Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:28]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([F:28])=[O:19])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)F
Temperature: -5 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a stirred solution of N-benzyloxycarbonyl-L-leucine (0.50 g, 1.87 mmol) and pyridine (0.15 ml, 1.88 mmol) in anhydrous DCM (5 ml) kept under a N2 atmosphere was added cyanuric fluoride (0.51 ml, 5.64 mmol) at −15 to −10° C. A white precipitate formed. After stirring for 1 hr at −5° C., IR of the crude reaction mixture indicated formation of the acyl fluoride. After 2 hrs crushed ice was added along with DCM (10 ml). The organic layer was separated and the aqueous layer extracted with DCM (5 ml). The combined DCM layers were washed with ice-cold water (10 ml), dried (MgSO4) and concentrated under reduced pressure to afford a colourless oil (0.36 g, 73%) which was used in subsequent reactions without further purification: νmax(polyethylene card) 3317 (N—H), 1843 (acid fluoride); δH (200 MHz, CDCl3) 0.97 (6H, d, J 6.0, CH(CH3)2), 1.62–1.78 (3H, m, CH(CH3)2 & CH2CH(CH3)2), 4.54–4.61 (1H, m, NHCH), 5.02 (1H, m, NH), 5.14 (2H, s, CH2Ph), 7.36 (5H, s, Ar—H).
Reaction SMILES: [N:1]1([CH:7]=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:10][CH2:11][CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>CO>[OH:13][CH2:12][CH2:11][CH2:10][N:4]1[CH2:5][CH2:6][N:1]([CH:7]=[O:8])[CH2:2][CH2:3]1
Reactant: O=CN1CCNCC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=CN1CCN(CCCO)CC1
Yield: 11.9 %

Procedure:
A solution of 1-piperazinecarboxaldehyde (25 g, 0.219 mol), 3-bromo-1-propanol (33.5 g, 0.241 mol) and potassium carbonate (38 g, 0.273 mol) in methanol (33 ml) was heated at reflux for 5 hours. After cooling, the solid was filtered, washed with methanol and the filtrate was evaporated. The residue was dissolved in methylene chloride and washed with a small amount of water. The organic layer was washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (90/10 followed by 80/20) to give 4-(3-hydroxypropyl)-1-piperazinecarboxaldehyde (4.5 g, 12%).
Reaction SMILES: CC(CC(C)C)=O.[CH2:8]([C:12]1[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:34]=[N:35][N:36](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:37]=3)=[CH:23][CH:22]=2)[C:14]([CH2:18][OH:19])=[C:15]([Cl:17])[N:16]=1)[CH2:9][CH2:10][CH3:11].[OH-].[K+:58].C>CO>[CH3:11][CH2:10][CH2:9][CH2:8][C:12]1[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37]=[N:36][N-:35][N:34]=3)=[CH:23][CH:22]=2)[C:14]([CH2:18][OH:19])=[C:15]([Cl:17])[N:16]=1.[K+:58]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)CC(C)C
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[n-]n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
Under nitrogen, in a 500 ml flask a mixture of 200 ml of dry methanol, 20 g (0.026 mol) of 2-n-butyl-4-chloro 1-[(2′-(2-triphenylmethyl-2H-tetrazol-5-yl)-1,1′biphenyl-4-yl) -methyl]-1H-imidazol-5-methanol methyl-isobutyl ketone solvate and 1.45 g (0.026 mol) of potassium hydroxide was refluxed for 3 h, treated with 0.4 g of charcoal and filtered at room temperature. The filtrate was concentrated to a volume of 30 ml under diminished pressure, and after addition of 160 ml of heptane again to a volume of 130 ml. The suspension was stirred at 0° C. for 2 h, the precipitated crystals were filtered, washed with cold heptane and dried at 70° C. to give 11.3 g (92.5%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)CCBr
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (200 mg, 0.73 mmol) was suspended in dimethylformamide (80 ml). To the suspension were added potassium carbonate (150 mg, 1.1 mmol) and methyl 3-bromopropionate (0.12 ml, 1.1 mmol) in order. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (146 mg, yield 56%).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([NH:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]1OS(C)(=O)=O)=[O:6])[CH3:3].[N-:23]=[N+]=[N-].[Na+]>CC(N(C)C)=O.C(OCC)(=O)C>[NH2:23][C@@H:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:8]1[NH:7][C:5]([O:4][C:2]([CH3:22])([CH3:3])[CH3:1])=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@@H]1OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@H]1N
Temperature: 90 °C
Reaction time: 24 h
Yield: 18.9 %

Procedure:
Cis-1-[(1,1-dimethylethoxy)carbonylamino]-2-methanesulphonyloxyindan (18.1 g, 55.3 mmol) was dissolved in dry dimethyl acetamide (100 ml). Sodium azide (5.4 g, 83.0 mmol) was added and the mixture heated to 90° C. for 6 hours. The reaction was cooled, diluted with ethyl acetate (150 ml), washed with water (6×200 ml) and dried over magnesium sulphate. 10% Palladium on activated carbon was added and the mixture stirred under a hydrogen atmosphere for 24 hours. Filtration through celite followed by evaporation gave the title compound (2.6 g, 98%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Solvent: CC(C)O
Product: C[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1

Procedure:
A solution of (S)-1-(tert-butoxycarbonyl)-4-methylenepyrrolidine-2-carboxylic acid (4 g, 17.60 mmol) in 2-propanol (10 mL) was added to a nitrogen purged suspension of 10% palladium on carbon (936 mg) in 2-propanol (240 mL) and the flask was charged with hydrogen gas (1 atm). After being stirred 18, the catalyst was removed by filtration over CELITE® and the filtrate concentrated. LC analysis showed the sample contained ˜14% of the trans-isomer, and recrystallization from toluene enriched the cis-isomer to 96% (16:1). LC-MS retention time 3.26 min; calcd. for C11H20N6O4: 230.14 m/z Found 252.14 [M+Na]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® 2×5 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min and an analysis time of 5 min where Solvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 90% methanol/10% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 4.21-4.17 (m, 1H), 3.76-3.67 (m, 1H), 2.96-2.92 (m, 1H), 2.49-2.46 (m, 1H), 2.30-2.29 (m, 1H), 1.59-1.51 (m, 1H), 1.47/1.43 (m, 9H), 1.10-1.06 (m, 3H).
Reaction SMILES: [N:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH:9]=[O:10])=[N+:2]=[N-:3].S(=O)(=O)([OH:13])N.Cl([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O>[N:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]([OH:13])=[O:10])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccsc1C=O
Reactant: NS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=Nc1ccsc1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
3-Azidothiophene-2-carbaldehyde (1.22 g, 8.0 mmol) was dissolved in 30 mL of acetone:H2O (2:1) and treated with sulfamic acid (1.16 g, 12.0 mmol). Sodium chlorite (1.27 g, 17.1 mmol) was added and stirred at 0° C. for 30 min. The mixture was alkalinized to pH 9 with sodium carbonate, and the product was washed with diethyl ether (10 mL). The aqueous layer was carefully treated with aqueous concentrated HCl to pH 1. The product was extracted with diethyl ether (3×10 mL), dried over Na2SO4, and concentrated in vacuo to give 13a (1.01 g, 75% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O-:20])=[O:19])[S:10][C:9]=12)=[O:4].[Na+].C(=O)([O-])O.[Na+].[C:35]([O:41][CH2:42]I)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C>[CH3:28][N:2]([CH3:1])[C:3]([C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O:20][CH2:42][O:41][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:19])[S:10][C:9]=12)=[O:4]
Reactant: C[C@@H]1C(c2cn3cnc(C(=O)N(C)C)c3s2)=C(C(=O)[O-])N2C(=O)[C@H]([C@@H](C)O)[C@@H]12
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3cn4cnc(C(=O)N(C)C)c4s3)[C@H](C)[C@H]12
Temperature: -30 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a solution of 50 mg of sodium (1R,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-carbapen-2-em-3-carboxylate in 0.7 ml of DMF was added 5.0 mg of sodium hydrogen carbonate, and the mixture was cooled to −30° C. under the atmosphere of argon. The reaction mixture was added with 43 mg of pivaloyloxymethyl iodide, stirred for 1 hour, extracted with 20 ml of ethyl acetate, and the organic layer was washed with 12 ml of semi-saturated aqueous saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to a volume of about 1 ml. The residue thus obtained was purified by column chromatography on silica gel (dichloromethane:methanol=95:5) to give 55 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:9][CH2:8][NH:7][NH:6][CH2:5][CH2:4]1.[CH2:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH2:19][CH3:20])[C:13]=1[CH:21]([C:25](N)=[O:26])[C:22](N)=[O:23])[CH3:11]>ClCCCl>[CH2:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH2:19][CH3:20])[C:13]=1[CH:21]1[C:25](=[O:26])[N:6]2[CH2:5][CH2:4][N:3]([O:2][CH3:1])[CH2:9][CH2:8][N:7]2[C:22]1=[O:23])[CH3:11]
Reactant: CON1CCNNCC1
Reactant: CCc1cc(C)cc(CC)c1C(C(N)=O)C(N)=O
Solvent: ClCCCl
Product: CCc1cc(C)cc(CC)c1C1C(=O)N2CCN(OC)CCN2C1=O

Procedure:
A degassed solution in a microwave vial of 5-methoxy-[1,2,5]triazepane (free base, 50 mg, 0.38 mmol) and 2-(2,6-diethyl-4-methyl-phenyl)-malonamide (95 mg, 0.38 mmol) in 1,2-dichloroethane (2.5 ml) under argon was irradiated with microwaves at 180° C. for 5 minutes. The solvent was evaporated, the residue dissolved in 5N aqueous sodium hydroxide, the aqueous layer extracted twice with ethyl acetate and the combined organic layers discarded. The aqueous alkaline phase was acidified with cooling to pH 2-3 by addition of a 4N HCl solution and the product thoroughly extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Yield: 20 mg of 8-(2,6-diethyl-4-methyl-phenyl)-3-methoxy-tetrahydro-pyrazolo[1,2-a][1,2,5]triazepine-7,9-dione (compound P2.3) as a tan solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1O.[N+:12]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])#[C-:13]>>[CH:13]1[N:1]2[C:10]3[C:5]([N:4]=[CH:3][C:2]2=[C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[N:12]=1)=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: [C-]#[N+]CC(=O)OC(C)(C)C
Reactant: Oc1cnc2ccccc2n1
Product: CC(C)(C)OC(=O)c1ncn2c1cnc1ccccc12

Procedure:
M.p. 187°-190° C., from 2-quinoxalinol and tert-butyl isocyanoacetate. (Compound 4)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[Na+].[OH-].[Na+].[O:10]1[CH:19]2[CH:11]1[CH2:12][C:13]1[C:18]2=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[N:1]1([CH:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:19][CH:11]2[OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: c1ccc2c(c1)CC1OC21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC1Cc2ccccc2C1N1CCCC1

Procedure:
10.8 ml of pyrrolidine in 6.75 g of 2,3-epoxy-indane [described by Mousseron et al. Bulletin de la, Societe Chimique de France, 1946, p. 629-630] in 10.8 ml of demineralized water. The temperature rose to 65° C. and the solution was stirred for 90 minutes at this temperature and 20 ml of demineralized water were added when the reaction was finished. Excess pyrrolidine was distilled off under reduced pressure to obtain an oily phase and an aqueous phase. These are saturated with sodium chloride at 20° C. and 1 ml of 32% sodium hydroxide was added. Extraction was done with ether and after drying and concentrating by distilling under reduced pressure, the oil obtained was purified by chromatography over silica (eluent:ethyl acetate with 5% of triethylamine) to obtain 8.31 g of [trans (±)] 2,3-dihydro-1-(1-pyrrolidinyl)-1H inden-2-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9]2)=[CH:4][C:3]=1[C:21]([NH:23][CH2:24][C:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2)=[O:22].Cl.CO>O1CCOCC1>[ClH:1].[NH2:13][CH:10]1[CH2:11][CH2:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:4]=2)[C:21]([NH:23][CH2:24][C:25]23[CH2:26][CH:27]4[CH2:28][CH:29]([CH2:30][CH:31]([CH2:33]4)[CH2:32]2)[CH2:34]3)=[O:22])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1CCN(c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)C1

Procedure:
Prepared as described in example 5d) above using (+/−)-[1-[4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]-3-pyrrolidinyl]-carbamic acid, 1,1-dimethylethyl ester (Example 7c), hydrochloric acid (0.5 ml of a 4N solution in dioxane) and methanol (5 ml). Evaporation under reduced pressure gave a solid on trirtuation with diethyl ether. Recrystallisation from methanol/diethyl ether gave the title compound as a solid (0.030 g).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([F:15])([F:14])[CH2:12][CH3:13])[N:10]=[C:6]2[N:5]=[C:4]([CH3:16])[CH:3]=1.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(O)C>[F:14][C:11]([C:9]1[N:10]=[C:6]2[N:5]=[C:4]([CH3:16])[CH:3]=[C:2]([NH:23][C:22]3[CH:24]=[CH:25][C:19]([C:18]([F:17])([F:26])[F:27])=[CH:20][CH:21]=3)[N:7]2[N:8]=1)([F:15])[CH2:12][CH3:13]
Reactant: CCC(F)(F)c1nc2nc(C)cc(Cl)n2n1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: CCC(F)(F)c1nc2nc(C)cc(Nc3ccc(C(F)(F)F)cc3)n2n1
Temperature: 50 °C

Procedure:
A suspension of Intermediate 7 (0.1 g, 0.405 mmol) and 4-(trifluoromethyl)aniline (ALDRICH, 0.051 mL, 0.405 mmol) in ethanol (5 mL) was heated at 50° C. for 1 h. The reaction mixture was concentrated under vacuum, redissolved in DCM (20 mL) and washed with aq. Na2CO3 (2×15 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([O:11][CH3:12])[CH:3]=1.[OH-:13].[Na+]>CO>[Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]([NH2:7])=[O:13])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Br)cc(C)c1C#N
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)cc(C)c1C(N)=O
Temperature: 25 °C
Yield: 90 %

Procedure:
4-Bromo-2-methoxy-6-methyl benzonitrile (7.3 g, 32.4 mmol) was stirred in MeOH (100 mL) and 5N NaOH (100 mL) at 100° C. for 12 hours. The reaction was cooled to room temperature and the methanol was removed under reduced pressure. The reaction mixture was extracted with CH2Cl2 and the solvent was removed under reduced pressure to yield the product (7.13 g, 90%). 1H NMR (300 MHz, CDCl3): δ 7.03 (d, 1H), 6.94 (d, 1H), 5.83 (br s, 2H), 3.85 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:10]2[N:22]([C:25](=[O:48])[CH:26]([NH:31][C:32](=[O:47])[CH:33]([N:35]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[CH3:36])[CH3:34])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:24][CH:9]12)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:40]([O:39][C:37](=[O:38])[N:35]([CH:33]([C:32](=[O:47])[NH:31][CH:26]([C:25]([N:22]1[CH2:23][CH2:24][CH:9]2[NH:8][CH2:12][CH:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:10]12)=[O:48])[C:27]([CH3:28])([CH3:30])[CH3:29])[CH3:34])[CH3:36])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C(=O)NC(C(=O)N1CCC2C1C(OCc1ccc(F)cc1)CN2C(=O)OC(C)(C)C)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)NC(C(=O)N1CCC2NCC(OCc3ccc(F)cc3)C21)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 97 %

Procedure:
A solution containing 48 (4.0 g, 5.98 mmol) in DCM (20 mL) was cooled to 0° C. and TFA (10 mL) was added. After 2.5 h, the reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc. The organic solution was washed successively with aqueous NaHCO3, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 3.3 g of 49 as a beige-colored foam which was used directly in the next reaction. Mass spectrum, m/z [569.1] (M+Na)+.
Reaction SMILES: [OH-].[K+:2].C([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[C:15]3[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=3[S:13][C:12]=2[CH:21]=1)=[O:7])C.[K]>C(O)C>[K+:2].[Cl:20][C:18]1[CH:17]=[CH:16][C:15]2[C:11]3[CH:10]=[CH:9][C:8]([C:6]([O-:7])=[O:5])=[CH:21][C:12]=3[S:13][C:14]=2[CH:19]=1
Reactant: CCOC(=O)c1ccc2c(c1)sc1cc(Cl)ccc12
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1ccc2c(c1)sc1cc(Cl)ccc12
Temperature: 25 °C

Procedure:
A solution of 4.1 g. of potassium hydroxide (85%) in 100 ml. of alcohol was added to a solution of 18.1 g. of 7-chlorodibenzothiophene-3-carboxylic acid ethyl ester in 450 ml. of warm ethanol. The combined solutions were stirred and refluxed for 8 hours. After cooling to room temperature, the mixture was filtered to give 16.5 g. of the potassium salt.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:11]([CH3:12])=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[CH3:13].[Cl:14][C:15]1[N:16]=[C:17](Cl)[C:18]2[S:23][CH:22]=[CH:21][C:19]=2[N:20]=1>CN1C(=O)CCC1.O>[Cl:14][C:15]1[N:16]=[C:17]([O:3][C:4]2[C:5]([CH3:13])=[CH:6][C:7]([C:8]#[N:9])=[CH:10][C:11]=2[CH3:12])[C:18]2[S:23][CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: Clc1nc(Cl)c2sccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Cl)nc2ccsc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 315 %

Procedure:
A stirred suspension of NaH (29.7 mg, 0.74 mmol) in dry NMP (3.5 mL) was added 4-hydroxy-3,5-dimethylbenzonitrile (108.2 mg, 0.74 mmol) and stirred at room temperature for 30 min under Argon. The reaction mixture was added to a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (39.6 mg, 0.19 mmol) in dry NMP (4 mL) and heated at 50° C. for 5 h. The resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1) to give the product as a white solid (189 mg, 81%):
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH:6]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:19]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH:6]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cccc(-c2cc(OCCO)cc(C)n2)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-c2cc(OCCOC(=O)c3ccccc3)cc(C)n2)n1

Procedure:
4-(2-Hydroxyethoxy)-6,6'-dimethyl-2,2'-bipyridine (24) (1.0 g, 4.1 mmoles) was dissolved in dry pyridine (20 ml), and benzoyl chloride (0.63 g, 4.5 mmoles) was added. After 30 minutes chloroform (50 ml) was added and the solution was extracted with saturated sodium bicarbonate. The chloroform phase was dried and the solvent was evaporated and coevaporated with dry toluene. The product was purified by means of flash chromatography (silica, 0-50% methanol/dichloromethane).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cc(O)ccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(O)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
to a stirred solution of 2-fluoro-5-hydroxybenzaldehyde (4.1 g) in methanol (50 mL) at 0° C. was added portionwise sodium borohydride (0.55 g). The mixture was warmed to room temperature, stirred for 1 hour then partitioned between water (200 mL) and ethyl acetate (2×200 mL). The combined organics were washed (brine), dried (magnesium sulfate) and concentrated to give 2-fluoro-5-hydroxybenzyl alcohol as a yellow oil which crystallised on standing overnight (4.1 g, 95% yield):
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[N:42](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:41]=[N:40][N:39]=3)=[CH:28][CH:27]=2)[C:15]1=[O:62])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([NH:13][CH:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[NH:42][N:41]=[N:40][N:39]=3)=[CH:30][CH:31]=2)[C:15]1=[O:62])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCC(=O)NC1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C1=O
Yield: 61.1 %

Procedure:
The intermediate obtained in Step B (150 mg, 0.18 mmol) dissolved in 5 mL methanol was hydrogenated over 30 mg of Pd(OH)2 on carbon at one atmosphere for 2 hours. The mixture was filtered through Celite and the filtrate concentrated under vacuum. The residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/acetonitrile/methanol (9:1:1) to afford 62 mg (0.11 mmol, 59%) of the product as a colorless glass. 1H NMR (200 MHz, CD3OD): 1.39 (s,9H), 2.0-2.5 (m,6H), 3.26 (t,7 Hz,2H), 4.31 (dd;7,12 Hz;1H), 4.83 (d,16 Hz,1H), 5.20 (d,16 Hz,1H), 6.98 (d,8 Hz,2H), 7.1-7.6 (m,10H). FAB-MS: calc. for C32H35N7O4 581; found 582 (M+H,19%).