Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:30])([C@H:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(C(C)C)[P:35]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(C)C.N1C=NN=N1.ClC1C=CC=C(C(OO)=[O:68])C=1>CN(C)C1C=CN=CC=1.ClCCl>[P:35]([O:30][C@@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([C@H:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:68]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)N(C(C)C)P(OCc1ccccc1)OCc1ccccc1
Reactant: C[C@@H](c1ccc(-c2ccnn2C)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: CN(C)c1ccncc1
Agent: c1nnn[nH]1
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccnn2C)cc1)[C@@](Cn1cncn1)(OP(=O)(OCc1ccccc1)OCc1ccccc1)c1ccc(F)cc1F
Temperature: 0 °C
Yield: 27.2 %

Procedure:
A solution of the product of step (j) (2.0 g, 4.4 mmol), dibenzyl diisopropylphosphoramidite (2.28 g, 6.6 mmol), tetrazole (0.92 g, 13.2 mmol) and 4-dimethylaminopyridine (50 mg) in dichloromethane (30 ml) was heated under reflux for 13 hours. The reaction mixture was cooled (0° C.) and m-chloroperbenzoic acid (1.52 g, 8.8 mmol) added. The solution was stirred at 0° C. for a further hour then allowed to warm to room temperature. The reaction mixture was washed with aqueous sodium sulphite solution (10%, 30 ml), saturated sodium bicarbonate solution (30 ml) and brine (30 ml). The organic layer was dried (Na2SO4) and solvent was evaporated in vacuo to give an oil. Purification by column chromatography (silica gel, 45 g, eluting with toluene to 3.5% diethylamine in toluene gradient) gave the required product as a colourless oil (0.8 g, 27%), m/z 671 (M++1). 1H N.M.R. (CDCl3) δ=1.3 (d, 3H); 3.8 (s, 3H); 3.85 (q, 1H); 4.8 (m, 2H); 4.9 (m, 2H), 5.2 (s, 2H); 6.25 (s, 1H); 6.6 (m, 1H); 6.8 (m, 1H); 7.05 (m, 1H); 7.15 (m, 2H); 7.2-7.35 (m, 12H); 7.5 (s,1H); 7.8 (s,1H); 8.23 (s,1H).
Reaction SMILES: [C:1]([CH2:3][C:4](N)=O)#[N:2].F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:19][C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]#[N:38])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>C1COCC1.C(O)C>[C:37]([CH2:36][C@H:33]1[CH2:32][CH2:31][C@H:30]([N:29]2[C:21]3=[C:22]4[S:28][CH:27]=[CH:26][C:23]4=[N:24][CH:25]=[C:20]3[N:19]=[C:4]2[CH2:3][C:1]#[N:2])[CH2:35][CH2:34]1)#[N:38]
Reactant: N#CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Reactant: N#CCC(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: N#CCc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-Cyanoacetamide (11 mg, 0.13 mmol) and triethyloxonium tetrafluoroborate (21 mg, 0.11 mmol) in THF (0.13 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue dissolved in ethanol (55 μL) and added to a suspension of {trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetonitrile (8.9 mg, 0.031 mmol) in ethanol (0.20 mL). The mixture was stirred at 85° C. for 2 h. The mixture was purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 60 mL/min) to give the desired product (2.7 mg, 26%) as TFA salt. LCMS calculated for C18H18N5S (M+H)+: m/z=336.1. Found: 336.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH2:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(NCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanamine (35 mg, 0.125 mmol) from Example 5 step 3 was dissolved in DMF (0.62 mL), cesium carbonate (203 mg, 0.62 mmol) was added, stirred at room temperature for 10 minutes. 2-bromo-5-(methylsulfonyl)pyridine (32.4 mg, 0.137 mmol) was added. Reaction was run at room temperature for 1 hour, then heated to 50° C. for 5 hours. Water (10 mL) was added, extracted with EtOAc (10 mL×2), second wash with brine (10 mL). The organic phase was dried by magnesium sulfate, filter, concentrated and purified by preparative-TLC (Analtech Silica Gel GF 1500 μM, 20×20 cm) using 30% acetone/hexane to give the title compound as a white solid.
Reaction SMILES: C(N(CC)CCC[N:7]1[C:15]2[C:10](=[C:11]([Cl:16])[CH:12]=[CH:13][CH:14]=2)[C:9](NCCCN(CC)CC)=[N:8]1)C.[ClH:28].C(OCC)C>C(O)C>[ClH:16].[ClH:28].[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[N:8][NH:7]2
Reactant: CCN(CC)CCCNc1nn(CCCN(CC)CC)c2cccc(Cl)c12
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: Clc1cccc2[nH]ncc12

Procedure:
In 50 ml of absolute ethyl alcohol was dissolved 3.2 g of the 1-(3-diethylaminopropyl)-3-(3-diethylaminopropylamino)-4-chloroindazole, and into the solution was introduced dried hydrogen chloride gas under cooling with ice. Then to the solution was added anhydrous diethyl ether to separate crystals. The crystals were obtained by filtration and dried to give 1-(3-diethylaminopropyl)-3-diethylaminopropylamino)-4-chloroindazole dihydrochloride having the following analytical value.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][C:10]2[CH:9]=[N:8][CH:7]=[CH:6][C:5]=2[C:4]=1[NH2:13].[F:16][C:17]([F:29])([F:28])[C:18]1[CH:27]=[CH:26][C:21]([CH2:22][N:23]=[C:24]=[O:25])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[F:15][C:2]([F:1])([F:14])[C:3]1[C:4]([NH:13][C:24]([NH:23][CH2:22][C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:29])[F:28])=[CH:27][CH:26]=2)=[O:25])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[CH:6]2
Reactant: Nc1c(C(F)(F)F)ccc2cnccc12
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1c(C(F)(F)F)ccc2cnccc12
Reaction time: 96 h
Yield: 4 %

Procedure:
To a solution of 6-(trifluoromethyl)isoquinolin-5-amine (Description 98; 100 mg, 0.47 mmol) in anhydrous toluene (5 ml) was added [4-(trifluoromethyl)benzyl]isocyanate (Description 58) [0.506M soln in DCM] (1.88 ml; 0.94 mmol) and the mixture heated at reflux overnight. Further [4-(trifluoromethyl)benzyl]isocyanate [0.506M soln in DCM] (1.88 ml; 0.94 mmol) was added and heating continued for 4 days. The toluene was removed, the residue dissolved in methanol (10 ml) and a spatula end of potassium carbonate added. The mixture was then heated at reflux for 15 mins. The mixture was cooled and filtered and the filtrate evaporated. The residue was purified by mass directed HPLC to give the title compound (8 mg, 4%) as a white solid. m/z (ES+) 414 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:5][C:6]([OH:8])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:50][C:51]1[CH:56]=[CH:55][C:54]([NH:57][CH2:58][CH2:59][NH2:60])=[CH:53][CH:52]=1>ClCCl>[CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:5][C:6]([NH:60][CH2:59][CH2:58][NH:57][C:54]1[CH:55]=[CH:56][C:51]([F:50])=[CH:52][CH:53]=1)=[O:8]
Reactant: COC(=O)[C@@H](CC(=O)O)CC1CCCCC1
Reactant: NCCNc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](CC(=O)NCCNc1ccc(F)cc1)CC1CCCCC1
Reaction time: 5 h

Procedure:
(R)-2-(Cyclohexylmethyl)succinic acid-1-methyl ester (211 mg, 0.93 mmol) from Acros Organics was treated with (500 μL, 2.87 mmol, 3.1 eq.) of diisopropylethylamine, HATU (360 mg, 1.096 mmol, 1.2 eq.) and (N-(4-Fluoro-phenyl)-ethane-1,2-diamine) (210 mg, 0.93 mmol, 1 eq.). The reagents were dissolved in dry dichloromethane (5 mL). The reaction was allowed to stir for 5 hours and monitored by LC/MS. Volatiles were removed and the reaction directly purified by automated normal-phase chromatography (0-100% ethyl acetate in hexanes gradient). (R)-2-cyclohexylmethyl-N-[2-(4-fluoro-phenylamino)-ethyl]-succinamic acid methyl ester was obtained as clear oil (220 mg, 0.60 mmol, 65%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([N:14]=[C:15]=[S:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH3:17]>CCOCC>[CH:1]1[C:13]2[CH:12]([NH:14][C:15]([NH2:17])=[S:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: S=C=NC1c2ccccc2-c2ccccc21
Solvent: CCOCC
Product: NC(=S)NC1c2ccccc2-c2ccccc21
Reaction time: 8 h

Procedure:
To 16.52 g (0.074 mole) of 9-fluorenylisothiocyanate in ether is added excess anhydrous NH3 with cooling. The reaction mixture is capped and allowed to stand overnight at 0° C. Filtration gives the product, N-(9-fluorenyl)-thiourea, m.p. (158°) 182°-189° C.
Reaction SMILES: FC1C(F)=CC([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15](CCS(C)(=O)=O)C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=C(OC)C=1.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1B(O)O.CCCCCCC.C[CH2:58][O:59][C:60]([CH3:62])=[O:61]>>[CH3:58][O:59][C:60](=[O:61])[CH2:62][NH:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[F:40]
Reactant: OB(O)c1ccccc1F
Reactant: CCOC(C)=O
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Solvent: CCCCCCC
Product: COC(=O)CNc1cnccc1-c1ccccc1F

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-ylamino)-acetic acid methyl ester (example 176, intermediate b) and 2-fluorophenylboronic acid (CAS RN 1193-03-9) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Off-white solid (37%). MS (ESI): m/z=261.104 [M+H]+.
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:49])[C:32]([C:47]#[N:48])=[CH:33][C:34]([N:37]([CH2:45][CH3:46])C(=O)OC(C)(C)C)([CH3:36])[CH3:35])[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.C(O)(C(F)(F)F)=O>C(Cl)Cl>[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:33][C:34]([NH:37][CH2:45][CH3:46])([CH3:35])[CH3:36])[C:47]#[N:48])=[O:49])[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: CCN(C(=O)OC(C)(C)C)C(C)(C)C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(C)(C)C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 5-((R)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl(ethyl)carbamate (60 mg, 0.089 mmol) in DCM (10 mL) was added 2.5 mL of CF3COOH. The mixture was stirred for 2 h at room temperature. The volatile phase was removed under reduced pressure and the residue was purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm. This resulted 12 mg (16%) of the title compound as a white solid and bis TFA salt. LC-MS: m/z 569 (M+H+). H-NMR (400 MHz, CD3OD, ppm): 8.37 (s, 1H), 7.72 (s, 1H), 7.57 (t, J=8.4 Hz, 1H), 7.48 (t, J=8.0 Hz, 2H), 7.28 (t, J=7.2 Hz, 1H), 7.17 (d, 8.0 Hz, 2H), 6.97 (dd, J=8.4 Hz, 2.0 Hz, 1H), 6.91 (dd, J=11.6 Hz, 2.0 Hz, 1H), 4.95-4.82 (m, 2H), 4.70-4.65 (m, 1H), 3.71-3.65 (m, 3H), 3.59-3.55 (m, 1H), 2.15-2.11 (m, 1H), 2.02-1.93 (m, 2H), 1.81-1.79 (m, 1H), 1.53 (s, 3H), 1.47 (s, 3H), 1.29 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH:54]1[CH2:59][CH2:58][CH:57]([NH:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=2[C:67]([F:70])([F:69])[F:68])[CH2:56][CH2:55]1>CN(C=O)C.O>[O:18]=[C:16]([N:54]1[CH2:55][CH2:56][CH:57]([NH:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=2[C:67]([F:68])([F:69])[F:70])[CH2:58][CH2:59]1)[CH2:15][NH:14][C:12](=[O:13])[C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1ccccc1NC1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2C(F)(F)F)CC1)c1ccc(Nc2ccccc2)cc1
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a stirred solution of (4-phenylamino-benzoylamino)-acetic acid (0.058 g, 0.00021 mol) in DMF (5 mL) was added DIPEA (0.069 g, 0.00054 mol), HOBt (0.028 g, 0.0002142 mol) and EDCI.HCl (0.085 g, 0.00045 mol) at ambient temperature. After 2 minutes piperidin-4-yl-(2-trifluoromethyl-phenyl)-amine dihydrochloride (0.050 g, 0.00019 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was collected, washed with brine solution, dried over sodium sulfate and concentrated under reduced. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 0.06 g (68%) of N-{2-oxo-2-[4-(2-trifluoromethyl-phenylamino)-piperidin-1-yl]-ethyl}-4-phenylamino-benzamide. LCMS: 497.21 (M+1)+, 95.3%, 1H NMR (DMSO-d6): δ 8.6 (s, 1H), 8.2 (t, 1H), 7.8 (d, 2H), 7.4 (m, 4H), 7.2 (d, 2H), 7.1 (m, 3H), 6.9 (t, 1H), 6.7 (t, 1H), 4.7 (d, 1H), 4.3 (d, 1H), 4.1 (s, 2H), 3.9 (d, 1H), 3.7 (s, 1H), 2.8 (t, 1H), 2.0 (t, 2H), 1.5 (m, 2H).
Reaction SMILES: [C:1]([NH:9][CH:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]([O:13][C@@H:14]1[CH:19]2[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]2)[CH2:15]1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:28][CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>CCOC(C)=O.C(#N)C>[Cl-:28].[C:1]([NH:9][CH:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]([O:13][C@@H:14]1[CH:19]2[CH2:18][CH2:17][N+:16]([CH2:29][C:30](=[O:31])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([CH2:21][CH2:20]2)[CH2:15]1)=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCl)c1ccccc1
Reactant: O=C(NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(NC(=O)c1ccccc1)c1ccccc1)C2)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-benzamido-2-phenylacetate (C85) (70 mg, 0.19 mmol) in EtOAc (1 ml) and acetonitrile (1 ml), was added 2-chloro-1-phenylethanone (32.7 mg, 0.21 mmol). The reaction was stirred at RT for 24 hours, and then the solvents were evaporated and the residue was triturated with EtOAc (8 ml) to obtain (3R)-3-(2-benzamido-2-phenylacetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane chloride (72 mg; 72% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH2:7][NH:8][CH2:9][CH2:10][O:11][CH3:12])([CH3:4])(C)C.C(O)[C:15]1[CH:20]=[CH:19]C=[CH:17][CH:16]=1.O.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1.O>C1C=CC=CC=1>[C:23]1([CH3:33])[CH:24]=[CH:25][C:26]([S:29]([OH:32])(=[O:30])=[O:31])=[CH:27][CH:28]=1.[CH2:1]([O:5][C:6](=[O:13])[CH2:7][NH:8][CH2:9][CH2:10][O:11][CH3:12])[C:4]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1
Reactant: OCc1ccccc1
Reactant: COCCNCC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COCCNCC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 55.8 g of N-(2-methoxyethyl)glycine tert-butyl ester in 200 ml of benzene was added 63.8 g of benzyl alcohol and 72.9 of p-toluenesulfonic acid monohydrate. The mixture was heated at reflux for 10 hours with the continuous removal of water through a Dean-Stark water trap. At the end of this period, the solution was concentrated in vacuo, and to the residue was added 300 ml of dry ethyl ether. After 2 hours at room temperature, the formed precipitate was filtered, washed with dry ethyl ether and then recrystallized from ethyl acetate to yield 99.2 g (85 percent) of N-(2-methoxyethyl)glycine benzyl ester p-toluenesulfonate, M.P. 95°-6° C.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH:5]1([CH:8]=O)[CH2:7][CH2:6]1.C[Si]([C:14]#[N:15])(C)C>CCOCC>[CH:5]1([CH:8]([NH:4][CH:1]2[CH2:3][CH2:2]2)[C:14]#[N:15])[CH2:7][CH2:6]1
Reactant: C[Si](C)(C)C#N
Reactant: O=CC1CC1
Reactant: NC1CC1
Solvent: CCOCC
Product: N#CC(NC1CC1)C1CC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
Following a procedure outlined in Synth. Commun. 15(2), 1985, 157-163, cyclopropylamine (2 g) and cyclopropanecarboxaldehyde (4.9 g) were combined in a pressure tube and heated to 100° C. for 10 minutes. The mixture was cooled to RT and trimethylsilylcyanide (8.76 mL) was added carefully with cooling by means of an ice bath (exothermic!). After addition, the mixture was reheated to 100° C. for another 10 minutes. After cooling, the mixture was diluted with ether and extracted two times with 2 N HCl. The combined aqueous extracts were basified with conc. NaOH to pH 10, saturated with NaCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography using ethyl acetate/heptane 1:1 as an eluent to give the desired material as a colorless oil (884 mg). MS (EI): 137.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([CH3:15])=[N:8]1)([CH3:6])[C:3]([OH:5])=O.[C:16]([NH:19][NH2:20])(=[O:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:16]([NH:19][NH:20][C:3](=[O:5])[C:2]([CH3:1])([N:7]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([CH3:15])=[N:8]1)[CH3:6])(=[O:18])[CH3:17]
Reactant: CC(=O)NN
Reactant: Cc1nn(C(C)(C)C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NNC(=O)C(C)(C)n1cc([N+](=O)[O-])c(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a mixture of 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanoic acid (500 mg, 2.38 mmol) in DCM (20 ml) was added acetohydrazide (211 mg, 2.86 mmol), HATU (1.8 g, 4.76 mmol), and DIPEA (618 mg, 4.76 mmol). The mixture was stirred at room temperature for 1 h. After concentration, the residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (1/3) to give the title product (600 mg, 95%) as light yellow oil. LC-MS (ESI): m/z=270.1 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=2)=[O:15])=[N:12][O:11][N:10]=1)(=O)=O.CCN(C(C)C)C(C)C.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(#N)C>[Cl:24][C:19]1[CH:18]=[C:17]([NH:16][C:14]([C:13]2[C:9]([CH2:8][CH2:7][CH2:6][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:10][O:11][N:12]=2)=[O:15])[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: CS(=O)(=O)OCCCc1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCN1CCOCC1
Temperature: 70 °C
Yield: 54.2 %

Procedure:
3-(4-[(3-Chloro-4-fluorophenyl)amino]carbonyl-1,2,5-oxadiazol-3-yl)propyl methane-sulfonate (19 mg, 0.051 mmol) was dissolved in anhydrous ACN (100 μL) followed by the addition of DIPEA (44 μL, 0.26 mmol) and morpholine (6.7 μL, 76.8 μmol). The reaction were stirred and heated at 70° C. for 3 h. The reaction was concentrated and purified by silica gel chromatography (60-100% ethyl acetate/hexanes) to give the desired product (10.2 mg, 54%). LCMS for C16H19ClFN4O3 (M+H)+ m/z=369.1.
Reaction SMILES: [Na].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[C:12](OCC)(=[O:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.O>C(O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:10]#[N:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccncc1
Reactant: N#CCc1ccc(F)cc1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: N#CC(C(=O)c1ccncc1)c1ccc(F)cc1

Procedure:
Sodium (2.48 g) was dissolved in dry ethanol (37 ml) under nitrogen atmosphere. To the solution was added 4-fluorophenylacetonitrile (11.65 g) and ethyl isonicotinate (16.41 ml) and the solution was refluxed for 3 hours. The reaction mixture was cooled and poured into water. The ethanol of the mixture was removed under reduced pressure. The resulting aqueous solution was washed with ether and neutralized with diluted hydrochloric acid. The separated solid was collected, washed with water and dried to give 2-(4-fluorophenyl)-3-oxo-3-(pyridin-4-yl)propanenitrile (16.43 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9]1[N:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-])=O.[CH3:19]OC(OC)OC.C(O)(C(F)(F)F)=O>CO.[Ni]>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:9]2=[N:14][C:13]([OH:15])=[CH:12][CH:11]=[C:10]2[N:16]=[CH:19]1
Reactant: CC1CCCCC1Nc1nc(O)ccc1[N+](=O)[O-]
Reactant: COC(OC)OC
Agent: [Ni]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC1CCCCC1n1cnc2ccc(O)nc21
Yield: 40.2 %

Procedure:
6-(2-Methylcyclohexylamino)-5-nitropyridin-2-ol (100 mg, 0.398 mmol) and nickel (11.68 mg, 0.199 mmol) in MeOH (10 mL) were stirred at 22° C. for 24 hr under H2. After filtration through Celite®, the solution was concentrated in the presence of a few drops of TFA. The residue was dissolved in trimethoxymethane (2112 mg, 19.90 mmol) and stirred overnight with a drop of TFA. The mixture was concentrated. The residue was diluted with water, neutralized with NaHCO3 solution and extracted with EtOAC. The EtOAc extract was concentrated and the residue was purified by column chromatography to give the title compound as a brown oil (37 mg). LCMS m/z=232.10 [M+H]+, 1H NMR (400 MHz, CDCl3) major isomer; δ ppm 0.75 (d, J=6.3 Hz, 3H), 1.22-2.20 (m, 9H), 4.18-4.27 (m, 1H), 6.89 (d, J=8.9 Hz, 1H), 8.17 (d, J=8.9 Hz, 1H), 8.52 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH2:14]([N:16]([CH2:22][CH3:23])[C:17](=[O:21])[CH2:18][C:19]#[N:20])[CH3:15]>>[CH2:14]([N:16]([CH2:22][CH3:23])[C:17](=[O:21])[C:18]([C:19]#[N:20])=[CH:5][C:4]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1)[CH3:15]
Reactant: CCN(CC)C(=O)CC#N
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Product: CCN(CC)C(=O)C(C#N)=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
The procedure described in Example 99 was repeated using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.5 g of N,N-diethylcyanoacetamide. Yield 2.23 g (73%), m.p. 153°-156° C.