Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([CH3:18])([CH3:17])[O:15][C:14](=[C:19]([C:22]#[N:23])[C:20]#[N:21])[C:13]=2[C:24]#[N:25])=[CH:8][CH:7]=1.[N-:26]=[N+:27]=[N-].[Na+]>O.Cl>[N:5]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:16]([CH3:17])([CH3:18])[O:15][C:14](=[C:19]([C:22]#[N:23])[C:20]#[N:21])[C:13]=2[C:24]#[N:25])=[CH:10][CH:11]=1)=[N+:26]=[N-:27]
Reactant: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1c1ccc(N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1c1ccc(N=[N+]=[N-])cc1
Reaction time: 0.77 h

Procedure:
A solution of NaNO2 (0.69 g, 10.0 mmol) in 10 mL water was added dropwise to a solution of 2-[4-(4-aminophenyl)-3-cyano-5,5-dimethyl-5H-furan-2-ylidene] malononitrile (1.4 g, 5.0 mmol) in 30 mL 4M HCl at 0-5° C. After stirring the mixture at this temperature for 46 min, a solution of NaN3 (0.53 g, 8.0 mmol) in 10 mL water was added dropwise to the mixture at the same temperature. Stirring was continued for 1 h below 5° C. and then at room temperature overnight. The precipitate formed was filtered off, washed with water and air-dried. The yellow product was recrystallized from dichloromethane/1-propanol. Yield: 1.25 g (82%). Mp; 184° C. IR (neat) 3056, 2990, 2235, 2122, 2091, 1601, 1568 cm−1; 1H NMR (400 MHz, DMSO) δ 7.90 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 1.86 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 177.1, 176.6, 145.0, 130.61, 123.4, 120.30, 112.35, 111.4, 111.3, 101.60, 100.30, 55.20, 24.90; Anal, Calcd for C16H10N6O: C, 63.57; H, 3.33; N, 27.80. Found: C, 63.51H, 3.44; N, 27.20; UV-Vis (CH2Cl2): λmax=384 nm ε=2.9×104 L.mol−1cm−1.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[C:32]([NH:31][C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][CH:28]=1)[N:22]([C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[CH:4][CH:3]=1)[CH:23]=[CH:24]2)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)C(=O)Nc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(NC(=O)C(C)(C)C)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-27, using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate and N-(1H-indol-5-yl)pivalamide; MS: 437.6 (M−56).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([OH:36])[CH:33]=[CH:32][C:31]=4[F:37])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:45][CH3:46].O>CN(C=O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH2:45][CH3:46])[CH:33]=[CH:32][C:31]=4[F:37])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cccc(COc2cnc(-c3cc(O)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1cccc(COc2cnc(-c3cc(OCC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(3-(((6-(2-fluoro-5-hydroxyphenyl)-5-neopentylpyridin-3-yl)oxy)methyl)phenyl)propanoate (50 mg) in DMF (989 μL) were added cesium carbonate (97 mg) and iodoethane (12.0 μL) at 0° C., and the mixture was stirred at room temperature for 20 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (49.8 mg) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[Na+].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1>O.CC(C)=O>[Cl:13][C:14]1[N:15]=[CH:16][N:17]=[C:18]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH:19]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Clc1cc(Oc2ccc3[nH]ccc3c2)ncn1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
5-Hydroxyindole (91.8 g, 0.69 mol) is added in portions to a stirred solution of NaOH (27.9 g, 0.69 mol) in water (560 m L) at 10° C., to give a solution which is then cooled to −10° C. A solution of 4,6-dichloropyrimidine (95.3 g, 0.63 mol) in acetone (560 mL) is then added over a period of 65 min. The mixture is stirred at 0° C. for 30 min and then the acetone is evaporated off under reduced pressure, to give a mixture which is extracted with CH2Cl2. The combined extracts are washed with cold aqueous NaOH (0.5 M), dried (Na2SO4) and the solvent is evaporated off under reduced pressure to afford the product to afford the crude product which is purified by chromatography (silica gel; eluent 10% EtOAc in CH2Cl2) and recrystallised from CH2Cl2—hexane to give the title compound as a colourless crystalline solid, m.p. 149-150° C. Utilising a similar procedure, but employing 2,4-dichloropyrimidine in lieu of 4,6-dichloropyrimidine afforded 5-[(2-chloro-4-pyrimidinyl)oxy]-1H-indole, as cream crystalline solid, m.p. 169-176° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:25]([O:26][CH3:27])=[CH:24][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:11]=2[CH:10]=1)[NH:18][CH:17]=[C:16]([C:21]#[N:22])[C:15]3=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:30])=O>>[CH2:1]([O:8][C:9]1[C:25]([O:26][CH3:27])=[CH:24][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:11]=2[CH:10]=1)[N:18]=[CH:17][C:16]([C:21]#[N:22])=[C:15]3[Cl:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2cc3c(=O)c(C#N)c[nH]c3cc2cc1OCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1OCc1ccccc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A mixture of 8-benzyloxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile (11.4 g, 31.9 mmol) and phosphorus oxychloride (147 g, 959 mmol) is heated under reflux for one hour. After cooling to room temperature, the reaction mixture is evaporated under vacuum to remove the volatiles. The residue is carefully slurried in cold saturated aqueous sodium bicarbonate solution (500 mL). The solids are collected by filtration, washed thoroughly with saturated aqueous sodium bicarbonate solution and water and dried to give 11.7 grams of crude 8-(benzyloxy)-4-chloro-7-methoxybenzo[g]quinoline-3-carbonitrile as a light orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>CN(C=O)C>[N:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])=[CH:20][CH:21]=1
Reactant: ClCc1ccncc1
Reactant: N#Cc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(OCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 107 %

Procedure:
To a mixture of 3-hydroxybenzonitrile (4.76 g, 0.04 mol), K2CO3 (16.6 g, 0.12 mol) and DMF (100 ml) under argon was added 4-chloromethylpyridine hydrochloride (6.56 g, 0.04 mol). The reaction mixture was stirred at room temperature for about two days, the solvent was evaporated and the residue was partitioned between water and CH2Cl2. The organic layer was washed with 2N aqueous NaOH (1×100 ml), brine, then was dried over MgSO4. The solvent was removed in vacuo to afford, as an amber solid, 9.0 g of 3-(4-pyridinylmethoxy)benzonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[NH2:26][CH2:27][CH:28]([C:30]1[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=1)[OH:29]>>[CH2:1]([O:3][C:4](=[O:25])[C:5](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][CH:21]([NH:26][CH2:27][CH:28]([OH:29])[C:30]3[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=3)[CH2:22][CH2:23]2)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc(N2CCC(=O)CC2)cc1)C(=O)OCC
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: CCOC(=O)C(=Cc1ccc(N2CCC(NCC(O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1)C(=O)OCC

Procedure:
The title compound was prepared from 2-[4-(4-oxo-piperidin-1-yl)-benzylidene]-malonic acid diethyl ester (which was obtained in Example 153) and N-[5-(-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 180 as a yellowish solid; mp>80° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.21 (t, J=7.0 Hz, 3 H), 1.23 (t, J=7.0 Hz, 3 H), 1.75–1.95 (m, 2 H), 2.50–3.50 (m, 7 H), 2.92 (s, 3 H), 3.75–3.90 (m, 2 H), 4.21 (q, J=7.0 Hz, 2 H), 4.31 (q, J=7.0 Hz, 2 H), 4.47 (dd, J=8.0, 4.2 Hz, 1 H), 6.81 (d, J=8.2 Hz, 1 H), 6.94 (d, J=9.0 Hz, 2 H), 7.00 (dd, J=8.2, 2.0 Hz, 1 H), 7.17 (d, J=2.0 Hz, 1 H), 7.33 (d, J=9.0 Hz, 2 H), 7.52 (s, 1 H); MS (ES) m/z: 576.1 (MH+); HRMS Calcd. for C28H38N3O8S(MH+): 576.2374. Found: 576.2375.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH3:13]>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:19][C:18]2[CH:20]=[CH:21][C:15]([O:14][CH2:12][CH3:13])=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCOc1ccc(N)cc1
Product: CCOc1ccc(NCc2ccc(N(C)C)cc2)cc1
Yield: 44.1 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-dimethylaminobenzaldehyde (11 g) and 4-ethoxyaniline (10 g) as starting materials, [(4-dimethylaminophenyl)methyl](4-ethoxyphenyl)amine (8.7 g) was obtained. melting point: 98–99° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[F:18])=[O:22])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: Nc1ccc(-c2cc3c(cc2Cl)OCC3)cn1
Reactant: O=C(Cl)c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-c2cc3c(cc2Cl)OCC3)cn1)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a solution of 5-(6-chloro-2,3-dihydrobenzo[3,4-b]furan-5-yl)-2-pyridylamine (144) (19 mg, 0.045 mmol) in 1 ml DCM was added 2-fluorobenzoyl chloride (16 μl, 3 eq) followed by addition of DIEA (39 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (100 μl) at r.t. for 2 h and before worked up with EA/aq. NaHCO3. Prep HPLC purification furnished N-[5-(6-chloro(2,3-dihydrobenzo[3,4-b]furan-5-yl))(2-pyridyl)](2-fluorophenyl)carboxamide (146) (7.6 mg, yield: 45.8%, purity>95%) as white solid.
Reaction SMILES: [C:1]1([C:6]2[NH:7][C:8]3[C:13]([CH:14]=2)=[C:12]([O:15][Si](C(C)C)(C(C)C)C(C)C)[CH:11]=[CH:10][CH:9]=3)[CH2:5][CH2:4][CH2:3][CH:2]=1.[F-].[Cs+].[CH2:28]([O:30][C:31](=[O:34])[CH2:32]Br)[CH3:29]>C(C#N)(C)=O.C(Cl)Cl>[CH2:28]([O:30][C:31](=[O:34])[CH2:32][O:15][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH:14]=[C:6]([C:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1)[NH:7]2)[CH3:29]
Reactant: CC(C)[Si](Oc1cccc2[nH]c(C3=CCCC3)cc12)(C(C)C)C(C)C
Reactant: CCOC(=O)CBr
Agent: CC(=O)C#N
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Product: CCOC(=O)COc1cccc2[nH]c(C3=CCCC3)cc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To 300 mg (0.845 mmol) of 2-cyclopent-1-enyl-4-triisopropylsilyloxy-1H-indole (14d step 1) in 3 mL AcCN was added 154 mg (1.01 mmol, 1.2 eq) of CsF and 282 μL (2.54 mmol, 3 eq) ethylbromoacetate and the reaction was stirred at 50° C. overnight. The reaction was diluted with CH2Cl2 and filtered through celite. The CH2Cl2 layer was washed with 2N Na2CO3 solution, H2O, aqueous NaCl solution, dried (Na2SO4), and concentrated in vacuole to yield 239 mg (99%) of (2-cyclopent-1-enyl-1H-indol-4-yloxy)-acetic acid ethyl ester as a dark oil.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=3)[C:15]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)=CC=1)([O-])=O.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][CH2:42][CH2:43][CH2:44][NH2:45])[CH:36]=1>O1CCCC1>[CH3:25][O:24][C:18]1[CH:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14](/[CH:13]=[CH:12]/[C:11]([NH:45][CH2:44][CH2:43][CH2:42][CH2:41][C:37]3[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=3)=[O:10])=[C:15]2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)=[CH:20][CH:19]=1
Reactant: NCCCCc1cccnc1
Reactant: COc1cccc(-c2c(/C=C/C(=O)Oc3ccc([N+](=O)[O-])cc3)ccc3ccc(OC)cc23)c1
Solvent: C1CCOC1
Product: COc1cccc(-c2c(/C=C/C(=O)NCCCCc3cccnc3)ccc3ccc(OC)cc23)c1
Yield: 67.5 %

Procedure:
As in Example 114, (E)-3-[7-methoxy-1-(3-methoxyphenyl)-2-naphthalenyl]-2-propenoic acid 4-nitrophenyl ester (1.2 g) was reacted with 3-pyridinebutanamine (0.46 g) in tetrahydrofuran (12 mL) for 2 hours at room temperature. The crude product, isolated in the usual manner was purified by using HPLC (ethyl acetate) and then was crystallized from diethyl ether to yield 0.83 g of (E)-3-[7-methoxy-1-(3-methoxyphenyl)-2-naphthalenyl]-N-[4-(3-pyridinyl)butyl]-2-propenamide, mp 108.5°-110° C. Anal. Calcd for C30H30N2O3O.15 H2O: C, 76.78; H, 6.51; N, 5.97; H2O, 0.57 Found: C, 76.68; H, 6.51; N, 6.04; H2O, 0.57
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10]2[C:11](=[O:26])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:13]=[C:14]([Cl:16])[N:15]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(CC)CC)C.[CH3:34][Si:35]([C:38]#[CH:39])([CH3:37])[CH3:36]>C1COCC1.[Cu](I)I.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:16][C:14]1[N:15]=[C:10]([NH:9][C:3]2[C:2]([C:39]#[C:38][Si:35]([CH3:37])([CH3:36])[CH3:34])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[C:11](=[O:26])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:13]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(Cn2cc(Cl)nc(Nc3ncc(C)cc3Br)c2=O)cc1
Agent: I[Cu]I
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2cc(Cl)nc(Nc3ncc(C)cc3C#C[Si](C)(C)C)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
In a 1 L round bottom combined 3-(3-bromo-5-methylpyridin-2-ylamino)-5-chloro-1-(4-methoxybenzyl)pyrazin-2(1H)-one (51.90 g, 119.12 mmol), triphenylphosphine (1.56 g, 5.96 mmol), (Ph3P)PdCl2 (4.18 g, 5.96 mmol) and suspended in anhydrous THF (450 mL). Triethylamine (18.08 g, 178.68 mmol) and trimethylsilyl acetylene (35.10 g, 357.36 mmol) were added next and mixture was stirred at ambient temperature, under N2 for 10 minutes. Copper iodide (catalytic) was added last and reaction was stirred at ambient temperature. Reaction was monitored by analytical LCMS at one hour intervals and CuI was added until reaction is complete. The completed reaction was concentrated in vacuo, taken up with ethyl acetate (700 mL) and brine (300 mL) and filtered off undissolved solids before taking on to extraction. The organic layer was washed with additional brine (4×300 mL), dried with MgSO4, filtered and concentrated in vacuo. Chromatography on silica gel plug with ethyl acetate/hexanes (1/9), two attempts, afforded the desired product (43.36 g. 81% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.11 (s, 9 H) 2.26 (s, 3 H) 3.73 (s, 3 H) 5.00 (s, 2 H) 6.91 (d, J=8.59 Hz, 2 H) 7.38 (d, J=8.59 Hz, 2 H) 7.45 (s, 1 H) 7.74 (d, J=2.27 Hz, 1 H) 8.25 (d, J=2.27 Hz, 1 H) 9.51 (s, 1 H). ESI-MS: m/z 453.3 (M+H)+.
Reaction SMILES: C(OC1N=NC(C#CC2C=CC(C(F)(F)F)=CN=2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[CH:58])=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.I[C:60]1[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[C:62]([O:68][CH3:69])[CH:61]=1>>[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[C:58][C:60]2[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[C:62]([O:68][CH3:69])[CH:61]=2)=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COc1ccc(I)cc1OC
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Product: COc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1OC
Yield: 17 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 4-iodo-1,2-dimethoxybenzene in 17% yield.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22](C(F)(F)F)=[CH:21][CH:20]=3)=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].NC1C=CC(C)=C([C:38](C2C=CC(NC3C=CC=C(OC)C=3)=CC=2Cl)=[O:39])C=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:39][CH3:38])[CH:20]=3)=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3]
Reactant: COc1cccc(Nc2ccc(C(=O)c3cc(N)ccc3C)c(Cl)c2)c1
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Product: COc1cccc(Nc2ccc(C(=O)c3cc(N=[N+]=[N-])ccc3C)c(Cl)c2)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 416, using compound 467 (1.77 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:9 and 1:6 as the eluent to afford the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].[CH2:12]([N:14](CC)[CH2:15][CH3:16])[CH3:13].C(OC(Cl)=O)C(C)C.C(NCC)C>C1COCC1>[CH2:12]([N:14]([CH2:15][CH3:16])[C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=1)[CH3:13]
Reactant: CCN(CC)CC
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C=O)cc1
Yield: 48.3 %

Procedure:
4-Formylbenzoic acid (11.2 g, 74.6 mmol) and triethylamine (10.4 mL, 75 mmol) was dissolved in THF (100 mL) and cooled to −10° C. i-Butylchloroformate (10.3 mL, 78 mmol) was added and stirring was continued for 10 minutes at −10° C. before diethylamine (9.7 mL, 94 mmol) was added and solution was allowed to reach 25° C. After concentration, aqueous workup and chromatography on silica (0-100% EtOAc in heptane), a total of 7.4 g (50%) compound I was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH3:15][NH2:16]>CCO>[CH3:15][NH:16][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CN
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1NC
Reaction time: 3 h
Yield: 87.5 %

Procedure:
A solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (42 g, 181 mmol) in EtOH (400 mL) was treated with a solution of methylamine (12.3 g, 397 mmol) in EtOH (100 mL) at 0° C. and the mixture was stirred for 3 h. The mixture was concentrated and then partitioned between H2O (200 mL) and CH2Cl2 (500 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to give ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate as a white solid (36.0 g, 88% yield). 1H NMR (300 MHz, CDCl3): 8.59 (s, 1 H), 8.18 (br s, 1 H), 4.31 (q, J=7.2 Hz, 2 H), 3.05 (d, J=4.8 Hz, 3 H), 2.52 (s, 3 H), 1.34 (t, J=7.2 Hz, 3 H); MS (ESI) m/z: 228.1 (M+H+).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH:11]([CH3:13])[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15].Cl>ClC1C=CC=CC=1>[CH:11]([C:5]1[CH:10]=[CH:9][C:8]([C:21]([C:20]2[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:25][CH:24]=2)=[O:22])=[CH:7][CH:6]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CC(C)c1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
710 parts of chlorobenzene and 160 parts of AlCl3 are initially introduced. A mixture of 120 parts of cumene, 185.6 parts of p-nitrobenzoyl chloride and 410 parts of chlorobenzene is added dropwise in the course of 1 hour at 20° to 25° C., HCl gas being liberated. The mixture is then heated in the course of 1 hour to 60° C. and stirred for 1 hour at 60° C., 1,400 parts of ice are added, the aqueous phase is separated off in a separating funnel and the organic phase is concentrated in vacuo. 247.6 parts of 4-isopropyl-4'-nitrobenzophenone having a melting point of 95° C. are obtained. Yield: 92% of theory.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])[C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH3:26].N1CCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]2[C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=[CH:8][CH:7]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC=O
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2ccnc12
Solvent: C1CCNC1
Solvent: CCO
Product: CCCCC=C1SC(=O)N(CCCCOc2cccn3ccnc23)C1=O

Procedure:
To a solution of 1.45 g (5 mmol) of 3-[4-(imidazo[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 0.53 ml (5 mmol) of 1-pentanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of pyrrolidine was added at 60° C., followed by refluxing for 19 hours (2.5 hours later, 0.53 ml (5 mmol) of 1-pentanal and 0.05 ml (0.5 mmol) of pyrrolidine were further added). After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/1→1/4), after which the solvent was distilled off, to yield 0.29 g (16.3%, yellow oily substance) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]#[N:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:34][O:35][CH:36](OC)OC>>[C:20]([C:3]1[C:4]([CH3:19])=[N:5][N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:11][C:12]=2[Cl:13])[C:2]=1[N:1]=[CH:34][O:35][CH3:36])#[N:21]
Reactant: COC(OC)OC
Reactant: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC=Nc1c(C#N)c(C)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
A mixture of 5-amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylpyrazole (5 g) and p-toluenesulphonic acid hydrate (0.1 g) in trimethylorthoformate (20 ml) was heated at reflux for 4.5 hours. After cooling, the reaction mixture was evaporated to dryness in vacuo. The residue was dissolved in diethyl ether and left to crystallize at 0° C. The dark colored solid was recrystallized from a mixture of ethanol and water to give 4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methyl-5-methoxymethyleneaminopyrazole (4.67 g), m.p. 75°-78° C. in the form of buff crystals.