Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[Br:15][C:16]1[C:17]([CH3:23])=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>CO.C(Cl)Cl>[Br:15][C:16]1[C:17]([CH3:23])=[C:18]([NH:19][CH2:2][C:3]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:4]=2[C:5]([O:7][CH3:8])=[O:6])[CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1cc(OC)ccc1CBr
Reactant: Cc1c(N)cccc1Br
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(OC)ccc1CNc1cccc(Br)c1C
Temperature: 85 °C
Yield: 17.9 %

Procedure:
Step 2 A mixture of methyl 2-(bromomethyl)-5-methoxybenzoate (1.435 g, 5.54 mmol), 3-bromo-2-methylaniline (1.03 g, 5.54 mmol) and TEA (1.158 mL, 8.31 mmol) in methanol (5 mL) was heated at 85° C. for 2 h. The mixture was diluted with DCM, washed with NaHCO3 (aq), and dried and concentrated. The residue was purified by column chromatography (eluting with EtOAc-hexane) to provide methyl 2-((3-bromo-2-methylphenylamino)methyl)-5-methoxybenzoate as a yellow oil (361 mg, 18%). Mass spectrum m/z 364, 366 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:23])[CH:9]([C:17]2[S:21][N:20]=[C:19]([CH3:22])[N:18]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH2:26].[NH2:27]O.O>>[C:1]1([NH:7][C:8](=[O:23])[CH:9]([C:17]2[S:21][N:20]=[C:19]([CH3:22])[N:18]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[NH:27])[NH:16][OH:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1nsc(C(CCCCCC#N)C(=O)Nc2ccccc2)n1
Reactant: NO
Reactant: O
Solvent: CO
Product: Cc1nsc(C(CCCCCC(=N)NO)C(=O)Nc2ccccc2)n1

Procedure:
To a stirred mixture of 7-cyano-2-(3-methyl[1,2,4]thiadiazol-5-yl)heptanoic acid phenylamide (2021044) (440 mg, 1.30 mmol) in 50% hydroxylamine/water (20 mL) was added methanol until the oil dissolved. The solution was then heated at reflux overnight. Water (100 mL) was added and the reaction mixture was then extracted with ethyl acetate (3×150 mL). The combined organic fractions were dried (MgSO4) and the solvent was removed under reduced pressure. The crude product (400 mg, 1.1 mmol) was purified by preparative liquid chromatography to afford 7-(N-hydroxycarbamimidoyl)-2-(3-methyl-[1,2,4]thiadiazol-5-yl)-heptanoic acid phenylamide (2021035) as a white solid.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=[C:3]([NH2:10])C=1F.Cl.Cl.Cl.Cl.[CH3:17][N:18]([CH3:35])[CH2:19][CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH2:30][NH:31][NH:32][CH:33]=O)[CH:28]=2)[NH:23][CH:22]=1.N1C=NC=NC=1>C(O)C>[CH3:17][N:18]([CH3:35])[CH2:19][CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH2:30][N:31]3[CH:3]=[N:10][CH:33]=[N:32]3)[CH:28]=2)[NH:23][CH:22]=1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: CN(C)CCc1c[nH]c2ccc(CNNC=O)cc12
Agent: Cl
Agent: c1ncncn1
Solvent: CCO
Product: CN(C)CCc1c[nH]c2ccc(Cn3cncn3)cc12
Yield: 84 %

Procedure:
A solution of the dihydrochloride of formic acid N′-[3-(2-dimethylamino-ethyl)-1H-indol-5-ylmethyl]-hydrazide (Example 18; 6.665 g, 20 mmol), and 1,3,5-triazine (1.081 g, 13.3 mmol) in ethanol (50 ml) is heated at reflux for six hours under a nitrogen atmosphere. From the slightly hazy yellow solution, the solvent is removed on the rotavapor, and the yellow residue is stirred with sodium hydroxide (100 ml 2N solution) and chloroform (100 ml). The organic layer is separated, washed with water (100 ml) and brine (100 ml) and dried (sodium sulfate). Removal of the solvent gives the product (4.54 g, 84%) as a slightly brown oil which solidifies on standing. 1H-NMR (CDCl3, 300 MHz) δ 2.26 (s, 6H, N(CH3)2); 2.56 (m, 2H, CH2); 2.83 (m, 2H, CH2NMe2); 5.27 (s, 2H, CH2N); 6.88 (d, 1H, J=2.0 Hz, H-2); 6.92 (dd, 1H, J=8.2 Hz, J=1.8 Hz, H-6); 7.15 (d, 1H, H-7); 7.40 (d, 1H, H-4); 7.84 (s, 1 H, triazol H-?); 7.89 (s, 1H, triazol H-?); 9.24 (br s, 1H, NH). 13C-NMR (CDCl3, 75 MHz) δ 23.68 (CH2); 45.50 (N(CH3)2); 54.88 (CH2N); 60.31 (CH2NMe2); 112.18 (C-7); 114.01 (C-3); 119.26 (C-4); 122.26 (C-6); 123.24 (C-2); 124.94 (C-5); 127.87 (C-9); 136.53 (C-8); 143.00 (triazol C-5); 151.88 (triazol C-3).
Reaction SMILES: [C:1]([C:3](=[CH:12]OCC)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C(O)C>[C:1]([C:3](=[CH:12][NH:21][C:20]1[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][CH:19]=1)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Reactant: Nc1ccc(Cl)cc1
Solvent: CCO
Product: CCOC(=O)NC(=O)C(C#N)=CNc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a warm solution of α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide (14.8 g) and ethanol is added p-chloroaniline (8.9 g) in ethanol. Precipitate appears instantaneously. The mixture is stirred at room temperature for one hour and filtered to yield α-cyano-β-(4-chloroanilino)-N-ethoxycarbonylacrylamide, m.p. 177°-183°.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].CCN(CC)CC.Cl[C:17]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[CH:20]=[C:19]([Cl:27])[N:18]=1>C1COCC1>[Cl:27][C:19]1[N:18]=[C:17]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[CH:20]=1
Reactant: COC(=O)CCN
Reactant: Clc1cc2nccnc2c(Cl)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCNc1nc(Cl)cc2nccnc12

Procedure:
A solution of methyl 3-aminopropanoate hydrochloride (4.88 mmol), Et3N (6.50 mmol) and 5,7-dichloropyrido[4,3-b]pyrazine (3.25 mmol) in THF (10 mL) was stirred at room temperature overnight. Volatiles were removed under reduced pressure, and the residue was treated with water and extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography to afford the title compound. MS (m/z): 267 (M+H)+.
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[CH3:2].C(N(CC)CC)C.[OH:12][CH2:13][C:14]1[C:15]([N:29]2[CH2:38][CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]2[CH3:39])=[N:16][C:17]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[N:18][C:19]=1[CH3:20]>ClCCl>[ClH:4].[ClH:4].[C:1]([O:12][CH2:13][C:14]1[C:15]([N:29]2[CH2:38][CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]2[CH3:39])=[N:16][C:17]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[N:18][C:19]=1[CH3:20])(=[O:3])[CH3:2]
Reactant: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3C2C)c1CO
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1c(C)nc(Nc2ccc(F)cc2)nc1N1CCc2ccccc2C1C
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Acetylchloride (2.71 μ1, 39.6 μmol) and triethylamine (20 μl, 142.6 μmol) were added to a suspension of 5-hydroxymethyl-6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(4-fluorophenylamino)pyrimidine (10 mg, 26.4 μmol) in dichloromethane(1 ml) and stirred for 1 day at a room temperature. The reaction mixture was purified by a silica gel column chromatography (ethylacetate/n-hexane=1/1) to give the titled compound.
Reaction SMILES: [F:1][C:2]([F:24])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])C(OCC)=O.[CH3:25][Mg]Br.CC[O:30][CH2:31][CH3:32]>>[F:1][C:2]([F:24])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:31]([CH3:32])([OH:30])[CH3:25]
Reactant: C[Mg]Br
Reactant: CCCCCCCCCCCCCCCCC(F)(F)C(=O)OCC
Reactant: CCOCC
Product: CCCCCCCCCCCCCCCCC(F)(F)C(C)(C)O

Procedure:
To a solution of 6.9 g of ethyl 2,2-difluorooctadecanoate in 100 ml of ether at 0° C. is added 33 ml of methyl magnesium bromide dropwise with stirring. Following complete addition the reaction is allowed to reach room temperature and stirred for 30 minutes. The reaction mixture is washed with saturated ammonium chloride solution. The organic layer is washed with 10% hydrochloric acid, water and 10% sodium bicarbonate. The organic layer is dried and evaporated to an oil which is purified by chromatography on silica gel using 1-10% ethyl acetate:hexanes to give 3.8 g of the desired product as a solid following petroleum ether crystallization.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([NH2:14])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH3:13])=[N:10][CH:11]=1.C(N(C(C)C)CC)(C)C.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:27](=[O:28])C1.[NH:43]1[CH2:48][CH2:47][CH:46]([N:49]2[CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[NH:51][C:50]2=[O:59])[CH2:45][CH2:44]1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:14][C:27]([N:43]1[CH2:44][CH2:45][CH:46]([N:49]2[CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[NH:51][C:50]2=[O:59])[CH2:47][CH2:48]1)=[O:28])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH3:13])=[N:10][CH:11]=1
Reactant: COC(=O)C(N)Cc1cnc(OC)nc1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Cc1cnc(OC)nc1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-Amino-3-(2-methoxy-pyrimidin-5-yl)-propionic acid methyl ester (125 mg) and diisopropylethylamine (0.3 mL) in methylene chloride (2 mL, 0° C.) was added N,N′-disuccinimidyl carbonate (155 mg). After 30 min, 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (120 mg) in methylene chloride (2 mL) was added via canula. The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated and purified by prep HPLC to give 99mg (36%). Mass spec.: 469.10 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15](=O)[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[N:31]1([C:36]([NH2:38])=[NH:37])[CH2:35][CH2:34][CH2:33][CH2:32]1.CC(C)([O-])C.[Na+]>CC(O)(C)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:37]=[C:36]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[N:38]=[C:15]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N=C(N)N1CCCC1
Reactant: Cc1ccc(C(=O)C2CN(C(=O)OC(C)(C)C)CCC2=O)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2nc(N3CCCC3)nc3c2CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
To a mixture of 3-(4-Methyl-benzoyl)-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.24 g, 0.74 mmol) and pyrrolidine-1-carboxamidine trifluoroacetate (0.14 g, 0.58 mmol) in t-BuOH (7.5 mL) was added sodium tert-butoxide (0.10 g, 1.1 mmol). The mixture was heated at reflux for 2 h, then cooled to rt, diluted with H2O and extracted with CH2Cl2 (2×). The combined organic extracts were dried and concentrated. The residue was purified by FCC to give the title compound (0.084 g, 29%) as a clear oil. MS (ESI): mass calcd. for C23H30N4O2, 394.5; m/z found, 395.5 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][N:38]=1>O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[O:11][C:10]([CH3:21])([CH3:22])[C:9](=[O:23])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][N:38]=3)=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(CCl)nc1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(c3ccc(OCc4ccc(C)cn4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 80 °C
Yield: 74.1 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2.0, 6.5 mmol) was added to a mixture of cesium carbonate (10.5 g, 32.2 mmol) and DMF (50 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min, upon which 2-(chloromethyl)-5-methylpyridine (1.36 g, 9.6 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture allowed to cool, diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh), to afford 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylpyridin-2-yl)methoxy)phenyl)furan-3(2H)-one (2.0 g, 76.9%,) as an off-white solid. 1H NMR: 200 MHz, DMSO-d6: δ 8.4 (s, 1H), 7.6 (d, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.2 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.2 (s, 2H) 3.8 (s, 3H), 2.3 (s, 3H), 1.45 (s, 6H). MS: [M+H]+: m/z=415.2. HPLC: (97.5%, Condition-A).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[CH:6]=1)[CH3:2].[OH:13][CH2:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].CO>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[OH:13][CH2:14][C:15]1[CH:20]=[C:19]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:12])[CH:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)c1cccc(-c2cccc(CO)c2)c1
Temperature: 80 °C

Procedure:
A mixture of ethyl-3-bromobenzoate (3.0 g, 13 mmol), [3-(hydroxymethyl)-phenyl]boronic acid (3.0 g, 20 mmol), PdCl2(PPh3)2 (0.46 g, 0.66 mmol), K2CO3 (3.6 g, 26 mmol), methanol (4 mL), and toluene (36 mL) was heated at 80° C. for 18 h under N2 and then allowed to cool to rt. The reaction mixture was filtered through Celite and then poured into a mixture of ethyl acetate and brine. The two layers were separated and the aqueous layer was extracted with ethyl acetate (×3). The organic extracts were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography to give ethyl 3′-(hydroxymethyl)biphenyl-3-carboxylate as an orange oil. A solution of CBr4 (5.8 g, 17 mmol) and CH2Cl2 (20 mL) was added dropwise to a solution of the above alcohol, PPh3 (4.6 g, 18 mmol), and CH2Cl2 (50 mL) at 0° C. under N2. The reaction was allowed to warm to rt, maintained for 2 h, concentrated, and purified by silica gel chromatography to give ethyl 3′-(bromomethyl)biphenyl-3-carboxylate as a clear oil. Ethyl 3′-(bromomethyl)biphenyl-3-carboxylate was used to alkylate 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol following the procedure outlined in example 1. A mixture of the above indole (0.66 g, 1.4 mmol), 1 N LiOH (8 mL), and THF (8 mL) was heated at 40° C. for 2 d and then cooled to 0° C.—acetone can used in place of THF if faster reaction rates are desired. The reaction was acidified to pH=1 with conc. HCl and extracted with ethyl acetate (×3). The organic extracts were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography to give a yellow oil. 1H NMR (CDCl3, 500 MHz) δ 8.39 (s, 1H), 8.11 (d, 1H), 7.85 (d, 1H), 7.76 (s, 1H), 7.59-7.48 (m, 4H), 7.12 (d, 1H), 7.05 (d, 1H), 6.96 (d, 1H), 6.46 (d, 1H), 5.16 (s, 2H), 3.84 (s, 2H), 2.95 (t, 2H), 1.76 (m, 2H), 1.01 (t, 3H), 0.99 (s, 9H). MS (ESI): 456 (M+H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:11])[CH2:6]2.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([Mg]Br)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1>CCOCC.Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:12][C:13]([F:26])([F:27])[C:14]1[CH:15]=[C:16]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[C:5]([CH3:11])[CH2:6]3)[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=1
Reactant: CC1=Cc2c(Br)cccc2C1
Reactant: FC(F)(F)c1cc([Mg]Br)cc(C(F)(F)F)c1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CC1=Cc2c(cccc2-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1

Procedure:
4-Bromo-2-methylindene (10.7 g, 51 mmol) and NiCl2(PPh3)2(1.8 g, 2.8 mmol) were dissolved in 150 mL of Et2O. 3,5-bis(trifluoromethyl)phenylmagnesium bromide (51 mmol) as a Et2O solution was added under vigorous stirring and the reaction stirred overnight at room temperature. After overnight stirring, the reaction was slowly quenched with H2O to neutralize unreacted Grignard. The solution was subsequently treated with 100 mL of 10% HCl(aq), and neutralized with saturated sodium bicarbonate aqueous solution. The organic layer was dried with magnesium sulfate and the solvent was removed by rotary evaporation. The remaining residue was loaded onto a silica gel column and eluted with hexane. Yield was 2.2 g (13%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>O1CCCC1>[N:1]1([C:9](=[O:10])[CH2:8][C:7](=[O:11])[CH3:6])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C1CC(=O)O1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
A solution of 21 ml (0.25 mol) of pyrrolidine in 50 ml tetrahydrofuran was added dropwise to a solution of 20 g of diketene (0.24 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue was purified by column chromatography. This gave 29.9 g (0.19 mol, 81% yield) of an oil.
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]2=[O:20].[CH2:23](C([SnH3])=C(CCCC)CCCC)[CH2:24]CC>C1(C)C=CC=CC=1.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>[CH:12]1([N:10]2[C:11]3[C:6](=[CH:5][C:4]([F:21])=[C:3]([F:22])[C:2]=3[CH:23]=[CH2:24])[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9]2)[CH2:14][CH2:13]1
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Br)c(F)c(F)cc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c12
Yield: 79.9 %

Procedure:
3.72 g of ethyl 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 4.4 g of tributylvinyl stannan and 0.46 g of tetrakis(triphenylphosphine)palladium(0) are refluxed in 40 ml of absolute toluene for 2 to 3 hours under a nitrogen atmosphere. The mixture is filtered under hot conditions, and the product which has precipitated at room temperature is filtered off with suction, washed with toluene and dried. 2.55 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylate are obtained (79% of theory).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14](Br)[CH:13]=2)[O:9][N:8]=1.B1([C:30]2[CH:35]=[N:34][CH:33]=[N:32][CH:31]=2)OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>CCCCCC.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.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)[CH:15]=[C:16]([C:18]#[N:19])[CH:17]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(Br)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: CC1(C)OB(c2cncnc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1cc(-c2cncnc2)cc(-c2nc(-c3ccccn3)no2)c1
Yield: 5.6 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(3-bromo-5-cyanophenyl)-1,2,4-oxadiazole (71 mg, 0.22 mmol), pyrimidyl-5-boronic acid pinacolate (89 mg, 0.43 mmol), and Pd(PPh3)4 (25 mg, 0.022 mMol) in a solution of 2M sodium carbonate (3 mL) and ethylene glycol dimethyl ether (3 mL) was heated in a sealed vial at 100° C. for 1 hour. Standard work up and silica gel chromatography using a gradient of 30% ethyl acetate in hexane to 100% ethyl acetate, followed by trituration with ethyl acetate afforded 4 mg (6%) of 3-(2-pyridyl)-5-(3-cyano-5-(5-pyrimidyl)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3):δ-9.37 (s, 1H), 9.07 (s, 2H), 8.89 (d, 1H), 8.76 (s, 1H), 8.67 (s, 1H), 8.26 (d, 1H), 8.11 (s, 1H), 7.94 (t, 1H), 7.52 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Cu](C#N)[C:10]#[N:11].N>CN(C)C=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]#[N:11])=[N:3][CH:4]=1
Reactant: N#C[Cu]C#N
Reactant: Cc1ccc(Br)nc1
Agent: N
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)nc1
Temperature: 50 °C

Procedure:
36 g (209 mmol) 2-bromo-5-methylpyridine and 37.5 g (418 mmol) copper cyanide are refluxed for two hours in 500 ml dimethylformamide. After cooling down to 50° C., 10% aqueous ammonia solution (500 ml) is added with stirring. The product is extracted with dichloromethane, the organic phase is dried over magnesium sulfate, and the solvent is removed in vacuo. The product is purified by column chromatography (silica, eluent: cyclohexane/ethyl acetate 9:1).
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[C:10](O)(=O)[CH3:11].N([O-])=[O:15].[Na+]>C(OCC)C>[OH:15][C@@H:2]([C@@H:3]([CH3:4])[CH2:5][CH3:6])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CC(=O)O
Reactant: O=N[O-]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)[C@@H](O)[C@@H](C)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
In a 300 ml flask were charged 20 g of L-isoleucine (compound (30), R1 =ethyl) and 200 ml of 50% acetic acid, and an aqueous solution of 21 g of sodium nitrite was added thereto dropwise under cooling with ice. After the addition, the mixture was stirred at room temperature for 1 hour and extracted with diethyl ether. Diethyl ether was removed by distillation, and to the residue were added 0.5 g of p-toluenesulfonic acid, 300 ml of ethanol, and 100 ml of benzene, followed by heat-refluxing while removing by-produced water azeotropically with benzene and ethanol. Diethyl ether was added to the reaction mixture, and the mixture was washed with water and dried over magnesium sulfate. The solvent was removed by distillation to obtain a crude product, which was then purified by distillation to obtain 9.5 g (43.7%) of the titled compound (b.p.: 60° C./5 mmHg).
Reaction SMILES: CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@@H](C/C=C/C)C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C[CH:81]([CH3:83])C)N(C)C(=O)CN(C)C1=O.FC(F)(F)S([O:91][Si:92]([CH2:97][CH3:98])([CH2:95][CH3:96])[CH2:93][CH3:94])(=O)=O.O>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:93]([Si:92]([O:91][Si:92]([CH2:81][CH3:83])([CH2:95][CH3:96])[CH2:93][CH3:94])([CH2:97][CH3:98])[CH2:95][CH3:96])[CH3:94]
Reactant: C/C=C/C[C@@H](C)[C@@H](O)[C@H]1C(=O)N[C@@H](CC)C(=O)N(C)CC(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](C(C)C)C(=O)N1C
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC[Si](CC)(CC)O[Si](CC)(CC)CC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Cyclosporin A (3.606 g, 3 mmol) was dissolved in dry pyridine (8 mL) and then DMAP (122 mg, 1 mmol) was added. The reaction mixture was cooled to 0° C. and then triethylsilyl trifluoromethanesulfonate (3.6 mmol) added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was then poured slowly into water with stirring. The precipitated triethylsilyl ether was filtered off and washed with water. The collected cake was dissolved in a minimum volume of methanol and added to a 5% citric acid solution and stirred for 30 minutes. The precipitated product was collected by filtration and washed with water until the pH of the filtrate reached that of the water. The solid triethylsilyl ether was dried at 50° C. under vacuum to give a colorless solid. Triisopropylsilyl and tert-butyldimethylsilyl protecting groups were also introduced by following an analogous procedure.