Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([O:20][CH2:21][CH:22]=[CH2:23])=[CH:18][C:17]([CH3:24])=[CH:16][C:15]=3[O:25][C@@H:26]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@H:27]3[OH:28])=[O:13])[CH:8]=[CH:9][C:2]1=2.N1C(C)=CC(C)=CC=1C.[P:46](Cl)([O:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)([O:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:47].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([O:20][CH2:21][CH:22]=[CH2:23])=[CH:18][C:17]([CH3:24])=[CH:16][C:15]=3[O:25][C@@H:26]3[O:34][C@H:33]([CH2:35][O:36][P:46]([O:48][C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)([O:55][C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)=[O:47])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@H:27]3[OH:28])=[O:13])[CH:8]=[CH:9][C:2]1=2
Reactant: C=CCOc1cc(C)cc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1C(=O)CCc1ccc2occc2c1
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: Cc1cc(C)nc(C)c1
Product: C=CCOc1cc(C)cc(O[C@@H]2O[C@H](COP(=O)(Oc3ccccc3)Oc3ccccc3)[C@@H](O)[C@H](O)[C@H]2O)c1C(=O)CCc1ccc2occc2c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 74.4 %

Procedure:
3-(5-Benzo[b]furanyl)-2'-(β-D-glucopyranosyloxy)-6'-allyloxy-4'-methylpropiophenone (300 mg) obtained in Example 2 is dissolved in tetrahydrofuran (3 ml), and thereto are added 2,4,6-collidine (315 mg) and diphenyl chlorophosphate (486 mg) under ice-cooling. The mixture is stirred at room temperature for 22 hours under argon atmosphere. The reaction mixture is poured into chilled 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer is washed successively with water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give 3-(5-benzo[b]furanyl)-2'-(6-O-diphenylphosphono-β-D-glucopyranosyloxy)-6'-allyloxy-4'-methylpropiophenone (327 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][C:8]([F:23])=[CH:7][N:6]=1.[H-].[Na+].[CH2:31]([O:33][C:34](=[O:39])[CH2:35][CH2:36][CH2:37]Br)[CH3:32]>CN(C=O)C>[CH2:31]([O:33][C:34](=[O:39])[CH2:35][CH2:36][CH2:37][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]([C:11]([C:10]2[C:5]([O:4][C:3]3[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:2]=3[Cl:1])=[N:6][CH:7]=[C:8]([F:23])[CH:9]=2)=[O:12])[CH2:14][CH2:15]1)[CH3:32]
Reactant: O=C(c1cc(F)cnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1CCN(C(=O)c2cc(F)cnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.6 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-5-fluoro-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (50.2 mg, 0.12 mmol, 1.0 equiv; Example 147) in anhydrous DMF (1 mL) was added sodium hydride (10.3 mg, 0.24 mmol, 2.0 equiv; 55% free-flowing powder moistened with oil; [CAS RN 7646-69-7]) and the reaction mixture stirred at rt. After 1 h, 4-bromo-butyric acid ethyl ester (545 mg, 400 μL, 2.80 mmol, 23.3 equiv; [CAS RN 2969-81-5]) was added and stirring continued under microwave heating to 120° C. for 30 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 5.5 mg (9%) of the title compound as a light yellow oil. MS (ISP): 532.2 [M+H]+.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1.Br[C:15]1[CH:16]=[C:17]([C:20](=[O:23])[CH2:21][CH3:22])[S:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CO.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>[OH:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:16]=[C:17]([C:20](=[O:23])[CH2:21][CH3:22])[S:18][CH:19]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCC(=O)c1cc(Br)cs1
Reactant: COCOc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCC(=O)c1cc(-c2cccc(O)c2)cs1

Procedure:
In a manner similar to that of Example 1(h), by reaction of 4.6 g (25 mmol) 3-methoxymethoxyphenylboronic acid (described in Example 1(g)) and 5 g (22.8 mmol) of 1-(4-bromo-2-thiophenyl)-1-propanone with 22.8 mL of 2.0M potassium carbonate and 1.32 g of tetrakis(triphenylphosphine)palladium, followed by deprotection in methanol, the desired product is obtained in the form of a white solid (m.p.=112° C.; m=3.87 g: Y=73%).
Reaction SMILES: [OH-:1].[Na+].[CH:3](=[C:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7]>>[OH:1][CH:3]([CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: [OH-]
Reactant: CCCCC=C1CCCC1=O
Agent: [Na+]
Product: CCCCC(O)C1CCCC1=O
Reaction time: 2 h
Yield: 2571.4 %

Procedure:
Additional 15.8 g (0.19 mol) 48% NaOH was added thereto, and the mixture was stirred at the same temperature for 2 hours. After the reaction was finished, the mixture was neutralized and analyzed in the same manner as in Example 1. The result indicated that the reaction mixture contained 521 g (3.06 mol) 2-(1-hydroxy-n-pentyl)cyclopentanone (yield 83.8%) and 18.2 g (0.119 mol) 2-pentylidene cyclopentanone.
Reaction SMILES: [F:1][C:2]1[C:21]2[C@@:16]([CH3:24])([CH:17]3[CH2:23][CH:18]3[C:19](=[O:22])[CH:20]=2)[C@H:15]2[C@H:4]([C@H:5]3[C@:12]([CH3:25])([CH2:13][CH2:14]2)[C@@:8]([OH:26])([C:9](=[O:11])[CH3:10])[CH2:7][CH2:6]3)[CH:3]=1.[CH3:27]N(C)C=O>CI.[Ag]=O>[F:1][C:2]1[C:21]2[C@@:16]([CH3:24])([CH:17]3[CH2:23][CH:18]3[C:19](=[O:22])[CH:20]=2)[C@H:15]2[C@H:4]([C@H:5]3[C@:12]([CH3:25])([CH2:13][CH2:14]2)[C@@:8]([O:26][CH3:27])([C:9](=[O:11])[CH3:10])[CH2:7][CH2:6]3)[CH:3]=1
Reactant: CN(C)C=O
Reactant: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C=C(F)C4=CC(=O)C5CC5[C@@]4(C)[C@@H]3CC[C@@]21C
Agent: O=[Ag]
Solvent: CI
Product: CO[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(F)C4=CC(=O)C5CC5[C@@]4(C)[C@@H]3CC[C@@]21C

Procedure:
A solution of 0.35 g of 6-fluoro-17α-hydroxy-1,2-methylene-9β,10α-pregna-4,6-diene-3,20-dione in 35 ml of dimethylformamide and 17.5 ml of methyliodide is stirred at 20°C for 70 hours in the presence of 3.5 g of silver oxide. Then the solid substance is filtered off and the filtrate is extracted subsequent to decanting in water, from methylene chloride and the resultant extract is evaporated to dryness after having been washed to neutral and subsequent to drying. The residue yields, subsequent to chromatography on silicagel, 6-fluoro-17α-methoxy-1,2-methylene-9β,10α-pregna-4,6-diene-3,20-dione.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)([OH:17])[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>CN(C=O)C>[CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([O:17][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:16])[C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)CCN(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(OC(=O)C(C)(C)C)c2cccnc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.8 %

Procedure:
1-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-3-yl-propan-2-ol (5.0 g, 14.9 mmol) was dissolved in DMF (100 mL) and sodium hydride (1.8 g, 45 mmol) was added, and the mixture stirred at RT for 15 min. Pivaloyl chloride (3 g, 25 mmol) was added dropwise at the same temperature, and the mixture stirred for 45 min. The reaction was monitored by TLC and LCMS. The reaction mixture was poured into 400 mL ice water to obtain a solid that was filtered. The solid was dissolved in DCM, dried over sodium sulfate and concentrated to obtain the crude product that was purified by column chromatography (silica gel: 100-200 mesh, Eluent:−4-6% MeOH in DCM) to obtain 1.8 g of 2,2-dimethyl-propionic acid 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-methyl-1-pyridin-3-yl-ethyl ester. The product was further purified by chiral preparative HPLC to give enantiomers II-16a and II-16b. 1H NMR (CDCl3, Free base): δ (ppm): 8.55 (d, 1H), 8.5 (s, 1H), 7.2 (d, 1H), 7.18 (m, 3H), 6.9 (d, 1H), 4.3 (dd, 2H), 3.65 (d, 1H), 3.52 (d, 1H), 2.65 (m, 2H), 2.5 (m, 2H), 2.5 (s, 3H), 2.4 (s, 3H), 2.3 (d, 1H), 2.0 (s, 3H), 2.0 (m, 1H), 1.2 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[C:14]([O:16][CH3:17])=[O:15]>CO>[CH3:17][O:16][C:14](=[O:15])[CH:13]([C:18]1[CH:19]=[CH:20][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:22][CH:23]=1)[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Oc1ccc(F)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 1.87 g of p-fluorophenol in 50 ml of methanol is added 1.07 g of sodium methoxide. To this solution is added 5.4 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate and the mixture is refluxed for 18 hours. The mixture is concentrated to 1/2 volume and poured into 150 ml of ice and water. The mixture is extracted with ether and the cold extracts washed with 50 ml of 2 N NaOH and with saline. After drying (MgSO4), the extracts are concentrated under vacuum to give the product as an amber colored oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:29][NH2:30]>>[CH3:29][NH:30][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:15]=2[O:14]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4F)c3O2)cc1
Product: CNCC1Cc2cccc(-c3ccccc3F)c2O1

Procedure:
The title compound was prepared (0.147 g, 66%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.300 g, 0.753 mmol) and methylamine (0.92 g, 29.5 mmol). mp 148-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[CH:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19]Br)=[CH:14][CH:13]=1.[OH-].[NH4+]>O>[CH2:19]([NH:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:18][C:15]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1
Reactant: BrCCc1ccccc1
Reactant: COc1cccc(CCN)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(CCNCCc2ccccc2)c1
Temperature: 165 °C
Reaction time: 0.08 h
Yield: 47.1 %

Procedure:
A mixture of 1.51 g of β-(3-methoxyphenyl)-ethylamine and 1.85 g of β-phenethyl bromide was heated to 70°-80° C. on a bath and then was progressively heated to 165° C. over 10 minutes. The mixture was held at 165° C. for 5 minutes and was then cooled. 50 ml of water and then 4 ml of concentrated ammonium hydroxide were added thereto and the mixture was extracted 3 times with 40 ml of methylene chloride. The combined organic extracts were washed with 100 ml of aqueous sodium chloride solution and was dried over magnesium sulfate and was filtered. The filtrate was evaporated to dryness to obtain 3.4 g of raw product which was chromatographed over silica gel. Elution was with a 9-1 chloroform-ethanol mixture and the homogenous fraction with an Rf = 0.45 was taken to obtain 1.2 g of N-phenethyl-3-methoxyphenethylamine in the form of a yellow oil.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11]2)[O:6][N:5]=1)([CH3:3])[CH3:2].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:27]=3[F:36])[N:24]=[CH:25][C:18]=12.C(=O)([O-])[O-].[K+].[K+].O>C1COCC1>[F:36][C:27]1[CH:28]=[C:29]([S:32]([CH3:35])(=[O:33])=[O:34])[CH:30]=[CH:31][C:26]=1[N:23]1[C:19]2=[N:20][CH:21]=[N:22][C:17]([NH:15][CH:12]3[CH2:13][CH2:14][N:10]([CH2:9][C:7]4[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=4)[CH2:11]3)=[C:18]2[CH:25]=[N:24]1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)c(F)c1
Reactant: CC(C)c1noc(CN2CCC(N)C2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1noc(CN2CCC(Nc3ncnc4c3cnn4-c3ccc(S(C)(=O)=O)cc3F)C2)n1
Yield: 91.4 %

Procedure:
A mixture of 1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-pyrrolidin-3-ylamine (354 mg, 1.68 mmol), 4-chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 1.53 mmol), and potassium carbonate (3.18 g, 23 mmol) in THF (20 mL) was refluxed for 2 hours. Water was added to the reaction mixture and the product was extracted with ethylacetate. The ethylacetate layer was dried over MgSO4. The organic layer was concentrated in vacuo to afford compound A133 as a white solid (700 mg, 91%). Exact mass calculated for C22H25FN8O3S 500.18, found 501.1 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[C:14]([C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)#[N:15]>>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N:19]2[CH2:18][CH2:17][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:14]#[N:15])[CH2:21][CH2:20]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: N#Cc1ccc(F)c2ccccc12
Product: N#Cc1ccc(N2CCC(C#N)(c3ccccc3)CC2)c2ccccc12
Yield: 2.5 %

Procedure:
The title compound (1 mg, 3% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and 4-cyano-4-phenylpiperidine (87 mg, 0.468 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[C:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5]>CCOC(C)=O.CCO.[Pd]>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5]
Reactant: CC(C)(C)C#Cc1cccc(N)c1C#N
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)CCc1cccc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
A suspension of 2-amino-6-(3,3-dimethylbut-1-ynyl)benzonitrile (Example 21c, 690 mg, 3.48 mmol) and 10% Pd/C (100 mg) in EtOAc/EtOH (1:1, 20 mL) was stirred under an atmosphere of H2 with a balloon at room temperature overnight. The Pd/C was removed by filtration, the filtrate was concentrated, and purified by chromatography on silica gel eluting with 20% EtOAc in hexanes to give the title compound as a light yellow oil (620 mg, 88%). 1H NMR (400 MHz, DMSO-d6) δ 0.92 (s, 9H), 1.36-1.40 (m, 2H), 2.52-2.56 (m, 2H), 5.88 (s, 2H), 6.45 (d, J=7.6 Hz, 1H), 6.57 (d, J=7.6 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H). MS 203 (MH+).
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[CH:20]1([C:26](O)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:26]([CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[O:27])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Reactant: O=C(O)C1CCCCC1
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)C3CCCCC3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and cyclohexanecarboxylic acid, the title compound was prepared as white powder. MS: m/e=391 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH2:13][CH2:14][CH3:15])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[BH4-].[Na+]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[C:9]([CH2:13][CH2:14][CH3:15])[C:10]=1[O:11][CH3:12]
Reactant: CCCc1cc(C=O)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CCCc1cc(CO)cc(OC)c1OC
Yield: 72 %

Procedure:
A solution of 3,4-dimethoxy-5-propylbenzaldehyde (11 g) and sodium borohydride (2 g) in 2-propanol (100 ml) was stirred at room temperature for 2 hours. The mixture was quenched with 2N HCl (200 ml) and extracted with ethyl acetate. The organic phase was separated, washed with brine, dried over MgSO4, filtered and evaporated to leave a yellow oil which was purified by Kugelrohr bulb to bulb distillation at 1 mm Hg air bath temperature 150° to give the sub-title compound as a colourless oil (8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[C:3]=1[N+:9]([O-:11])=[O:10].CS(C)=[O:14]>O>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([OH:14])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccnc(Cl)c1[N+](=O)[O-]
Reactant: CS(C)=O
Solvent: O
Product: Nc1ccnc(O)c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A solution of 18.0 g (104 mmol) of 4-amino-2-chloro-3-nitropyridine in 120 ml dimethylsulphoxide and 30 ml of water was stirred for four hours at 130° C. The solution was then cooled and left to stand overnight while cooling with ice. The product that crystallised out was suction filtered, washed with a little water and dried at 50° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]([CH3:21])=[CH:12][C:13]=1[O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:8](O)=[O:9])(=[O:4])=[O:3].[Cl-].C[N+]1C=CC=CC=1Cl.[Cl-].[NH2:32][C:33]([NH2:35])=[NH2+:34].C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[NH2:34][C:33]([NH2:35])=[N:32][C:8](=[O:9])[C:7]1[C:11]([CH3:21])=[CH:12][C:13]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=1
Reactant: Cc1cc(Oc2cccnc2)c(S(C)(=O)=O)cc1C(=O)O
Reactant: NC(N)=[NH2+]
Agent: C[n+]1ccccc1Cl
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cccnc2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Reaction time: 0.25 h

Procedure:
1.0 g of 3-methylsulfonyl-4-(3-pyridyloxy)-6-methylbenzoic acid [obtainable by reacting 3-methylsulfonyl-4-chloro-6-methylbenzoic acid with 3-hydroxypyridine] is dissolved in 15 ml of 1-methylpyrrolidone, and 0.67 g of 1-methyl-2-chloropyridinium chloride is added to this solution, which is stirred for 15 min. 0.9 g of guanidinium chloride and 2.6 ml of N-ethyldiisopropylamine are then added, and the mixture is stirred at room temperature for one hour. Following customary working-up, N-diaminomethylene-3-methylsulfonyl-4-(3-pyridyloxy)-6-methylbenzamide is obtained, m.p. 221-224°.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[C:9]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])=[N:10][O:11][C:12]=2[CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:26].[Li]CCCC.[O:32]=[C:33]1[CH2:36][CH:35]([C:37]2[CH:38]=[C:39]([CH:44]=[CH:45][CH:46]=2)[C:40]([O:42][CH3:43])=[O:41])[CH2:34]1.CC(=O)OCC>C1COCC1>[Cl:26][C:3]1[CH:4]=[C:5]([O:6][CH2:7][C:8]2[C:9]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])=[N:10][O:11][C:12]=2[CH:13]2[CH2:15][CH2:14]2)[CH:24]=[CH:25][C:2]=1[C:33]1([OH:32])[CH2:34][CH:35]([C:37]2[CH:38]=[C:39]([CH:44]=[CH:45][CH:46]=2)[C:40]([O:42][CH3:43])=[O:41])[CH2:36]1
Reactant: COC(=O)c1cccc(C2CC(=O)C2)c1
Reactant: Clc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C2CC(O)(c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)cc3Cl)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To a stirring solution of compound 1a (1.67 g, 3.5 mmol) in dry THF (30 mL) was added n-BuLi (2.5 M in hexane, 1.2 eq, 1.69 mL) dropwise over 10 min at −78° C. under a nitrogen atmosphere. This was stirred for 1 h at this temperature before adding a solution of compound 1c (0.72 g, 1 eq) in dry THF (10 mL) dropwise and stirred for 1 h at this temperature. The reaction mixture was allowed to warm to rt slowly and left stirring overnight. The reaction was quenched with a solution of saturated ammonium chloride solution (50 mL) and EA (250 mL). The organic layer was separated and the aq. layer was washed with EA (2×100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the crude product as a brown oil. The product was isolated following CC with PE/EA (19:1 to 3:1). The reaction and purification was repeated twice on the same scale and the combined product (3.13 g) was repurified under the same conditions to afford the final product 1 (1.7 g, 19%). 1H NMR (CDCl3): 7.93 (m, 1H), 7.90-7.85 (m, 1H), 7.50-7.30 (m, 5H), 6.88 (s, 1H), 6.75-6.72 (m, 1H), 4.80 (s, 2H), 3.88 (s, 3H), 3.20-3.10 (m, 1H), 3.00-2.91 (m, 2H), 2.60-2.49 (m, 2H), 2.15-2.08 (m, 1H), 1.30-1.25 (m, 2H), 1.15-1.10 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@@H:12]3[CH2:15][C@H:14]([C:16]([NH2:18])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:19]1([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][C:29](B4OC(C)(C)C(C)(C)O4)=[CH:30][CH:31]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>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.O>[NH2:1][C:2]1[C:3]2[C:10]([C:29]3[CH:28]=[C:27]4[C:32]([CH:33]=[CH:34][C:25]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[N:26]4)=[CH:31][CH:30]=3)=[CH:9][N:8]([C@@H:12]3[CH2:15][C@H:14]([C:16]([NH2:18])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(I)cn2[C@H]1C[C@@H](C(N)=O)C1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@@H](C(N)=O)C1
Temperature: 80 °C

Procedure:
A mixture of cis-3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylic acid amide (131 mg, 0.367 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (146 mg, 0.441 mmol), Na2CO3 (97.2 mg, 0.917 mmol), Pd(PPh3)4 (25.5 mg, 0.0221 mmol), DMF (5 mL), and water (1 mL) was purged with nitrogen for 30 min and heated to 80° C. for 18 h. To the cooled reaction solution was added water (15 mL), the mixture was extracted with EtOAc (3×20 mL), the combined organic layers were washed with water (2×15 mL) and brine, dried over MgSO4, filtered, and concentrated. The residue was triturated with MeOH to give the title compound as yellow solid. 1H NMR (CDCl3, 400 MHz): δ=2.60-2.70 (m, 4H), 2.84-2.90 (m, 1H), 5.14-5.23 (quintet, 1H, J=8.7 Hz), 6.31 (brs, 2H), 6.92 (s, 1H), 7.40 (s, 1H), 7.50-7.62 (m, 3H), 7.78-7.82 (m, 2H), 8.08-8.10 (d, 1H, J=8.4 Hz), 8.15-8.23 (m, 3H), 8.30-8.37 (m, 2H), 8.49-8.51 (d, 1H, J=8.4 Hz). MS (ES+): 435.0 [MH+]. HPLC: tR=2.4 min (polar—5 min).