2.74 (dd, 1H, J=14.7, 7.3 Hz), 1.35 (s, 6H, (CH3)2); 13C NMR (125 MHz, CDCl3) δ 173.48, 165.44, 143.27, 139.13, 128.48, 127.66, 127.53, 120.34, 75.85, 65.24, 46.06, 37.57, 26.51, 26.29; IR (neat film) ˜3500-2500 (br m), 3031 (w), 2977 (m), 1843 (s), 1745 (s), 1497 (w), 1453 (w), 1149 (m) cm−1; LRMS (ESI) calc'd for C17H20O5Na 327.1, found 326.9.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[K].[OH:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:17]([CH:16]=1)[C:18]([OH:20])=[O:19])[CH:11]=[CH:10]2
Reactant: O=C(O)c1cccc(O)c1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Agent: [K]
Solvent: CS(C)=O
Product: O=C(O)c1cccc(Oc2ccc3cc(Cl)ccc3n2)c1

Procedure:
Substantially equimolar amounts of 2,6-dichloroquinoline and the potassium salt of 3-hydroxybenzoic acid are reacted, in an inert organic solvent, e.g., dimethylsulfoxide giving 5-(6-chloro-2-quinolinoxy)benzoic acid which is nitrated, with, for example, potassium nitrate in the presence of concentrated sulfuric acid to give the corresponding 2-nitrobenzoic acid. The 2-nitrobenzoic acid is then reacted with a suitably substituted--halo compound, e.g., 2-chloropropionate, as described hereinabove.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:8])[CH2:5][CH2:6][NH2:7].[NH2:9][C:10]1[C:11]([C:18](N2C=CN=C2)=[O:19])=[N:12][C:13]([Cl:17])=[C:14]([NH2:16])[N:15]=1>O1CCCC1>[NH2:9][C:10]1[C:11]([C:18]([NH:1][CH2:2][CH2:3][N:4]([CH2:5][CH2:6][NH2:7])[CH3:8])=[O:19])=[N:12][C:13]([Cl:17])=[C:14]([NH2:16])[N:15]=1
Reactant: Nc1nc(N)c(C(=O)n2ccnc2)nc1Cl
Reactant: CN(CCN)CCN
Solvent: C1CCOC1
Product: CN(CCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Yield: 69354.8 %

Procedure:
To a stirred solution of 84.0 g (0.744 mol) of N-(2-aminoethyl)-N-methyl-1,2-ethanediamine (see U.S. Pat. No. 3,201,472 for a method of obtaining this compound) in 700 ml of tetrahydrofuran was added 88.6 g (0.372 mmol) of 1-(3,5-diamino-6-chloropyrazinoyl)imidazole in 10 portions over 1 5 h. After 1 h at ambient temperature the reaction mixture was filtered and concentrated to 300 ml. The solution was added dropwise to 1.4 liters of ether with vigorous stirring. The solid was filtered, washed with ether and dried. There was obtained 74.3 g (0.258 mol, 70%) of 3,5-diamino-N-[2-[(2-aminoethyl)methylamino]ethyl]-6chloropyrazinecarboxamide. A sample was filtered through a pad of silica gel and eluted with 5:95 (v/v) methanol:methylene chloride saturated with ammonia gas mp 138°-139.5° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[C:26](F)[CH:27]=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH2:49]1COCC1.O[Li].O>CO.[Pd]>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:49])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: C1CCOC1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Agent: [Pd]
Agent: [Li]O
Solvent: O
Solvent: CO
Product: Cc1ccc2c(c1)-c1cccc(c1)-c1cn3c(c([C@H](OC(C)(C)C)C(=O)O)c(C)cc3n1)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Temperature: 60 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a solution of methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate (20 mg, 0.030 mmol, 1 equiv) in MeOH (2 mL) was added 10% Pd/C (6 mg, 0.006 mmol, 0.2 equiv). The reaction was then stirred under a balloon of H2 for 2 h. The reaction was then filtered through Celite eluting with MeOH. The filtrate was then concentrated in vacuo. The crude hydrogenation product was taken upon in MeOH (1.5 mL), water (1 mL0, and THF (0.5 mL) and LiOH.H2O (37 mg, 0.913 mmol, 30 equiv) was added. The reaction was heated to 60° C. for 2 h. Upon cooling to ambient temperature, the reaction was filtered and purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 50-90% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to provide the product (5.2 mg, 27%). 1H NMR (500 MHz, DMSO-d6) δ 8.07 (br. s., 2H), 7.97 (s, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.29-7.21 (m, 2H), 7.08 (d, J=11.0 Hz, 1H), 6.83 (t, J=8.1 Hz, 1H), 5.79 (br. s., 1H), 4.70 (br. s., 1H), 3.82 (t, J=11.3 Hz, 1H), 2.63 (d, J=8.2 Hz, 1H), 2.39 (s, 3H), 1.94-1.57 (m, 12H), 1.52 (br. s., 1H), 1.19 (s, 3H), 1.15 (s, 9H), 1.12 (d, J=5.8 Hz, 3H); LCMS (ESI, M+1): 644.35.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH:11]=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)Cl.C[Si]([Br:20])(C)C.BrBr>O.O1CCOCC1>[Br:20][CH:10]([CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH:11]=[O:12]
Reactant: C[Si](C)(C)Br
Reactant: O=CCCc1ccc(Cl)c(Cl)c1
Agent: BrBr
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=CC(Br)Cc1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of the product of example 37 (10 mmol, 2.0 g) in a mixed solvent of DCM (40 ml) with dioxane (4.0 ml) was added TMSBr (15 mmol, 2.3 g) at room temperature. After the mixture was kept at 25° C. for one hour, bromine (1.6 g, 10.0 mmol) was added. Another one hour later, the mixture was poured into water (50 ml) and extracted with DCM three times. The combined organic layers were washed with brine, dried and evaporated into dryness to give the crude title product, which was used directly in the next step reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].I[CH2:14][CH2:15][F:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:14][CH2:15][F:16])[C:8](=[O:11])[C:7]2=[O:12]
Reactant: FCCI
Reactant: O=C1Nc2c(F)cccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C(=O)N(CCF)c2c(F)cccc21

Procedure:
7-Fluoro-1H-indole-2,3-dione (prepared according to the method of Gassman as described in U.S. Pat. No. 4,188,325 (2.00 g, 12.1 mmol), 1-iodo-2-fluoroethane (4.21 g, 24.2 mmol) and potassium carbonate (3.30 g, 24.2 mmol) in DMF (20 ml) are stirred at room temperature for 20 hours. The reaction mixture is diluted with cold water and the resulting precipitate filtered and dried to give the title compound as an orange solid. HPLC r.t. 4.18 min; MS for C10H7F2NO2 m/z 212.1 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>CO.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[C:23]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:10][CH2:9]1
Reactant: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(Cc5ccccc5)CC4)cc23)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCNCC4)cc23)cc1
Reaction time: 3 h

Procedure:
179 (4 g, 9.1 mmol) is dissolved in 100 ml of methanol, flushed with argon and, after addition of Pd—C (100 mg) and 2M HCl (5.5 ml, 11 mmol), the mixture is hydrogenated at room temperature for 3 h. The mixture is filtrated over celite and evaporated.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)(C)C>[CH2:1]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: CCO[SiH](OCC)OCC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CCO[Si](CCc1ccccc1)(OCC)OCC
Temperature: 50 °C
Yield: 1.5 %

Procedure:
130 mg Of styrene and 217 mg of triethoxysilane were placed in a glass reaction tube and 0.01 ml of an isopropyl alcohol solution of chloroplatinic acid (platinum content: 0.02 Wt. %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the tube contents were analyzed by GC-MS following cooling, the conversion rate of styrene was 3% and phenethyltriethoxysilane was produced at a yield of 1.5%. The yield of (α-methylbenzyl) triethoxysilane was 0.5%.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH:6]1([C:12]2[N:17]=[C:16](O)[C:15]([CH3:19])=[C:14]([CH3:20])[N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[Cl:3][C:16]1[C:15]([CH3:19])=[C:14]([CH3:20])[N:13]=[C:12]([CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[N:17]=1
Reactant: Cc1nc(C2CCCCC2)nc(O)c1C
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc(C2CCCCC2)nc(Cl)c1C
Temperature: 25 °C

Procedure:
POCl3 (220 ml, 2.4 mol, ˜26 eq) was cooled to ˜−50° C. before being carefully treated with 2-cyclohexyl-5,6-dimethylpyrimidin-4-ol (28.9 g, ‘92 mmol’, 1 eq). The cooling bath was then removed and the pot allowed to warm to RT followed by heating to reflux for 6 h. The RM was concentrated, treated with ice and saturated NaHCO3 and extracted into Et2O before being dried (sodium sulfate)/concentrated. The resulting oil was subjected to column chromatography using EtOAc (10%): 40-60 Petrols (90%) as eluent to yield 4-chloro-2-cyclohexyl-5,6-dimethylpyrimidine as an oil (5.7011 g, 28% over first two steps). 1H (400 MHz, DMSO) 1.16-1.90 (10H, m), 2.26 (3H, s), 2.46 (3H, s), 2.60-2.75 (1H, m). ES+225.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:12]([C@@H:21]([CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:22])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:33][NH2:34]>CO>[NH:33]([C:10]([C@@H:9]([C@@H:12]([C@@H:21]([CH2:23][O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[OH:22])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11])[NH2:34]
Reactant: O=C[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Reaction time: 24 h

Procedure:
18.1 g (43 mmoles) of 2,3,5-tri-O-benzyl-D-ribose are dissolved in 18 ml of absolute methanol and, while cooling and stirring 21.5 g (43.0 mmoles) of 100% hydrazine hydrate (dissolved in 20 ml of absolute methanol) are added to the solution. After a few minutes the ice bath is removed and stirring is carried out for 24 hours at room temperature. The excess hydrazine hydrate is drawn off (oil pump) together with the methanol in a rotary evaporator at room temperature. A viscous yellow oil remains which is dried further using an oil pump. Yield: 17.9 g (96%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:15][C@H:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:13]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][CH:10]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.C(Br)(=O)C([Br:41])=O>ClCCl>[CH2:1]([O:8][C@@H:9]1[CH2:15][C@H:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:13]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][CH:10]1[Br:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)C[C@H]1OCc1ccccc1
Reactant: O=C(Br)C(=O)Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: BrC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)C[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Deoxy-2,4,6-tri-O-benzyl-glucopyranose (2.2 g) was dissolved in dichloromethane (20 mL) and dry DMF (880 μL) was added. The reaction solution was cooled at 0° C. and oxalyl bromide (500 μL) was added and the resulting solution stirred at 0° to 5° C. for 1 hour. The solution was then diluted with dichloromethane (100 mL) and washed with water (3×100 mL), dried over sodium sulfate, filtered and evaporated to dryness to obtain 3-deoxy-2,4,6-tri-O-benzyl-glucopyranosyl bromide (compound 13).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[O:11][CH:10]=[CH:9][C:8]2=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=1)([CH3:3])[CH3:2].C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)Cl>[Br:25][C:10]1[O:11][C:7]2[C:8](=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=2)[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(OC(C)C)cc2occc12
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(OC(C)C)cc2oc(Br)cc12
Temperature: 60 °C
Reaction time: 1.2 h
Yield: 87 %

Procedure:
A mixture of methyl 6-isopropoxybenzofuran-4-carboxylate (344a) (2.17 g, 9.25 mmol) and NBS (4.12 g, 23.1 mmol) in 50 mL of CHCl3 was heated at 60° C. for 5 hrs, followed by addition of another batch of NBS (2.50 g, 14.0 mmol). After stirring for an additional 1.2 h, the reaction was concentrated, and the residue was purified with Biotage column chromatography eluting with CHCl3 to give a yellow oil (2.52 g, 87% yield). 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J=2.27 Hz, 1 H) 7.22 (s, 1 H) 7.18 (d, J=2.01 Hz, 1 H) 4.56-4.64 (m, 1 H), 3.97 (s, 3H), 1.37 (d, J=6.04 Hz, 6 H); LCMS for C13H13BrO4 m/z 312.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17]N(C)C)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21]C(OC(C)C)=O.O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][Cl:21])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)Cc1cn(C(=O)OC(C)(C)C)c2ncccc12
Reactant: CC(C)OC(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1cc(CCl)c2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 3-dimethylaminomethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (511, 2.60 g, 9.44 mmol) in toluene (50.00 mL) was added isopropyl chloroformate (11.3 mL, 1.0 M in toluene) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 3 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (512, 2.0 g, 79.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:20]O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(N(CC)CC)C>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]3[N:20]=2)=[CH:4][CH:3]=1
Reactant: ON=C(Cc1ccc(C(F)(F)F)cn1)c1ccc(F)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Fc1ccc(-c2cc3ccc(C(F)(F)F)cn3n2)cc1
Temperature: 35 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a suspension of 1-(4-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime (189 g, 630 mmol) in DME (700 ml) at −3° C. was added methanesulfonyl chloride (50.5 ml, 650 mmol) and the mixture stirred for 15 minutes. Triethylamine (182 ml, 1.31 mol) in DME (74 ml) was then added dropwise over 15 min. After the addition was complete, the reaction was then warmed to 35° C. for 45 minutes. It was then cooled and filtered, washing with DME (180 ml). To the filtrate was added iron (II) chloride (0.87 g) and the mixture was then heated to 75° C. for 2.5 hour then allowed to cool. Water (700 ml) was added, the resulting solid removed by filtration, washed with water and dried. This solid was dissolved in dichloromethane (1.5 l) and purified in two portions by Biotage chromatography eluting with hexane-ethyl acetate (3:1). Combination and concentration of the appropriate fractions gave 148.3 g (84%) of the title compound.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.O[CH2:35][C@@H:36]1[C@H:41]([CH3:42])[CH2:40][CH2:39][CH2:38][N:37]1[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44].[C:53]1(=[O:63])[NH:57][C:56](=[O:58])[C:55]2=[CH:59][CH:60]=[CH:61][CH:62]=[C:54]12>C1COCC1>[O:58]=[C:56]1[C:55]2[C:54](=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:53](=[O:63])[N:57]1[CH2:35][C@@H:36]1[C@H:41]([CH3:42])[CH2:40][CH2:39][CH2:38][N:37]1[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]
Reactant: C[C@@H]1CCCN(C(=O)OCc2ccccc2)[C@@H]1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H]1CCCN(C(=O)OCc2ccccc2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 110 %

Procedure:
A solution of PPh3 (21.5 g, 82 mmol) in 30 ml of THF was cooled to 0° C. DIAD (16.1 mL, 82 mmol) was then added dropwise and reaction stirred for 20 min. A solution of (2S,3R)-benzyl 2-(hydroxymethyl)-3-methylpiperidine-1-carboxylate (8.7 g, 32.9 mmol) in 15 mL THF was then added dropwise and stirred at 0° C. for 30 min. Phthalimide (6.3 g, 42.7 mmol) was then added and the reaction was warmed to rt overnight. The resulting suspension was concentrated in vacuo, diluted with EtOAc, washed with water and brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give the title compound (14.2 g, 110%, DIAD contamination), which was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.72-7.71 (m, 1H), 7.62-7.60 (m, 3H), 7.17-7.13 (m, 3H), 7.05-7.04 (m, 1H), 6.98-6.96 (m, 1H), 4.76-4.69 (m, 1H), 4.54-4.39 (m, 1H), 4.03-3.98 (m, 2H), 3.63-3.54 (m, 1H), 3.25-3.07 (m, 1H), 1.91-1.80 (m, 1H), 1.73-1.54 (m, 2H), 1.47-1.25 (m, 2H), 1.07-1.04 (m, 3H). ESI-MS (m/z): 263.93 [M+1]+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([CH3:16])[CH3:15])[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:15][N:14]([CH3:16])[CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: [H][H]
Reactant: CN(C)C1CCCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CN(C)C1CCCNC1

Procedure:
A mixture of 1-benzyl-3-dimethylaminopiperidine and 0.5 g. of 10 percent palladium on carbon in 100 ml. of methanol was heated to ca. 56°C. and shaken under ca. 40 psi of hydrogen until uptake ceased. The catalyst was filtered, and the solvent distilled at atmospheric pressure. Distillation of the residue afforded 3-dimethylaminopiperidine, b.p. 87°-89°C./28 mm.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33].O>CS(C)=O>[F:27][C:28]([F:37])([F:38])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH:33][CH2:11][CH:12]1[O:25][C:16]2=[C:17]3[C:21](=[CH:22][CH:23]=[C:15]2[O:14][CH2:13]1)[NH:20][C:19](=[O:24])[CH2:18]3
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Solvent: O
Solvent: CS(C)=O
Product: O=C1Cc2c(ccc3c2OC(CNCc2cccc(C(F)(F)F)c2)CO3)N1
Temperature: 85 °C
Yield: 19.6 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.01 g, 2.70 mmole) and 3-trifluoromethylbenzylamine (1.75 ml, 12.0 mmole) were combined in 15 ml of dry DMSO and heated to 85° C. for 4 hours under a nitrogen atmosphere. After cooling to room temperature, 200 ml of water was added and the mixture was extracted twice with 250 ml portions of 50% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 2% methanol/CH2Cl2 as eluant. The free base of the title compound (0.20 g, 20%) thus obtained was crystallized from isopropanol with the addition of one equivalent of fumaric acid to give 0.17 g of the (S) enantiomer of the title compound as a light yellow solid fumarate, one-half hydrate, m.p. 158°-160° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[N:9][N:8]([CH3:11])[C:7]=2[CH:12]=1.[NH:13]1[CH:17]=[N:16][N:15]=[N:14]1>>[CH3:11][N:8]1[C:7]2[CH:12]=[C:3]([CH2:2][N:14]3[N:15]=[N:16][CH:17]=[N:13]3)[CH:4]=[CH:5][C:6]=2[N:10]=[N:9]1
Reactant: c1nnn[nH]1
Reactant: Cn1nnc2ccc(CBr)cc21
Product: Cn1nnc2ccc(Cn3ncnn3)cc21

Procedure:
The bromomethyl compound (b) is reacted with tetrazole, yielding the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([N:20]([CH3:19])[C:21]3[CH:22]=[CH:23][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:25][CH:26]=3)=[O:18])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CNc1ccc(CN2CCCCC2)cc1
Reactant: O=C(O)/C=C/c1ccc(-c2ccc(Cl)cc2)cc1
Product: CN(C(=O)/C=C/c1ccc(-c2ccc(Cl)cc2)cc1)c1ccc(CN2CCCCC2)cc1

Procedure:
Prepared analogously to Example 172 starting from (E)-3-(4′-chloro-biphenyl-4-yl)-acrylic acid and methyl-(4-piperidin-1-ylmethyl-phenyl)-amine.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([CH2:13][O:14][C:15]2[O:19][C:18]([CH:20]([OH:24])[CH2:21][C:22]#[N:23])=[CH:17][CH:16]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.N.CO.C(Cl)Cl>>[NH2:23][CH2:22][CH2:21][CH:20]([C:18]1[O:19][C:15]([O:14][CH2:13][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:16][CH:17]=1)[OH:24]
Reactant: N#CCC(O)c1ccc(OCC2CCCCC2)o1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Product: NCCC(O)c1ccc(OCC2CCCCC2)o1

Procedure:
LiAlH4 reduction of 3-(5-(cyclohexylmethoxy)furan-2-yl)-3-hydroxypropanenitrile following the method used in Example 1 gave after flash chromatography purification (2%-20% 7N NH3/MeOH—CH2Cl2 gradient) Example 24 as a light yellow oil which solidified upon standing. Yield (0.26 g, 46%); 1H NMR (400 MHz, CD3OD) δ 6.11 (d, J=3.4 Hz, 1H), 5.10 (d, J=3.4 Hz, 1H), 4.56 (t, J=6.8 Hz, 1H), 3.79 (d, J=6.3 Hz, 2H), 2.65-2.77 (m, 2H), 1.82-1.96 (m, 2H), 1.66-1.82 (m, 6H), 1.15-1.37 (m, 3H), 1.00-1.13 (m, 2H); ESI-MS m/z 254.2 [M+H]+.