Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:21]1(=[O:26])[CH2:25][CH2:24][CH:23]=[CH:22]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:22]2[C:21](=[O:26])[CH2:25][CH2:24][CH:23]=2)=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][N:9]=1
Reactant: O=Cc1cc(-c2ccccc2)cnc1Cl
Reactant: O=C1C=CCC1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CO
Product: O=C1CCC=C1C(O)c1cc(-c2ccccc2)cnc1Cl
Yield: 95 %

Procedure:
The clear solution of 2-Chloro-5-phenylnicotinaldehyde (10 mmol, 2.17 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-1-one (10.2 mmol., 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 95% yield (2.84 g).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[O:24][CH2:25][CH:26]=[CH2:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH2:25]([O:24][C:18]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:28])[CH:26]=[CH2:27]
Reactant: C=CCOc1c(Cl)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOc1c(Cl)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
The mixture of 2-(2-allyloxy-3-chloro-benzoylamino)-indan-2-carboxylic acid ethyl ester (17) (140 mg, 0.35 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (5 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until pH˜3. After filtration, the solid is purified by HPLC to give a pure product (18) as white solid (88 mg, 68%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]1[N:15]=[C:14]([CH3:16])[NH:13][N:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:12]2[C:11]([CH3:10])=[N:15][C:14]([CH3:16])=[N:13]2)[N:3]=[C:4]([CH3:9])[N:5]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: Cc1n[nH]c(C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(Cl)cc(-n2nc(C)nc2C)n1
Temperature: 25 °C
Reaction time: 66 h
Yield: 68.8 %

Procedure:
4,6-dichloro-2-methylpyrimidine (2-1) (137.8 g, 845 mmol), 3,5-dimethyl-1H-1,2,4-triazole (2-2) (82 g, 845 mmol), and Cs2CO3 (275 g, 845 mmol) were suspended in DMF (1 L) and the resulting mixture was stirred at room temperature for 66 h. The mixture was then poured into water (2 L) and stirred for 1 hour. The precipitate was filtered, washed with water (2×) and dried under vacuum to afford Intermediate 2 as an off-white solid (130 g, 69%). MS: m/z=224.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([N:21]2[CH2:26][CH2:25][C:24]([F:28])([F:27])[CH2:23][CH2:22]2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([N:21]2[CH2:22][CH2:23][C:24]([F:28])([F:27])[CH2:25][CH2:26]2)[CH2:19][NH:20][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])=[CH:16][CH:17]=1
Reactant: NCC(c1ccc(Cl)cc1)N1CCC(F)(F)CC1
Reactant: Cc1ccccc1C(=O)O
Product: Cc1ccccc1C(=O)NCC(c1ccc(Cl)cc1)N1CCC(F)(F)CC1

Procedure:
From 2-methylbenzoic acid and 2-(4-chloro-phenyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCCc1ccc(Cl)c(Cl)c1
Agent: B
Solvent: C1CCOC1
Product: OCCCCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
At 0° C. to a solution of 4-(3,4-dichlorophenyl)butanoic acid (3.7 g, 16 mmol) in dry THF (50 mL) was added borane THF complex (31.7 mL, 1.00 M in THF, 31.7 mmol) cautiously over 15 min and the reaction mixture allowed to warm to rt overnight. The reaction mixture was cooled to 0° C. and quenched by the cautious addition of 1 M NaOH. The reaction mixture was diluted with ether, washed with water twice, then brine, dried over MgSO4, filtered and concentrated. The residue was triturated with 10% ethyl acetate/hexanes (300 mL) to give Intermediate 20A (3.50 g, 100%) as white powder. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47-1.66 (4H, m), 2.53 (2H, t, J=7.5 Hz), 3.55-3.61 (2H, m), 6.94 (1H, dd, J=8.2, 2.1 Hz), 7.17-7.21 (1H, m), 7.26 (1H, d, J=8.3 Hz).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1.[CH3:21][C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][C:25](O)=[O:26]>>[F:20][C:2]([F:19])([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:25](=[O:26])[CH2:24][CH2:23][C:22]([CH3:29])([CH3:28])[CH3:21])[CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)C1CCNCC1
Reactant: CC(C)(C)CCC(=O)O
Product: CC(C)(C)CCC(=O)N1CCC(C(=O)Nc2ccc(OC(F)(F)F)cc2)CC1
Yield: 89 %

Procedure:
This material was prepared in analogy to example 8 step C) from piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (0.144 g) and 4,4-dimethyl-pentanoic acid (0.065 g) to give the desired 1-(4,4-dimethyl-pentanoyl)-piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (0.178 g) as an off-white solid. MS (ESI): 401.25 (MH+).
Reaction SMILES: [H-].[Na+].[C:3](#[N:5])[CH3:4].[F:6][C:7]([F:22])([F:21])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](OCC)=[O:17])=[CH:10][CH:9]=1.Cl>C1COCC1.O>[O:17]=[C:16]([CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([F:6])([F:21])[F:22])=[CH:9][CH:10]=1)[CH2:4][C:3]#[N:5]
Reactant: CCOC(=O)CCc1ccc(C(F)(F)F)cc1
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CCC(=O)CCc1ccc(C(F)(F)F)cc1
Yield: 52.5 %

Procedure:
To a suspension of sodium hydride (40 mmol) in THF (50 ml) was added acetonitrile (5.2 ml, 100 mmol) dropwise. The the resulting anion was added a solution of ethyl 3-[4-(trifluoromethyl)phenyl]propanoate (34.4 mmol) in THF (10 ml). The reaction mixture was refluxed for 3 h and then allowed to cool. To the resulting slurry was added water (50 ml) and the solution was acidified to pH 2 with 6 N HCl. The aqueous solution was extracted three times with diethyl ether. The organic layer was dried (Na2SO4) and concentrated. The product was purified by silica gel column chromatography (silica gel/25% ethyl acetate in petroleum ether) giving A as an oil (4.36 g, 53% yield). 1H NMR (300 MHz, CDCl3) δ 7.47 (m, 2H), 7.31 (m, 2H), 3.44 (s, 2H), 2.99 (s, 4H).
Reaction SMILES: N1C=CC=CC=1.[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:28][CH2:27]4)[CH:25]=3)=[C:17]([NH2:20])[CH:18]=2)[N:13]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:12][C@@H:11]1[CH3:35])(=[O:9])[CH3:8].[C:36](OC(=O)C)(=[O:38])[CH3:37]>ClCCl>[C:36]([NH:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[C:21]1[CH:22]=[N:23][N:24]([CH:26]3[CH2:28][CH2:27]3)[CH:25]=1)[N:13]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:12][C@H:11]([CH3:35])[N:10]2[C:7](=[O:9])[CH3:8])(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N1c2cc(N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc2c(cc1-c1cnn(C3CC3)c1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pyridine (5.09 μL, 0.063 mmol) was added to a solution of isopropyl (S)-4-acetyl-6-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.010 g, 0.025 mmol) in dichloromethane (200 μL). Acetic anhydride (3.56 μL, 0.038 mmol) was added, and the reaction stirred at rt for 18 h. The reaction mixture was concentrated and ethyl acetate was added. The solution was washed with 1 N aqueous HCl, and the organic phase was separated and concentrated. The residue was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford isopropyl (S)-6-acetamido-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 440 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[N:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.C([O-])=O.[Na+].Cl.[NH2:19]O>C(O)=O>[OH:1][C:2]1[N:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:19]
Reactant: O=Cc1cc(C(F)(F)F)cnc1O
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: N#Cc1cc(C(F)(F)F)cnc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 2-hydroxy-5-(trifluoromethyl)nicotinaldehyde (3.80 g, 17.9 mmol) (approx. 90% purity), sodium formate (1.46 g, 20.8 mmol), hydroxylamine hydrochloride (1.47 g, 20.8 mmol) in formic acid (36.6 mL) was stirred at room temperature for 2 h (cloudy brown solution) and then heated to reflux overnight (first clear brown solution, then cloudy again). After being cooled to room temperature, the reaction mixture was quenched with water and extracted with EtOAc three times. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated in vacuo to yield 3.03 grams (90%) of the desired crude product (approx. 75% purity) as a brown solid. MS calculated for C7H3F3N2O: (M+H)+189; found 189.0.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:26](O)=[O:27])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH:10][C:26]([C:23]2([C:20]3[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=3)[CH2:25][CH2:24]2)=[O:27])=[N:7][CH:6]=1
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Reactant: Nc1ncc(Cc2ccccc2Cl)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C2(C(=O)Nc3ncc(Cc4ccccc4Cl)s3)CC2)cc1
Reaction time: 16 h
Yield: 54.4 %

Procedure:
5-(2-Chloro-benzyl)-thiazol-2-ylamine (0.250 g, 1.11 mmol) and 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid (0.213 g, 1.11 mmol) were dissolved in acetonitrile (20 mL) containing triethylamine (0.28 mL, 2.0 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 0.494 g, 1.3 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was evaporated to dryness and purified by column chromatography on silica gel using a gradient of 5-40% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (0.2408 g, 0.6036 mmol, 54.4%). ESI-MS m/z calc. 398.1. found 399.0 (M+1)+. Retention time of 3.77 minutes. 1H NMR (400 MHz, CD3CN) d 1.21 (q, J=3.6 Hz, 2H), 1.59 (q, J=3.6 Hz, 2H), 3.78 (s, 3H), 4.19 (s, 2H), 6.88-6.96 (m, 2H), 7.07 (s, 1H), 7.23-7.46 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][C:13]2[CH:18]=[CH:17][N:16]([CH2:19][CH:20]([O:24]CC)[O:21]CC)[C:15](=[O:27])[N:14]=2)=[O:11])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][C:13]2[CH:18]=[CH:17][N:16]([CH2:19][CH:20]([OH:24])[OH:21])[C:15](=[O:27])[N:14]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(Cn1ccc(NC(=O)/C=C/c2ccc(Cl)cc2)nc1=O)OCC
Solvent: O=C(O)C(F)(F)F
Product: O=C(/C=C/c1ccc(Cl)cc1)Nc1ccn(CC(O)O)c(=O)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 100 %

Procedure:
(E)-3-(4-chloro-phenyl)-N-[1-(2,2-diethoxy-ethyl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-acrylamide (c, 2.48 g, 6.8 mM) was dissolved in trifluoroacetic acid (37 mL) and stirred at room temperature for 4.5 hours. Trifluoroacetic acid was removed in vacuo, and toluene (40 mL) was added to remove the solvent in vacuo. The residual solid was added with ethyl acetate (15 mL) and 5% aqueous sodium bicarbonate (15 mL) and stirred at room temperature. The precipitated crystal was filtered to afford 2.28 g of the desired compound (E)-3-(4-chloro-phenyl)-N-[1-(2,2-dihydroxy-ethyl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-acrylamide (d) (yield 100%, colorless crystal).
Reaction SMILES: [CH3:1][C:2](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:3].[NH2:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>O>[C:2]([NH:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: Nc1cccc(O)c1
Solvent: O
Product: CC(=O)Nc1cccc(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Acetic anhhydride (21.2 ml, 220 mmol) was slowly added to a suspension of m-aminophenol (24.0 g, 220 mmol) in 60% of crushed ice and 60 ml of cold water. The reaction mixture was vigorously stirred for 30 minutes. The white precipitate was filtered, washed with cold water, and air-dried to give 30.5 g (92%) of pure 3-acetamidophenol, m.p. 147°-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]([C@H:12]2[CH2:17][CH2:16][C@H:15](C3C=CC(CNC)=CC=3)[CH2:14][CH2:13]2)[CH:9]2[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.Br[CH2:30][CH2:31][CH2:32][OH:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:4]3[CH:3]=[CH:2][C:28]([CH2:30][CH2:31][CH2:32][OH:33])=[CH:27][C:5]=3[CH2:6][NH:8][CH3:9])[CH2:14][CH2:13]2)[CH:9]2[CH2:10][CH2:11]2)=[O:7])=[CH:27][CH:28]=1
Reactant: CNCc1ccc([C@H]2CC[C@H](N(C(=O)c3ccc(Cl)cc3)C3CC3)CC2)cc1
Reactant: OCCCBr
Product: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](N(C(=O)c2ccc(Cl)cc2)C2CC2)CC1

Procedure:
from trans-N-(4-chlorobenzoyl)-N-cyclopropyl-4-(4-methylaminomethylphenyl)cyclohexylamine and 3-bromo-1-propanol. Melting point: 118°-123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=[O:31])OC3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:31])=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)N1CCCCC1

Procedure:
Piperidine-1-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate M and piperidine. MS calcd. for C22H23ClN3O2 [(M+H)+] 396.1, obsd. 395.9.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[C:8]([Cl:12])=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[CH3:13].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>CN1C(=O)CCC1.O>[C:14]([NH:18][C:2]1[N:7]=[C:6]2[C:8]([Cl:12])=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[CH3:13])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N
Reactant: Cc1nc2ccnc(Cl)c2nc1Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nc2ccnc(Cl)c2nc1NC(C)(C)C
Temperature: 60 °C
Yield: 11.8 %

Procedure:
A glass microwave reaction vessel was charged with 3,5-dichloro-2-methylpyrido[3,4-b]pyrazine (110 mg, 0.51 mmol) and tert-butylamine (0.16 mL, 1.54 mmol) (Sigma Aldich) in NMP (1.0 mL). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 60° C. for 2 h. The mixture was diluted with water and extracted with DCM (30 mL×3). The combined organic layers was washed with water (30 mL×3) and dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography (10-30% EtOAc in Hexanes) to give N-(tert-butyl)-5-chloro-2-methylpyrido[3,4-b]pyrazin-3-amine (15 mg, 0.060 mmol, 11% yield). MS (ESI, pos. ion) m/z: 251.1 (M+1).
Reaction SMILES: [BH4-].[Na+].[CH:3]([CH:6]1[CH2:14][C:13]2[C:8](=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[CH:10]=[CH:11][CH:12]=2)[C:7]1=O)([CH3:5])[CH3:4].C1(C)C=CC=CC=1.S(=O)(=O)(O)O>CO>[CH:3]([C:6]1[CH2:14][C:13]2[C:8]([CH:7]=1)=[C:9]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:17][CH:16]=1)[CH:10]=[CH:11][CH:12]=2)([CH3:5])[CH3:4]
Reactant: CC(C)C1Cc2cccc(-c3ccc(C(C)(C)C)cc3)c2C1=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)C1=Cc2c(cccc2-c2ccc(C(C)(C)C)cc2)C1
Temperature: 50 °C
Reaction time: 6 h
Yield: 96.3 %

Procedure:
4.83 g of sodium borohydride and 39.1 g of 2-isopropyl-7-(4′-tert-butylphenyl)-1-indanone together with 118 ml of toluene are placed in a reaction vessel. At 50° C., 22.5 ml of methanol are slowly added and the reaction mixture is stirred for 6 hours at 50° C. After cooling to room temperature, 50 ml of 2N sulfuric acid are added and the mixture is stirred vigorously for another 30 minutes. The mixture is subsequently transferred to a separating funnel, the phases are separated and the aqueous phase is shaken twice with a total of 60 ml of 2N sulfuric acid. The organic phases are combined and dried over magnesium sulfate. The solvent of the reaction mixture is removed virtually completely and 200 ml of toluene and 0.4 g of p-toluenesulfonic acid are subsequently added to the residue. Water is distilled from the reaction mixture by heating for 1.5 hours on a water separator until reaction is complete. The reaction mixture is subsequently washed once with 100 ml of saturated sodium hydrogen carbonate solution and dried over magnesium sulfate. After separating off the magnesium sulfate, the residue is dried in an oil pump vacuum. This gives 35.7 g of 2-isopropyl-4-(4′-tert-butylphenyl)indene (total yield: 96%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[N:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=1)[C:4]([O:7]C(=O)C)([CH3:6])[CH3:5].[OH-].[K+].Cl>C(O)C>[CH3:1][NH:2][C:3](=[N:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:13]=1)[C:4]([OH:7])([CH3:6])[CH3:5]
Reactant: CNC(=Nc1ccc(Br)c(C(F)(F)F)c1)C(C)(C)OC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CNC(=Nc1ccc(Br)c(C(F)(F)F)c1)C(C)(C)O
Temperature: 25 °C

Procedure:
To a solution of 38.1 g. (0.1 moles) of N1 -methyl-N2 -(4-bromo-3-trifluoromethylphenyl)-2-acetoxy isobutyramidine in 500 ml. of ethanol, add 5.6 g. (0.1 moles) of potassium hydroxide, maintaining the reaction at room temperature. Stir at room temperature for several hours (until there is no evidence of starting ester by tlc). Remove the solvent in vacuo, partition the residue between ether and water, dry the ether extract over sodium sulfate, filter, and precipitate the product of this reaction as its hydrochloride salt, by adding 25 ml. of 4.0N ethereal hydrogen chloride.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[C:10]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24]I)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[OH-].[Na+]>C(Cl)Cl>[C:10]([N:17]1[CH2:18][CH2:19][CH:20]([CH2:23][CH2:24][N:6]2[CH2:7][CH2:8][C:9]3[S:1][CH:2]=[CH:3][C:4]=3[CH2:5]2)[CH2:21][CH2:22]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Reactant: c1cc2c(s1)CCNC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCN2CCc3sccc3C2)CC1
Reaction time: 20 h

Procedure:
A suspension of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine.HCL (2-1) (1.76 g, 0.01 moles) in CH2Cl2 (15 ml) was treated with 2-(N-BOC-4-piperidinyl)ethyl iodide (2--2) (3.73 g, 0.011 moles) followed by 20% NaOH (10 ml) and Aliquot-336 (Aldrich). After stirring for 20 hours the reaction mixture was diluted with CH2Cl2 and the organic phase was separated, washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with CHCl3 (98)/MeOH(2) to give pure 2-3.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]([F:17])([F:16])[F:15])[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:38]=[CH:39][CH:40]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]([F:15])([F:16])[F:17])[C:3]=1[C:18]([N:44]1[CH2:43][CH2:42][N:41]([C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([O:34][CH3:33])[CH:36]=2)[CH2:46][CH2:45]1)=[O:20]
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: Nc1onc(-c2ccccc2OC(F)(F)F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(N2CCN(C(=O)c3c(-c4ccccc4OC(F)(F)F)noc3N)CC2)c1
Yield: 69.6 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (592 mg, 1.28 mmol, 70%) was obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=[O:13].C1C(=O)N([Br:23])C(=O)C1.CCCCCC>C1COCC1>[Br:23][C:10]1[CH:9]=[C:8]([CH:12]=[O:13])[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:15])([CH3:14])[CH3:1])[CH:11]=1
Reactant: C[Si](C)(C)CCOCn1cccc1C=O
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)CCOCn1cc(Br)cc1C=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 85.4 %

Procedure:
To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carbaldehyde (4.51 g) in THF (79 mL) was added NBS (4.27 g) at −20° C., and the mixture was stirred at 0° C. for 6 hr. To the reaction mixture was added hexane (240 mL), the precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.2 g).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:8])[CH3:7].N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:8])[CH3:7])(=[O:19])=[O:18]
Reactant: CC(O)CCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(O)CCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
(±)-Heptan-1,6-diol (1.06 g, 8 mmol) and pyridine (1.36 ml, 1.33 g, 16.8 mmol) were dissolved in dichloromethane (20 ml) and the mixture was cooled in ice. Methanesulfonyl chloride (0.65 ml, 0.96 g, 8.4 mmol) was added dropwise and the mixture was stirred at room temperature for 18 hours. Dichloromethane (50 ml) was added and the mixture was washed with aqueous HCl (1M, 50 ml) and brine (30 ml), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/20% hexane, to give the alcohol as an oil (1.01 g, 60%).