Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][S:16]([NH:19]CC2C=CC(OC)=CC=2OC)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([Li])C=CC=CC=1.[CH3:38][C:39]([CH3:41])=[O:40].FC(F)(F)C(O)=O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([S:16]([NH2:19])(=[O:17])=[O:18])[C:39]([OH:40])([CH3:41])[CH3:38])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: COc1ccc(CNS(=O)(=O)Cc2cccc(OCc3ccccc3)c2)c(OC)c1
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)C(c1cccc(OCc2ccccc2)c1)S(N)(=O)=O
Temperature: -75 °C

Procedure:
Under inert gas, 3.10 g of C-(3-benzyloxyphenyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide were initially charged in 60 ml of THF, and then, at a temperature of −75° C., 12.00 ml of a 1.8 N phenyllithium solution were added dropwise. The reaction mixture was allowed to come to 0° C. and stirred briefly, then cooled again to −75° C., and 3.80 ml of acetone were added dropwise. After stirring for 10 minutes, 3 ml of trifluoroacetic acid were added and the mixture was allowed to come to room temperature. After the removal of the solvent under reduced pressure, the residue was dissolved in 20 ml of dichloromethane and admixed with 5.00 ml of trifluoroacetic acid. After stirring at room temperature for 2.5 hours, the reaction solution was neutralized cautiously with 2 N aqueous sodium hydroxide solution and then stirred overnight. The precipitate formed was filtered off with suction, washed with dichloromethane and cold water, and coevaporated twice with toluene. The crude product was purified by means of normal phase chromatography using a Flashmaster with a dichloromethane/methanol gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (2.06 g) with a molecular weight of 335.4 g/mol (C17H21NO4S).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13]3[N:21]=[C:20]4[C:16]([N:17]=[CH:18][N:19]4COCC[Si](C)(C)C)=[C:15]([O:30][C:31]4[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=4)[N:14]=3)[CH:9]=[N:8]2)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13]3[N:21]=[C:20]4[C:16]([N:17]=[CH:18][NH:19]4)=[C:15]([O:30][C:31]4[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=4)[N:14]=3)[CH:9]=[N:8]2)[CH2:3]1
Reactant: C=CC(=O)Nc1cccc(Oc2nc(Nc3cnn(C4CCN(C)C4)c3)nc3c2ncn3COCC[Si](C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3cnn(C4CCN(C)C4)c3)nc3[nH]cnc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a mixture of N-{3-[(2-{[1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl]amino}-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purin-6-yl)oxy]phenyl}prop-2-enamide (271 mg, 0.471 mmol) in DCM (5.89 mL) was added TFA (1.81 mL, 23.6 mmol). The resulting solution was stirred at rt overnight, then concentrated and dried under vacuum. The resulting residue was taken up in water and neutralized with NaHCO3 to get a slightly sticky suspension. The solid was filtered off, washed with water, dried, and collected to give the crude product, which was purified by SFC to afford the title compound (21 mg, 10 yield) as a lyophilized solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.80 (br. s., 1H) 10.37 (br. s., 1H) 9.20 (br. s., 1H) 8.01-8.11 (m, 1H) 7.61-7.78 (m, 1H) 7.48 (br. s., 1H) 7.37 (d, J=6.32 Hz, 1H) 7.03 (d, J=7.33 Hz, 2H) 6.36-6.59 (m, 1H) 6.20-6.34 (m, 1H) 5.77 (dd, J=10.23, 1.89 Hz, 1H) 4.57 (br. s., 1H) 3.99-4.27 (m, 1H) 3.65-3.94 (m, 3H) 3.00 (br. s., 2H) 2.79 (m, J=15.66 Hz, 1H) 2.00 (br. s., 1H) 1.23 (s, 1H). m/z (APCI+) for C22H23N9O2 446.05 (M+H)+.
Reaction SMILES: Cl[C:2]1(Cl)[C:8](=[O:9])[CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[N+](=[CH2:20])=[N-].CO.CCOCC>C(O)(=O)C.[Zn]>[CH2:10]([CH:6]1[CH2:5][CH2:4][CH:3]2[CH:7]1[CH2:20][C:8](=[O:9])[CH2:2]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCC1CCC2C1C(=O)C2(Cl)Cl
Reactant: C=[N+]=[N-]
Agent: [Zn]
Solvent: CO
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCCCC1CCC2CC(=O)CC12
Temperature: 70 °C

Procedure:
The procedure followed is the same as that described in Example 29 substituting the starting material from Example 34, 6,6-dichloro-2-(hept-1-yl)bicyclo[3.2.0]heptan-7-one {7,7-dichloro-4-heptylbicyclo[3.2.0]heptan-6-one} and isomers (14.2 g, 0.051 moles), an etheral diazomethane solution (175 ml), methanol (5 ml), and acetic acid (15 ml). After the acetic acid is added the solvent is removed under vacuum leaving a clear yellow oil. The crude product is then dissolved in acetic acid (100 ml) and stirred while zinc powder (29 g) is slowly added. The reaction is heated in a 70° C. water bath for 1 hour, after which time ether (500 ml) is added and the solution filtered. The filtrate is washed with brine (100 ml) and then with a solution of saturated bicarbonate. The ether layer is separated and dried over anhydrous sodium sulfate. The solvent is removed under vacuum leaving a clear yellow oil. The crude product is chromatographed on silica gel and subsequently kugelrohred under vacuum leaving a clear, colorless oil (4.3 g, 0.015 moles).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17](Br)[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[CH:21]([Zn]C(C)C)([CH3:23])[CH3:22].C([Zn]CCC)CC.NCC1C(F)=C(OC2C=C(C=C(C(C)C)C=2)C#N)C(Cl)=CC=1>C1COCC1.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>[NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH2:22][CH2:21][CH3:23])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: CC(C)[Zn]C(C)C
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)c1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CCC[Zn]CCC
Solvent: C1CCOC1
Product: CCCc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 70 °C
Yield: 55.2 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.400 g, 1.125 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.130 g, 0.112 mmol) were combined in THF (7 mL) and treated with an apparent mixture of diisopropylzinc and di-n-propylzinc (1 M in toluene, Aldrich 568112) (2.250 mL, 2.250 mmol) with stirring under an inert atmosphere. The reaction mixture was heated to 70° C. and stirred for 2 h. The reaction mixture was concentrated to dryness and partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted successively with EtOAc and 10% CH3OH/DCM to give a mixture of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(1-methylethyl)benzonitrile and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-propylbenzonitrile (1:6 ratio) (0.198 g, 0.621 mmol, 55.2% yield) as a clear oil. Diagnostic peaks in the aliphatic region of the NMR are as indicated below and were found to be in a ratio of ˜1:6, 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(1-methylethyl)benzonitrile to 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-propylbenzonitrile. 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(1-methylethyl)benzonitrile: 1H NMR (400 MHz, DMSO-d6) δ ppm 2.95 (spt, J=6.82 Hz, 1H), 1.19 (d, J=6.87 Hz, 6H). 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-propylbenzonitrile: 1H NMR (400 MHz, DMSO-d6) δ ppm 2.58 (t, J=7.55 Hz, 2H), 1.49-1.63 (m, 2H), 0.85 (t, J=7.33 Hz, 3H). LC-MS (ES−) m/z 317.12, 319.14 [M−1]. LC-MS (ES+) m/z 318.99, 320.99 [M+H].
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]([CH3:8])[CH3:7])[C@H:3]1[C:9](Cl)=[O:10].[CH3:13][C:14]1[CH:15]([OH:22])[CH2:16][C:17](=[CH2:21])[C:18]=1[CH2:19][CH3:20].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]([CH3:8])[CH3:7])[C@H:3]1[C:9]([O:22][CH:15]1[CH2:16][C:17](=[CH2:21])[C:18]([CH2:19][CH3:20])=[C:14]1[CH3:13])=[O:10]
Reactant: CC(C)=C[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: C=C1CC(O)C(C)=C1CC
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=C1CC(OC(=O)[C@@H]2[C@@H](C=C(C)C)C2(C)C)C(C)=C1CC
Yield: 90 %

Procedure:
540 mg of (1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylic acid chloride was added under ice-water cooling to a mixed solution of 400 mg of (RS)-2-methyl-4-methylidene-3-ethylcyclopent-2-en-1-ol, 5 mg of 2,6-di-t-butyl-4-methylphenol and 274 mg of pyridine in 6 ml of toluene. The reaction was allowed to react at an ambient temperature for eight hours. The reaction solution was added to a 5% citric acid solution under ice-water cooling and extracted three times with diethyl ether. The combined ether layer was washed successively with a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the obtained residue was subjected to silica gel column chromatography to yield 751 mg of (RS)-2-methyl-4-methylidene-3-ethyl-2-cyclopenten-1-yl (1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate (Compound No.1). Yield 72% (Eluent: n-hexane/ethyl acetate=30/1, 2,6-di-t-butyl-4-methylphenol 0.1%) nD20.5 1.5070
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[C:16]([OH:18])=O)=[O:9])[CH2:4][CH2:3]1.[NH2:20][C:21]1[S:22][C:23]([CH2:32][CH3:33])=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:25]=1.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>ClCCl>[CH2:32]([C:23]1[S:22][C:21]([NH:20][C:16]([C@@H:11]2[CH2:12][CH2:13][CH2:14][CH2:15][N:10]2[C:8]([N:5]2[CH2:4][CH2:3][S:2](=[O:1])(=[O:19])[CH2:7][CH2:6]2)=[O:9])=[O:18])=[N:25][C:24]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:33]
Reactant: CCc1sc(N)nc1-c1ccccc1
Reactant: O=C(O)[C@@H]1CCCCN1C(=O)N1CCS(=O)(=O)CC1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: CCc1sc(NC(=O)[C@@H]2CCCCN2C(=O)N2CCS(=O)(=O)CC2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-1-(1,1-Dioxo-1λ6-thiomorpholine-4-carbonyl)-piperidine-2-carboxylic acid (92 mg; 0.317 mmol) and 2-amino-5-ethyl-4-phenyl-1,3-thiazole (64.8 mg; 0.317 mmol) in dichloromethane (4 mL) is added 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (79.1 mg; 0.32 mmol). The reaction mixture is left stirring at room temperature for 18 hours. The reaction mixture is directly purified by preparative HPLC provides the title compound, m/z 477 [M+H+].
Reaction SMILES: CO[C:3]([CH2:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]([OH:17])=O)=[O:7])=O.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([NH2:26])[CH:20]=1>>[OH:17][C:15]1[C:14]2[C:9](=[CH:10][N:11]=[CH:12][CH:13]=2)[NH:8][C:6](=[O:7])[C:5]=1[C:3]1[NH:26][C:21]2[CH:20]=[C:19]([CH3:18])[CH:24]=[CH:23][C:22]=2[N:25]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: COC(=O)CC(=O)Nc1cnccc1C(=O)O
Product: Cc1ccc2nc(-c3c(O)c4ccncc4[nH]c3=O)[nH]c2c1

Procedure:
The title compound was synthesized as described in Example 50 using 3-[2-(methoxycarbonyl)acetylamino]-pyridine-4-carboxylic acid and 4-methyl-1,2-phenylenediamine. The crude product was purified by reversed-phase HPLC (DMSO/5% TFA). LC/MS m/z 293.3 (MH+), Rt 1.99 minutes.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[NH:21][C:14]=23)[CH2:3][CH2:2]1.Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:14]=23)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C)ccc3OCC3CC3)ccnc12
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(C)ccc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl 7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example D.a6) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is prepared as pale yellow viscous oil.
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N(CC)C(C)C)(C)C.[O:37]=[C:38]1[N:47]([CH2:48][CH2:49][CH3:50])[C:46](=[O:51])[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([C:52]([C:54]3[N:58]4[CH:59]=[CH:60][CH:61]=[CH:62][C:57]4=[C:56]([C:63]4[CH:64]=[C:65]([CH:69]=[CH:70][CH:71]=4)[C:66](O)=[O:67])[N:55]=3)=[O:53])[CH:44]=2)[NH:39]1>CN(C=O)C>[C:1]([NH:4][NH:5][C:66](=[O:67])[C:65]1[CH:69]=[CH:70][CH:71]=[C:63]([C:56]2[N:55]=[C:54]([C:52]([C:43]3[CH:44]=[C:45]4[C:40](=[CH:41][CH:42]=3)[NH:39][C:38](=[O:37])[N:47]([CH2:48][CH2:49][CH3:50])[C:46]4=[O:51])=[O:53])[N:58]3[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=23)[CH:64]=1)(=[O:3])[CH3:2]
Reactant: CCCn1c(=O)[nH]c2ccc(C(=O)c3nc(-c4cccc(C(=O)O)c4)c4ccccn34)cc2c1=O
Reactant: CC(=O)NN
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCn1c(=O)[nH]c2ccc(C(=O)c3nc(-c4cccc(C(=O)NNC(C)=O)c4)c4ccccn34)cc2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
29.6 mg (0.4 mmol) of acetohydrazide, 98.4 mg (0.3 mmol) of TOTU and 0.104 ml (0.6 mmol) of N,N-diisopropylethylamine are added, under an inert atmosphere, at 0° C., to 93.7 mg (0.2 mmol) of 3-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoic acid in 6 ml of DMF. The reaction medium is stirred for 1 hour at 0° C. and then for 6 hours at 50° C. and then concentrated under reduced pressure. The residue is taken up in 10 ml of methanol. The precipitate obtained is filtered off, washed with dyethyl ether and with pentane, and then dried under reduced pressure at 40° C. overnight. 45 mg of a yellow solid are obtained.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].[CH3:17][C:18]1([CH3:25])[C:22]([CH3:24])([CH3:23])[O:21][BH:20][O:19]1.C(N(CC)CC)C>C(Cl)Cl.[H-].[Cl-].C1([Zr+2]C2C=CC=C2)C=CC=C1>[CH3:17][C:18]1([CH3:25])[C:22]([CH3:24])([CH3:23])[O:21][B:20](/[CH:3]=[CH:2]/[CH2:1][CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[O:19]1
Reactant: CC1(C)OBOC1(C)C
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: C1=CC([Zr+2]C2C=CC=C2)C=C1
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C/C=C/B2OC(C)(C)C(C)(C)O2)CC1
Temperature: 25 °C
Yield: 51.8 %

Procedure:
A solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (0.162 g, 0.725 mmol) synthesized in Example B58, Step 1 in methylene chloride (1 mL) was added with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.139 g, 1.09 mmol) and triethylamine (0.00734 g, 0.0725 mmol), and the mixture was stirred at room temperature. The reaction mixture was added with bis(cyclopentadienyl)zirconium(IV) chloride hydride (0.0281 g, 0.109 mmol), and the mixture was stirred at room temperature for 40 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (E)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl]piperidine-1-carboxylate (0.132 g, 52%).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:16][C:15](=[O:17])[C:14]3=[CH:18][CH:19]=[CH:20][N:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[OH2:21].[C:22]1([CH3:32])C=CC(S(O)(=O)=O)=CC=1.O>C(O)CO>[OH:21][CH2:22][CH2:32][O:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:16][C:15](=[O:17])[C:14]3=[CH:18][CH:19]=[CH:20][N:13]3[N:12]=2)=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(O)c1ccc(-c2nn3cccc3c(=O)[nH]2)cc1
Solvent: OCCO
Product: CC(C)(OCCO)c1ccc(-c2nn3cccc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To a suspension of 2-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (53.9 mg, 0.20 mmol) in ethane-1,2-diol (0.7 ml) is added toluene-4-sulfonic acid monohydrate (3.8 mg, 20 μmol). The reaction mixture is stirred for 7 days at ambient temperature. Water is added to the reaction mixture. The resulting precipitate is filtered off, washed with water and dried under vacuum. It is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 2-{4-[1-(2-hydroxy-ethoxy)-1-methyl-ethyl]-phenyl}-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one as white crystals; HPLC/MS 2.18 min (B), [M+H] 314;
Reaction SMILES: [CH3:1][C:2]([CH3:17])=[CH:3][CH2:4][NH:5][C:6](=[O:16])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[N+:13]([O-:15])=[O:14].[ClH:18].N=C=O.[N:22]([O:24]CCC(C)C)=O>>[Cl:18][C:2]([CH3:17])([CH3:1])[C:3](=[N:22][OH:24])[CH2:4][NH:5][C:6](=[O:16])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[N+:13]([O-:15])=[O:14]
Reactant: CC(C)CCON=O
Reactant: Cl
Reactant: CC(C)=CCNC(=O)Cn1ccnc1[N+](=O)[O-]
Agent: N=C=O
Product: CC(C)(Cl)C(CNC(=O)Cn1ccnc1[N+](=O)[O-])=NO

Procedure:
N-(3-methyl-2-butenyl)-2-(2-nitro-1H-imidazol-1-yl)acetamide (3.4 g, 14.3 mmol) was dissolved in isoamyl nitrite (50 mL) at room temperature. The solution was cooled to 0°-5° C. in an ice-salt bath. Concentrated HCl (1.39 mL) was added dropwise. The reaction temperature was maintained between 0° to 5° C. during the addition of HCl. The reaction mixture was stirred in the ice-salt bath for 1 h, filtered, and washed with 1:2 ethanol-ether to give a white solid. Yield: 3.7 g (85%). mp: 154°-160° C. (decomp.). 1H NMR (DMSO-d6) ε 1.74 and 1.88 [s, 6H, =C(CH3)2 ], 4.17 (q, 2H, HNCH2CH=), 5.08 (s, 2H, COCH2 -imidazolyl), 5.14 (t, 1H, CH2CH=), 7.18 and 7.63 (s, 2H, 2-nitroimidazolyl-H), 8.51 (t, 1H, HNCO), 11.60 (b, 1H, HON=C).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C@@H:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.[CH3:31][PH:32](=[O:34])[CH3:33]>CCCCCC.C(O)(C)C>[Cl:20][C:13]1[C:14]([F:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C@H:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:22]2[CH:27]=[CH:26][C:25]([P:32]([CH3:33])([CH3:31])=[O:34])=[CH:24][CH:23]=2)[CH:3]=1)[CH3:11]
Reactant: C[PH](C)=O
Reactant: C[C@@H](Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: OB(O)c1ccc(Br)cc1
Solvent: CC(C)O
Solvent: CCCCCC
Product: C[C@@H](Oc1cc(-c2ccc(P(C)(C)=O)cc2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared from 5-bromo-3-[(1R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine, 4-bromophenyl boronic acid, and dimethylphosphine oxide following the same procedures as Example 1 Step 1 and Step 3; ESMS: m/z 453 (M+H)+; chiral purity 99.87% (column AD-H 4.6*250 mm 5 um; solvent:hexane/isopropanol).
Reaction SMILES: S(=O)(=O)(O)O.[NH:6]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[N:7]1.[CH3:14]O>>[CH3:14][O:12][C:11]([C:8]1[CH:9]=[CH:10][NH:6][N:7]=1)=[O:13]
Reactant: O=C(O)c1cc[nH]n1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc[nH]n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
Sulfuric acid (5.8 mL) was added dropwise to a stirred solution of 1H-pyrazole-3-carboxylic acid (1 g, 8.92 mmol) in MeOH (65 mL) at 0° C. After the addition was completed the mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was concentrated in vacuo and the residue was dissolved in water and basified with NaHCO3 (aq. sat. solution). The mixture was extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield 1H-pyrazole-3-carboxylic acid methyl ester (0.7 g, 62% yield) as a white solid which was used in the next step without further purification.
Reaction SMILES: C(O)(=O)CCCCCCCCC#CC#CCCCCCCCCCC.CO.C(Cl)(Cl)Cl.[C:32]([O:58][CH3:59])(=[O:57])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]#[C:42][C:43]#[C:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]CC>S(=O)(=O)(O)O.C(O)C>[C:32]([O:58][CH3:59])(=[O:57])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]#[C:42][C:43]#[C:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCCCCCC#CC#CCCCCCCCCC(=O)OC
Agent: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)OC
Temperature: 25 °C

Procedure:
10,12-tricosadiynoic acid (10 gm, GFS Chemicals) was dissolved in a solution containing 10 ml methanol (HPLC grade) and 10 ml chloroform (HPLC grade). The solution was stirred at room temperature and 10 drops of neat sulfuric acid was added drop wise. The solution was warmed to 100° F. for 2 hour. The reaction mixture was purified using column chromatography. The product (MeTDA) was dried using a rotovap and the material stored in a chloroform solution. The solid form of MeTDA was very unstable to polymerization and therefore kept dissolved in organic solutions. Alcoholic solutions of MePDA and MeTDA: Solids MePDA or MeTDA were dissolved in reagent grade ethanol to a concentration of 150 mg/ml. An residual polymer was removed by filtration through Whatman No. 1 filter paper. The solutions was held at room temperature or slightly above (70-75° F.) to avoid crystallization or precipitation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:16]1([CH2:20]Br)[CH2:19][CH2:18][CH2:17]1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:20][CH:16]3[CH2:19][CH2:18][CH2:17]3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: BrCC1CCC1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1CC1CCC1

Procedure:
The title compound, MS: m/e=286.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and cydobutyl-methylbromide.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:7]2)[CH:2]=[CH2:3].C[N+]1([O-])CC[O:27]CC1.[OH2:31]>C(O)(C)(C)C.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[OH:31][CH:2]([CH2:3][OH:27])[CH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:7]2
Reactant: C=CCc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1Cc2ccc(CC(O)CO)cc2C1
Reaction time: 3 h

Procedure:
To a suspension of benzyl 5-allylisoindoline-2-carboxylate (294 mg, 1 mmol) in tert-butanol (2.5 mL) and water (2.5 mL) was added N-methylmorpholine-N-oxide (257 mg, 2.2 mmol) followed by osmium tetroxide solution (0.1 mL of 4% wt in water). The resulting mixture was stirred for 3 hr (during which time the mixture becomes homogeneous). This solution was diluted with ethyl acetate, washed with saturated sodium thiosulfate solution then brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by silica chromatography (25 g silica eluted with 3-40% ethyl acetate in hexane) to give the title compound as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:5][CH:4]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: CC(=O)c1ccccc1
Product: CSc1ccc(C=CC(=O)c2ccccc2)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from commercial 4-(methylthio)benzaldehyde and acetophenone, 3-[4-(methylthio)phenyl]-1-phenylprop-2-en-1-one was obtained as yellowish solid.