Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([NH:33]C(=O)OC(C)(C)C)[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]([NH:31][OH:32])=[O:30])=[CH:22][CH:21]=2)=[O:18])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:33][CH:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][N:13]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]([NH:31][OH:32])=[O:30])=[CH:22][CH:21]=1)=[O:18]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(OCc2ccccc2)cn1)C(=O)Nc1ccc(CCCC(=O)NO)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1ccc(OCc2ccccc2)cn1)C(=O)Nc1ccc(CCCC(=O)NO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.8 %

Procedure:
t-Butyl 3-(5-(benzyloxy)pyridin-2-yl)-1-(4-(4-(hydroxyamino)-4-oxobutyl)-phenylamino)-1-oxopropan-2-ylcarbamate (0.1 g, 0.19 mmol) was dissolved in DCM/TFA (v/v=1:1) (30 mL), and stirred at room temperature for 4 h (monitored by TLC). The solution was evaporated in vacuo to give Compound 5 (0.062 g, 61%). mp>300° C.; NMR (400 MHz in CDCl3, Bruker AVANCE-400): δ 1.75 (m, 2H, CH2), 1.95 (t, 2H, CH2, J=7.37 Hz), 2.52 (t, 2H, CH2, J=7.55 Hz), 3.16 (m, 2H, CH2), 4.30 (m, 1H, CH), 5.16 (s, 2H, OBn), 7.13 (d, 2H, Ar—H, J=8.06 Hz), 7.24 (d, 1H, Ar—H, J=8.47 Hz), 7.33-8.46 (m, 9H, Ar—H), 8.22 (br, 2H, NH2), 8.30 (m, 1H, NH), 8.64 (br, 1H, NH), 10.33 (br, 1H, OH), 10.36 (br, 1H, TFA).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[C:12]1(C)C=CC(S(O)(=O)=O)=CC=1>>[N+:8]([C:7]1[C:2]2[N:1]=[CH:12][O:11][C:3]=2[CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: O=[N+]([O-])c1cccc2ocnc12

Procedure:
Compounds of Formula I also can be prepared as illustrated by exemplary reaction in Scheme 3. Reaction of 2-amino-3-nitro-phenol and triethyl orthformate in the presence of a acid such as p-toluenesulfonic acid produced 4-nitrobenzooxazole. The nitro group was reduced to give the 4-amino-benzooxazole, which was converted to the methylamino-benzooxazole in two steps. Treatment of the compound with base, such as sodium ethoxide converted the 4-methylamino-benzooxazole into a 4-hydroxy-1-methylbenzimidazole. Reaction of 4-hydroxy-1-methylbenzimidazole with an aryl-aldehyde such as 5-bromoveratraldehyde and malononitrile in the presence of a base, such as piperidine produced the substituted 7-methyl-imidazo[4,5-h]chromene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:19][N:18]=[N:17][N:16]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:47]=[CH:46][C:40]([O:41][CH2:42][C:43](O)=[O:44])=[CH:39][CH:38]=2)[S:31]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:41][CH2:42][C:43]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[NH:16][N:17]=[N:18][N:19]=5)=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:44])=[CH:46][CH:47]=2)[S:31]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3nnn[nH]3)cc2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3nnn[nH]3)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 89.5 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-{2-amino-5-[4-(tetrazol-5-yl)phenoxy]phenyl}-N-methylcarbamate (0.69 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.37 g), diethyl cyanophosphonate (0.21 g), triethylamine (0.13 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified to give the desired product (0.76 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:38]1([CH:44]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:45](Cl)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CO>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][C:45](=[O:46])[CH:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 73 %

Procedure:
By the procedure of Example 13, Step C, 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step C) was reacted with diphenylacetyl chloride. The crude product was evaporated twice from toluene and flash chromatographed twice on silica gel (gradient elution with 0.1-1% MeOH in CH2Cl2 and then approx. 0.01-1% MeOH in CH2Cl2) to give a 73% yield of the title compound as off-white crystals, mp 144°-146° C.; homogeneous by TLC in 19:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 725 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:7]2[CH2:8][CH:3]1[CH:4]=[CH:5][C:6]2(OC(=O)C)[O:9]C(=O)C.[CH3:18][C:19]([C:27]1[CH:28]=[C:29]([OH:34])[CH:30]=[C:31]([CH:33]=1)[OH:32])([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].B(F)(F)F.CCOCC>>[OH:34][C:29]1[C:30]2[C@@H:4]3[CH2:5][C:6](=[O:9])[CH2:7][CH2:8][C@H:3]3[C:2]([CH3:17])([CH3:1])[O:32][C:31]=2[CH:33]=[C:27]([C:19]([CH3:18])([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:28]=1
Reactant: CC(=O)OC1(OC(C)=O)C=CC2CC1C2(C)C
Reactant: CCCCCCC(C)(C)c1cc(O)cc(O)c1
Agent: FB(F)F
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(=O)C[C@@H]21

Procedure:
Following the same procedure as set forth above, (+)-6,6-dimethyl-2,2-diacetoxy-3-norpinene was reacted with 5-(1,1-dimethylheptyl)resorcinol in the presence of boron trifluoride diethyl etherate to afford (-)-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9].C(N(CC)CC)C>O1CCCC1>[CH3:2][C:1]([NH:9][C:8]1[CH:10]=[CH:11][CH:12]=[C:6]([Br:5])[CH:7]=1)=[O:3]
Reactant: Nc1cccc(Br)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
A solution of acetyl chloride (44.0 ml, 0.619 mol) in tetrahydrofuran (20 ml) was added dropwise to a 0° C. solution of 3-bromoaniline (101.5 g, 0.590 mol) and triethylamine (87.4 ml, 0.625 mol) in tetrahydrofuran (550 ml). The resulting mixture was stirred 16 h at room temperature. The reaction mixture was quenched with ice/water (500 ml), acidified to pH 1 with 5N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate extracts were washed with 1N hydrochloric acid, water, brine, then dried over sodium sulfate. The solvent was removed under reduced pressure to give 125.5 g of a red solid. Recrystallization from ethyl acetate/hexanes gave 69.2 g of an off white powder. Filtered a second crop of product to give 26 g of a tan powder. Total yield=75%.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][C:7]([CH3:19])([C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)[OH:8].C(N(CC)CC)C.O1CCCC1>O>[C:1]([O:8][C:7]([C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)([CH3:19])[CH3:6])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(O)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC(C)(C)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A total of 15 mmole of acrylic chloride was added dropwise to a mixture containing 10 mmole of the above-prepared α,α-dimethyl-1-adamantanemethanol, 20 mmole of triethylamine, and 40 ml of tetrahydrofuran, over about 30 minutes. After the completion of addition, the resulting mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the resulting mixture was concentrated, and the concentrate was subjected to column chromatography on a silica gel to yield the title compound in a yield of 76%.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[C:10](=[O:11])[C:9]([C:12]2[N:16]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[N:15]=[CH:14][CH:13]=2)=[CH:8][N:7]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[C:6]1=[O:35])[CH3:4].F[C:37](F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(N(CC)C(C)C)(C)C.CO>ClCCl>[CH3:37][O:1][CH2:2][C@H:3]([N:5]1[C:10](=[O:11])[C:9]([C:12]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=3)[N:15]=[CH:14][CH:13]=2)=[CH:8][N:7]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=2)[C:6]1=[O:35])[CH3:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C[C@H](CO)n1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)cn(-c2cccc(C(F)(F)F)c2)c1=O
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H](C)n1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)cn(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
To a solution of (R)-4-(5-(3-(1-hydroxypropan-2-yl)-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 111) (95.1 mg) in dichloromethane (1.0 ml) were added under ice-cooling trifluoromethanesulfonic anhydride (50.2 μl) and N,N-diisopropylethylamine (70.2 μl) and the resulting mixture was stirred under ice-cooling for one hour. To the reaction mixture was added methanol (5 ml) and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-4-(5-(3-(1-methoxypropan-2-yl)-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (51.0 mg) as pale yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:21])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20].[CH2:22](Br)[C:23]#[CH:24].C1(C)C=CC=CC=1>C1COCC1>[CH2:19]([OH:20])[CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:21][CH2:24][C:23]#[CH:22]
Reactant: C#CCBr
Reactant: OCCOCCOCCOCCOCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#CCOCCOCCOCCOCCOCCOCCO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
Sodium hydride, 60% dispersion in mineral oil, (0.86 g, 21.4 mmol) was added in portions to the solution of hexaethylene glycol (5.5 g, 19.4 mmol) in anhydrous THF (40 mL) at 0° C. (FIG. 3). The reaction mixture was stirred at 0° C. for 15 minutes then propargyl bromide, 80% in toluene, (2.4 mL, 21.4 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 3 hours. The formed sodium bromide was removed by filtration and the solvent was evaporated. The crude product was purified on SiO2 column using methanol/dichloromethane gradient 0-100% to yield 3.4 g (54%) of 1 as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 2.45 (t, J=2.4 Hz, 1H), 2.74 (bs, 1H), 3.61-3.71 (m, 24H), 4.21 (d, J=2.4 Hz, 2H); 13C NMR (100.6 MHz, CDCl3): δ 58.4, 61.7, 69.1, 70.3-70.6, 72.5, 74.5, 79.7; MS ESI (m/z): [M+H]+ calcd. for C15H29O7, 321.38; found 321.4.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Cc1c2n(c3c(-c4ccc(C(F)(F)F)cc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (78 mg, 85%), MS (ISP) m/z=370.5 [(M+H)+], mp 282° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5](Br)=[CH:4][C:3]=1[F:12].[Mg].C[O:15][B:16](OC)[O:17]C>O1CCCC1>[F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([B:16]([OH:17])[OH:15])=[CH:4][C:3]=1[F:12]
Reactant: Fc1cc(Br)c2occc2c1F
Reactant: COB(OC)OC
Agent: [Mg]
Solvent: C1CCOC1
Product: OB(O)c1cc(F)c(F)c2ccoc12
Temperature: -5 °C
Reaction time: 1.5 h
Yield: 123.7 %

Procedure:
A mixture of 2.0 gm (8.58mMol) 4,5-difluoro-7-bromobenzofuran and 0.202 gm (8.58 mMol) magnesium in 10 mL tetrahydrofuran was heated at reflux for 50 minutes. The resulting mixture was then cooled to −5° C. and treated dropwise with 1.01 mL (8.93 mMol) trimethylborate over 20 minutes. The reaction mixture was stirred at room temperature for 1.5 hours and was then concentrated under reduced pressure. The residue was partitioned between 50 mL deionized water and 50 mL ethyl acetate. The mixture was treated with 0.3 mL acetic acid to adjust to a neutral pH. The phases were separated and the aqueous phase was extracted well with ethyl acetate. The organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure to provide 2.1 gm of the title compound.
Reaction SMILES: COC(=O)C=CC1C2N(C3C=CC=CC=3)C=NC=2C=C(C(F)(F)F)C=1.[CH3:26][N:27]1[CH2:32]C[N:30]([C:33](=[O:55])[CH:34]=[CH:35][C:36]2[C:44]3[N:43]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH:42]=[N:41][C:40]=3[CH:39]=[C:38]([C:51]([F:54])([F:53])[F:52])[CH:37]=2)[CH2:29][CH2:28]1>>[CH3:32][N:27]([CH3:26])[CH2:28][CH2:29][NH:30][C:33](=[O:55])[CH:34]=[CH:35][C:36]1[C:44]2[N:43]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:42]=[N:41][C:40]=2[CH:39]=[C:38]([C:51]([F:52])([F:54])[F:53])[CH:37]=1
Reactant: CN1CCN(C(=O)C=Cc2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)CC1
Agent: COC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Product: CN(C)CCNC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Yield: 5 %

Procedure:
This was prepared from 3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methyl ester in a similar manner to 1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one. The oily residue was purified by flash chromatography over silica gel (eluted with dichloromethane/methanol 2-5% gradient) to afford the title compound as a white solid (29 mg, 5%), m/z 403.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.N1(C(N2C=CN=C2)=O)C=CN=C1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH2:34]>C1COCC1>[OH:1][C:2]1[C:3]([C:12]([NH:34][CH2:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: NCc1ccccn1
Reactant: O=C(O)c1ccc2cccnc2c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NCc1ccccn1)c1ccc2cccnc2c1O
Temperature: 60 °C
Yield: 61.3 %

Procedure:
A mixture of 8-hydroxyquinoline-7-carboxylic acid (100 mg, 0.53 mmol) and di(1H-imidazol-1-yl)methanone (86 mg, 0.53 mmol) in THF (5 mL) was heated to 60° C. for 3 h, under nitrogen. The reaction mixture was allowed to cool to RT and pyridin-2-ylmethanamine (46 mg, 0.424 mmol) was added. The resulting mixture was heated to 40° C. for 2 h and then stirred at RT. The reaction mixture was quenched with H2O and an aqueous saturated solution of sodium hydrogen carbonate, and twice extracted with DCM. The separated organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by SPE-SI cartridge (2 g, DCM to DCM:MeOH 99:1) affording the title compound (73 mg, 0.26 mmol) as a off-white solid.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)[S:4][N:3]=1.[CH2:18]([C:20]1[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])=[CH:24][CH:23]=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1)[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:9]1[CH:8]=[C:7]([C:5]2[S:4][N:3]=[C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])[C:20]=3[CH2:18][CH3:19])[N:6]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1Cl
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(/C=C/OC)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Temperature: 120 °C
Yield: 64.9 %

Procedure:
To a solution of 3-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazole (D43) (388 mg), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (335 mg) and tripotassium phosphate (741 mg) in N,N-dimethylformamide (DMF) (10 mL) and water (1.000 mL) stirred under nitrogen was added Pd(Ph3P)4 (134 mg). The mixture was sealed and heated under microwave at 120° C. for 10 min. After cooling the reaction, the mixture was concentrated and purified by column chromatography to give 5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-3-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,2,4-thiadiazole (D51) (313 mg) as a colorless oil. MS (ES): C22H23ClN2O2S requires 414. found 415.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=1)([CH3:5])[C:3]#[N:4].O.O.Cl[Sn]Cl.[OH-].[Na+]>CCOC(C)=O>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]([CH3:5])([CH3:1])[C:3]#[N:4])=[N:7][CH:8]=1
Reactant: CC(C)(C#N)c1ccc([N+](=O)[O-])cn1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1ccc(N)cn1
Temperature: 25 °C
Yield: 101.4 %

Procedure:
The mixture of 2-methyl-2-(5-nitropyridin-2-yl)propanenitrile (I-1d, 2 g, 10.4 mmol) and SnCl2.2H2O (9.3 g, 41.6 mmol) in EtOAc (10 mL) was stirred at reflux for 4 h. After cooling to room temperature, aqueous 2 M NaOH (80 mL) was added to adjust the pH to 8˜9, the solid was filtered off, and the filtrate was extracted with ethyl acetate (3×40 mL). The combined organic layers were dried over anhydrous Na2SO4, and concentrated to afford 2-(5-aminopyridin-2-yl)-2-methylpropanenitrile (I-1) (1.7 g, 65.3% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH2:7]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O>N1C=CC=CC=1>[CH2:7]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:1][C:2]2[S:3][CH:4]=[N:5][N:6]=2)(=[O:21])=[O:20])=[CH:17][CH:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nncs1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
To a stirred solution of 2-amino-1,3,4-thiadiazole (2.0 g, 19.7 mmol) in pyridine (30 mL) under argon at −20° C. was added p-hexylbenzenesulfonyl chloride (5.48 g, 21 mmol) over 10 min. The reaction mixture was stirred at room temperature for 16 hours. Water (300 mL) was added to quench the reaction. The mixture was extracted with CH2Cl2 and the organic extracts washed with 2N HCl (2×150 mL), brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluted with methanol:DCM 1:33 to give the product (3.72 g, 11.4 mmol, 58% yield) as a solid, mp 125-126° C.; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, 3H, J=7 Hz), 1.28 (m, 6H), 1.58 (m, 2H), 2.63 (t, 2H, J=7 Hz), 7.27 (d, 2H, J=8 Hz), 7.83 (d, 2H, J=8 Hz), 8.24 (s, 1H); 13C NMR (75 MHz, CDCl3) 14.1, 22.6, 28.9, 31.1, 31.6, 35.9, 126.5, 129.0, 138.1, 142.6, 148.6, 167.4; MS (Q-TOF) Calcd for C14H20N3O2S2 326.0997, found 326.0931 (M+H)+; Calcd for C14H19N3NaO2S2 348.0816, found 348.0816 (M+Na)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:16]([C:26]#[CH:27])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[N:3]=1.[OH:32][CH:33]1[CH2:37][CH2:36][O:35][CH2:34]1>>[O:35]1[CH2:36][CH2:37][CH:33]([O:32][C:2]2[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]3[CH:19]=[C:18]([F:20])[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:16]([C:26]#[CH:27])[CH:15]=3)=[O:11])=[CH:6][CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[N:3]=2)[CH2:34]1
Reactant: OC1CCOC1
Reactant: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc(F)c1NS(C)(=O)=O
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2OC2CCOC2)cc(F)c1NS(C)(=O)=O
Yield: 39.6 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (50 mg, 0.11 mmol) and 3-hydroxytetrahydrofuran (18 μl, 0.22 mmol) was reacted as in example 72 to give the title compound (23 mg, 21%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:9]\[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.O1CCCC1.[CH2:40]([N:43]1[CH:47]=[CH:46][CH:45]=[N:44]1)[C:41]#[CH:42]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.C(N(CC)CC)C>[CH3:24][C:14]1[CH:13]=[C:12]([O:11][CH2:10]/[CH:9]=[C:8](\[C:5]2[CH:4]=[CH:3][C:2]([C:42]#[C:41][CH2:40][N:43]3[CH:47]=[CH:46][CH:45]=[N:44]3)=[CH:7][CH:6]=2)/[C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:30]=2)[CH:23]=[CH:22][C:15]=1[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: C#CCn1cccn1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCn3cccn3)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of the above ester (375 mg, 0.644 mmol) in the mixture of tetrahydrofuran (5 mL) and triethylamine (5 mL) was degassed and 1-propargylpyrazole (123 mg, 1.16 mmol) was added in argon atmosphere. The solution was cooled down; tetrakis(triphenylphosphine)palladium (59.5 mg, 0.052 mmol) and copper(I) iodide (19.6 mg, 0.103 mmol) were added. The reaction mixture was stirred at ambient temperature for 48 h. The mixture was evaporated in vacuo and the residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yielding methyl (E)-[2-methyl-4-[3-[4-[3-(pyrazol-1-yl)prop-1-ynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]-phenoxy]acetate.