Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10].[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[S:6][C:5](/[CH:7]=[CH:12]/[N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: Cc1ccc(C=O)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(/C=C/[N+](=O)[O-])s1
Temperature: 10 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of 10.3 g (80 mmol) 5-methyl-2-thiophenecarboxaldehyde (commercially available) and 13.5 mL nitromethane in 160 mL methanol was cooled to −5° C. A 50% sodium hydroxide solution (80 mL) was added drop wise maintaining the temperature between 5 and 10° C. (formation of a yellow precipitate). After complete addition the mixture was stirred at 10° C. for 1 h. The suspension was poured onto an ice-cold solution of HCl 37% (340 mL) and water (560 mL). The crude product separated as a yellow solid, which was filtered and dissolved in dichloromethane. The solution was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified on a silica eluting with a gradient formed from heptane and ethyl acetate. Evaporation of the product fractions yielded 6.9 g (51%) of the title compound as yellow solid.
Reaction SMILES: C(NCC)C.[C:6]([OH:12])(=[O:11])[CH2:7][CH2:8][C:9]#[CH:10].[I:13][C:14]1[S:15][CH:16]=[C:17](I)[CH:18]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[I:13][C:14]1[S:15][C:16]([C:10]#[C:9][CH2:8][CH2:7][C:6]([OH:12])=[O:11])=[CH:17][CH:18]=1
Reactant: Ic1csc(I)c1
Reactant: C#CCCC(=O)O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: O=C(O)CCC#Cc1ccc(I)s1
Reaction time: 8 h

Procedure:
To 75ml of diethylamine was added with stirring 3.76g of 4-pentynoic acid, 22g of 2,4-diiodothiophene, and 300mg of tetrakis(triphenylphosphine)palladium(o). The slurry was degassed with argon and 960mg of CuI was added. The slurry was maintained under argon and allowed to stir overnight, producing a dark brown solution. Thereafter, the solvent was removed under reduced pressure and 100ml of 10% HCl was added to the residue. The residue was filtered and then extracted 3x with ethyl acetate. The combined extracts were washed 1x with water, dried over anhydrous MgSO4, filtered, and stripped. The resulting residue was flash chromatographed on a column of silica gel. Elution with a mixture of 30/70/2 parts ethyl acetate/hexane/acetic acid produced 3.5 g of the titled product as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:24][CH3:25])[CH:17]=3)[CH2:11][CH2:10]2)=[O:7])=[CH:4][N:3]=1.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[CH2:13][CH2:14][CH:9]([NH:8][C:6](=[O:7])[C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:31]([CH:28]4[CH2:30][CH2:29]4)=[O:32])=[N:3][CH:4]=3)[CH2:10][CH2:11]2)=[CH:17][C:18]=1[O:23][CH2:24][CH3:25]
Reactant: O=C(Cl)C1CC1
Reactant: CCOc1cc(CN2CCC(NC(=O)c3ccc(N)nc3)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(NC(=O)C4CC4)nc3)CC2)ccc1Cl
Yield: 26 %

Procedure:
The title compound (12 mg, 26%) was prepared analogously to example 7 by coupling of 6-amino-N-[1-(4-chloro-3-ethoxy-benzyl)piperidin-4-yl]-nicotinamide with cyclopropanecarbonyl chloride. MS: 457.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]=[O:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[CH3:15][Mg]Br.CCOCC>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH:13]([OH:14])[CH3:15])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cnc(-c2ccc(F)cc2)s1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1cnc(-c2ccc(F)cc2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 2-(4-fluorophenyl)thiazole-5-carbaldehyde (500 mg, 2.41 mmol) in THF (25 mL) was added 3M methyl magnesium bromide in ether (1.61 mL, 4.83 mmol) slowly at 0° C. The reaction mixture stirred for 1 hour at 0° C. and then at room temperature for about 1 hour. The reaction mixture was quenched with saturated NH4Cl solution (25 mL), extracted with ethyl acetate (3×150 mL), the organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain crude product. The crude product was purified by flash chromatography (100-200μ; 30% ethyl acetate in hexane) to afford 1-(2-(4-fluorophenyl)thiazol-5-yl)ethanol as light yellow solid (420 mg, 78% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.93 (t, 2H), 7.67 (s, 1H), 7.30 (t, 2H), 5.71 (d, 1H), 5.01 (t, 1H), 1.45 (d, 3H); LC-MS m/z calculated for [M+H]+ 224.05, found 224.4
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:7]([S:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[C:11]([O:17][CH3:18])[CH:10]=3)=[CH:6][C:5](=[O:19])[CH:4]=1.[Br:20]Br.CO>C(O)(=O)C>[Br:20][C:6]1[C:5](=[O:19])[CH:4]=[C:3]([O:2][CH3:1])[C:16]2[C:7]=1[S:8][C:9]1[C:14](=[CH:13][CH:12]=[C:11]([O:17][CH3:18])[CH:10]=1)[N:15]=2
Reactant: BrBr
Reactant: COc1ccc2nc3c(OC)cc(=O)cc-3sc2c1
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc2nc3c(OC)cc(=O)c(Br)c-3sc2c1
Reaction time: 0.25 h

Procedure:
To a suspension of 1,7-dimethoxy-3H-phenothiazin-3-one (300 mg) in acetic acid (9 ml) was added a 0.63M solution of Br2 in acetic acid (1.92 ml). After 15 minutes, methanol was added and the solid filtered, washed with ether and air dried to afford the title compound (353 mg), m.p. 267°-270° C. (dec).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:29][CH:28]=[N:27][CH:26]=1)[CH:20]([NH:30]C(OC(C)(C)C)=O)[C:19]2=[O:38])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O)(=O)=O>C(#N)C>[NH2:30][CH:20]1[C:19](=[O:38])[N:18]2[CH:21]1[S:22][CH2:23][C:24]([C:25]1[S:29][CH:28]=[N:27][CH:26]=1)=[C:17]2[C:15]([O:14][CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cncs3)CSC12
Agent: CS(=O)(=O)O
Solvent: CC#N
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cncs3)CSC12
Yield: 100.3 %

Procedure:
Following the working method described in Example 15, 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-(thiazol-5-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (10 g) is treated with methanesulphonic acid (10 cc) in acetonitrile (100 cc). 7-Amino-2-benzhydryloxycarbonyl-8-oxo-3-(thiazol-5-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (8.2 g) is obtained in the form of a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:35]2[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:34])[N:11]([CH:21]2[CH2:33][CH2:32][C:24]3([O:28][C@H:27]4[CH2:29][O:30][CH2:31][C@H:26]4[O:25]3)[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].C([BH3-])#N.[Na+].O1CCCC1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:35]2[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:34])[N:11]([C@H:21]2[CH2:22][CH2:23][C@H:24]([O:25][C@H:26]3[C@@H:27]([OH:28])[CH2:29][O:30][CH2:31]3)[CH2:32][CH2:33]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)O[C@H]2COC[C@H]2O3)c2ncnn12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O[C@@H]3COC[C@@H]3O)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 48 h

Procedure:
A mixture of 3′-fluoro-4′-({5-oxo-7-propyl-4-[(3a′R,6a′S)-tetrahydrospiro[cyclohexane-1,2′-furo[3,4-d][1,3]dioxol]-4-yl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (1.3 g), sodium cyanoborohydride (2.9 g), boron trifluoride-diethyl ether complex (5.9 mL) and tetrahydrofuran (50 mL) was stirred at 70° C. for 2 days. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.39 g, 30%).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=1>ClCCl>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH:20][S:33]([C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)(=[O:35])=[O:34])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(NS(=O)(=O)c2cccnc2)c1
Reaction time: 48 h
Yield: 59.8 %

Procedure:
To a solution of 3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 12, 220 mg, 0.809 mmol) in dichloromethane (5 ml) at room temperature was added pyridine (0.196 ml, 2.42 mmol) then dropwise over 5 minutes 3-pyridinesulfonylchloride (198 mg, 1.21 mmol). The mixture was stirred for 48 hours, concentrated in vacuo and the residue was purified by silica (10 g) column chromatography eluting with ethyl acetate then 90:10:1 ethyl acetate:methanol:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale orange oil (200 mg, 60%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31]Br)[CH2:26][CH2:25]2)=[C:20](/[CH:34]=[CH:35]\[CH3:36])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:37]1[C:46]2[CH:45]=[C:44]([C:47]3([CH3:54])[NH:51][C:50](=[O:52])[NH:49][C:48]3=[O:53])[N:43]=[CH:42][C:41]=2[O:40][CH2:39][CH2:38]1>>[CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31][N:49]3[C:48](=[O:53])[C:47]([C:44]4[N:43]=[CH:42][C:41]5[O:40][CH2:39][CH2:38][O:37][C:46]=5[CH:45]=4)([CH3:54])[NH:51][C:50]3=[O:52])[CH2:26][CH2:25]2)=[C:20]([CH:34]=[CH:35][CH3:36])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(c2cc3c(cn2)OCCO3)NC(=O)NC1=O
Reactant: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)CC1
Product: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3cc4c(cn3)OCCO4)C2=O)CC1

Procedure:
(Z)-1-(4-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-2-(prop-1-en-1-yl)phenyl}piperazin-1-yl)-2-bromoethanone and 5-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-5-methyl imidazolidine-2,4-dione were used for a similar reaction and treatment as Example 14-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[NH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>CN(C)C=O>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][NH:13][CH2:3][CH2:2][C:1]([NH2:5])=[O:4]
Reactant: C=CC(N)=O
Reactant: NCc1ccccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)CCNCc1ccccn1
Temperature: 40 °C
Reaction time: 72 h

Procedure:
Acrylamide (3.29 g; 46.24 mmol) and triethylamine (0.468 g; 4.624 mmol; 6.62 μl)) are added dropwise in succession at ambient temperature, with stirring and under an argon atmosphere, to a solution of 2-(aminomethyl)-pyridine (5 g; 46.24 mmol; 4.77 ml) in 19 ml of dimethylformamide. The reaction mixture is then heated to 40° C. and stirred at that temperature for 72 hours. At the end of the reaction, the reaction mixture is concentrated and the residue is purified by chromatography on silica gel (eluant: CH2Cl2/EtOH/NH4OH 80/20/2) to yield the title product in the form of a yellow oil.
Reaction SMILES: [H-].[Na+].[C:3](=O)(OCC)[O:4]CC.F[C:12]1[CH:13]=[CH:14][C:15]([OH:21])=[C:16]([C:18](=[O:20])[CH3:19])[CH:17]=1.[OH-].[Na+]>C1C=CC=CC=1>[OH:20][C:18]1[C:16]2[C:15](=[CH:14][CH:13]=[CH:12][CH:17]=2)[O:21][C:3](=[O:4])[CH:19]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cc(F)ccc1O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: O=c1cc(O)c2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a stirred suspension of sodium hydride (Aldrich, 60% dispersion in mineral oil) (1.2 g, 30.0 mmol) and diethyl carbonate (Aldrich) (5.9 g, 50 mmol) in anhydrous benzene (Aldrich) (100 mL) under a dry nitrogen atmosphere was added dropwise a solution of 5'-fluoro-2'-hydroxy-acetophenone (Aldrich) (1.54 g, 10 mmol) in anhydrous benzene. The mixture was then refluxed under a nitrogen atmosphere overnight. The reaction mixture was cooled and 50 mL 1N NaOH was added. The mixture was stirred at room temperature for 1 hour. The aqueous layer was separated and washed with ether (100 mL×2). The dark solution was acidified to pH 2 with 6N HCl. The white precipitate was collected by filtration, washed with water and dried to afford product (4) (4-hydroxy-6-fluoro-coumarin) as an off-white solid (1.38 g, 7.66 mmol, 77%). 300-MHz 1H-NMR (CDCl3) δ 5.79 (s,1H), 7.25-7.28 (m,2H), 7.52 (d,1H). Mass/EI: 179 (M-H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][N:10]=[CH:9][N:8]=1>>[Cl:3][C:7]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][N:10]=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncncc1Oc1ccccc1
Product: Clc1ncncc1Oc1ccccc1
Reaction time: 1.5 h

Procedure:
To 500 ml. of phosphorus oxychloride was added 85.5 g. (0.455 mol) of 4-hydroxy-5-phenoxy pyrimidine and the suspension heated at 70° in an oil bath. After 1 hr the reaction mixture became homogeneous and after 1.5 hr total reduction time the bulk of the phosphorus oxychloride was removed by distillation at reduced pressure. The residue was slowly added to well stirred iced water and the residual acid was cautiously neutralized with ammonium hydroxide solution to pH 8 and was extracted with 3 × 700 ml. of chloroform. The chloroform extracts were dried over anhydrous sodium sulfate filtered and concentrated in vacuo to 85.7 g. (90%) of a black oil. A colorless oil could be obtained by evaporative distillation of this material at 130° (0.1 mm).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([OH:14])=O)[NH:9]2)=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.[CH:25]1([C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[O:29])[CH2:27][CH2:26]1>>[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([N:33]3[CH2:34][CH2:35][N:30]([C:28]([CH:25]4[CH2:26][CH2:27]4)=[O:29])[CH2:31][CH2:32]3)=[O:14])[NH:9]2)=[CH:5][C:4]=1[O:15][CH:16]1[CH2:17][CH2:18][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:20][CH2:21]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)O)[nH]c3cc2Br)CC1
Reactant: O=C(C1CC1)N1CCNCC1
Agent: Cl
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(C(=O)C5CC5)CC4)[nH]c3cc2Br)CC1
Yield: 48 %

Procedure:
The title compound was synthesized in analogy to example 1, from 6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate a) and 1-(cyclopropanecarbonyl)piperazine to afford the title compound as a light-yellow foam (48%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:28])=[CH:24][C:25]=4[F:27])[NH:20][N:19]=3)[N:16]=2)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:10]=1)=[O:8])[CH3:5].[H-].[Na+].I[CH3:40]>CN(C=O)C>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:28])=[CH:24][C:25]=4[F:27])[N:20]([CH3:40])[N:19]=3)[N:16]=2)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:36])[CH3:35])[CH:10]=1)=[O:8])[CH3:5]
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)cc(F)c34)nc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)cc(F)c34)nc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33.3 %

Procedure:
A 50 mL round-bottomed flask was charged with 2-(6-chloro-4-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (120 mg, 0.225 mmol) and DMF (0.45 ml) to give a light yellow solution. The reaction mixture was placed under argon atmosphere and cooled in a 0° C. bath. NaH (60% in mineral oil, 23 mg, 0.575 mmol) was added. The reaction mixture was stirred at 0° C. for 10 min and at room temperature for 10 min then returned to the cooling bath and iodomethane (21 μl, 0.34 mmol) was added. The reaction was stirred at 0° C. for 10 min then the bath was removed and stirring continued at room temperature for an additional 18 h. The reaction was quenched with water and the precipitate collected by filtration. The crude material was purified by chromoatography over SiO2 with EtOAc/heptane (gradient: 0-100% EtOAc) to afford 41 mg (33%) of 2-(6-chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as an off-white solid. MS: [M+H]+=547.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:4]=1[OH:5]>O>[CH3:1][O:2][C:3]1[C:4](=[O:5])[CH:6]=[CH:7][C:8](=[O:10])[CH:9]=1
Reactant: COc1cc(O)ccc1O
Solvent: O
Product: COC1=CC(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
The procedure employed was a modification of that used by Okamato et al. (Chem. Pharm. Bull 32:4593-4599 (1984)). To a vigorously stirred solution of NaIO4 (15.4 g, 72.2 mmol, Baker) in water (500 mL), there was added solid 2methoxyhydroquinone (37, 3.20 g, 22.8 mmol) in portions. The reaction immediately became dark orange. The reaction was allowed to stir for 1 h at rt and was extracted with CH2Cl2 (3×100 mL). The extract was washed with half saturated brine (1×100 mL), filtered through cotton and the solvent removed in vacuo to yield 17 as an orange solid (3.07 g, 97%), which was of sufficient purity (TLC analysis, 10% EtOAc, 90% CHCl3) for further reaction. The crude 17 was combined with hydroquinone (300 mg, Mallinkrodt), toluene (20 mL) and freshly distilled cyclopentadiene (15 mL, from the distillation of dicyclopentadiene, Aldrich). The reaction was allowed to stir at rt for 35 min at which point an orange homogeneous solution was present. TLC analysis (10% EtOAc, 90% CHCl3) indicated total conversion of the 2-methoxybenzoquinone to the lower Rf adduct. The lower boiling volatiles were removed in vacuo to give an orange liquid. Washing the liquid with ice cold hexanes yielded a beige solid (4.4 g). This was purified chromatographically (silica gel, 2.5×25 cm, CHCl3 elution) to yield an oil. Trituration with hexanes (50 mL), ice cold ether (3×10 mL) and hexanes (1×10 mL) yielded 46 as a pinkish powder (3.00 g, 64%, pure by TLC and 1H NMR); mp 95°-97° C., lit. (Okamato et al.) 97°-99.5° C.; 1H NMR (CDCl3) δ1.44 (d, J=9.0 Hz, 1H), 1.55 (m, 1H), 3.24 (m, 2H), 3.55 (m, 2H) 3.72 (s, 3H), 5.89 (s, 1H), 6.07 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)=[N:7][CH:8]=1)[CH3:2].[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([N:9]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][C:22]([F:21])([F:32])[F:33])[CH:25]=2)[CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1cnc(NCCCc2ccc(OC)cc2)nc1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Product: CCc1cnc(N(CCCc2ccc(O)cc2)Cc2cccc(OC(F)(F)F)c2)nc1

Procedure:
Similarly prepared from 5-ethyl-N-[3-(4-methoxyphenyl)propyl]pyrimidin-2-amine and 3-trifluoromethoxy benzyl bromide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15](F)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH3:22]>O1CCCC1>[NH2:22][C:15]1[CH:16]=[CH:17][C:12]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)=[CH:13][C:14]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1F
Reactant: N
Solvent: C1CCOC1
Product: Nc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 72 h

Procedure:
A solution of 50.0 g of 3-chloro-2-(4-fluoro-3-nitrophenyl)-5-trifluoromethylpyridine in 200 ml of tetrahydrofuran was treated with 200 g of a 25% strength by weight aqueous ammonia solution. After stirring at 23° C. for three days, the tetrahydrofuran was removed by distillation, whereupon the product crystallized. The crystals were separated off, washed with water and dried in a vacuum drying oven. Yield: 48.7 g (98%) of colorless crystals; m.p.: 126-127° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=O)=[CH:5][N:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]([Cl:16])[CH:12]2[CH2:14][CH2:13]2)=[CH:5][N:4]=1
Reactant: COc1ccc(NC(=O)C2CC2)cn1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(N=C(Cl)C2CC2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2-methoxy-5-pyridyl)-cyclopropane carboxamide (5.0 g, 0.026 mol) was added portionwise to stirred solution of phosphorus pentachloride (5.42 g, 0.026 mol) in dichloromethane (25 ml) under a nitrogen atmosphere at room temperature. After complete addition the mixture was stirred at room temperature for one hour and then heated at reflux for a further one hour. The reaction mixture was then evaporated under vacuum to give a solid product which was washed with diethyl ether (50 ml) and air dried to give N-(2-methoxy-5-pyridyl)-cyclopropylmethanimidoyl chloride as the hydrochloride salt (6.2 g, 97%) which was used in Stage 3 without further purification or characterisation.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:14][C:13]([O:22][CH2:23][C:24]#[C:25][CH3:26])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:12]1)=[O:10])(C)(C)C.Cl>C(OCC)(=O)C>[NH2:7][C@H:8]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[C:9]([N:11]1[CH2:12][C:13]([O:22][CH2:23][C:24]#[C:25][CH3:26])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:14]1)=[O:10]
Reactant: CC#CCOC1(c2ccccc2C)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC#CCOC1(c2ccccc2C)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.5 %

Procedure:
1.7 g (3.5 mmol) of tert-butyl[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxo-ethyl]carbamate are solubilised in 45 ml (135 mmol) of a 3M solution of hydrochloric acid in ethyl acetate. After stirring for 3 h at ambient temperature, the mixture is concentrated. 1.6 g of (R)-2-amino-1-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)-propan-1-one are obtained in the form of a beige solid with a quantitative yield.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:16][O:17][CH3:18])[C:13]([NH2:15])=[O:14])(=O)C.[CH3:19]N.CO>CO>[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:16][O:17][CH3:18])[C:13]([NH:15][CH3:19])=[O:14]
Reactant: CON=C(C(N)=O)c1ccccc1COC(C)=O
Reactant: CN
Solvent: CO
Product: CNC(=O)C(=NOC)c1ccccc1CO

Procedure:
A mixture of 2-(2-acetoxymethylphenyl)-2-methoxyiminoacetamide (194 mg, E/Z≠79/21), methanol (3.0 ml) and a 40% methylamine/methanol solution (1.0 ml) was stirred at 40° C. for 3 hours. After the mixture was ice-cooled, the solvent was evaporated under reduced pressure to obtain the crude product (203 mg, E/Z≠91/9) of the title compound.