Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[CH2:17][C@@H:16]([O:18][CH3:19])[CH2:15][NH:14]2)=[O:12])=[CH:6][CH:5]=1.C(N(CC)C(C)C)(C)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C@H:13]2[CH2:17][C@@H:16]([O:18][CH3:19])[CH2:15][N:14]2[C:38](=[O:39])[NH:37][C:34]2[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=2)=[O:12])=[CH:8][CH:9]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(NC(=O)[C@H]2C[C@@H](OC)CN2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@H]2C[C@@H](OC)CN2C(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
Into a solution of 8 (9.19 g, 33.0 mmol) in anhydrous THF (200 mL) at 0° C. was added N,N-diisopropylethylamine (DIEA) (28.7 mL, 165 mmol) and 4-chlorophenyl isocyanate (5.07 g, 33.0 mmol). The solution was stirred at RT overnight before concentrating under reduced pressure. The crude material was purified on a silica gel column eluted with 10% moving to 50% EtOAc in hexanes. Combined and concentrated pure fractions. Remaining EtOAc was azeotroped off with acetonitrile and was lyophilized from acetonitrile/water to give 9 (13.37 g, 94%) as a solid. MS: APCI (AP+): 432.1 (M)+, (AP−): 430.1 (M)−.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26].CN(C)C(=O)C>O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:8]=1)[C:25]([C:21]1[O:20][CH:24]=[CH:23][CH:22]=1)=[O:26]
Reactant: CNc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(Cl)c1ccco1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C(=O)c1ccco1)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.20 g, 0.74 mmol), 2-furoyl chloride (0.26 g, 2.0 mmol) and N,N-dimethylacetamide (10 ml) was stirred at 80° C. for 2 hrs. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine and dried. The solvent was evaporated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (1:1, v/v). The obtained crystals were recrystallized from ethyl acetate-hexane to give the titled compound (0.21 g, 63%).
Reaction SMILES: N[C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[H+].[B-](F)(F)(F)[F:16].N([O-])=O.[Na+]>O>[CH3:13][O:12][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:10][CH3:11])[C:2]=1[F:16])[CH:6]=[O:7]
Reactant: COc1cc(C=O)cc(OC)c1N
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: COc1cc(C=O)cc(OC)c1F

Procedure:
A solution of 1.4 g. of 4-amino-3,5-dimethoxybenzaldehyde in 20 ml. of 50% hydrogen tetrafluoroborate was diazotized at 0° C. with a solution of 0.59 g. of sodium nitrite in about 2 ml. of water. After irradiation with a low pressure mercury lamp (Hanau NK 6620) for 6 hours at room temperature, the solution was extracted with ether, the ether extracts dried over magnesium sulfate and concentrated. After recrystallization from heptane, the residue produced 3,5-dimethoxy-4-fluoro-benzaldehyde of melting point 97°-98° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:44])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([NH:39][CH2:40][CH2:41][O:42][CH3:43])[N:36]=[CH:35][N:34]=2)[CH:28]=1)=O)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[C:37]([NH:39][CH2:40][CH2:41][O:42][CH3:43])[N:36]=[CH:35][N:34]=4)[CH:28]=3)[CH2:24][C:23](=[O:44])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: COCCNc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Product: COCCNc1cc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)ncn1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (128 mg, 0.5 mmol) and 3-{3-[6-(2-methoxy-ethylamino)-pyrimidin-4-yl]-phenyl}-3-oxo-propionic acid tert-butyl ester (Example K56) (204 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (118 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=[O:2]>C(O)C.CCN(C(C)C)C(C)C.[Pd]>[OH:2][CH2:1][C:3]1[CH:13]=[CH:12][C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(O)CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
A mixture of 4-formyl cinnamic acid (2.82 g, 16.0 mmol) and Pd/C (350 mg, 10% Pd) in ethanol (120 mL) and DIPEA (3 mL) is stirred at rt for 2 h under 1.0 bar H2. The reaction mixture is filtered and the filtrate is evaporated to give 3-(4-hydroxymethyl-phenyl)-propionic acid (2.18 g) as a colourless oil; LC-MS: tR=0.62 min.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[C:6]2[C:12](=[CH:13][CH:14]=1)[C:10](=[O:11])[CH:9]=[C:8]([OH:15])[C:7]2=[O:16]>C(Cl)(Cl)Cl>[Br:1][C:9]1[C:10]([C:12]2[C:6]([C:7](=[O:16])[C:8]=1[OH:15])=[CH:5][C:4]([F:3])=[CH:14][CH:13]=2)=[O:11]
Reactant: BrBr
Reactant: O=C1C=C(O)C(=O)c2cc(F)ccc21
Solvent: ClC(Cl)Cl
Product: O=C1C(O)=C(Br)C(=O)c2ccc(F)cc21
Reaction time: 4 h

Procedure:
A solution of bromine (12.5 g), in chloroform (50 ml) was added to a stirred suspension of 6-fluoro-3-hydroxynaphtho-1,4-quinone (12.5 g; 0.065 mole) in chloroform (50 ml) over 15 mins. During the addition the mixture became a clear dark red solution. Stirring was continued for a further 4 hours and a yellow solid which had been deposited as crystals was filtered off, washed with ice-cold chloroform and dried. Yield 13.95 g (80%), mp 183° C. (CHCl3).
Reaction SMILES: [C:1](=[O:16])([S:3][CH2:4][CH2:5][CH2:6][N:7](C(OC(C)(C)C)=O)[CH3:8])[CH3:2].[ClH:17]>C(O)C.C1(C)C=CC=CC=1>[ClH:17].[C:1](=[O:16])([S:3][CH2:4][CH2:5][CH2:6][NH:7][CH3:8])[CH3:2]
Reactant: CC(=O)SCCCN(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: CNCCCSC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
S-3-(tert-Butoxycarbonyl(methyl)amino)propyl ethanethioate (206 mg, 0.834 mmol) in 4 ml of EtAc was added 1.0 ml of HCl (conc.) at RT. The mixture was stirred at RT for 1 h, diluted with ethanol/toluene (6 ml, 1:1), evaporated and co-evaporated with ethanol/toluene (3×10 ml), crystallized with ethanol/EtAc/Hexane, filtered, and dried over a vacuum to afford 135 mg (88%) of the title compound. 1H NMR (CDCl3) 9.70 (br, 1H), 8.56 (br, 1H), 3.42 (m, 2H), 2.52 (m, 2H), 2.35 (s, 3H), 2.05 (s, 3H), 1.88 (m, 2H); 13C NMR 174.64, 40.57, 31.57, 27.69, 20.94, 15.62; MS m/z+ 170.0 (M+Na), 148.10 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5]C(C)(C)C)=[O:4].N1C=CC=CC=1.[Br:16][CH2:17][C:18](Br)=[O:19].Cl>C(Cl)Cl>[Br:16][CH2:17][C:18]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:19]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(O)CNC(=O)CBr
Reaction time: 3 h
Yield: 153.1 %

Procedure:
To a solution of 4 g (0.02 mol) of t-butyl glycinate and 4 ml of pyridine in 100 ml of methylene dichloride at 0° under nitrogen was added a solution of 2.01 ml (0.024 mol) of bromoacetyl bromide in 10 ml of methylene dichloride. After the addition, the mixture was stirred for 3 hrs and poured into 1 N aqueous hydrochloride. The organic layer was separated and then washed successively with 1 N HCl, water and brine. After drying over anhydrous sodium sulfate, the mixture was evaporated to dryness in vacuo to yield 6 g of a light brown product, which upon recrystallization from hexane-ethyl acetate, yielded a product with mp 90°-91°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:28]2[C:32]([OH:33])=[C:31](C(OCC)=O)[CH:30]=[N:29]2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)=[N:9]1.[OH-].[Na+].CCO.Cl>O>[F:1][C:2]1[CH:3]=[C:4]([N:28]2[C:32]([OH:33])=[CH:31][CH:30]=[N:29]2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]2[N:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:20]=[CH:19][CH:18]=2)=[N:9]1
Reactant: CCOC(=O)c1cnn(-c2ccc(-n3cc(OC)c(=O)c(-c4ccnn4-c4ccccc4)n3)c(F)c2)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cn(-c2ccc(-n3nccc3O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
A mixture of ethyl 1-{3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl}-5-hydroxy-1H-pyrazole-4-carboxylate (1.41 g, 2.73 mmol), 4 M NaOH (40 mL), and EtOH (40 mL) was refluxed for 4 h. After cooling to room temperature, conc. HCl (20 mL) was added slowly. The mixture was stirred for 30 min at room temperature and then refluxed for 1 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt/THF (2/1) and recrystallized from THF/MeOH to give the title compound (387 mg, 32% yield) as a pale yellow solid: mp 221-229° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 3.78 (3H, s), 5.57 (1H, d, J=1.5 Hz), 6.99 (1H, d, J=1.9 Hz), 7.14 (1H, t, J=9.0 Hz), 7.31-7.51 (6H, m), 7.64-7.68 (1H, m), 7.79-7.84 (2H, m), 8.52 (1H, d, J=1.9 Hz), 12.17 (1H, brs). LC-MS (ESI) m/z 445 [M+H]+.
Reaction SMILES: CON(C)[C:4](=[O:15])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([NH2:12])=[CH:7][C:6]=1[O:13][CH3:14].C[Li].[CH3:19]COCC.Cl>C1COCC1>[NH2:12][C:8]1[C:9]([Cl:11])=[CH:10][C:5]([C:4](=[O:15])[CH3:19])=[C:6]([O:13][CH3:14])[CH:7]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N(C)OC
Reactant: CCOCC
Agent: Cl
Agent: [Li]C
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1C(C)=O
Temperature: 0 °C
Yield: 75 %

Procedure:
N-Methoxy-N-methyl-4-amino-5-chloro-2-methoxybenzamide (24.4 g, 100 mmol) was dissolved in THF (400 mL) and the solution was cooled to -400° C. Methyl-lithium in ether (143 mL, 4.4 g, 200 mmol) ) was added and the mixture was allowed to warm to 0° C. Aqueous hydrochloric acid was added and the mixture was extracted into ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and evaporated to leave a solid. Crystallization from ethyl acetate-hexane gave 4'-amino-5'-chloro-2'-methoxyacetophenone (15.0 g, 75 mmol), m.p. 114°-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4](=O)[C:5](=O)[NH:6]2.[F:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][C:20]2[N:21]([NH2:26])[C:22]([NH2:25])=[N:23][N:24]=2)=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]1[C:5]([NH:6]2)=[N:25][C:22]2=[N:23][N:24]=[C:20]([CH2:19][C:18]3[CH:27]=[CH:28][C:15]([F:14])=[CH:16][CH:17]=3)[N:21]2[N:26]=1
Reactant: Cc1ccc(Cl)c2c1NC(=O)C2=O
Reactant: Nc1nnc(Cc2ccc(F)cc2)n1N
Product: Cc1ccc(Cl)c2c1[nH]c1nc3nnc(Cc4ccc(F)cc4)n3nc12

Procedure:
According to the general cyclization procedure (for Example 27), 0.60 mmol of 4-chloro-7-methyl-1H-indole-2,3-dione (117.5 mg) and 0.70 mmol of 5-(4-fluoro-benzyl)-[1,2,4]triazole-3,4-diamine (145 mg) was used for the preparation.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C:10](=[CH:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[Br:28]N1C(=O)CCC1=O>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([Br:28])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc2cc3n(c2n1)[C@H](C)CN(C(=O)OC(C)(C)C)C3
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Cc1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reaction time: 1.5 h

Procedure:
To a stirred solution of 0.20 g (0.66 mmol) (R)-4,6-dimethyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 5, intermediate b)) in 2 mL tetrahydrofuran 0.12 g (0.69 mmol) was added N-bromosuccinimide; the reaction was stirred for 1.5 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:dichloromethane (1:19) as eluant.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1ccc(OCc2ccccc2)cc1
Yield: 64.6 %

Procedure:
4-Bromophenol (17.3 g, 0.1 mol), 19.03 g (0.15 mol) benzyl chloride, and 27.64 g (0.2 mol) pulverized K2CO3 were suspended in 150 mL Me2CO and heated to reflux 2 h. The resulting suspension was concentrated on a rotary evaporator. The mixture was then diluted with 200 mL 5% NaOH and extracted with 100 mL Et2O. The organic layer was washed with an additional 100 mL 5% NaOH, dried (MgSO4), filtered, and concentrated to give a yellow oil, which was crystallized and recrystallized from boiling EtOH to yield 17 g (65%) of Benzyl 4-bromo phenyl ether as white needles, mp: 60°-61° C. NMR δ 7.35 and 6.82 (AA'BB', c, 4H, C6H4), 7.36 (s, 5H, C6H5), 5.0 (s, 2H, OCH2).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:2]2[CH2:7][CH2:6][O:5][C:3]2=[O:4])=[CH:11][CH:10]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=C1OCCC1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: O=C1OCCC1Oc1ccc(F)cc1
Temperature: 25 °C

Procedure:
α-Bromobutyrolactone (12.4 g, 0.075 mol) is added to a mixture of 4-fluorophenol (5.6 g, 0.05 mol) and caesium carbonate (17.9 g, 0.055 mol) in acetone (100 ml). The reaction medium is refluxed for two hours. After cooling to room temperature, the reaction is filtered through a bed of Celite and the filtrate is evaporated. The oily residue is purified by flash chromatography (1/2 EtOAc/heptane) to give the expected product in the form of an oil (9.8 g, 87%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[N:6]=1)=[O:4].[OH-].[Na+]>C1COCC1.O>[Cl:25][C:23]1[CH:24]=[C:19]([C:13]2([C:15]([F:17])([F:16])[F:18])[O:12][N:11]=[C:10]([N:7]3[CH:8]=[CH:9][C:5]([C:3]([OH:4])=[O:2])=[N:6]3)[CH2:14]2)[CH:20]=[C:21]([Cl:26])[CH:22]=1
Reactant: COC(=O)c1ccn(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccn(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of methyl ester of example 18.1 (408 mg) in 5 ml THF:water (4:1) was added sodium hydroxide (60 mg). The reaction was stirred 2 hours at room temperature before evaporation of the solvent in vacuo. The aqueous layer was extracted with ethyl acetate before being acidified. It was then extracted several times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford the title acid (369 mg) as a yellowish solid. 1H-NMR (CDCl3, 400 MHz): 8.20 (s, 1H), 7.50 (m, 2H), 7.45 (m, 1H), 7.05 (s, 1H), 4.45 (d, 1H), 4.10 (d, 1H).
Reaction SMILES: [CH2:1]([NH2:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:24](OCC)(=[O:28])[CH:25]([CH3:27])[OH:26]>>[CH2:1]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[OH:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)C(C)O
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCCN
Product: CCCCCCCC/C=C\CCCCCCCCCCCCNC(=O)C(C)O
Temperature: 130 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A one-liter, 3-neck flask equipped with a stirrer, thermometer, Dean-Stark receiver and condenser was charged with erucyl amine (320 grams; 1.0 mol), and ethyl lactate (130 grams; 1.1 mol) and stirred at 130° C. for 8 hours under a nitrogen atmosphere. The reaction was followed by total amine value and infrared spectrum analyses. The reaction mixture was then stripped at 35° C., 30mmHg vacuum for 30 minutes to afford 368 g (94% yield) of N-erucyl lactamide. This product had a total amine value of 1.6; a hydroxy value of 139.8 and a melting point of 50° C. The structure of this product was confirmed by infrared analysis showing disappearance of the absorption band at about 5.7 microns for ethyl lactate and the presence of a strong amide absorption band at about 6.15 microns, along with hydroxy absorption band at about 2.0 to 3.1 microns.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:5]=[C:4]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[N:3]=1.[C:31]([SiH2:35][O:36][C:37]([CH3:48])([CH3:47])[C:38]1[CH:39]=[C:40]([CH2:44][C:45]#[N:46])[CH:41]=[CH:42][CH:43]=1)([CH3:34])([CH3:33])[CH3:32].[H-].[Na+]>CN(C=O)C>[C:31]([SiH2:35][O:36][C:37]([CH3:48])([CH3:47])[C:38]1[CH:39]=[C:40]([CH:44]([C:2]2[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:5]=[C:4]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[N:3]=2)[C:45]#[N:46])[CH:41]=[CH:42][CH:43]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: COc1ccc(COc2nc(Cl)c(C(C)C)c(OCc3ccc(OC)cc3)n2)cc1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2nc(OCc3ccc(OC)cc3)c(C(C)C)c(C(C#N)c3cccc(C(C)(C)O[SiH2]C(C)(C)C)c3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
To a stirred mixture of 4-chloro-5-isopropyl-2,6-bis-(4-methoxy-benzyloxy)-pyrimidine (5.65 g, 13.17 mmol) and [3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-acetonitrile (3.27 g, 12.54 mmol) in anhydrous DMF (25 ml) in a water bath under a nitrogen atmosphere, was added 60% sodium hydride (1.0 g, 25.09 mmol). After 30 min., water bath was removed and the mixture was stirred for overnight at room temperature. The reaction mixture was neutralized with aqueous saturated ammonium chloride solution. The mixture was then partitioned between ether and water. The ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product as a yellow oil. The crude product was purified by silica gel column chromatography (eluent, EA:hexanes (1:15)) to afford 5.34 g (65%) of a pale yellow syrup. 1H NMR (200 MHz, CDCl3) δ 0.06 (6H, s), 0.90 (9H, s), 1.06 (6H, d, J=7.0 Hz), 3.01 (1H, m), 3.81 (6H, s), 4.71 (2H, s), 5.32 (2H, s), 5.35 (2H, s), 5.41 (3H, s), 6.86-6.91 (4H, m), 7.20-7.35 (6H, m), 7.41-7.49 (2H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:12]([C:5]1([CH2:16][CH2:17][CH2:18][CH3:19])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[CH:3]=2)[S:8][CH2:7][CH2:6]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCC1(CCCC)CCSc2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCC1(CCCC)CCSc2ccc(C#C[Si](C)(C)C)cc21
Temperature: 0 °C

Procedure:
A mixture of 1.68 g (5.38 mmol) of 6-bromo-4,4-dibutylthiochroman (Compound 33), 0.28 g (1.5 mmol) of copper (I) iodide and 2.5 g (25 mmol) of triethylamine was degassed with argon for 15 minutes at -780° C. To the suspension was added 1.18 g (71 mmol) of (trimethylsilyl)acetylene and 0.24 g (0.35 mmol) of bis(triphenylphosphine)palladium (II) chloride. The solution was degassed with argon for an additional 5 minutes and the resulting mixture was allowed to warm to 0° C. The tube was sealed and the mixture was heated to 55° C. for 22 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[NH:4][N:3]=1.[C:14]1([CH2:20][C:21](O)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[NH:4][N:3]=[C:2]([NH:1][C:21](=[O:22])[CH2:20][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Nc1cc(-c2ccc(Cl)cc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)Nc1cc(-c2ccc(Cl)cc2)[nH]n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
3-Amino-5-(4-chlorophenyl)pyrazole (96.8 mg) and phenylacetic acid (74.9 mg) were dissolved in pyridine (2.5 ml) to which was subsequently added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (143.8 mg), and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate (30 ml), washed with 1 N aqueous potassium hydrogensulfate solution (15 ml×2) and saturated brine (15 ml) and then dried over anhydrous magnesium sulfate. The solvent was distilled away under a reduced pressure, and the resulting residue was crystallized from ethyl acetate and hexane to obtain the title compound (107.8 mg) as white crystals (melting point: 222-224° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:25][CH2:24][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.[CH3:26][N:27]1[CH:31]=[C:30]([NH2:32])[CH:29]=[N:28]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:26][N:27]1[CH:31]=[C:30]([NH:32][C:2]2[N:7]=[C:6]([NH:8][CH:9]3[CH2:10][CH2:11][C:12]4([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:14][CH2:13]4)[CH2:24][CH2:25]3)[CH:5]=[CH:4][N:3]=2)[CH:29]=[N:28]1
Reactant: Cn1cc(N)cn1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3ccnc(Cl)n3)CC2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cn1cc(Nc2nccc(NC3CCC4(CC3)CCN(C(=O)OC(C)(C)C)C4)n2)cn1
Temperature: 150 °C
Reaction time: 16 h
Yield: 109.4 %

Procedure:
To a solution of tert-butyl 8-((2-chloropyrimidin-4-yl)amino)-2-azaspiro[4.5]decane-2-carboxylate (0.4 g, 1.09 mmol) and 1-methyl-1H-pyrazol-4-amine (0.16 g, 1.64 mmol) in n-BuOH (5 mL) was added DIPEA (0.28 g, 2.18 mmol). The mixture was stirred at 150° C. for 16 h then concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the product as a red solid (0.51 g, 98%).