Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]([C:12]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:14])[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(O)c1cc(Br)c2cccnc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cc(Br)c2cccnc2c1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
To a solution of 5-bromo-8-hydroxyquinoline-7-carboxylic acid (0.402 g) of Preparation 2 and 4-chlorobenzylamine (0.219 g) in 20 mL DMF is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g) and 1-hydroxybenzotriazole monohydrate (0.217 g). The mixture is stirred overnight. The solution is then poured into 30 mL ice-water. The resulting solid is collected and dried to yield 0.157 g of the title product as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:22]([F:40])([F:39])[C:23]([F:38])([F:37])[C:24]([F:36])([F:35])[C:25]([F:34])([F:33])[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([N:15]([CH3:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=O)=[CH:8][CH:7]=[CH:6]2.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:42].N1C=CC=CC=1>O>[CH3:1][O:2][C:3]1[C:4]([C:22]([F:40])([F:39])[C:23]([F:38])([F:37])[C:24]([F:36])([F:35])[C:25]([F:34])([F:33])[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[S:42])[N:15]([CH3:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:8][CH:7]=[CH:6]2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)CN(C)C(=O)c1cccc2c(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(OC)ccc12
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)CN(C)C(=S)c1cccc2c(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
N-[[6-methoxy-5-(tridecafluorohexyl)-1-naphthalenyl]carbonyl-N-methylglycine, methyl ester (100 mg, 0.165 mmol), prepared as in Example 5, phosphorus pentasulfide (67 mg) and dry pyridine (2 ml) were refluxed for 2 hours. After stirring overnight at room temperature, the mixture was refluxed for 2 additional hours, poured into water and extracted with ether. The ether extract was washed with 1N aqueous hydrochloric acid, water, saturated sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated giving 92.8 mg of the crude N-[[6-methoxy-5-(tridecafluorohexyl)-1-naphthalenyl]thioxomethyl]-N-methylglycine, methyl ester, which was used in the next preparation without further purification. ms: m/e 622 (M+H)+, 562, 519, 503, 352. nmr (CDCl3): δ2.84 & 3.04 (2s, 3H, N--CH3, rotamers); δ3.82 & 3.95 (2s, 3H, O--CH3, rotamers) δ3.4 & 5.5 (2d, 2 H, CH2, J=17); δ7.3 (m, 3H, Har); δ8.2 (m, 2H, Har).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:34]([F:37])([F:36])[F:35])[CH:23]=[C:24]([C:25]3[CH:30]=[C:29]([F:31])[C:28]([F:32])=[C:27]([F:33])[CH:26]=3)[C:18]=2[N:17]=1>>[Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([C:16]3[NH:17][C:18]4[C:24]([C:25]5[CH:26]=[C:27]([F:33])[C:28]([F:32])=[C:29]([F:31])[CH:30]=5)=[CH:23][C:22]([C:34]([F:37])([F:35])[F:36])=[CH:21][C:19]=4[N:20]=3)[C@H:10]([CH3:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Reactant: C[C@@H]1CN(c2ncccc2Cl)CCN1
Product: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1

Procedure:
The piperazine from step (a) above (84 mg. 0.4 mmol) reacted with 2-chloro-6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzoimidazole (105 mg, 0.3 mmol, Example 51b) under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 526 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH:4]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:3]1=[O:19].[H][H]>CO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH:4]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:3]1=[O:19]
Reactant: CC(C)CC1C(=O)N(C)CCN1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)CC1NCCN(C)C1=O

Procedure:
1-Methyl-3-(2-methylpropyl-4-(phenylmethyl)piperazinone (Example 47, 2.1 g.) is dissolved in methanol (200 ml.), 10% palladium charcoal (1.0 g.) is added and the product is hydrogenated (50 lb. initial hydrogen pressure until the uptake of hydrogen ceased. The solution is filtered and the methanol is removed under reduced pressure to give the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10]([OH:14])[CH2:11][C:12]#[CH:13].BrC1C=C(C=CC=1)C=O.C(N(CC)CC)C>C1COCC1>[OH:14][CH2:10][CH2:11][C:12]#[C:13][C:9]1[CH:2]=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: C#CCCO
Reactant: O=Cc1ccccc1Br
Agent: O=Cc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1cccc(C#CCCO)c1

Procedure:
This is an example of a coupling reaction to form compounds such as the title compound by coupling compounds such as bromo benzaldehyde and 3-butyn-1-ol. A 1-L, 3-necked round-bottom flask was equipped with a magnetic stirring bar, a condenser with a nitrogen inlet, and two stoppers. The vessel was charged with 3-bromobenzaldehyde (18.5 g, 0.1 mol), 3-butyn-1-ol (10.5 g, 0.15 mol), triethylamine (100 mL), and THF (100 mL). To this mixture was then added PdCl2 (PPh3)2 (1.4 g, 2 mmol) and CuBrMe2S (0.405 g, 4 mmol). In other examples, the title compound was also obtained by using CuI together with a palladium-containing entity. The reaction mixture was heated to reflux using a heating mantle. After 4 h when TLC (thin layer chromatography) showed complete consumption of the bromide, the mixture was allowed to cool to room temperature, transferred to a 1-L round-bottom flask and concentrated under reduced pressure. The residue was dissolved in 250 mL of ethyl acetate. The solution was washed with water and brine, dried over MgSO4, and filtered. After filtration, the solvents were removed from the filtrate by evaporation under reduced pressure to obtain the title compound as pale yellow oil (16.8 g, yield 97%). Purity of the compound so obtained was determined by HPLC to be greater than 95%. TLC (Rf=0.32, SiO2, ethyl acetate/hexanes, 1:1). MS (electro spray, positive mode), M+ 174. 1H NMR (400 MHz, CDCl3)δ: 2.72 (t, 2H, J=6.3), 3.84 (t, 2H, J=6.2), 7.47 (t, 1H, J=7.7), 7.66 (dt, 1H, J=7.7, 1.4), 7.81 (dt, 1H, J=7.7, 1.4), 7.91 (t, 1H, J=1.4), 9.98 (s, 1H). It was found in the context of this invention, as illustrated by the embodiment given in this example, that the amount of palladium catalyst can be reduced down to catalyst amounts in the order of 0.1% (mol/mol). In contrast, conventional methodologies rely on Pd catalyst amounts in the range 1%-5%, with the percentages referred to the same units. This reduction in the amount of palladium catalyst leads to a significant cost reduction. Furthermore, this reduction in the amount of palladium catalyst leads to a reduction in the palladium contamination of the final product.
Reaction SMILES: C[N:2]1[C:8](=O)[O:7][C:5](=O)[C:4]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:3]12.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[NH:15][NH2:16].C(O)C>C(OCC)(=O)C>[CH3:8][NH:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([NH:16][NH:15][C:14]([O:18][CH2:19][CH3:20])=[O:17])=[O:7]
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Reactant: CCOC(=O)NN
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)NNC(=O)c1ccccc1NC
Yield: 50.5 %

Procedure:
A mixture of 8.86 g of N-methylisatoic anhydride, 5.73 g of ethyl carbazate and 25 ml of ethanol was heated to reflux for 2 hours. After the reaction mixture was allowed to around room temperature, ethyl acetate was added thereto and the mixture was washed with water two times. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was washed with methyl tert-butyl ether to obtain 5.99 g of N-(2-methylaminobenzoyl)-N′-ethoxycarbonylhydrazine of the formula:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[O:19])=[CH:13][CH:12]=1.C([N-]C(C)C)(C)C.[Li+].[I:40]I.C(O)(=O)C>O1CCCC1>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([I:40])[N:6]2[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:30])([F:31])[F:29])[CH:22]=2)=[O:19])=[CH:15][CH:16]=1
Reactant: II
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1ncnc2c1nc(I)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: -70 °C
Yield: 63.2 %

Procedure:
In 18 mL of tetrahydrofuran, 300 mg (0.67 mmol) of 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea was suspended, and the suspension was cooled to −70° C. To the suspension, 3 mL of a tetrahydrofuran solution of lithium diisopropylamide (1.8 M) was added dropwise, and with stirring the temperature of the suspension was raised to 0° C. over two hours. Again, the suspension was cooled to −70° C., and 350 mg (1.38 mmol) of iodine was added thereto, and the suspension was stirred one hour. To the reaction solution, 100 μL of acetic acid was added, and the reaction solution was concentrated, and purified by a silica gel column (dichloromethane:methanol=9:1) to obtain 243 mg (63%) of a target product as a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C:5]2([CH2:11][CH2:10][N:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=4)[N:15]=[CH:14][C:13]=3[F:24])[CH2:8][CH2:7]2)[CH2:4][C@H:3]1[OH:25].[O-]S([O-])(=O)=O.[Na+].[Na+].[O:33]=[C:34]1[CH2:39][S:38][C:37]2[CH:40]=[CH:41][C:42]([CH:44]=O)=[N:43][C:36]=2[NH:35]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[F:24][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:12]=1[N:9]1[CH2:10][CH2:11][C:5]3([CH2:6][C@H:2]([NH:1][CH2:44][C:42]4[CH:41]=[CH:40][C:37]5[S:38][CH2:39][C:34](=[O:33])[NH:35][C:36]=5[N:43]=4)[C@H:3]([OH:25])[CH2:4]3)[CH2:7][CH2:8]1)=[N:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2ncc(F)c(N3CCC4(CC3)C[C@@H](O)[C@@H](N)C4)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2ncc(F)c(N3CCC4(CC3)C[C@@H](O)[C@@H](NCc3ccc5c(n3)NC(=O)CS5)C4)c2n1
Reaction time: 12 h
Yield: 83.8 %

Procedure:
To a solution of (2R,3S)-3-amino-8-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-8-azaspiro[4.5]decan-2-ol (0.26 mg, 75.1 μmol) in DCM-EtOH (1 mL, 1:1) were added Na2SO4 (16 mg, 0.112 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (15 mg, 75.1 μmol). After 12 h at 25° C., the imine was quenched by addition of NaBH(OAc)3 (32 mg, 0.150 mmol) in one portion. After an additional 1 h, the solution was partitioned between NaHCO3-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried (Na2SO4), concentrated and purified by column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) affording the title compound (33 mg, 84%) as a light yellow oil: LCMS (ES) m/e 525 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=5.5 Hz, 1H), 8.11 (d, J=9.0 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.01 (d, J=9.0 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.12-4.19 (m, 1H), 4.03 (s, 3H), 3.92 (AB quart., 2H), 3.52-3.67 (m, 4H), 3.46 (s, 2H), 3.00-3.21 (m, 1H), 1.94-1.96 (m, 1H), 1.79-1.91 (m, 1H), 1.65-1.71 (m, 4H).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C>[CH3:35][C:29]([O:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][CH:9]=2)=[CH:20][CH:19]=1)([CH3:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: Oc1ccc(OCCc2coc(-c3ccccc3)n2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2coc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-[2-(2-Phenyloxazol-4-yl)ethoxy]phenol (3.7 g, 13.0 mmol) and cesium carbonate (4.71 g, 14.5 mmol) were suspended in anhydrous DMF (100 mL) and treated with dropwise addition of ethyl 2-bromoisobutyrate (2.54 g, 13.0 mmol, 1.93 mL). The reaction mixture was stirred at ambient temperature for 24 h and then partitioned between ether (200 mL) and 1.0 N HCl (200 mL). The organic layer was washed with water (100 mL), dried over MgSO4 and concentrated to a brown oil, which was purified by gradient column chromatography (200 mL SiO2, 100% hexanes to 20% EtOAc/hexanes) to provide 2-methyl-2-{4-[2-(2-phenyloxazol-4-yl)ethoxy]phenoxy}propionic acid, ethyl ester (2.54 g,
Reaction SMILES: [OH-].[K+].O.C([O:6][C:7](=[O:19])[C:8]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([CH3:10])[CH3:9])C.Cl>C(O)C>[F:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][C:8]([CH3:10])([CH3:9])[C:7]([OH:19])=[O:6]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(Oc1cccc(F)c1)C(=O)O
Temperature: 40 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a solution of KOH (2.38 g, 42.4 mmol) in mixed solvents of water (50 mL) and ethanol (70 mL) was added ethyl-2-(3-fluorophenoxy)-2-methylpropanoate (3.20 g, 14.1 mmol) in one portion and the mixture was stirred at 40° C. for 2 h. The mixture was cooled to 0° C., acidified to pH 3 with concentrated hydrochloric acid and extracted with DCM (20 mL×2). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a white solid (1.70 g, 61%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.[C:10]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=[CH:14][C:13]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)O)=[CH:12][CH:11]=1.S(C1NC=CN=1)(C1NC=CN=1)=O>C(#N)C>[C:10]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:11]=[CH:12][C:13]([CH:16]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:15]=1
Reactant: OC(c1ccccc1)c1ccc(-c2ccccc2)cc1
Reactant: c1c[nH]cn1
Agent: O=S(c1ncc[nH]1)c1ncc[nH]1
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: c1ccc(-c2ccc(C(c3ccccc3)n3ccnc3)cc2)cc1
Reaction time: 15 h

Procedure:
13.6 g (0.2 mol) of imidazole are dissolved in 150 ml of acetonitrile and 3.5 ml of thionyl chloride are added at 10° C. 13 g (0.05 mol) of (biphenyl-4-yl)-phenyl-carbinol are added to the solution of thionyl-bis-imidazole thus obtained. After standing for 15 hours at room temperature, the solvent is removed by distillation in vacuo. The residue is taken up in chloroform and the solution is washed with water. The organic phase is collected, dried over sodium sulfate and filtered and the solvent is distiller off in vacuo. The oily residue is dissolved in ethyl acetate and freed from insoluble, resinous constituents by filtration. The solvent is again distilled off in vacuo and the residue is purified by recrystallization from acetonitrile. 8.7 g (56% of theory) of (biphenyl-4-yl)-imidazol-1-yl-phenylmethane [alternatively named as diphenyl-imidazolyl-(1)-phenyl-methane or as 1-(α-biphenyl-4-ylbenzyl)imidazole] of melting point 142° C. are obtained.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38]>CC#N>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH2:5][CH2:4][C@@H:3]4[NH:2][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[N:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CN[C@H]1CCc2c(-c3nnc(-c4ccc(OC(C)C)c(C#N)c4)s3)cccc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 90.4 %

Procedure:
Prepared using General Procedure 9. To a suspension of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 (150 mg, 0.36 mmol) in CH3CN (5 mL) was added K2CO3 (150.9 mg, 1.09 mmol) and methyl 2-bromoacetate (67 mg, 0.43 mmol). The suspension was stirred at 80° C. After 6 h more methyl 2-bromoacetate (6.7 mg, 0.043 mmol) was added and heating continued for 12 h. The reaction mixture was filtered and concentrated. The residue was re-suspended in EA (15 mL), washed with water and brine, dried and concentrated. The product was purified by a silica gel column chromatography (MeOH/DCM) to afford 146 mg (90%) of (S)-methyl 2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate as white solid. LCMS-ESI (m/z) calculated for C24H24N4O3S: 448.2; found 449.1 [M+H]+, tR=2.48 min.
Reaction SMILES: [C:1]([C:3](=[C:6](O)[C:7]([CH3:10])([CH3:9])[CH3:8])[C:4]#[N:5])#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:13].S(=O)=O>C(Cl)Cl>[Cl:13][C:6]([C:7]([CH3:10])([CH3:9])[CH3:8])=[C:3]([C:4]#[N:5])[C:1]#[N:2]
Reactant: CC(C)(C)C(O)=C(C#N)C#N
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=S=O
Solvent: ClCCl
Product: CC(C)(C)C(Cl)=C(C#N)C#N
Temperature: 25 °C
Reaction time: 22 h
Yield: 88 %

Procedure:
To a solution of 69.6 g of 2-cyano-3-hydroxy-4,4-dimethyl- 2-pentenenitrile in 600 ml of methylene chloride was added in small portions 104.1 g of phosphorus pentachloride. The mixture was stirred for 22 hours at room temperature. Sulfur dioxide was passed through the mixture for 20 minutes and the mixture stirred for an additional hour. The mixture was concentrated and poured into 500 ml of ice. After stirring for 1 hour, the cold mixture was filtered, the solid was washed with cold water and dried in a vacuum oven at room temperature for 60 hours to give 68.8 g of 3-chloro-2-cyano-4,4-dimethyl- 2-pentenenitrile, mp 52°-53°.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([N:17]2[CH:21]=[N:20][N:19]=[CH:18]2)[C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H][H]>[Ni].C(O)C>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([N:7]([N:17]2[CH:18]=[N:19][N:20]=[CH:21]2)[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:23][CH:22]=2)=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(N(Cc2ccc(Br)cc2)n2cnnc2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(N(Cc2ccc(Br)cc2)n2cnnc2)cc1
Yield: 32 %

Procedure:
A catalytic amount of Raney nickel was added to 50 ml of an ethanol solution containing 3.74 g of 4-[N-(4-bromobenzyl)-N-(4-nitrophenyl) amino]-4H-1,2,4-triazole, and the mixture was stirred for about 2 hours in the presence of hydrogen gas at room temperature. After the catalyst was removed by filtration, the resulting filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 1.1 g of 4-[N-(4-aminophenyl)-N-(4-bromobenzyl)amino]-4H-1,2,4-triazole from the chloroform/methanol (50:1) eluate.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13]>C1(C)C=CC=CC=1>[CH3:10][O:11][C:12](=[O:13])/[CH:14]=[CH:8]/[C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C=O)cn1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(C)nc1
Yield: 84.5 %

Procedure:
A mixture of 6-methylpyridine-3-carboxaldehyde (2 g, 16.5 mmol) and methyl (triphenylphosphoranylidene) acetate (6.1 g, 1.1 eq.) in toluene (100 mL) was stirred at reflux for 18 hours. The solvent was removed in vacuo, the residue washed with diethyl ether (100 mL) and filtered. The crude product was purified by chromatography eluting with CH2Cl2/MeOH (99/1) to give the title compound as a white solid (2.47 g, 85%). 1H NMR (CDCl3, 250 MHZ) δ(ppm); 8.60 (d, 1H); 7.70 (dd, 1H); 7.65 (d, J=15 Hz, 1H); 7.20 (d, 1H); 6.50 (d, J=15 Hz, 1H); 3.85 (s, 3H); 2.60 (s, 3H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[C:16]([CH2:18][C:19]([OH:21])=[O:20])#[N:17].N1C=CC=CC1=O>C1(C)C=CC=CC=1.O>[C:16]([C:18](=[CH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[C:19]([OH:21])=[O:20])#[N:17]
Reactant: COc1ccc(C=O)cc1
Reactant: N#CCC(=O)O
Agent: CC(=O)[O-]
Agent: O=c1cccc[nH]1
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C=C(C#N)C(=O)O)cc1

Procedure:
A stirred mixture of p-anisaldehyde (60.7 ml), ammonium acetate (7.5 g), cyanoacetic acid (42.5 g), pyridone (70 ml) in toluene (390 ml) is refluxed using a Dean Stark trap until about 9 ml of water is collected. The reaction mixture is cooled and the solid precipitate filtered and stirred with 10% aqueous HCL. The solid is filtered and recrystallized from methanol yielding the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13]([O:15]C(C)(C)C)=O)[C:6]1=[O:20])=[O:4].C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:45][C:46]1[CH:55]=[C:54]2[C:49]([C:50]([N:57]3[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]3)=[CH:51][C:52]([NH2:56])=[N:53]2)=[CH:48][CH:47]=1>>[NH2:56][C:52]1[CH:51]=[C:50]([N:57]2[CH2:58][CH2:59][N:60]([C:13]([NH:12][C@H:7]3[CH2:8][CH2:9][CH2:10][CH2:11][N:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]3=[O:20])=[O:15])[CH2:61][CH2:62]2)[C:49]2[C:54](=[CH:55][C:46]([Cl:45])=[CH:47][CH:48]=2)[N:53]=1
Reactant: COC(=O)N1CCCC[C@@H](NC(=O)OC(C)(C)C)C1=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CCCC[C@H](NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1=O

Procedure:
As described for example 213, (3R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]hexahydro-2-oxo-1H-azepine-1-carboxylic acid-methyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the title product as a light yellow solid. LC-MS: 475 (M++1). 1H NMR (CDCl3): δ 1.45–2.05 (m, 5H), 2.15 (m, 1H), 3.12 (m, 4H), 3.42 (dd, 1H), 3.66 (m, 4H), 3.90 (s, 3H), 4.45 (m, 1H), 4.75˜4.85 (m, 3H), 5.95 (d, 1H), 6.15 (s, 1H), 7.19 (dd, 1H), 7.62 (d, 1H), 7.74 (d, 1H).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl[C:13]1[C:14]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][C:15]=2[S:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([SH:37])[CH:34]=[CH:35][CH:36]=1>CN(C)C=O>[OH:28][CH2:27][C:24]1[CH:25]=[CH:26][C:14]2[C:13]([S:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=3)=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:16][C:15]=2[CH:23]=1
Reactant: COc1cccc(S)c1
Reactant: CCOC(=O)c1sc2cc(CO)ccc2c1Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1sc2cc(CO)ccc2c1Sc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.5 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU--1.1 ml, 7.23 mmol) was added to a mixture of ethyl 3-(chloro)-6-(hydroxymethyl)benzo[b]thiophene-2-carboxylate (Preparation 15--1.63 g, 6.02 mmol) and 3-methoxybenzenethiol (1.1 ml, 9.03 mmol) in anhydrous dimethylformamide (8 ml) under a nitrogen atmosphere. The solution was stirred at ambient temperature for 18 hours, and then heated to 60° C. for 3 hours. The solution was partitioned between diethyl ether and water. The organics were separated and washed with water, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was crystallised from diethyl ether and hexane to give the title compound as a colourless solid (1.77 g).