Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[CH2:12][CH2:11][N:10]2[C:24]([C:23]2[CH:27]=[CH:28][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[O:25])=[CH:7][CH:8]=1
Reactant: COc1ccc(C2NCCc3ccsc32)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)N2CCc3ccsc3C2c2ccc(OC)cc2)cc1
Yield: 80 %

Procedure:
was prepared from 7-(4-methoxyphenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin (80 mg) in toluene (10 ml), 4-methoxybenzoyl chloride (66.5 mg) and triethylamine (90 uL) as described in example 2. Yield 80% of the title compound, MS: M+=379.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[CH2:23][N:22]([CH2:27][C:28]3([NH:36]C(=O)OC(C)(C)C)[CH2:33][O:32]C(C)(C)[O:30][CH2:29]3)[CH2:21]4)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C(OC1C=C(C2ON=C(C3C=CC=C4C=3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)N=2)C=CC=1OCC)C>>[NH2:36][C:28]([CH2:27][N:22]1[CH2:21][C:20]2[C:24](=[CH:25][CH:26]=[C:18]([C:15]3[N:14]=[C:13]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH3:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=4)[O:17][N:16]=3)[CH:19]=2)[CH2:23]1)([CH2:29][OH:30])[CH2:33][OH:32]
Reactant: CCOc1ccc(-c2nc(-c3ccc4c(c3)CN(CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)C4)no2)cc1OCC
Agent: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Product: CCOc1ccc(-c2nc(-c3ccc4c(c3)CN(CC(N)(CO)CO)C4)no2)cc1OCC
Yield: 57 %

Procedure:
When the product of Step F was substituted for tert-butyl 5-((4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)methyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 34, Step E, the identical process afforded the title compound in 57% yield, as a colourless solid. 1H-NMR (CDCl3) 1.45-1.56 (m, 6H); 1.97 (broad s, 4H+2H2O); 2.94 (s, 2H); 3.59 (s, 4H); 4.14-4.25 (m, 8H); 6.97 (d, 1H, J=8.5 Hz); 7.3 (d, 1H, J=8 Hz); 7.66 (d, 1H, J=2 Hz); 7.77 (dd, 1H, J=2, 8.5 Hz); 7.9-8.04 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13](Cl)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl.[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C=O>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]([NH:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc2oc(C(Cl)C3CCCCC3)c(Br)c2c1
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2oc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)c(Br)c2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
To a mixture of 3-bromo-2-[chloro(cyclohexyl)methyl]-5-methoxy-1-benzofuran (1.73 g) synthesized above, methyl 4-aminobenzoate (878 mg), sodium iodide (1.45 g) and N,N-dimethylformamide (30 mL) was added sodium carbonate (1.03 g), and the mixture was stirred at 80° C. for 8 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate/hexane) to give a yellow oil. To a mixture of the obtained oil, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10.0 mL), and the mixture was stirred with heating under reflux for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (10.0 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (318 mg, 14%) as a pale-brown solid.
Reaction SMILES: CS([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]([CH2:42]C)=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27]4[C:31]([CH:32]=[O:33])=[CH:30][N:29]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[N:28]=4)=[CH:21][C:20]=3[O:40][CH3:41])[N:16]=2)[CH:7]=1)(=O)=O.O1CCCC1.[OH-].[Na+].Cl>C(O)C>[OH:5][C:6]1[CH:7]=[C:8]([C:12]2[O:13][C:14]([CH3:42])=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27]4[C:31]([CH:32]=[O:33])=[CH:30][N:29]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:28]=4)=[CH:21][C:20]=3[O:40][CH3:41])[N:16]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCc1oc(-c2cccc(OS(C)(=O)=O)c2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccc(O)c2)oc1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a mixture of 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-ethyl-1,3-oxazol-2-yl}phenyl methanesulfonate (0.20 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added dilute hydrochloric acid to acidify the solution, and the precipitated crystals were collected by filtration to give 3-[(4-{[2-(3-hydroxyphenyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (0.10 g, yield 59%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 193-194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15](=O)[CH3:16])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].N1C=CC=CC=1>CO.CCOCC>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15](=[N:21][OH:22])[CH3:16])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(=O)/C=C/c1cccc(Oc2ccc(Cl)cc2)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: c1ccncc1
Product: CC(/C=C/c1cccc(Oc2ccc(Cl)cc2)c1)=NO
Reaction time: 1 h
Yield: 101.3 %

Procedure:
The product from step (a) (19 g) and hydroxylamine hydrochloride (6.9 g) were taken up in methanol (100 ml), pyridine (20 ml) was added and the mixture stirred for 1 hour. The mixture was then stripped, redissolved in ether (200 ml), washed with 2 N aqu. HCl and satd. aqu. NaCl, dried over MgSO4, and stripped to give the desired product (20.3 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][O:6][P:5]([C:9]#[C:10][CH3:11])(=[O:8])[O:4][CH2:3]1.[OH2:13].NN.Cl>C(#N)C>[CH2:9]([P:5]1(=[O:8])[O:4][CH2:3][C:2]([CH3:12])([CH3:1])[CH2:7][O:6]1)[C:10]([CH3:11])=[O:13]
Reactant: O
Reactant: CC#CP1(=O)OCC(C)(C)CO1
Agent: Cl
Agent: NN
Solvent: CC#N
Product: CC(=O)CP1(=O)OCC(C)(C)CO1
Reaction time: 30 h

Procedure:
0.69 g (3.7 mmol) of 5,5-dimethyl-2-(1-propynyl)-2-oxo-1,3,2-dioxaphosphorinane (III) was dissolved in 3 ml of acetonitrile, and 0.22 g (4.4 mmol) of hydrazine monohydrate was added thereto. The mixture was left for 30 hours at room temperature. Then, 4.8 g of 10% by weight hydrochloric acid was added thereto and stirred for one hour. The solvent was distilled off to about one-half of its initial volume under reduced pressure, and the reaction mixture diluted with 30 ml of 20% by weight sodium chloride aqueous solution, was extracted 2 times with 40 ml of chloroform. The chloroform layers were combined and dried over anhydrous sodium sulfate, followed by filtration. The solvent was distilled off to obtain 0.77 g (yield: about quantitative amount) of the desired product of 2-acetonyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane (IV) as colorless solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH:19]=[CH:20]2)[CH:15]=[CH:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C(OC(C)=C)(=O)C>C(OCCCC)(=O)C>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][CH:18]([OH:28])[CH:19]=[CH:20]2)=[CH:15][CH:14]=3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: C=C(C)OC(C)=O
Solvent: CCCCOC(C)=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4CC(O)C=C[C@]4(C)[C@H]3CC[C@]12C
Yield: 65.9 %

Procedure:
To a mixture of 38 g (0.1 mol) of cholesta-1,4,6-trien-3-one (I) and 34 g (0.2 mol) of paratoluenesulfonic acid were added 200 ml of butyl acetate and further 200 g (2 mol) of isopropenyl acetate, and the resulting mixture was heated under reflux for 5 hours. After completion of the reaction, the same treatment as in Example 1 was carried out to yield 25.2 g of cholesta-1,5,7-trien-3-ol (IV). The yield was 66%.
Reaction SMILES: [C:1]([C@H:5]1[O:9][C:8](=[O:10])[C@:7]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:6]1)([CH3:4])([CH3:3])[CH3:2].C([C@@H]1OC(=O)[C@@H](C2C=CC=C(Cl)C=2)O1)(C)(C)C>>[C:1]([C@@H:5]1[O:9][C:8](=[O:10])[C@@:7]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCC[C@]1(c2cccc(Cl)c2)O[C@@H](C(C)(C)C)OC1=O
Agent: CC(C)(C)[C@@H]1OC(=O)[C@@H](c2cccc(Cl)c2)O1
Product: CCCCCCC[C@@]1(c2cccc(Cl)c2)O[C@H](C(C)(C)C)OC1=O

Procedure:
Prepared in the same manner as (2R,5R)-2-(tert-Butyl)-5-(3-chlorophenyl)-5-heptyl-1,3-dioxolan-4-one using (2S,5R)-2-(tert-Butyl)-5-(3-chlorophenyl)-1,3-dioxolan-4-one. 1H NMR (400 MHz, CDCl3, δ): 0.84 (t, J=7 Hz, 3H), 0.96 (s, 9H), 1.16-1.35 (m, 10H), 1.88-2.06 (m, 2H), 5.35 (s, 1H), 7.26-7.30 (m, 2H), 7.50-7.54 (m, 1H), 7.62-7.63 (m, 1H). 13C NMR (100 MHz, CDCl3, δ): 14.3, 22.8, 23.7, 23.8, 29.2, 29.5, 31.9, 35.2, 38.9, 82.3, 109.1, 123.4, 125.4, 128.3, 129.7, 134.5, 140.5, 173.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:19])[NH:14]C(C)(C)C)=[S:11]>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:19])[NH2:14])=[S:11]
Reactant: CC(C)(C)NC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Agent: Cl
Product: NC(=O)NC(=S)Nc1c(Cl)cccc1Cl

Procedure:
A mixture of 32 g (0.1 mole) of 1-(2,6-dichlorophenyl)-3-(t-butylcarbamyl)thiourea and 200 ml of conc. hydrochloric acid is refluxed for 1/2 hour. The reaction mixture is cooled, filtered and washed with 10 ml of 1:1 HCl/H2O and dried. The product is then recrystallized from ethanol-ether to obtain 1-(2,6-dichlorophenyl)-3-carbamylthiourea.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)[CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>O1CCOCC1>[Cl:18][C:13]1[CH:14]=[C:15]([CH:16]=[C:11]([O:10][C:8]2[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=2)[CH:12]=1)[O:17][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: N#Cc1cc(Cl)cc(Oc2cc(O)cc(Cl)c2)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)COc1cc(Cl)cc(Oc2cc(Cl)cc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a dioxane solution (5 mL) of 240 mg (0.857 mmol) of 3-chloro-5-(3-chloro-5-hydroxyphenoxy)benzonitrile (B-4) was added 363 mg (1.12 mmol) of cesium carbonate. This was stirred for 30 minutes at 25° C. and then 217 mg (1.12 mmol) of t-butyl bromoacetate (5-1) was added and the reaction was stirred until the LC/MS analysis indicated that the reaction was complete. The solids were then removed by filtration and the filtrate was concentrated and purified on a CombiFlash silica column eluted with an ethyl acetate:hexanes gradient to recover desired product 5-2 as an oil. Rf=0.9 (EtOAc:hexanes 1:4). MS: M+1=395. 1H NMR(CDCl3): 1.49 (s, 9H), 4.49 (s, 2H), 6.48 (t, 1H), 6.66 (t, 1H), 6.74 (t, 1H), 7.14 (m, 1H), 7.21 (m, 1H), 7.38 (m, 1H).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][CH:10]1[C:40]1[C:45]2[CH2:46][CH2:47][O:48][C:44]=2[C:43]([Cl:49])=[C:42]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([CH2:57][CH3:58])=[CH:53][CH:52]=2)[CH:41]=1)C1C=CC=CC=1>C1COCC1.CO.[Pd]>[CH2:57]([C:54]1[CH:53]=[CH:52][C:51]([CH2:50][C:42]2[CH:41]=[C:40]([C@H:10]3[C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]3)[C:45]3[CH2:46][CH2:47][O:48][C:44]=3[C:43]=2[Cl:49])=[CH:56][CH:55]=1)[CH3:58]
Reactant: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Cl)OCC3)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A suspension of compound 72 (490 mg, 0.61 mmol) and Pd/C (10% wt., 74 mg) in THF (4 mL) and MeOH (2 mL) was stirred at room temperature under an atmosphere of H2 for 14 hours. The mixture was filtered through a Celite pad and concentrated in vacuo. The residue was purified by prep HPLC (C18) to afford the product E020 (25 mg, 8%) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:44]2[CH:45]=[C:46]([NH:50][CH2:51][CH2:52][OH:53])[CH:47]=[CH:48][CH:49]=2)O1.[OH-].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13]([C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([NH:50][CH2:51][CH2:52][OH:53])[CH:45]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Reactant: CC1(C)OB(c2cccc(NCCO)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(NCCO)c5)nc43)cc2)CCC1
Temperature: 160 °C
Yield: 86.3 %

Procedure:
A mixture of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (70.0 mg, 0.143 mmol), 2-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amino}ethanol (75.0 mg, 0.285 mmol), bis(di-tert-butyl(4-dimethylaminophenyl) phosphine)dichloropalladium(II) (10.1 mg, 0.0143 mmol), and 2M NaOH aq. (0.430 mL, 0.214) in DMF (2 mL) was heated at 160° C. for 1 hour under microwave irradiation. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water (3×) and brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (CHCl3/EtOAc=1:1→1:2→EtOAc) to afford desired product (73.0 mg, 86.5%) as yellow solid.
Reaction SMILES: ClCC1C=NC=CN=1.C(N)CN.[N:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[CH2:19][NH:20][CH2:21][CH2:22][NH2:23].[C:24]([NH:26][C:27](=[N:30][CH3:31])SC)#[N:25]>>[C:24]([NH:26][C:27]([NH:30][CH3:31])=[N:23][CH2:22][CH2:21][NH:20][CH2:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][N:13]=1)#[N:25]
Reactant: NCCNCc1cnccn1
Reactant: CN=C(NC#N)SC
Agent: ClCc1cnccn1
Solvent: NCCN
Product: CNC(=NCCNCc1cnccn1)NC#N

Procedure:
Reacting 2-chloromethylpyrazine with ethylenediamine by the procedure of Example 34 and reacting the resulting N-(2-pyrazinylmethyl)ethylenediamine with N-cyano-N',S-dimethylisothiourea by the procedure of Example 3 gives the title compound.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].C1[C:11]2[CH:12]=[CH:13][C:10]=2[CH:9]=[C:8](C=O)C=1.[NH4+].[Cl-].C([O-])(O)=O.[Na+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:4]([C:3]1[CH:2]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:12][C:11]=12)=[CH2:5]
Reactant: O=Cc1ccc2c(c1)C=C2
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cccc2c1CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a 500 mL round bottom neck flask was added methyltriphenylphosphonium bromide 1.1 (48.6 g, 136.2 mmol), 220 mL of anhydrous THF, and the solution was cooled to −78 C. n-BuLi (2.5 M in hexane, 52.8 mL, 132 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature. The yellow-orange solution was cooled to −78 C, and the aldehyde 1.2 (14.32 g, 108.4 mmol), diluted in anhydrous THF (70 mL) added slowly. The mixture was warmed to room temperature and stirring continued for 2 h. The reaction was treated sequentially with saturated NH4Cl and saturated NaHCO3 solution and the crude product was filtered over Celite, washed with diethyl ether/hexane (1:1), and evaporated to dryness (no heat) to give the crude product. Further purification by column chromatography using 5% diethyl ether/hexane as eluting solvents followed by vacuum distillation (75 C, 1.0 mm) gave the pure 4-Vinylbenzocyclobutene 1.3 as a colorless liquid (11 g, 78%). 1H NMR (300 MHz, CDCl3): δ 7.26 (d, 1H), 7.20 (s, 1H), 7.04 (d, 1H), 6.74 (dd, 1H), 5.70 (d, 1H), 5.20 (d, 1H), 3.19 (s, 4H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.N1CCC[C@@H](O)C1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:28][C@@H:24]([OH:25])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Agent: O[C@@H]1CCCNC1
Product: CC(C)(C)c1nc(N2CCC[C@@H](O)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-piperidin-3-ol hydrochloride and isolated as colorless gum (8.3 mg, 44%). MS (m/e): 401.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH2:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=O)[CH:30]=2)=[C:24]([CH3:37])[CH:23]=1)[CH3:17]>C1(C)C=CC=CC=1>[CH2:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][NH:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=3)[CH:30]=2)=[C:24]([CH3:37])[CH:23]=1)[CH3:17]
Reactant: CCOC(=O)C(F)Cc1ccc(N)cc1
Reactant: CCOCCOc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Solvent: Cc1ccccc1
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CC(F)C(=O)OCC)cc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.7 %

Procedure:
To a solution of ethyl 3-(4-aminophenyl)-2-fluoropropanoate (400 mg, 1.89 mmol) and 4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-carbaldehyde (434 mg, 1.45 mmol) in toluene (25 mL) were added molecular sieves (0.4 nm, beads, 1.6 g), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (20 mL) and ethanol (20 mL), 10% palladium-carbon (50% water-containing product, 0.40 g) was added, and the mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 3 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-40% hexane/ethyl acetate) to give the title compound (320 mg, yield 45%) as a colorless oil.
Reaction SMILES: [OH-].[K+].[CH3:3][CH2:4][CH2:5][C:6]([C:8]([OH:10])=[O:9])=[O:7].[C:11]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(=[O:13])[CH3:12]>O.C(O)C>[OH:7][C:6]([CH2:5][CH2:4][CH3:3])([CH2:12][C:11](=[O:13])[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[C:8]([OH:10])=[O:9]
Reactant: CCCC(=O)C(=O)O
Reactant: CC(=O)c1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCC(O)(CC(=O)c1cccs1)C(=O)O
Reaction time: 48 h
Yield: 41.3 %

Procedure:
11.2 g (200 mmol) of potassium hydroxide in 75 ml of water are added at 0° dropwise to a suspension of 11.6 g (100 mmol) of 2-oxo-n-valeric acid and 12.6 g (100 mmol) of 2-acetylthiophene in 75 ml of ethanol and the suspension is held at 0° for 48 hours. After evaporation of the ethanol the residue is made acidic with 25% hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate extracts are dried, filtered and evaporated. After chromatography on silica gel using a 5:1 mixture of methylene chloride and methanol as the eluent and crystallisation from ether there are obtained 10.0 g (41%) of rac-α-hydroxy-α-propyl-γ-oxo-2-thiophenebutyric acid as a colorless powder, melting point 128°-131°, MS: 197 (M-COOH)+.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:20]=4[S:19](=[O:29])(=[O:28])[N:18]=3)[C:7]2=[O:30])[CH2:3][CH2:2]1.Cl.[CH2:32]([N:39]1[CH:43]=[CH:42][N:41]=[C:40]1[CH2:44]Cl)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:32]([N:39]1[CH:43]=[CH:42][N:41]=[C:40]1[CH2:44][O:27][C:25]1[CH:24]=[CH:23][C:21]2[NH:22][C:17]([C:8]3[C:7](=[O:30])[N:6]([NH:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:15]4[C:10]([C:9]=3[OH:16])=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:18][S:19](=[O:28])(=[O:29])[C:20]=2[CH:26]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: ClCc1nccn1Cc1ccccc1
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc2n1NCC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=c1c(C2=NS(=O)(=O)c3cc(OCc4nccn4Cc4ccccc4)ccc3N2)c(O)c2ccccc2n1NCC1CC1
Temperature: 25 °C
Yield: 74.9 %

Procedure:
Product of Example 320C (20 mg, 0.047 mmol) in N,N-dimethylformamide (1 mL) was was heated with 1-benzyl-2-(chloromethyl)-1H-imidazole hydrochloride (23 mg, 0.095 mmol), potassium carbonate (0.061 g, 0.187 mmol) and tetrabutylammonium iodide (catalytic) at 120° C. for 2 hours in a microwave reactor. The solution was cooled to 25° C. and concentrated. The residue was triturated with ethyl acetate, filtered and washed with water to give title compound (21 mg, 75%).