Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:15]1[C:19]2[CH:20]=[C:21]([CH2:24][NH2:25])[CH:22]=[CH:23][C:18]=2[CH:17]=[CH:16]1>>[O:15]1[C:19]2[CH:20]=[C:21]([CH2:24][NH:25][S:2]([C:5]3[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])[CH:22]=[CH:23][C:18]=2[CH:17]=[CH:16]1
Reactant: NCc1ccc2ccoc2c1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3ccoc3c2)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from methyl 4-(chlorosulfonyl)benzoate and benzofuran-6-ylmethanamine.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][OH:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.O1CCOC[CH2:18]1.Cl>C(OCC)(=O)C>[NH:10]1[CH2:9][CH2:8][C:7]2([C:1]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:18][O:14][CH2:13]2)[CH2:12][CH2:11]1
Reactant: C1COCCO1
Reactant: OCC1(c2ccccc2)CCNCC1
Agent: C=O
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)COCC21CCNCC1
Yield: 50 %

Procedure:
A mixture of (4-phenyl-piperidin-4-yl)-methanol (0.1 g, 0.5 mmol), paraformaldehyde (0.11 g, 3.7 mmol), 1,4-dioxane (5 ml) and concentrated hydrochloric acid solution (1.3 ml) was heated at reflux for 80 h. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with 0.5 M aqueous sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography of the crude product with dichloromethane/methanol as eluent gave the title compound (0.053 g, 50%) as yellow solid. MS m/e: 204 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]([CH3:14])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.O1CCOCC1>C1(C)C=CC=CC=1.O>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]([CH3:14])=[CH:4][CH:3]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)Cc1nc(Cl)ccc1C
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1nc(-c2ccc(OC)cc2)ccc1C

Procedure:
Following the same procedure described for Example 472 (Step 1) and starting from ethyl (6-chloro-3-methyl-2-pyridinyl)acetate (Example 478, 0.20 g, 0.94 mmol), Na2CO3 (0.24 g, 2.24 mmol), 4-methoxyphenyl boronic acid (0.57 g, 3.74 mmol), and PdCl2(dppf)CH2Cl2 (0.15 g, 0.19 mmol) in a mixture of toluene (1.50 mL), 1,4-dioxane (0.50 mL) and water (0.60 mL), the title compound was obtained (0.25 g, 94%). 1H NMR (400 MHz, CD2Cl2) δ 7.95 (d, 2H), 7.53 (s, 2H), 6.98 (d, 2H), 4.20 (q, 2H), 3.92 (s, 2H), 3.86 (s, 3H), 2.33 (s, 3H), 1.29 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[CH3:9][C:10](C)=[O:11].C(=O)=O.C1OC1>CO>[CH3:1][C:2]1([CH3:8])[CH2:7][O:6][CH2:5][CH2:4][N:3]1[CH2:9][CH2:10][OH:11]
Reactant: CC(C)=O
Reactant: CC1(C)COCCN1
Agent: O=C=O
Solvent: CO
Solvent: C1CO1
Product: CC1(C)COCCN1CCO
Temperature: 25 °C
Reaction time: 20 h
Yield: 82 %

Procedure:
In a pressure vessel containing 3,3-dimethylmorpholine (12.15 g, 106 mmol) in MeOH (17 mL) at −78° C. (external temperature, acetone/CO2(s)) was added ethylene oxide (6.2 mL, 125 mmol, 1.2 equiv., condensed at −78° C.). The solution was sealed and stirred over 20 hours, during which time the temperature warmed to room temperature. The reaction mixture was concentrated in vacuo and the crude product was distilled (75° C., 0.5 torr) to provide 2-(3,3-dimethyl-morpholin-4-yl)-ethanol (14 g, 82%) as a colorless oil contaminated with ˜15% of 3,3-dimethyl-morpholine. LC/MS found 160.10 (M++H, C8H18NO2 requires 160.13).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])/[C:7]/2=[CH:14]\[C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([OH:23])=O)[C:16]=1[CH3:24])([O-:3])=[O:2].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[NH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[NH:61][C:62](=[O:73])[C:63]1[CH:68]=[CH:67][C:66]([NH:69][CH2:70][CH2:71][NH2:72])=[N:65][CH:64]=1>[Cl-].[Na+].O.CN(C=O)C>[NH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[NH:61][C:62](=[O:73])[C:63]1[CH:68]=[CH:67][C:66]([NH:69][CH2:70][CH2:71][NH:72][C:21]([C:17]2[C:16]([CH3:24])=[C:15](/[CH:14]=[C:7]3\[C:8](=[O:13])[NH:9][C:10]4[C:6]\3=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=4)[NH:19][C:18]=2[CH3:20])=[O:23])=[N:65][CH:64]=1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c(C)c1C(=O)O
Reactant: NCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c(C)c1C(=O)NCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66 %

Procedure:
5-(5-Nitro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (327 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-aminophenyl)-6-(2-aminoethylamino)nicotinamide (284 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (383 mg, 66%) as a yellow solid. LC-MS (m/z) 581 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([CH:19]=[CH:20][C:21]([O:23]C(C)(C)C)=[O:22])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:30])[CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:21]([CH:20]=[CH:19][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:6][C:5]3[CH:28]=[CH:29][C:2]([Cl:1])=[CH:3][C:4]=3[F:30])=[N:8][CH:9]=[N:10]2)=[CH:15][C:14]=1[O:17][CH3:18])([OH:23])=[O:22]
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1C=CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.6 %

Procedure:
A solution of 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(2-(tert-butoxycarbonyl)vinyl)quinazoline (581 mg, 1.31 mmol) in a mixture of methylene chloride/TFA (2.5 ml/2.5 ml) was stirred at ambient temperature for 1.5 hours. After removal of the volatiles under vacuum, the residue was partitioned between ethyl acetate and water. The aqueous layer was adjusted to pH3 with 0.5M sodium hydroxide. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and evaporated to give 7-(2-carboxyvinyl)-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (430 mg, 85%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].F[C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:17]([O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5])[C:16]1[CH:19]=[CH:20][CH:13]=[CH:14][CH:15]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COc1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(OCc2ccccc2)c(C=O)c1
Reaction time: 4 h
Yield: 86.7 %

Procedure:
To a solution of 2-hydroxy-5-methoxybenzaldehyde (0.152 g, 1.0 mmol) in dry MeCN (50 mL) was added 4-fluorobenzyl bromide (0.145 mg, 1.0 mmol), and anhydrous K2CO3 (0.27 g, 2.0 mmol). The mixture was refluxed under stirring for 4 h, and then evaporated in vacuo. Water (100 mL) was added and the mixture was extracted with EtOAc. The separated organic layer was dried with MgSO4, and then evaporated in vacuum. Finally, the residue was eluted through a silica gel column with n-hexane/EtOAc (4:1) to give white compound I (0.21 g, 88%).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26](O)=[O:27])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.N1C=CC=CC=1>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:27])#[N:2]
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Reactant: Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)Nc3ccccc3)n([C@H]3CCCc4ccccc43)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml)and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of aniline (0.157 ml, 1.62 mmol), pyridine (0.262 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the objective product as a solid material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:44]#[N:45])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:41][CH3:42])[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[NH:27][C:28]([C:31]([F:40])([F:39])[C:32]([F:38])([F:37])[C:33]([O:35]C)=[O:34])=[N:29][N:30]=4)=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:43])[CH:9]=2)[CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:44]#[N:45])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:41][CH3:42])[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[NH:27][C:28]([C:31]([F:39])([F:40])[C:32]([F:38])([F:37])[C:33]([OH:35])=[O:34])=[N:29][N:30]=4)=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:43])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)Nc1ccc(-c2nnc(C(F)(F)C(F)(F)C(=O)OC)[nH]2)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Agent: [Li+]
Agent: [OH-]
Product: CCC(C(=O)Nc1ccc(-c2nnc(C(F)(F)C(F)(F)C(=O)O)[nH]2)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
96 mg (purity 94%, 0.14 mmol) of methyl 3-{5-[4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)phenyl]-4H-1,2,4-triazol-3-yl}-2,2,3,3-tetrafluoropropanoate (racemate) were hydrolysed with lithium hydroxide according to General Method 3. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 28 mg (32% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[NH:10][N:9]=1.[CH2:23](Br)[CH3:24]>>[CH2:23]([N:9]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])=[N:10]1)[CH3:24]
Reactant: FC(F)(F)c1ccccc1-c1nc(-c2ccccc2Cl)n[nH]1
Reactant: CCBr
Product: CCn1nc(-c2ccccc2C(F)(F)F)nc1-c1ccccc1Cl

Procedure:
starting from 3-(o-chlorophenyl)-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole and ethyl bromide there is obtained a mixture of isomeric N-ethyltriazoles and therefrom there are obtained pure 1-ethyl-5-(o-chlorophenyl)-3-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole as a resinous product, 1H-NMR(CDCl3): 1.47 (t, CH2CH3), 4.10 (q, CH2CH3); and pure 1-ethyl-3-(o-chlorophenyl)-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, likewise as a resinous product, 1H-NMR(CDCl3): 1.45 (t, CH2CH3), 4.04 (q, CH2CH3);
Reaction SMILES: CC([O-])(C)C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:17])=[O:16])=[CH:10][CH:9]=1.Cl[N:19]1[C:23](=O)CC[C:20]1=O.CNC>C(#N)C>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]=[S:15]([CH3:17])([N:19]([CH3:23])[CH3:20])=[O:16])=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CS(=O)Nc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: CNC
Agent: [K+]
Solvent: CC#N
Product: CN(C)S(C)(=O)=Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Potassium tert-butylate (958 mg) is added to a mixture of N-(4-bromophenyl)methanesulfinamide (1.00 g), N-chlorosuccinimide (684 mg), and dimethylamine solution (2 M in tetrahydrofuran; 6.41 mL) in acetonitrile at room temperature under an argon atmosphere. The reaction mixture is stirred at room temperature for 2 days. The reaction mixture is partitioned between water and ethyl acetate and the aqueous phase is extracted with ethyl acetate. The combined extracts are washed with brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 50:500:100) to give the title compound. LC (method 1): tR=0.95 min; Mass spectrum (ESI+): m/z=277, 279 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([C@H:7]([CH3:24])[C@:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH:6]=1.C(N(CC)CC)C.[CH2:32]([O:34][CH:35]([O:38][CH2:39][CH3:40])[CH2:36]Br)[CH3:33]>CN(C)C=O>[CH2:32]([O:34][CH:35]([O:38][CH2:39][CH3:40])[CH2:36][NH:1][C:2]1[CH:3]=[N:4][N:5]([C@H:7]([CH3:24])[C@:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH:6]=1)[CH3:33]
Reactant: C[C@@H](n1cc(N)cn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCOC(CBr)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(CNc1cnn([C@H](C)[C@](O)(Cn2cncn2)c2ccc(F)cc2F)c1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
(2R,3R)-3-(4-amino-1H-pyrazol-1-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol obtained in Step 2 (0.12 g, 0.35 mmol) was dissolved in N,N-dimethylformamide (2 mL) and triethylamine (0.058 g, 0.42 mmol) was slowly added thereto. The mixture was stirred at room temperature for 30 minutes, and bromoacetaldehyde diethyl acetal (0.065 mL, 0.42 mmol) was added thereto, followed by stirring at 80° C. for 4 hours. The reaction was terminated by adding ice water (0.1 mL) thereto. The resulting residue was extracted with ethyl acetate (20 mL), and the extract was washed successively with saturated ammonium chloride (20 mL) and brine (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under a reduced pressure. The resulting residue was purified by silica gel chromatography to obtain the title compound (0.071 g, yield 44%).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[N:15]1[CH:20]=[CH:19][C:18]([CH:21]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1>>[N:15]1[CH:20]=[CH:19][C:18]([CH:21]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][N:4]3[C:8](=[O:9])[C:7]4=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]4[C:5]3=[O:14])[CH2:30][CH2:29]2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: c1ccc(C(c2ccncc2)N2CCNCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(C(c2ccccc2)c2ccncc2)CC1
Yield: 77 %

Procedure:
The title compound was prepared in a yield of 77% in a similar manner to that described in Preparation 1' by reacting N-(2-bromoethyl)phthalimide and 4-[α-(4-pyridyl)benzyl]piperazine.
Reaction SMILES: [Cl:1][C:2]1[C:16]([F:17])=[CH:15][C:5]2[NH:6][C:7]([CH:9]([OH:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.CC1(C)N([O-])C(C)(C)CC(OC)C1.[Br-].[K+].Cl[O-].[Na+]>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[C:16]([F:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:11])[F:12])=[N:8][C:4]=2[CH:3]=1
Reactant: OC(c1nc2cc(Cl)c(F)cc2[nH]1)C(F)(F)F
Agent: COC1CC(C)(C)N([O-])C(C)(C)C1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1nc2cc(Cl)c(F)cc2[nH]1)C(F)(F)F
Temperature: 25 °C

Procedure:
1-(5-Chloro-6-fluoro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanol (0.34 g; 1.3 mmoles), 4-methoxy-2,2,6,6-tetramethyl-1-piperdinyloxy free radical (4-methoxy-TEMPO free radical; 6.1 mg; 0.03 mmoles) and potassium bromide (KBr; 18 mg; 0.15 mmoles) were dissolved in THF (3.5 mL). The reaction mixture was stirred while cooled to −10° C., after 10 min. a sodium hypochlorite solution (bleach; 10-13% aqueous; 3.0 mL; 5.04 mmoles) was added and allowed to stir for 15 min., then warmed to room temperature and stirred for 15 min. The reaction mixture was diluted with water (20 mL) and ethyl acetate (30 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (3×30 mL). The extracts were combined and washed with water (30 mL) and brine (40 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo and purified by column chromatography (SiO2; 100% diethyl ether) to yield the title compound as a light yellow solid.
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:41]=[CH:42][C:43]=1[O:44][CH3:45])[C:32]([C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1)=O.C(OP([CH2:54][C:55]#[N:56])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)=[CH:54][C:55]#[N:56])[CH:41]=[CH:42][C:43]=1[O:44][CH3:45]
Reactant: COc1ccc(C(=O)c2ccc(C)cc2)cc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(C(=CC#N)c2ccc(C)cc2)cc1OC

Procedure:
3-(3,4-Dimethoxyphenyl)-3-(4-methylphenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-dimethoxy-4′-methylbenzophenone(2.3 g, 9 mmol), diethylcyanomethylphosphonate (1.8 mL, 9.9 mmol) and lithium hexamethyldisilazide (10 mL, 9.9 mmol, 1 M) with a reaction time of 22 hours at room temperature. The crude product was purified by chromatography (silica gel, 1% ethyl acetate/methylene chloride) to afford 1.83 g (73%) of a mixture of the E and Z isomers as a white solid: mp 83.5-86.5° C.; 1H NMR (CDCl3) δ 7.35-7.20 (m, 8 H), 7.04-6.81 (m, 6 H), 5.62 (s, 1 H), 5.59 (s, 1 H), 3.90 (s, 3 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.82 (s, 3 H), 2.41 (s, 3 H), 2.39 (s, 3 H); 13C NMR (CDCl3) δ 162.7, 162.6, 160.0, 150.4, 148.8, 148.5, 140.6, 140.1, 136.3, 134.1, 131.6, 129.5, 129.2, 129.0, 128.5, 123.0, 122.1, 118.4, 118.3, 112.6, 111.1, 110.7, 92.6, 92.4, 55.9, 55.9, 55.8, 21.3, 21.2; Anal. Calcd for C18H17NO2. Theoretical: C, 77.40; H, 6.13; N, 5.01. Found: C, 77.64; H, 5.93; N, 5.01.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[O:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][CH2:16][CH2:15]4)[C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[CH2:29][C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[O:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([C:30](=[O:31])[CH2:29][C:23]3[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=3[F:21])[CH2:16][CH2:15]4)[C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(Cl)c2occ(-c3ccc4c(c3)CCN4)c12
Reactant: O=C(O)Cc1cc(F)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Cl)c2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Reaction time: 1 h
Yield: 73.9 %

Procedure:
A solution of 7-chloro-3-(2,3-dihydro-1H-indol-5-yl)furo[3,2-c]pyridin-4-amine (58.9 mg, 0.206 mmol), (2,5-difluorophenyl)acetic acid (35.5 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol), and DIEA (0.036 mL, 0.206 mmol) in N,N-Dimethylformamide (DMF) (3 mL) was stirred overnight at room temperature. LCMS analysis at this time indicated good conversion, so the reaction mixture was poured into water (10 mL) and stirred for one hour. The resulting precipitate was collected by filtration, dried at the pump for an hour, adsorbed onto silica and purified by flash chromatography (0-10% MeOH in EtOAc) to afford 7-chloro-3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine (67 mg, 73.9% yield) as a white solid. LC-MS (ES) m/z=440, 442 [M+H]+. 1H NMR (400 MHz, DMSO-d6) ppm 3.29 (t, J=8.46 Hz, 2H), 3.96 (s, 2H), 4.31 (t, J=8.34 Hz, 2H), 5.72 (s, 2H), 7.13-7.34 (m, 4H), 7.41 (s, 1H), 7.92 (s, 1H), 8.07 (s, 1H), 8.13 (d, J=8.34 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[CH:4][CH3:5])[CH3:2].[Li]CCCC.CN([CH:21]=[O:22])C>C1COCC1>[CH2:4]([C:3]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([CH:7]=1)[CH:21]=[O:22])=[CH:1][CH3:2])[CH3:5]
Reactant: CC=C(CC)c1ccc(F)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC=C(CC)c1ccc(F)c(C=O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48.6 %

Procedure:
A solution of 1-(1-ethyl-propenyl)-4-fluoro-benzene (15.3 g, 93.2 mmol) in THF (150 mL) at −78° C. is treated with n-BuLi (70 mL, 1.6 M). The reaction mixture is allowed to warm to 0° C. over 60 min, cooled to −78° C., and treated with DMF (10.2 g, 140 mmol). The mixture is stirred for 10 min and quenched with HOAc (10 mL) and water (200 mL). The mixture is allowed to warm to RT, and the THF is removed under vacuum. The residue is extracted with EtOAc (2×100 mL, and the organic layer is dried over Na2SO4 and concentrated. The crude product is purified using silica gel column chromatography (7% EtOAc/Hex) to afford the title compound (8.70 g, 49%).
Reaction SMILES: [CH3:1]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.[C:13]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([O:25][CH:26]([S:37][CH3:38])[C:27]([NH:29][C:30]([CH2:34][O:35][CH3:36])([CH3:33])[CH:31]=O)=[O:28])=[CH:20][C:19]=2[CH3:39])#[CH:14].C([O-])([O-])=O.[K+].[K+]>CO.C(OCC)(=O)C>[C:13]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([O:25][CH:26]([S:37][CH3:38])[C:27]([NH:29][C:30]([CH2:34][O:35][CH3:36])([CH3:33])[C:31]#[CH:1])=[O:28])=[CH:20][C:19]=2[CH3:39])#[CH:14]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: C#Cc1cnc2c(C)cc(OC(SC)C(=O)NC(C)(C=O)COC)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1cnc2c(C)cc(OC(SC)C(=O)NC(C)(C#C)COC)cc2c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 55.1 %

Procedure:
A mixture of (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (Bestmann's reagent) (77 mg) and 2-(3-ethynyl-8-methyl-quinolin-6-yloxy)-N-(1-methoxymethyl-1-methyl-2-oxo-ethyl)-2-methylsulfanyl-acetamide (110 mg) in MeOH (10 ml) was cooled to 0° C. Solid K2CO3 (71 mg) was added and the mixture stirred during 16 hour allowing the temperature raising to 25° C. The reaction mixture was diluted with ethyl acetate and poured onto brine. The water phase was extracted twice with ethyl acetate and the combined organic phases dried over sodium sulfate, filtered and evaporated. The crude residue was purified by column chromatography to give 2-(3-ethynyl-8-methyl-quinolin-6-yloxy)-N-(1-methoxymethyl-1-methyl-prop-2-ynyl)-2-methylsulfanyl-acetamide (60 mg) as a light brown solid as a mixture of diastereoisomers.