Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[C:14]([O:16]CC)=[O:15])=[N:6][CH:7]=1.[H-].[Na+].CI.[CH3:23]CCCCC>C1COCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2([CH3:23])[C:14]([OH:16])=[O:15])=[N:4][CH:3]=1
Reactant: CCOC(=O)C1CCCCN1c1ncc(Br)cn1
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCCCN1c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 32 %

Procedure:
To an ice-cold solution of ethyl 1-(5-bromopyrimidin-2-yl)piperidine-2-carboxylate (0.37 g, 1.18 mmol) in THF (25 mL) was added NaH (60% dispersion in mineral oil, 0.06 g, 1.41 mmol) portion wise. The mixture was stirred at the same temperature for 45 min followed by addition of MeI (0.52 mL, 8.26 mmol) at 0° C. The temperature of the reaction was slowly raised up to rt and left to stir for 16 h. The reaction was then cooled to 0° C., quenched by drop wise addition of ice-cold water then extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 2% EtOAc: hexane to obtain the desired product as off-white solid (0.115 g, 32% yield). MS: 300.09 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH2:29]([O:31][C:32]1[NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[N:33]=1)[CH3:30]>>[CH2:29]([O:31][C:32]1[N:33]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:17][CH2:18]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:30]
Reactant: CCOc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CCOc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-ethoxy-1H-benzo[d]imidazole were reacted to give 337. LCMS: M+H+=535.3
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[NH2:16].[C:17](OC)(OC)(OC)[CH2:18][CH2:19][CH3:20].Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][S:2][CH2:3][CH2:4][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:17]1[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(OC)(OC)OC
Reactant: CSCCNc1c(N)cnc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCc1nc2cnc3ccccc3c2n1CCSC
Temperature: 140 °C
Yield: 89.4 %

Procedure:
N4-[2-(Methylthio)ethyl]quinoline-3,4-diamine (4.2 g, 19.2 mmol), trimethyl orthobutyrate (2.86 g, 19.2 mmol), pyridine hydrochloride (catalytic amount) and toluene were combined in a pressure vessel and heated at 140° C. for 1 hour. The reaction mixture was allowed to cool and then it was concentrated under reduced pressure to provide 4.9 g of 1-[2-(methylthio)ethyl]-2-propyl-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[N:23]([CH3:24])[C@H:12]1[CH2:11]3.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>CO>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([NH:30][CH:27]3[CH2:29][CH2:28]3)=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[N:23]([CH3:24])[CH:13]3[C:14]12[O:21][CH3:22]
Reactant: NC1CC1
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@@H]3[C@H](CN21)N3C
Solvent: CO
Product: COC12C(CO)C3=C(C(=O)C(C)=C(NC4CC4)C3=O)N1CC1C2N1C
Product: NC(=O)O
Yield: 59.7 %

Procedure:
To a solution of 75 mg (0.2 mmol) of N-methylmitomycin A in 10 ml of anhydrous methanol, 2ml of cyclopropylamine was added with stirring. The reaction mixture was stirred overnight, whereupon TLC indicated no remaining starting material. The solvent was then evaporated under reduced pressure and the residue was chromatographed using silica-gel as adsorbent. The fraction obtained by eluting the column with ethyl acetate was evaporated under reduced pressure. Recrystallization from a mixture of methylene chloride and hexane gave 47.8 mg (59.7% yield) of the desired product as purple-colored crystals having a melting point of 166°-167° (decomposing) and providing the following analysis:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].Cl.C(O[C:10]([CH:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=N)C.C([OH:27])C>>[NH:1]1[CH2:2][CH2:3][CH2:4][N:5]=[C:10]1[C:12]1([OH:27])[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: CCO
Reactant: CCOC(=N)C1c2ccccc2-c2ccccc21
Reactant: NCCCN
Agent: Cl
Product: OC1(C2=NCCCN2)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1,3-Diaminopropane (4.92 ml.) was added dropwise to a stirred, ice-cooled suspension of 9H-fluorene-9-carboximidic acid ethyl ester hydrochloride (14.8 g.) in absolute ethanol (100 ml.). The mixture was stirred for 30 minutes at 0°C, 30 minutes at room temperature and then heated under reflux overnight (16 hours). After evaporation of the ethanol the residue was dissolved in 2N hydrochloric acid, extracted once with ether and then basified (2N NaOH). The precipitate was filtered and recrystallised from isopropanol/ether to give the crude title compound (4.012 g.). The hydrochloride salt of the title compound crystallised from isopropanol/ethereal HCl, m.p. 242°-245°. Found: C, 67.6; H, 5.95; N, 9.05%. C17H16N2O.HCl requires C, 67.9; H, 5.7; N, 9.3%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([F:20])[C:18]=1[F:19].C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl.Cl[Pd]Cl>[F:12][C:13]1[CH:14]=[C:15]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:16]=[C:17]([F:20])[C:18]=1[F:19]
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: COC(=O)c1ccnc(Br)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccnc(-c2cc(F)c(F)c(F)c2)c1
Temperature: 100 °C
Yield: 52.9 %

Procedure:
Methyl 2-bromoisonicotinate (4 g, 18.52 mmol), 3,4,5-trifluorophenylboronic acid (4.89 g, 27.77 mmol), potassium carbonate (3.84 g, 27.77 mmol) and PdCl2 (dppf) (0.402 g, 0.56 mmol) were mixed in methanol (30 mL) in two separate 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. Water and DCM were added and the phases were separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield a brown solid. The residue was dissolved in DCM and purified by SCX-2 cation exchange chromatography. Methyl 2-(3,4,5-trifluorophenyl)isonicotinate (2.62 g, 52%) was isolated as a slightly yellow solid. MS m/z 268 (M+H)+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([O:23]C)=[O:22])[CH2:12][CH2:11]2)=[CH:2]1.[H-].[Na+].Br[CH2:32][CH2:33][O:34][CH3:35]>>[CH3:35][O:34][CH2:33][CH2:32][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([OH:23])=[O:22])[CH2:12][CH2:11]2)=[CH:2]1
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Product: COCCn1cc(C2CCN(CCOc3ccccc3C(=O)O)CC2)c2ccccc21

Procedure:
This compound was prepared following the procedure described in Example 138 (part B) starting with 3 g (7.9 mmol) of methyl 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoate, 0.54 g (13.5 mmol) of NaH in 60% of mineral oil and 1.04 mL (11.08 mmol) of bromoethylmethyl ether. The crude mixture was hydrolised following the procedure described in Example 138 (part C) and purified by chromatography over silica gel affording 1.3 g (39% of yield) of the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[O:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB([C:39]2[CH:44]=[CH:43][N:42]=[C:41]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[CH:40]=2)O1>O1CCOCC1.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>[CH3:15][C:14]1[N:13]=[C:12]([NH:16][C:17]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[O:18])[CH:11]=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:39]2[CH:44]=[CH:43][N:42]=[C:41]([N:45]3[CH2:46][CH2:47][O:48][CH2:49][CH2:50]3)[CH:40]=2)[CH:7]=1
Reactant: CC1(C)OB(c2ccnc(N3CCOCC3)c2)OC1(C)C
Reactant: Cc1nc(NC(=O)NC(=O)C(C)C)ccc1Oc1ccnc(Cl)c1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(NC(=O)NC(=O)C(C)C)ccc1Oc1ccnc(-c2ccnc(N3CCOCC3)c2)c1
Temperature: 95 °C
Yield: 28 %

Procedure:
A mixture of N-((5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)isobutyramide (0.136 g, 0.390 mmol), K2CO3 (0.108 g, 0.780 mmol) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (0.136 g, 0.468 mmol) in dioxane (8 mL) and water (2 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.045 g, 0.039 mmol), sparged again with Ar and heated at 95° C. overnight. The mixture was cooled to RT, treated with EtOAc and the solids removed via filtration through a pad of diatomaceous earth and Na2SO4. The filtrate was concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was purified twice more via silica gel chromatography (MeOH/EtOAc). The resulting material was treated with Et2O, sonicated and the solid collected via filtration to afford N-((6-methyl-5-((2′-morpholino-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)carbamoyl)isobutyramide (52 mg, 28%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.05 (s, 1H), 10.84 (s, 1H), 8.54 (d, J=5.6 Hz, 1H), 8.21 (d, J=5.2 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.44 (s, 1H), 7.30 (dd, J=5.2, 1.3 Hz, 1H), 6.80 (dd, J=5.6, 2.4 Hz, 1H), 3.70 (m, 4H), 3.51 (m, 4H), 2.66 (m, 1H), 2.27 (s, 3H), 1.09 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 477.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][NH2:3].C(N(CC)CC)C.[O:11]=[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]([N:22]=[C:23]=[O:24])[CH2:14][CH2:13]1>C(Cl)Cl>[CH3:1][O:2][NH:3][C:23]([NH:22][CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12](=[O:11])[CH2:13][CH2:14]1)=[O:24]
Reactant: CON
Reactant: O=C=NC1CCC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CONC(=O)NC1CCC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of N-methoxyamine (2.5 g), triethylamine (3.04 g) and dry methylene chloride (50 ml) is stirred at room temperature for 20 minutes under a nitrogen atmosphere. Then a solution of 1,2,3,4-tetrahydro-4-oxo-1-naphthyl isocyanate (5.62 g) in dry methylene chloride (50 ml) is added dropwise. After stirring at room temperature for 40 minutes, the reaction mixture is evaporated to dryness in vacuo and the solid residue washed with water (3 × 150 ml) to yield 6.1 g. title product, m.p. 148° to 151° C. Recrystallization from benzene affords crystals, m.p. 155° to 158° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[O:13]([NH2:15])[CH3:14].N1C=CC=CC=1>C(O)C>[CH3:14][O:13]/[N:15]=[C:7]1\[CH2:6][CH2:5][C:4]2[C:8]\1=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CO/N=C1\CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To 5-bromoindanone (6.03 g) in 40 mL ethanol was added 3.58 g methoxylamine hydrochloride and 3.5 mL pyridine. The mixture was stirred at ambient temperature for 1 hour and heated at 80° C. for 3 hours. The volatiles were removed under vacuum and the solid residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The ethyl acetate was washed with brine, dried over magnesium sulfate, filtered, and evaporated under vacuum to yield 6.74 g (98% yield) of a tan solid. 1H NMR (CDCl3) was consistent with an isomeric mixture of the desired structure, with the E oxime isomer as the major component. LC/MS indicated 2 close peaks, both with a M+1 molecular ion of m/z 242.0 by positive ESI.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[N:14]=[CH:13][C:12]=1[C:21](OCC)=[O:22]>C(O)CCC>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:21](=[O:22])[C:12]3=[CH:13][NH:14][C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=4[C:11]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CCCC2
Reactant: NNc1ccc(Cl)cc1
Solvent: CCCCO
Product: Cl
Product: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CCCC3

Procedure:
A mixture of 3.0 g of p-chlorophenylhydrazine and 4.5 g of ethyl 4-chloro-5,6,7,8-tetrahydroquinoline-3-carboxylate (Example 2b) in 150 mL of n-butanol is refluxed for 24 hours under nitrogen atmosphere. The mixture is then evaporated to dryness and the residue is triturated with ether obtaining a yellow solid. This material is dissolved in 750 mL of hot ethanol, decolorized with charcoal, and concentrated to a smaller volume to precipitate a yellow crystalline solid. This material is recrystallized from ethanol containing hydrogen chloride. Crystals are collected, washed with ether and dried in vacuum oven at 80° overnight obtaining 2-p-chlorophenyl-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one hydrochloride, m.p. 284°.
Reaction SMILES: [NH2:1][CH:2]([CH3:34])[CH2:3][CH2:4][N:5](CC1C=CC=CC=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:22][CH2:23][CH:24]([NH2:26])[CH3:25])CC1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[NH2:26][CH:24]([CH3:25])[CH2:23][CH2:22][NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3][CH:2]([NH2:1])[CH3:34]
Reactant: CC(N)CCN(CCCCCCCCN(CCC(C)N)Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(N)CCNCCCCCCCCNCCC(C)N
Yield: 55.5 %

Procedure:
Combine 5.0 g (0.01 mol) of the product of Step D, 0.5 g of 20% Pd(OH)2 on carbon (Pearlman's Catalyst), and 50 ml of ethanol and treat the mixture with H2 at 45 lb/in2 in a shaker flask until no more gas is taken up. Remove the catalyst by filtration and remove the solvent at reduced pressure. Subject the residue to short path distillation to yield 1.59 g of the title compound (bp 145°-148° C. at 0.012 mmHg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[C:30]1([C@H:36]2[CH2:41][CH2:40][CH2:39][CH2:38][C@H:37]2[OH:42])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:42][C@@H:37]2[CH2:38][CH2:39][CH2:40][CH2:41][C@@H:36]2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:12][C:11]=1[F:18])(=[O:8])=[O:9]
Reactant: O[C@@H]1CCCC[C@@H]1c1ccccc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@@H]3CCCC[C@@H]3c3ccccc3)cc2F)c(OC)c1
Yield: 22.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO 2010/079443; 177 mg, 0.397 mmol), (1R*,2R*)-2-phenylcyclohexanol (70.0 mg, 0.397 mmol), sodium hydride (63%; 30.3 mg, 0.794 mol) and DMSO (5.0 mL), to yield the title compound (53.0 mg, 22%) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
To a solution of 4-phenyl phenol (5.00 g, 29.38 mmol) in acetone (100 mL) was added at room temperature, methyl bromoacetate (2.92 mL, 30.84 mmol) and cesium carbonate (14.36 g, 44.06 mmol). The mixture was stirred at room temperature for 5 h. The white precipitate was filtered and the filtrate was concentrated to dryness. Purification by flash chromatography (Hex:EtOAc/7:3) gave 6.76 g of (biphenyl-4-yloxy)-acetic acid methyl ester as a white solid.
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([C:11]1[CH:12]=[CH:13][C:14]([C:17]([OH:19])=[O:18])=[N:15][CH:16]=1)[CH2:8][CH2:9][CH3:10].S(Cl)(Cl)=O.[CH3:24][C:25]1[C:34]([CH3:35])=[C:33]2[C:28]([CH2:29][CH2:30][C:31]([CH2:37][CH2:38][CH2:39][CH:40]([CH2:42][CH2:43][CH2:44][CH:45]([CH2:47][CH2:48][CH2:49][CH:50]([CH3:52])[CH3:51])[CH3:46])[CH3:41])([CH3:36])[O:32]2)=[C:27]([CH3:53])[C:26]=1O>N1C=CC=CC=1>[CH3:10][CH2:9][CH2:8][CH2:7][C:11]1[CH:12]=[CH:13][C:14]([C:17]([O:19][C:26]2[C:27]([CH3:53])=[C:28]3[CH2:29][CH2:30][C:31]([CH2:37][CH2:38][CH2:39][CH:40]([CH2:42][CH2:43][CH2:44][CH:45]([CH2:47][CH2:48][CH2:49][CH:50]([CH3:52])[CH3:51])[CH3:46])[CH3:41])([CH3:36])[O:32][C:33]3=[C:34]([CH3:35])[C:25]=2[CH3:24])=[O:18])=[N:15][CH:16]=1
Reactant: CCCCc1ccc(C(=O)O)nc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCc1ccc(C(=O)Oc2c(C)c(C)c3c(c2C)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O3)nc1
Temperature: 0 °C
Yield: 46.6 %

Procedure:
Ten milliliters of benzene was added to 4.51 g of 5-butylpicolinic acid, and 9 g of thionyl chloride was further added. The mixture was heated under reflux for 22 minutes. The excess of thionyl chloride and benzene were disiled off under reduced pressure, and 10 ml of benzene was added to the residue. The mixture was cooled to 0° C. and stirred. To the solution was added dropwise a solution of 5 g of dl-α-tocopherol in 4.25 ml of pyridine to perform the reaction for 1 hour and 40 minutes. The insoluble matter was removed by filtration from the reaction mixture, and the residue was washed with water, 1 N hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in this order. Benzene was distilled off, and the residue was chromatographed on a silica gel column using benzene/ethyl acetate (4:1) as an eluent to give 3.2 g of dl-α-tocopheryl 5-butylpicolinate.
Reaction SMILES: C[O:2][C:3](=O)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[F:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)/[CH:5]=[CH:4]/[CH2:3][OH:2]
Reactant: COC(=O)/C=C/c1cccc(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OC/C=C/c1cccc(F)c1
Temperature: -30 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of trans-3-fluorocinnamic acid methyl ester (69.61 g, 386 mmol) in dry dichloromethane (1 L) at −78° C. under nitrogen was added dropwise diisobutylaluminum hydride (neat, 172 mL, 965 mmol, 2.5 equiv.) via an addition funnel. After the addition was complete, the reaction mixture was allowed to warm to −30° C. and stirred for an additional 1 hour, then quenched with methanol (150 mL). Upon warming to room temperature, the reaction mixture was treated with saturated aqueous solution of sodium/potassium tartrate (300 mL) and stirred for 30 minutes. The organic layer was washed sequentially with 1 N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, brine, and dried (anhydrous sodium sulfate). The crude oil was purified by silica gel chromatography (0-50% ethyl acetate:hexane) to give 53.07 g (90%) of trans-3-fluorocinnamyl alcohol as a colorless oil. MS (ES) m/z 152.1 (M+).
Reaction SMILES: [CH2:1]([C:3]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[N:16]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:17]=[C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)[N:19]=2)=[O:14])[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].[BH4-].[Na+].O>CCO>[CH2:1]([C:3]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:15]2[N:16]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:37])[CH3:35])[CH:17]=[C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)[N:19]=2)[OH:14])[O:4][CH2:5][CH2:6][O:7]1)[CH3:2]
Reactant: CCC1(CCCCCC(=O)c2nc(-c3ccc4ccccc4c3)cn2COCC[Si](C)(C)C)OCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC1(CCCCCC(O)c2nc(-c3ccc4ccccc4c3)cn2COCC[Si](C)(C)C)OCCO1
Reaction time: 1 h

Procedure:
To a solution of the ketone F1 in EtOH (0.04 M solution) at 0° C. was added NaBH4 (2.0 eq.) and the mixture was stirred for 1 hr. Water was slowly added and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (MgSO4) and solvents were removed under reduced pressure. The crude product was used without purification in the next step. MS (ES) C30H44N2O4Si requires: 525, found: 526 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[CH:2].[CH3:12][N:13]1[C:17]([NH2:18])=[CH:16][C:15]([CH3:19])=[N:14]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:12][N:13]1[C:17]([NH:18][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:1]#[CH:2])[CH:4]=2)=[CH:16][C:15]([CH3:19])=[N:14]1
Reactant: Cc1cc(N)n(C)n1
Reactant: C#Cc1cccc(C(=O)O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#Cc1cccc(C(=O)Nc2cc(C)nn2C)c1
Temperature: 50 °C
Yield: 78.1 %

Procedure:
3-Ethynylbenzoic acid (0.1 g, 0.685 mmol) was added to a dry 50 mL round bottom flask and dissolved in DMF (6.85 mL). To the resulting solution was added 1,3-dimethyl-1H-pyrazol-5-amine (0.076 g, 0.685 mmol), followed by BOP (0.393 g, 0.890 mmol), and 0.238 mL of DIPEA (1.37 mmol). This reaction mixture was heated to 50° C. for 3 h. After allowing the reaction to cool to room temperature it was taken up in EtOAc (15 mL) and extracted with brine (3×15 mL). The EtOAc layer was then washed with saturated aqueous NaHCO3 (2×15 mL). The organics were dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude residue was purified via column chromatography (silica gel, gradient eluant mixture of EtOAc in Hexanes: 0% to 100% EtOAc) affording N-(1,3-dimethyl-1H-pyrazol-5-yl)-3-ethynylbenzamide (0.128 g, 78%).