Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CC(C)=O>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:3]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cn1nc(C)cc1C
Temperature: 0 °C
Yield: 42.2 %

Procedure:
A mixture of 3,5-dimethyl-1H-pyrazole (Aldrich, 10 g, 104 mmol), K2CO3 (43.1 g, 312 mmol), and ethyl 2-bromoacetate (12.69 mL, 114 mmol) in acetone (100 mL) was refluxed overnight. The salts were removed by filtration and the filtrate was evaporated under reduced pressure. The residue was dissolved in diethyl ether and the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The oily residue was dissolved in hot hexane and the insoluble material was filtered and discarded. The filtrate was cooled at 0° C. and the precipitate obtained was filtered and dried to give the title compound ethyl 2-(3,5-dimethyl-1H-pyrazol-1-yl)acetate (8 g, 43.9 mmol, 42.2% yield) as a gum. 1H NMR: (CDCl3-d6, 300 MHz) δ 5.82 (s, 1H), 4.72 (s, 2H), 4.18 (q, 2H), 2.18 (s, 3H), 2.17 (s, 3H), 1.24 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:15]#[N:16])[CH:6]=[CH:7][C:8]=2[N+:12]([O-])=O)[O:3]1.Cl[Sn]Cl.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[NH2:12][C:8]1[CH:7]=[CH:6][C:5]([C:15]#[N:16])=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([CH3:17])([CH3:1])[O:3]2
Reactant: CC1(C)C=Cc2c([N+](=O)[O-])ccc(C#N)c2O1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC1(C)C=Cc2c(N)ccc(C#N)c2O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.9 %

Procedure:
To a stirred solution of compound 6B (230 mg, 1 mmol) in EtOAc (5 mL) was added SnCl2 2H2O (780 mg, 3.5 mmol). The resulting mixture was stirred at rt for 20 h, then saturated aqueous K2CO3 was added. After stirring for 30 min, the reaction was treated with solid K2CO3 (550 mg). The resulting suspension was stirred at rt for another 2 h, and then filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was chromatographed (silica gel) eluting with 20% to 60% EtOAc/hexane to afford the title compound (160 mg) as a light yellow oil.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([N:18]3[CH2:22][CH2:21][N:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][C:28]=4[CH3:29])[C:19]3=[O:30])[S:17][C:11]=2[CH2:10]1)=O)(C)(C)C>CO.C(Cl)Cl>[ClH:1].[CH3:29][C:28]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[N:20]1[CH2:21][CH2:22][N:18]([C:16]2[S:17][C:11]3[CH2:10][NH:9][CH2:14][CH2:13][C:12]=3[CH:15]=2)[C:19]1=[O:30]
Reactant: Cc1ccncc1N1CCN(c2cc3c(s2)CN(C(=O)OC(C)(C)C)CC3)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1ccncc1N1CCN(c2cc3c(s2)CNCC3)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
6N HCl (5 mL) was added dropwise to stirred solution of 2-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (70 mg, 0.16887 mmol) in methanol (2 mL) at 0° C. The reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC (5% MeOH in DCM). The solvent was distilled from the reaction mixture under reduced pressure, followed by the addition of diethyl-ether. The precipitate was washed with ether and dried under reduced pressure to afford 36 mg of the product (61% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]1[CH2:28][C:20]3([CH2:25][O:24]C(C)(C)[O:22][CH2:21]3)[CH2:19][C:7]1=[C:8]2[C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].Cl>C1COCC1>[CH3:29][N:2]([CH3:1])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]1[CH2:28][C:20]([CH2:21][OH:22])([CH2:25][OH:24])[CH2:19][C:7]1=[C:8]2[C:13](=[O:18])[C:14]([CH3:15])([CH3:17])[CH3:16]
Reactant: CN(C)c1cccc2c(C(=O)C(C)(C)C)c3c(cc12)CC1(COC(C)(C)OC1)C3
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)c1cccc2c(C(=O)C(C)(C)C)c3c(cc12)CC(CO)(CO)C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
An oven-dried 25 mL one-necked round-bottomed flask was charged with compound 6b (0.014 g, 0.035 mmol) and THF (5 mL). HCl (2 mL of a 1 N aqueous solution) was added and the mixture was stirred at rt for 1 h. The consumption of the starting material was monitored by TLC (AcOEt/n-hexane 1:1). The reaction was basified to pH 7 by the dropwise addition of sat'd aq NaHCO3. The layers were separated and the aqueous phase was extracted with ether (3×15 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, gravity filtered, and concentrated under reduced pressure to provide 0.012 g of the title compound as a yellow solid in 96% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:2]=1.[CH:17]1([Bi](C2CC2)C2CC2)[CH2:19][CH2:18]1.N1C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Cu+2].ClCCl>[CH:17]1([N:12]2[C:13]3[C:9](=[CH:8][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:15][CH:14]=3)[CH2:10][C:11]2=[O:16])[CH2:19][CH2:18]1
Reactant: O=C1Cc2cc(-c3cccnc3)ccc2N1
Reactant: C1CC1[Bi](C1CC1)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1Cc2cc(-c3cccnc3)ccc2N1C1CC1
Temperature: 75 °C

Procedure:
To 5-pyridin-3-yl-1,3-dihydro-indol-2-one (CAS#220904-98-3, 63 mg, 0.3 mmol) was added freshly prepared tricyclopropyl-bismuthine [(J. Am. Chem. Soc., 2007, 129, 44-45), CAS#925430-09-7, 250 mg, 0.75 mmol], Cu(OAc)2 (82 mg, 0.45 mmol) and dichloromethane (3 ml). The reaction mixture was degassed by sparging with argon for 5 min. Then pyridine (0.073 ml, 0.9 mmol) was added and the reaction was heated at 75° C. for 1.5 hr. The reaction mixture was cooled to room temperature and then directly loaded on to a silica gel flash chromatography column. The 1-cyclopropyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one was eluted via a gradient of ethyl acetate-heptane (0 to 100%); HRMS: (ESI) m/z 251.1173 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 0.88-1.01 (m, 2H), 1.07-1.19 (m, 2H), 2.60-2.76 (m, 1H), 3.60 (s, 2H), 7.22-7.31 (m, 1H), 7.49 (s, 1H), 7.55 (d. J=8.5 Hz, 1H), 7.81 (br. s., 1H), 8.36 (d, J=7.7 Hz, 1H), 8.63 (br. s., 1H), 8.92 (br. s., 1H.
Reaction SMILES: CCO[CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=1.[S:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22].N1CCCCC1.Cl>C(O)C>[CH:11]([C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[C:20]2[S:16][C:17](=[O:22])[NH:18][C:19]2=[O:21])=[CH:10][CH:9]=1)=[O:12]
Reactant: O=C1CSC(=O)N1
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a mixture of terephthalaldehyde mono-(diethyl acetal) (3.96 mL, 20.0 mmol) and 2,4-thiazolidinedione (2.81 g, 24.0 mmol) in ethanol (40 mL) was added piperidine (2.0 mL, 20.0 mmol). The reaction mixture was heated to reflux for 4 h. After cooling on an ice-bath, hydrochloric acid (0.2 mol/L, 100 mL) was added and the precipitated products were collected by filtration. The cake was washed with water and dried. To a solution of this product (5.50 g) in tetrahydrofuran (180 mL) was added hydrochloric acid (1 mol/L, 18 mL) and the mixture was stirred at room temperature for 2 h. Water was added, and the precipitated products were collected by filtration to give 5-(4-formylbenzylidene)-2,4-thiazolidinedione (3.91 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13](Cl)=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:22][C@H:23]([CH2:28][OH:29])[CH2:24][CH:25]([CH3:27])[CH3:26].C(Cl)(Cl)Cl>C(Cl)Cl>[OH:29][CH2:28][CH:23]([NH:22][C:13]([C:6]1[C:7](=[O:12])[NH:8][C:9]2[C:4]([C:5]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)=[O:14])[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: O=C(Cl)c1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Reactant: CC(C)C[C@H](N)CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)CC(CO)NC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Reaction time: 0.08 h
Yield: 52.9 %

Procedure:
To a stirring suspension of 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid chloride (29 mg, 0.09 mmol) in DCM (0.5 mL) was added (S)-(+)-leucinol (30 μL, 0.23 mmol). Within 5 min, the mixture became homogeneous and the reaction was complete as determined by LCMS. Chloroform (2 mL) was added, and the solution was extracted with IN HCl (4×1 mL) and water (2×1 mL). The chloroform layer was purified directly by flash chromatography eluting with chloroform, then chloroform/methanol (100:1)->(50:1)->(25:1) to afford 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid (1-hydroxymethyl-3-methylbutyl)amide (b) (19 mg, 52%) as a white powder. MS: 399.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]O.CN(C=O)C.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5][Cl:20]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(CO)ccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(CCl)ccc1[N+](=O)[O-]

Procedure:
3-methyl-4-nitrobenzylalcohol (2 g) and 0.2 ml of DMF were dissolved in 20 ml of toluene. The solution was added with 1 ml of thionyl chloride and stirred under heating with reflux for 3 hours. The reaction mixture was concentrated and thus 2.2 g of an oil, 3-methyl-4-nitrobenzyl chloride, was obtained. This compound was used for the following reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:50][CH2:51][CH3:52])[C@@H:5]([N:7]([CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]2[C:49]=1[N:48]=[CH:47][CH:46]=[CH:45]2)[C:8](=[O:38])[C@@H:9]([NH:33]C(=O)OC)[CH2:10][C:11](=[O:32])[NH:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:6])[CH3:2].N1CCCCC1.CC(=O)OCC.CO>C(Cl)Cl>[NH2:33][C@@H:9]([CH2:10][C:11]([NH:12][C:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:32])[C:8]([N:7]([C@@H:5]([CH3:6])[CH:4]([O:3][CH2:1][CH3:2])[O:50][CH2:51][CH3:52])[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]2[C:49]=1[N:48]=[CH:47][CH:46]=[CH:45]2)=[O:38]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: CO
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.9 %

Procedure:
9H-Fluoren-9-yl)methyl (S)-1-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-1,4-dioxo-4-(tritylamino)butan-2-ylcarbamate (Compound III-20) 23.4 g (27 mmol) and piperidine 22.7 g (270 mmol) were added in DCM (90 ml). The mixture was stirred for 1.5 h at room temperature. The mixture was diluted with DCM (200 ml) and washed with water (150 ml×3). The solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel with PE:EA=50:1 to DCM:MeOH=10:1 to give the title compound 15.3 g, (yield 88%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2Br)[O:6][CH2:5][CH2:4][O:3]1.C([Li])CCC.[CH3:19][C:20]1[C:21](=[O:28])[CH:22]([CH3:27])[CH:23]([CH3:26])[C:24]=1[CH3:25].C1(C)C=CC=CC=1>C(OCC)C.CCCCCC.O>[CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:21]2([OH:28])[CH:22]([CH3:27])[CH:23]([CH3:26])[C:24]([CH3:25])=[C:20]2[CH3:19])[O:6][CH2:5][CH2:4][O:3]1
Reactant: CC1=C(C)C(C)C(C)C1=O
Reactant: CC1(c2ccccc2Br)OCCO1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CC1=C(C)C(O)(c2ccccc2C2(C)OCCO2)C(C)C1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, a solution of 2-(2-methyl-1,3-dioxolan-2-yl)-bromobenzene (24.31 g, 100.0 mmol) in diethyl ether (146 g) was cooled to −70° C. and a solution of n-butyllithium in n-hexane (1.56 M, 67.3 mL) was added dropwise thereto. After keeping the temperature for 1 hr, a solution of 2,3,4,5-tetramethylcyclopentenone (14.51 g, 5.3 mmol) in diethyl ether (97 g) was added dropwise to the mixture. After raising the temperature to 25° C., the mixture was stirred for 3 hrs. After quenching the reaction by addition of toluene and water, the aqueous layer was removed. The obtained organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was removed to give a crude product of 1-(2-methyl-1,3-dioxolan-2-yl)-2-(1-hydroxy-2,3,4,5-tetramethyl-2-cyclopentenyl)benzene. To the obtained crude product were added tetrahydrofuran (320 g), 3% aqueous hydrochloric acid solution (80 g) and acetone (32 g) and the mixture was stirred at 25° C. for 24 hrs. After the reaction, toluene was added to the reaction mixture. The organic layer was washed with water and saturated brine and dried over sodium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography to give 2-(2,3,4,5-tetramethylcyclopentadienyl)acetophenone (10.00 g, yield 41.6%).
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:4]([Cl:18])[CH:3]=1.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([O:12][C:11]([NH:10][C:5]1[C:4]([Cl:18])=[CH:3][C:2]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]2)=[C:7]([C:8]#[N:9])[CH:6]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)c(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)Nc1cc(C#N)c(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1Cl
Temperature: 95 °C
Yield: 82.4 %

Procedure:
A mixture of tert-butyl (4-bromo-2-chloro-5-cyanophenyl)carbamate (150 mg, 0.452 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (118 mg, 0.588 mmol), Pd2(dba)3 (20.7 mg, 0.023 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (26 mg, 0.045 mmol), and Cs2CO3 (442 mg, 1.36 mmol) in a dried microwave vial was flushed with nitrogen. Dioxane (4 mL) was added and the vial was sealed and heated at 95° C. overnight. The reaction was diluted with EtOAc and filtered through celite. The solvent was removed from the filtrate and radial silica gel chromatography of eluting with hexane/EtOAc afforded tert-butyl 4-((4-((tert-butoxycarbonyl)amino)-5-chloro-2-cyanophenyl)amino)piperidine-1-carboxylate (168 mg). This was dissolved in DCM (4 mL) and TFA (4 mL) was added. After 1 hr, the solvent was removed and the residue was dissolve in MeOH and applied onto an SCX column. After washing with MeOH, the product was eluted with 2 N NH3 in MeOH. Removal of the solvents left tert-butyl 4-((4-((tert-butoxycarbonyl)amino)-5-chloro-2-cyanophenyl)amino)piperidine-1-carboxylate (89 mg) as an oil. A portion of this (49.6 mg, 0.198 mmol) was dissolved in DCM (1 mL) and Boc2O (0.051 ml, 0.218 mmol) and TEA (0.030 ml, 0.218 mmol) were added. After stirred at rt for 1 hr, the solvent was removed and radial silica gel chromatography with hexane containing 0 to 30% EtOAc afforded tert-butyl 4-((4-amino-5-chloro-2-cyanophenyl)amino)piperidine-1-carboxylate (67 mg) as a yellow oil that solidified.
Reaction SMILES: [OH-].[Na+].Cl.[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][S:11][C:12](=N)N)[CH:5]=1.BrC[CH2:17][CH2:18][Cl:19]>O>[Cl:19][CH2:18][CH2:17][CH2:12][S:11][CH2:10][C:6]1[CH:5]=[N:4][CH:9]=[CH:8][CH:7]=1
Reactant: ClCCCBr
Reactant: N=C(N)SCc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCCSCc1cccnc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 59.6 %

Procedure:
A 10 N aqueous solution of sodium hydroxide (50 cc) is added, in the course of 10 minutes and whilst allowing the temperature to rise to 14° C. to a solution, cooled to 12° C. of 2-(pyrid-3-yl-methyl)isothiourea monohydrochloride (100 g) in distilled water (250 cc). After heating for 30 minutes at a temperature of 100° C. and then cooling to 12° C. a 10 N aqueous solution of sodium hydroxide (60 cc) is added dropwise and in the course of 10 minutes. 1-Bromo-3-chloropropane (82 g) is then added, whilst stirring, and stirring is continued for 20 hours at a temperature of about 20° C. The reaction mixture is then extracted three times with methylene chloride (430 cc in total). The organic extracts are combined and washed with distilled water (250 cc) and then dried over anhydrous magnesium sulphate. After filtration, the solution obtained is poured onto neutral silica gel (100 g) contained in a column of diameter 3 cm; the column is then eluted with methylene chloride (2300 cc). The first fraction (700 cc) is discarded; the second fraction (1600 cc) is collected and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 35° C. Pyrid-3-yl-methyl 3-chloropropyl sulphide (59 g) is thus obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].C(O)(=O)C(C(C(O)=O)O)O.C(=O)C1C=CC=CC=1>C(O)C>[CH3:1][CH2:2][O:3][C:4]([C@H:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: CCOC(=O)C(N)c1ccccc1
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CCO
Solvent: O=Cc1ccccc1
Product: CCOC(=O)[C@H](N)c1ccccc1
Reaction time: 0.08 h

Procedure:
A mixture of ethyl DL-phenylglycinate (5.021 g., 96% pure i.e. 27.0 mmole) and (+)-tartaric acid (2.027 g., 13.5 mmole, 0.5 equiv.) in ethanol (47 ml.) and benzaldehyde (2.75 ml., 2.88 g., 27.1 mmole, 1 equiv.) was stirred at 20°; crystallisation began within 5 minutes. After 10 days the mixture was filtered and the product washed with ethanol (2 × 7 ml.) and dried at 20°/4 mm. for 3 hours giving ethyl D-phenylglycinate (+)-hemitartrate solvated with 1.0 mole ethanol (3.922 g., 39% yield based on ester present or 78 % yield based on (+)-tartaric acid present), [α]D21 - 45.9° (c 2.506, H2O).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[O:5][C:4](=O)[NH:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:4][NH:3][C@H:2]([C@H:6]([OH:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:1]
Reactant: CCCCCCCCCCCCCCC[C@H]1OC(=O)N[C@H]1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCC[C@@H](O)[C@H](C)NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
To a cold (0° C.) solution of 107 (160 mg, 0.52 mmol) in THF(20 mL), LiAlH4 (1M in THF, 1.04 mL, 1.04 mmol), was added dropwise. The mixture was stirred overnight at room temperature. A further portion of LiAlH4 (1.04 mL, 1.04 mmol) was added and the reaction left for 2 more days. The reaction was quenched with H2O containing a few drops of NH4OH (20 mL) and extracted with EtOAc (3×20 mL). The combined extracts were successively washed with. H2O (30 mL) and brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The crude was purified by column chromatography on silica (50% to 75% CH2Cl2/hexane to 100% CH2Cl2 to 10% MeOH/CHCl3 and a few drops of NH4OH) to give 108 as a white solid (35 mg, 23% yield).
Reaction SMILES: [F:1]/[C:2](=[C:8](/[CH3:14])\[CH:9]([O:12][CH3:13])[O:10][CH3:11])/[C:3](OCC)=[O:4].[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>O.CCCCCC>[F:1]/[C:2](=[C:8](/[CH3:14])\[CH:9]([O:10][CH3:11])[O:12][CH3:13])/[CH:3]=[O:4]
Reactant: CCOC(=O)/C(F)=C(\C)C(OC)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(OC)/C(C)=C(\F)C=O
Temperature: -75 °C
Reaction time: 1 h

Procedure:
15.8 g. (77 mmol) of ethyl Z-2-fluoro-4,4-dimethoxy-3-methyl-2-butenoate was dissolved in 250 ml. of hexane in a 500 ml. round-bottomed flask fitted with a thermometer, argon inlet and dropping funnel. The resulting mixture was cooled to -75° C. and 63.5 ml. of di-isobutylaluminum hydride (1.45 equivalent of hydrogen) were added slowly thereto. The reaction mixture was stirred for 1 hour. Ethyl acetate (8.8 g., 100 mmol) was added thereto and the reaction mixture was allowed to come to -30° C. A mixture of 20 g. of sodium sulfate containing 3.6 g. of water was added thereto and stirring continued for 1 hour at 25°-35° C. The resulting material was twice filtered through celite and evaporated on a rotary evaporator at 31° C. (in glassware which had been rinsed with 8 N ammonium hydroxide and dried) to yield Z-2-fluoro-3-methyl-4,4-dimethoxy-2-buten-1-al obtained (approximately 10 g.). An inert gas atmosphere was maintained during all workup operations.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)=[O:10])=[C:6]([CH3:8])[N:7]=1)[CH3:2].Br[C:28]1[CH:33]=[CH:32][C:31]([C:34]23[CH2:41][CH2:40][C:37]([CH2:42][C:43]([O:45][CH3:46])=[O:44])([CH2:38][CH2:39]2)[O:36][CH2:35]3)=[CH:30][CH:29]=1.O.[F-].[Cs+]>O1CCOCC1.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH2:1]([C:3]1[O:4][C:5]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:28]3[CH:29]=[CH:30][C:31]([C:34]45[CH2:39][CH2:38][C:37]([CH2:42][C:43]([O:45][CH3:46])=[O:44])([CH2:40][CH2:41]4)[O:36][CH2:35]5)=[CH:32][CH:33]=3)=[CH:16][CH:17]=2)=[O:10])=[C:6]([CH3:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(C)c(C(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)o1
Reactant: COC(=O)CC12CCC(c3ccc(Br)cc3)(CC1)CO2
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc(C)c(C(=O)Nc2ccc(-c3ccc(C45CCC(CC(=O)OC)(CC4)OC5)cc3)cc2)o1
Temperature: 90 °C
Yield: 58 %

Procedure:
To a solution of 2-ethyl-4-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazole-5-carboxamide (200 mg, 0.561 mmol) and methyl 2-(4-(4-bromophenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (190 mg, 0.561 mmol) in dioxane (3 ml) was added H2O (0.33 ml). CsF (256 mg, 1.684 mmol) and Pd(amphos)Cl2 (39.8 mg, 0.056 mmol) were then added and the mixture was degassed before being heated at 90° C. for overnight. The reaction mixture was then cooled to room temperature and directly purified by column chromatography to afford the title compound as white solid after drying (159 mg, 58% yield). LC/MS, ESI-MS(+): 489.0, RT: 1.40 (Condition E).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:19]([C:20]#[N:21])=[C:18]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[N:17]=[C:16](SC)[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=O)C=1.FC1C=CC(C2CCN(C3C(C#N)=C(OCC(F)(F)F)N=C(S(C)(=O)=O)N=3)CC2)=CC=1.[N:72]1[CH:77]=[CH:76][CH:75]=[C:74]([CH2:78][NH2:79])[CH:73]=1>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:19]([C:20]#[N:21])=[C:18]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[N:17]=[C:16]([NH:79][CH2:78][C:74]4[CH:73]=[N:72][CH:77]=[CH:76][CH:75]=4)[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: NCc1cccnc1
Reactant: CSc1nc(OCC(F)(F)F)c(C#N)c(N2CCC(c3ccc(F)cc3)CC2)n1
Agent: CS(=O)(=O)c1nc(OCC(F)(F)F)c(C#N)c(N2CCC(c3ccc(F)cc3)CC2)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Product: N#Cc1c(OCC(F)(F)F)nc(NCc2cccnc2)nc1N1CCC(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 57c, the 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methylsulfanyl-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile was oxidized by 3-chloro-perbenzoic acid to 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methanesulfonyl-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile which was then treated with 3-picolylamine in dioxane at 40° C. during 18 hours to yield the 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-[(pyridin-3-ylmethyl)-amino]-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M+H]+=487.