Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[BH4-].[Na+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1ccc(F)c(Br)c1

Procedure:
A solution of 5 g (24.6 mmol) 3-bromo-4-fluoro-benzaldehyde in 20 ml anhydrous methanol is mixed in portions with 1.38 g (36.58 mmol) sodium borohydride while stirring and stirred for another hour at room temperature. After adding water, an extraction is carried out using diethyl ether, and the organic phase is dried over sodium sulfate. After the solvent is removed under vacuum, the appropriate alcohol is obtained. The product is obtained in pure form and can be used for further reactions.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.Cl>C(O)C.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:3]=1)[NH2:10]
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COc1ccc(Br)cc1N
Temperature: 25 °C
Yield: 72.2 %

Procedure:
A stirred mixture of 4-bromo-2-nitroanisole (98.56 g) and iron powder (113.7 g) in ethanol (1.51) was heated to reflux and treated dropwise with hydrochloric acid (350 ml, 0.5N) over 1 hour. After refluxing for a further 3 hours the reaction mixture was cooled to room temperature then filtered through hyflosupercel. The filtrate was evaporated and the residue was treated with saturated sodium bicarbonate solution (21 ) then filtered. The solid was washed with water then recrystallised from cyclohexane to give the title compound (61.98 g) as a pale brown solid, m.p. 93-93° C.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7](O)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.N1C=CC=CC=1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([Cl:24])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1-c1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a dry nitrogen atmosphere 10 g (0.05 mole) of 2-biphenylcarboxylic acid was dissolved with stirring in 116 ml of dry toluene. Pyridine, 4.2 g (0.054 mole), was then added to the reaction mixture followed by 6.4 g (0.054 mole) of thionyl chloride. The reaction mixture was stirred at room temperature for two hours, then filtered to remove a white precipitate. The toluene was removed from the filtrate under reduced pressure to give [1,1'-biphenyl]-2-carbonyl chloride as a liquid residue, which was used without purification in Step B below.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:68][CH:69]=[CH2:70].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:70][CH:69]=[CH2:68])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:60])([CH3:61])[CH3:62])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: C=CCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CC1OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (820 mg in 9 ml 33% methylene chloride in cyclohexane) allyl trichloroacetimidate (366 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (16 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 17 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×15 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ether:hexane (2:3)) gave the title compound (800 mg). (1H NMR was consistent with the desired structure).
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:28][C@H:26]([OH:27])[CH2:25][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([N:16]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:17])=[O:15])[CH2:7][C:8]1[CH:13]=[N:12][CH:11]=[CH:10][CH:9]=1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]1[CH2:28][C@H:26]([OH:27])[CH2:25][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([N:16]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:17])=[O:15])[CH2:7][C:8]1[CH:13]=[N:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1cccnc1)NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1ccccc1)C(=O)[C@H](Cc1cccnc1)NC(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The resultant Boc-Hyp-Pal-N(Me)Bzl-is dissolved in 40 ml of CH2Cl2 and mixed with 20 ml of TFA whilst cooling with ice. The mixture is stirred for 15 minutes at ambient temperature, concentrated on the rotary evaporator, the residue is taken up in ethyl acetate and extracted twice with saturated NaHCO3 solution. The aqueous phase is extracted successively with ethyl acetate and CH2Cl2. All the organic phases are united, dried with MgSO4, concentrated and the residue is chromatographed over silica gel by means of acetonitrile/water/MeOH (4:1:1). 0.39 g of H-Hyp-Pal-N(Me)Bzl is obtained as a highly viscous, colourless oil.
Reaction SMILES: Br[CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CC(C)=O>[N:22]1([CH2:2][C:3]([N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[CH3:6])=[O:4])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNCC1
Reactant: CN(C(=O)CBr)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C(=O)CN1CCCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5.4 g (20 mmol) of 4-(N-bromomethylcarbonyl-N-methyl-amino)-nitrobenzene are dissolved in 100 ml of acetone and combined with 5.5 g (40 mmol) of potassium carbonate. 3 ml (30 mmol) of piperidine are slowly added dropwise and the mixture is stirred for 18 hours at ambient temperature. The reaction solution is filtered, and the filtrate is evaporated to dryness. The residue is dissolved in ethyl acetate, washed with water, dried over magnesium sulphate and evaporated to dryness.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:12])[N+:7]([O-])=[C:8]([CH3:10])[CH:9]=1)([O-])=O.C.C(O)(=O)C>CO>[NH2:1][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH3:12])[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)[n+]1[O-]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(N)cc(C)n1
Reaction time: 10 h
Yield: 122.8 %

Procedure:
A mixture of 4-Nitro-2,6-lutidine 1-oxide (21, 5.1 g, 30 mmol), palladized charcoal (10% Pd, 1 g) and acetic acid (2 ml) in methanol (200 ml) is hydrogenated under pressure (40 psi) over 10 hours using a hydrogenation apparatus. The reaction is followed with LC-MS. After filtration, the filtrate is concentrated. The remaining oil is further dried by lyophilization, yielding 4.5 g of 4-amino-2,6-lutidine (22) containing approximately 15% acetic acid. 1H NMR (300 MHz, CDCl3) δ 2.3 (s, 6H), 7.2 (s, 2H). MS, m/z 123 (M+1), 243 (2M−1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1B(O)O>>[OH:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:25]3[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=3[OH:23])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(O)c(B(O)O)c1
Reactant: COc1ccc(O)c(-c2cccc(-c3cccc(Br)n3)n2)c1
Product: COc1ccc(O)c(-c2cccc(-c3cccc(-c4cc(C)ccc4O)n3)n2)c1
Yield: 50 %

Procedure:
6-(2-Hydroxy-5-methoxyphenyl)-6′-(2-hydroxy-5-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine and 2-hydroxy-5-methylphenylboronic acid in 50% yield using method F; δH [2H6]-DMSO 13.27,(1H, b), 12.64,(1H, b), 8.37,(1H, d), 8.33,(1H, d), 8.21,(2H, t), 8.14,(2H, d), 7.93,(1H, s), 7.64,(1H, s), 7.17,(1H, d), 7.00,(1H, d), 6.93,(1H, d), 6.89,(1H, d), 3.82,(3H, s), 2.34,(3H, s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32].C(#N)C>O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=3[O:31][CH3:32])[CH2:6][CH2:5]2)=[N:8]1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Reactant: c1ccc2c(C3CCNCC3)n[nH]c2c1
Solvent: CC#N
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2n[nH]c3ccccc23)CC1
Yield: 78.6 %

Procedure:
A mixture of 3-(4-piperidinyl)-1H indazole (3.2 g, 0.016 mol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.0 g, 0.016 mol) K2CO3 (2.2) and acetonitrile (100 ml) was stirred and refluxed for 6hours. The reaction was poured into water and the resulting yellow solid that formed was collected to afford 5.3 g of product. The compound was recrystallized from acetonitrile and then from ethyl acetate to yield 3.0 g (45%) of a slightly yellow solid of 1-[4-[4-[4-(1H-indazol-3-yl)-1-piperidiyl]butoxy]-3-methoxyphenyl]ethanone, m.p.=133°-135° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>C(Cl)Cl>[CH3:15][S:16]([O:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC1CO
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1COS(C)(=O)=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.0 g, 5.0 mmol) and TEA (1.0 g, 9.9 mmol) in CH2Cl2 (40 mL) was slowly added MsCl (0.63 g, 5.5 mmol). The reaction mixture was stirred for 30 min at −20° C. and then water (60 mL) was added. The aqueous phase was separated and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the crude tert-butyl 2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate that was used directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10].[Cl:11]Cl>ClC1C=CC=CC=1>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([Cl:11])=[O:10]
Reactant: Cc1nn(C)c(Cl)c1C=O
Reactant: ClCl
Solvent: Clc1ccccc1
Product: Cc1nn(C)c(Cl)c1C(=O)Cl
Temperature: 30 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To a solution of 48 g of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde in 230 ml of chlorobenzene under protective gas, 19.2 g of chlorine gas are introduced while illuminating with a mercury lamp at 30° C. within 4 hours. After the gas introduction has ended, the reaction solution is stirred with illumination at 30° C. for a further 20 minutes. The reaction solution is cooled to 5° C. and the solid is filtered off and washed with a little chlorobenzene. After the solvent has been removed, 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride is obtained in a yield of 87%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].Br[CH2:18][C:19]#[N:20]>CN(C=O)C>[C:19]([CH2:18][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:20]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccccc2n1CC#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with ethyl indole-2-carboxylate (10.0 g, 52.9 mmol) and DMF (100 mL). The solution was cooled to 0° C. using an ice bath. NaH (60% dispersion in mineral oil, 2.54 g, 63.5 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. After that time, bromoacetonitrile (7.62 g, 63.5 mmol) was added. The mixture was stirred at room temperature for 14 h. After that time, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (300 mL) and water (900 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a 66% yield (8.00 g) of 102a as an off-white solid: mp 65-67° C.; 1H NMR (300 MHz, CDCl3) d 7.72 (d, 1H, J=8.1), 7.44 (m, 3H), 7.25 (m, 1H), 5.62 (s, 2H), 4.42 (q, 2H, J=7.2 Hz), 1.43 (t, 3H, J=7.2 Hz); MS (ESI+) m/z 229.1 (M+H).
Reaction SMILES: C[O-].[Na+].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.O.Cl>CO>[NH:13]1[CH2:14][CH:15]=[C:16]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][CH:5]=2)[CH2:17][CH2:18]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C1=C(c2c[nH]c3ccccc23)CCNC1

Procedure:
To a solution of sodium methoxide (450 ml, 30% in methanol, 2.5 mol) in 1000 ml of methanol was added indole (50 g, 0.427 mol) and 4-piperidone.H2O.HCl (162 g, 1.05 mol). The mixture was heated under reflux for 18 h forming a yellow precipitate. The mixture was concentrated and water (1000 ml) was added. The precipitate was collected, washed with water and petroleum ether and then dried in a vacuum oven at 50° C. Yield 77 g (91%) of a pale yellow solid.
Reaction SMILES: C(OC([NH:11][C:12]1[C:13](=[O:27])[N:14]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1)=O)C1C=CC=CC=1>C(O)C.O>[NH2:11][C:12]1[C:13](=[O:27])[N:14]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Solvent: O
Solvent: CCO
Product: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Yield: 80.7 %

Procedure:
To tert-butyl 2-[3-{[(benzyloxy)carbonyl]amino}-6-methyl-2-oxo-1(2H)-pyridinyl]acetate (6.19 g, 16.6 mmol) in the reactor a mixture of 4:1 ethanol/water (77 mL) was added and degassed with argon for several minutes. During degassing Pd(OH)2 (0.613 g) was added and subjected to catalytic hydrogenation in the reactor containing a hydrogenating agent under the conditions: p(H2)=100 psi, t=2 h. The reaction mixture was filtered through Celite and the solvent evaporated under reduced pressure. To obtain a solid ethanol was added to the resulting material several times and the azeotropic mixture with water was distilled under reduced pressure to give 3.18 g (13.4 mmol) of a grey compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](C)(C)C)[S:10][C:3]=12.Br[C:16]1[N:21]=[C:20]([CH:22]=[O:23])[CH:19]=[CH:18][CH:17]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:16]3[N:21]=[C:20]([CH:22]=[O:23])[CH:19]=[CH:18][CH:17]=3)[S:10][C:3]=12
Reactant: C[Sn](C)(C)c1cc2nccc(Cl)c2s1
Reactant: O=Cc1cccc(Br)n1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=Cc1cccc(-c2cc3nccc(Cl)c3s2)n1
Yield: 27 %

Procedure:
This material was prepared by coupling 7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.707 g, 2.17 mmole) with 6-bromopyridine-2-carbaldehyde (0.396 g, 2.17 mmole) using tereakis (triphenylphosphine) palladium(0) (100 mg) as catalyst in a manner as previously described for example 39b to give a white solid (0.161 g, 27%). 1H NMR (300 MHz, CDCl3) δ10.15 (1H, s), 8.61 (1H, d, J=5.1 Hz), 7.93-8.09 (4H, m) 7.31 (1H, d, J=5.1 Hz); ESIMS (MH+): 275.00.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:11][O:12][CH2:13][CH2:14][OH:15].[OH-].[K+]>O>[CH3:11][O:12][CH2:13][CH2:14][O:15][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COCCO
Reactant: Clc1ncnc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COCCOc1ncnc2[nH]ccc12
Temperature: 100 °C
Yield: 90.5 %

Procedure:
To 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 5.00 g, 32.6 mmol) in 12.5 mL of 2-methoxy-ethanol (23, 158 mmol), potassium hydroxide (3.3 g, 59 mmol) is added. The reaction is heated at 100° C. overnight, then poured into water and extracted with ethyl acetate. The organic layer is dried with sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (24, 5.70 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([CH2:14]Cl)[CH:13]=1>>[Br:7][C:8]1[CH:13]=[C:12]([CH2:14][N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[CH:11]=[N:10][CH:9]=1
Reactant: O=C1CCCN1
Reactant: ClCc1cncc(Br)c1
Product: O=C1CCCN1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates B-1 [B], pyrrolidin-2-one has been coupled to 3-bromo-5-chloromethyl-pyridine (intermediate B-1 [A]) to yield the title compound as a white solid. MS: 251.1, 257.1 (M+H+).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[N:8]=[C:9]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:10]2[S:15][CH:14]=[N:13][C:11]=2[N:12]=1.[I:22]I>CCCCCC.C1COCC1>[Cl:6][C:7]1[N:8]=[C:9]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[C:10]2[S:15][C:14]([I:22])=[N:13][C:11]=2[N:12]=1
Reactant: Clc1nc(N2CCOCC2)c2scnc2n1
Reactant: II
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Clc1nc(N2CCOCC2)c2sc(I)nc2n1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Following the procedures in U.S. Pat. No. 6,492,383, 2.5 M of n-butyllithium (9.4 mL, 22.48 mmol) in hexane solution was added to a mixture of 4-(5-chlorothiazolo[4,5-d]pyrimidin-7-yl)morpholine 16 (3.0 g, 11.74 mmol) in 60 mL of THF at −78° C. The reaction mixture was allowed to warm to −40° C. and stirred for 30 min. A solution of iodine (6.0 g, 23.48 mmol) in 10 mL of THF was added dropwise. After the addition was completed. The reaction mixture was brought to room temperature and stirred for 2 h. The mixture was quenched by diluting with dichloromethane and extracting with H2O (2×100 mL). The organic layer was washed with Na2S2O3 (2×100 mL), H2O (2×100 mL), dried over MgSO4, filtered and evaporated to afford 4-(5-chloro-2-iodothiazolo[4,5-d]pyrimidin-7-yl)morpholine 27.
Reaction SMILES: [NH:1]([CH3:13])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(C)(C)C>C(O)(C)(C)C.[OH-].[Na+].O>[C:19]([N:1]([CH3:13])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:25]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CN[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3.6 g of H-MePhe-OH are dissolved in a mixture of tert.-butanol, 25 ml of 10% aqueous KHCO3 solution and 5 ml of 4 N sodium hydroxide. 8 ml of di-tert.-butylcarbonate are added and the mixture stirred for 2 days at room temperature. The reaction mixture is diluted with ca. 100 ml of water and extracted with ether. The aqueous phase is acidified, with stirring to pH 2. The precipitated product is extracted with acetic acid, the extract washed with water and dried over Na2SO4. The liquid is evaporated and the product crystallised from ether/petroleum ether to yield Boc-MePhe-OH. M.P. 87°.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:11][NH:12][CH3:13]>C1COCC1>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([N:12]([CH3:13])[CH3:11])=[N:6][CH:7]=1
Reactant: COc1nc(Cl)ncc1Br
Reactant: CNC
Solvent: C1CCOC1
Product: COc1nc(N(C)C)ncc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.9 %

Procedure:
A mixture of 5-bromo-2-chloro-4-methoxypyrimidine (3 g, 13.4 mmol) and dimethylamine (2 M in THF, 33.6 mL, 67.1 mmol) in THF (20 mL) was stirred for 18 h at rt and concentrated. The residue was purified by flash chromatography (hexane/EtOAc, 9:1) to afford 2.95 g of the title compound. tR: 1.04 min (LC-MS 2); ESI-MS: 232.0/234.0 [M+H]+ (LC-MS 2); Rf: 0.34 (hexane/EtOAc 9:1).
Reaction SMILES: [Cl:1][C:2]1[C:18]([N+:19]([O-])=O)=[C:17]([F:22])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][S:7]([N:10]([CH:12]([CH3:14])[CH3:13])[CH3:11])(=[O:9])=[O:8])=[O:5].CO.[H][H]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:18]([NH2:19])=[C:17]([F:22])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][S:7]([N:10]([CH:12]([CH3:14])[CH3:13])[CH3:11])(=[O:9])=[O:8])=[O:5]
Reactant: CC(C)N(C)S(=O)(=O)NC(=O)c1ccc(F)c([N+](=O)[O-])c1Cl
Reactant: [H][H]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)N(C)S(=O)(=O)NC(=O)c1ccc(F)c(N)c1Cl
Temperature: 70 °C
Reaction time: 11 h

Procedure:
8.00 g (0.023 mol) of N-(2-chloro-4-fluoro-3-nitrobenzoyl)-N′-isopropyl-N′-methylsulfamide in 75 g of toluene and 8 g of methanol were admixed with 0.24 g (0.05 mol %) of 2.4% Pt/2.4% Pd/C and hydrogenated with 5 bar of hydrogen with stirring at 70° C. After 11 h the solution was depressurized, the reaction mixture was filtered and the solvent was removed by distillation. This gave 6.48 g (90%) of the title compound in the form of a solid (m.p.: 147-149° C.).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7](O)(=O)[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]CC>C(Cl)(Cl)Cl>[C:2]([Cl:4])(=[O:3])[CH2:1][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of oxalyl chloride (53.5 g, 422 mmol) in 150 mL of chloroform was added drop wise to a solution of stearic acid (30.0 g, 105 mmol) in 250 mL of chloroform. After stirring overnight at ambient temperature the solution was concentrated and co-evaporated twice with chloroform. Drying under vacuum for 1 hour yielded a quantitative yield of a white solid. 1H-NMR (CDCl3): δ=2.85 (t, 2H), 1.70 (q, 2H), 1.30 (m, 28H), 0.85 (t, 3H) ppm. 13C-NMR (CDCl3): δ=173.6, 47.1, 31.9, 29.7, 29.7, 29.6, 29.5, 29.4, 29.3, 29.1, 28.4, 25.1, 22.7, 14.1 ppm. FT-IR: ν=2292, 2853, 1799 (C═O stretch), 1466, 953, 720, 680 cm−1.