Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:8][NH:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]2[C:13]([CH3:16])=[N:14][N:15]=[C:3]12.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[CH3:16][C:13]1[N:4]2[C:5]3[CH:12]=[CH:11][C:10]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:9][C:6]=3[NH:7][CH2:8][CH2:2][C:3]2=[N:15][N:14]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1nnc2n1-c1ccccc1NCC2Br
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nnc2n1-c1ccc(-c3ccccc3)cc1NCC2
Yield: 52.6 %

Procedure:
A solution of bromo-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (30 mg, 0.11 mmol), phenylboronic acid (26 mg, 0.22 mmol), Tetrakis(triphenylphosphine)palladium(0) (10 mg) and Cs2CO3 (72 mg, 0.22 mmol) in dioxane (5 mL) and water (1 mL) was heated at 120° C. under microwave for 20 min. The reaction mixture was concentrated to give the crude product, which was purified by prep-TLC (DCM:MeOH=10:1) to afford 1-methyl-8-phenyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (16 mg, yield 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH:5]([N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[CH:6]([OH:12])[C:7]([CH3:11])([CH3:10])[CH2:8][F:9].[CH3:23][N:24]=[C:25]=[O:26].C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH:5]([N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[CH:6]([O:12][C:25](=[O:26])[NH:24][CH3:23])[C:7]([CH3:11])([CH3:10])[CH2:8][F:9]
Reactant: CN=C=O
Reactant: CC(C)(CF)C(O)C(Oc1ccc(Cl)cc1Cl)n1cncn1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CNC(=O)OC(C(Oc1ccc(Cl)cc1Cl)n1cncn1)C(C)(C)CF
Yield: 86 %

Procedure:
8.4 g (0.024 mol) of 1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-1-(1,2,4-triazol-1-yl)-butan-2-ol were dissolved in 100 ml of dioxane, and 2 ml of methyl isocyanate and 3.5 ml of triethylamine were added. The mixture was heated under reflux for 10 hours and concentrated by distilling off the solvent in vacuo. The residue was heated in 50 ml of ethyl acetate and the mixture was filtered. 8 g (86% of theory) of 1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-2-methylcarbamoyloxy-1-(1,2,4-triazol-1-yl)-butane were obtained in the form of colorless crystals of melting point 124°-27° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][CH2:6][C@H:7]1[O:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]1)=[O:4]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[OH:1][CH2:2][C:3]([NH:5][CH2:6][C@H:7]1[O:12][CH2:11][CH2:10][NH:9][CH2:8]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CNC(=O)CO)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CO)NC[C@@H]1CNCCO1
Temperature: 25 °C

Procedure:
(R)-tert-butyl 2-((2-hydroxyacetamido)methyl)morpholine-4-carboxylate (1.0 equiv.) was dissolved in DCM:TFA (4:1, 0.5 M) and stirred at room temperature. After one hour the solution was concentrated to yield (S)-2-hydroxy-N-(morpholin-2-ylmethyl)acetamide. LCMS (m/z) (M+H)=175.1, Rt=0.12 min.
Reaction SMILES: O.NN.[CH3:4][C@H:5]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:6][N:7]1C(=O)C2C(=CC=CC=2)C1=O.[ClH:23]>C(O)C>[ClH:23].[CH3:4][C@H:5]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:6][NH2:7]
Reactant: C[C@@H](CN1C(=O)c2ccccc2C1=O)CC(F)(F)F
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: C[C@@H](CN)CC(F)(F)F
Yield: 88 %

Procedure:
Hydrazine monohydrate (3.1 mL) was added to a stirred solution of (R)-2-(2-methyl-4,4,4-trifluorobutyl)-1H-isoindole-1,3(2H)-dione (17.1 g) in anhydrous ethanol (85 mL) was heated to reflux. After three hours' reflux, the solution was cooled; ethanol (40 mL) was added; and the solution was acidified to pH 1 by addition of concentrated hydrochloric acid and was filtered. The filtrate was evaporated, and the residue was purified by sublimation (bath temperature 170° C., at 6.6 Pa) to yield (R)-2-methyl-4,4,4-trifluorobutylamine hydrochloride as a white solid (9.89 g, 88%); mp 187°-191° C.; partial NMR (300 MHz, DMSO-d6 -D2) shake): 1.05 (d,3H,CH3), 2.06-2.36(m,2H,CF3CH2) 2.36-2.54(m,1H,CHCH3) 2.73(dd,1H,CH2N), 2.87(dd,1H,CH2N) 8.20(br s,2H,NH2).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (290 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) according to the general procedure M. Obtained as a white foam (430 mg, 82%).
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][OH:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Na].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(OCC)(=O)C>[N:1]1([CH2:10][CH2:11][CH:12]=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: OCCCn1cnc2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=CCCn1cnc2ccccc21
Reaction time: 5 h
Yield: 81.6 %

Procedure:
3-(benzimidazol-1-yl)propan-1-ol (100 mg, 0.57 mmol) was dissolved in dichloromethane (6 mL), and treated with sodium periodinane (290 mg, 0.68 mmol). After stirring 5 hours, the mixture was treated with sodium bicarbonate (10 mL), ethyl acetate (10 mL), sodium thiosulfate (2 g) and extracted with ethyl acetate (2×10 mL). The organic phases were combined and washed with brine (15 mL), dried (MgSO4), filtered, and concentrated to yield the desired 3-(benzimidazol-1-yl)propanal (81 mg, 80%) as a yellow oil. 1H NMR (CDCl3) δ 3.09 (t, 2H, J=6 Hz), 4.54 (t, 2H, J=6 Hz), 7.32 (m, 2H), 7.38 (m, 1H), 7.80 (d, 1H, J=6 Hz), 8.00 (s, 1H), 9.81 (s, 1H).
Reaction SMILES: Cl.C(=N)(OCC)C.C(N)(C)C.[CH:12]1([N:15]2[C:19]([CH:20]=[O:21])=[CH:18][N:17]=[C:16]2[CH3:22])[CH2:14][CH2:13]1>>[CH:12]([N:15]1[C:19]([CH:20]=[O:21])=[CH:18][N:17]=[C:16]1[CH3:22])([CH3:14])[CH3:13]
Reactant: Cc1ncc(C=O)n1C1CC1
Agent: CCOC(C)=N
Agent: Cl
Solvent: CC(C)N
Product: Cc1ncc(C=O)n1C(C)C

Procedure:
3-Isopropyl-2-methyl-3H-imidazole-4-carbaldehyde was prepared from ethyl acetimidate hydrochloride and isopropylamine in the same manner as 3-cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde (Example 45).
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].C([Sn](CCCC)(CCCC)[C:23]1[S:24][CH:25]=[CH:26][N:27]=1)CCC>C1(C)C=CC=C(C)C=1>[CH3:17][C:3]1[C:2]([C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[C:6]([CH3:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[N:4]=1
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Solvent: Cc1cccc(C)c1
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1-c1nccs1
Yield: 5.2 %

Procedure:
A mixture of 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2 of Example 11) (855 mg, 2.5 mmol), 2-tributylstannylthiazole (3 mmol) and tetrakistriphenylophosphinepalladium (346 mg, 0.3 mol) in m-xylene (6 mL) was refluxed for 16 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated. The crude product was purified by TLC with hexane/ethyl acetate (1:1) to afford 39 mg (5%) of the title compound as yellow oil: MS (EI) m/z 299 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:19][N:18]=[C:17]2[CH2:25]O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].CS(Cl)(=O)=O.[CH:32]1([CH2:35][NH2:36])[CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:19][N:18]=[C:17]2[CH2:25][NH:36][CH2:35][CH:32]2[CH2:34][CH2:33]2)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: NCC1CC1
Reactant: CN(C)Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: CS(=O)(=O)Cl
Product: CN(C)Cc1nnc(CNCC2CC2)n1-c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
In the manner given in Example 47, 5-chloro-2-[3-(hydroxymethyl)-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4- yl]benzophenone is treated first with methanesulfonyl chloride followed by (cyclopropylmethyl)amine to give 5-chloro-2-[3-[[(cyclopropylmethyl)amino]methyl]-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: CCN(C(C)C)C(C)C.CS(O[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH2:31][CH2:32][C:33]4[N:34]([C:36]([C:39]([F:42])([F:41])[F:40])=[N:37][N:38]=4)[N:35]=3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1)(=O)=O.[CH2:43]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][C:46]1=[O:51])[CH3:44]>CN(C=O)C.C(Cl)Cl>[CH2:43]([N:45]1[CH2:50][CH2:49][N:48]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH2:31][CH2:32][C:33]5[N:34]([C:36]([C:39]([F:41])([F:40])[F:42])=[N:37][N:38]=5)[N:35]=4)[CH2:28][CH2:29]3)=[CH:20][CH:19]=2)[CH2:47][C:46]1=[O:51])[CH3:44]
Reactant: CS(=O)(=O)OCCOc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Reactant: CCN1CCNCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN1CCN(CCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1=O
Temperature: 110 °C
Reaction time: 3 h
Yield: 36.1 %

Procedure:
DIPEA (0.219 mL, 1.23 mmol) was added to 2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl methanesulfonate (200 mg, 0.41 mmol) and 1-ethylpiperazin-2-one (52.6 mg, 0.41 mmol) in DMF (5 mL) at 20° C. under nitrogen. The resulting solution was stirred at 110° C. for 3 hours and the solvent was removed in vacuo to give an orange gum, which was dissolved in DCM (100 mL) and the solution washed with water (100 mL). The organic layer was passed through a phase separating cartridge and then evaporated to dryness to give an orange gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in isohexane then 10% methanolic ammonia in EtOAc. Pure fractions were evaporated to dryness to afford a yellow gum, which was triturated with ether to give 1-ethyl-4-[2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl]piperazin-2-one (77 mg, 36.1%) as a white solid.
Reaction SMILES: [CH:1](O)=O.C=O.[Br:6][C:7]1[CH:20]=[C:19]([CH3:21])[C:10]([O:11][CH2:12][C@H:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[C:9]([CH3:22])[CH:8]=1>>[Br:6][C:7]1[CH:20]=[C:19]([CH3:21])[C:10]([O:11][CH2:12][C@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([CH3:1])[CH2:14]2)=[C:9]([CH3:22])[CH:8]=1
Reactant: O=CO
Reactant: Cc1cc(Br)cc(C)c1OC[C@H]1CCCNC1
Agent: C=O
Product: Cc1cc(Br)cc(C)c1OC[C@H]1CCCN(C)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Alternatively, formic acid (16.7 mL, 333 mmol) and aqueous formaldehyde (37%, 9.1 mL) were added dropwise to (S)-3-(4-bromo-2,6-dimethylphenoxymethyl)piperidine (24.1 g, 80.8 mmol) that was being chilled in an ice bath. After the addition was complete, the reaction was placed in an oil bath at a temperature of 95° C. for 4 hours. The mixture was cooled to room temperature and partitioned between 15% aqueous sodium hydroxide (200 mL) and ether (600 mL). The aqueous phase was extracted twice more with additional ether (300 mL), and the ether layers combined, washed with brine (150 mL), dried and concentrated. The residue was chromatographed on silica gel, eluting with acetone/hexanes (1:1) and concentrated to give (S)-3-(4-bromo-2,6-dimethylphenoxymethyl)-1-methylpiperidine as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[NH:13][CH:14]=[C:15]([CH2:17][OH:18])[N:16]=2)=[O:11])=[C:4]([F:19])[C:3]=1[O:20][C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[C:23]([Cl:29])[CH:22]=1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[NH:13][CH:14]=[C:15]([CH:17]=[O:18])[N:16]=2)=[O:11])=[C:4]([F:19])[C:3]=1[O:20][C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[C:23]([Cl:29])[CH:22]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3nc(CO)c[nH]3)c2F)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3nc(C=O)c[nH]3)c2F)c1

Procedure:
A solution of N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-4-(hydroxymethyl)-1H-imidazole-2-carboxamide (0.40 g, 0.92 mmol) and MnO2 (0.80 g, 9.2 mmol) in CH2Cl2 (10 mL) was stirred at RT for 2 h. The solution was filtered through celite and evaporated to provide the crude title compound which was used without further purification.
Reaction SMILES: O1CCOCC1.Br.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:31][CH2:30]3)=[C:25]([O:32]C)[N:24]=2)=[CH:16]\[C@@H:17]2[NH:21][C:20](=[O:22])[CH2:19][CH2:18]2)=[CH:11][CH:10]=1>O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12](/[C:15](/[C:23]2[NH:24][C:25](=[O:32])[C:26]([CH:29]3[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[CH:16]\[C@H:17]2[CH2:18][CH2:19][C:20](=[O:22])[NH:21]2)=[CH:13][CH:14]=1
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(Cl)cc2)ccc1C1CC1
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: O=C1CC[C@H](/C=C(\c2ccc(Cl)cc2)c2ccc(C3CC3)c(=O)[nH]2)N1
Temperature: 65 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
1,4-Dioxane (4 mL) and 48% hydrobromic acid (2 mL) were added to (5R)-5-[(E)-2-(4-chlorophenyl)-2-(5-cyclopropyl-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one (250 mg), and the mixture was stirred at 65° C. for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→90:10) to give the title compound as a colorless powder (65 mg, 68% (two steps)).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:35][Mg]Cl>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([OH:34])([CH3:35])[CH3:33])=[CH:30][CH:31]=2)=[CH:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Mg]Cl
Reactant: CC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 1-{4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-ethanone (prepared as in Example 80, 450 mg, 0.95 mmol) in dry tetrahydrofuran (20 mL) at 0° C. was added methylmagnesium chloride solution in tetrahydrofuran (3.0 M, 0.7 mL, 2.1 mmol) dropwise. After stirring at 0° C. for 1 h, the reaction was quenched with a saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 2-{4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-propan-2-ol (440 mg, 94%) as a white solid: LC/MS m/e calcd for C29H30N2O3S [M+H]+ 487.64, observed 487.2.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH2:23][CH3:24])[NH:10][C:11](=[O:14])[C:12]=1[NH2:13].O.[CH:26]([CH:28]=O)=O.O>C(O)CCC>[CH2:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:9]1[NH:10][C:11](=[O:14])[C:12]2[C:7](=[N:6][CH:26]=[CH:28][N:13]=2)[N:8]=1)[CH2:23][CH3:24]
Reactant: O=CC=O
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Agent: O=S(=O)(O)O
Solvent: CCCCO
Solvent: O
Product: CCCOc1ccccc1-c1nc2nccnc2c(=O)[nH]1
Yield: 97.5 %

Procedure:
A stirred mixture of 4,5-diamino-2-(2-propoxyphenyl)pyrimidin-6-one sulphate (1.25 g), glyoxal hydrate (0.4 g), water (62.5 ml) and n-butanol (1 ml) was heated under reflux for one hour to afford a crude product (0.97 g) which was collected and washed with water. The crude product together with another sample (0.12 g) similarly prepared was eluted from a silica column with chloroform. The combined fractions containing product were evaporated under reduced pressure to afford a solid (0.96 g) which was recrystallised from ethanol-water to afford the title compound, 0.8 g, m.p. 177.5°-178.5° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.CCN(CC)CC.[CH2:27]([O:34][C:35](Cl)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([O:34][C:35]([NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](N)C2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](NC(=O)OCc3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
A solution of compound 17 (4.37 g, 16.72 mmol) in THF (30 mL) was cooled to 0° C. and treated successively with Et3N (4.6 mL, 3.38 g, 33 mmol) and benzylchloroformate (2.8 mL, 3.42 g, 20 mmol). The reaction mixture was allowed to stir for 2 hrs at 0° C., quenched by adding an aqueous saturated NH4Cl solution (30 mL) and extracted with EtOAc. The extract was dried over Na2SO4, filtered and concentrated. Crude product was purified by flash chromatography using 30% EtOAc in hexanes as an eluent to provide title compound 115 (3 g, 45% yield). LRMS (ESI): (calc) 396.20 (found) 397.2 (MH)+.
Reaction SMILES: [CH2:1]([O:17][CH2:18][C:19](=[CH2:22])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].N1C=CN=C1>CN(C)C=O.CCOCC>[CH3:27][C:26]([Si:23]([O:21][CH2:20][C:19]([CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH2:22])([CH3:25])[CH3:24])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C(CO)COCCCCCCCCCCCCCCCC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C(COCCCCCCCCCCCCCCCC)CO[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 5.0 g of 2-[(hexadecyloxy)-methyl]-2-propen-1-ol in 50 ml of dry N,N-dimethylformamide is added 6.05 g of tert-butyldimethylsilyl chloride followed by 8 g of imidazole. This mixture is stirred overnight, then diluted with ether, washed with saturated aqueous sodium bicarbonate, water and brine, dried and evaporated, to give 6.49 g of the desired compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([NH:19][CH2:20][CH2:21][C:22]3[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:24][CH:23]=3)=[O:18])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([NH:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:33][CH:34]=3)=[O:18])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)COc1ccc(CCNC(=O)c2cc3c(s2)CCN(C(=O)OC(C)(C)C)C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2sc(C(=O)NCCc3ccc(OCC(=O)O)cc3)cc2C1
Yield: 90.8 %

Procedure:
To the solution of the compound prepared in (a) (250 mg) in ethanol was added 1N sodium hydroxide (2.6 ml), and the mixture was stirred under ice-cooling for 3 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added. The mixture was acidified with 1N hydrochloric acid. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 214 mg of 4-[2-[[(5-t-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2 -c]pyridin-2 -yl)carbonyl]amino]ethyl]phenoxyacetic acid (yield, 91% ).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][CH2:5][CH:6]([OH:13])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.COC1C=CC(COCC(O)CN2C=CN=C2)=CC=1>>[CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][CH2:5][C:6](=[O:13])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CC(C)(C)CCCC(O)Cn1ccnc1
Agent: COc1ccc(COCC(O)Cn2ccnc2)cc1
Product: CC(C)(C)CCCC(=O)Cn1ccnc1

Procedure:
Utilising the procedure described in Example 1c and employing α-(4,4-dimethylpentyl)-1H-imidazole-1-ethanol in lieu of α-[[(4-methoxyphenyl)methoxy]methyl]-1H-imidazole-1-ethanol yielded a crude product which was purified by column chromatography (silica gel, chloroform) to yield 6,6-dimethyl-1-(1H-imidazol-1-yl)-2-heptanone as a colourless crystalline solid, having a melting point of 45°-46° C. (ether-hexane) and the following structural characteristics:
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[N:20]=2)=[O:18])[CH2:13][C:12]1([CH3:28])[CH3:27])=O)C1C=CC=CC=1>[Pd].CO>[CH3:27][C:12]1([CH3:28])[NH:11][CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[N:20]=2)=[O:18])[CH2:13]1
Reactant: COc1cccc(C(=O)N2CCN(C(=O)OCc3ccccc3)C(C)(C)C2)n1
Agent: [Pd]
Solvent: CO
Product: COc1cccc(C(=O)N2CCNC(C)(C)C2)n1
Reaction time: 12 h

Procedure:
A mixture of 1.10 g (2.87 mmol) 4-(6-methoxy-pyridine-2-carbonyl)-2,2-dimethyl-piperazine-1-carboxylic acid benzyl ester and 100 mg palladium on carbon in 20 mL methanol was hydrogenated at RT for 12 h at 3 bar. The catalyst was removed by filtration and the solvent was evaporated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Cl[C:12]([S:14]Cl)=[O:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][C:12](=[O:13])[S:14][N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=c1oc(-c2ccc(Cl)cc2)ns1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed 4-chlorobenzamide (3.0 g, 19.28 mmol, 1.00 equiv), chloro(chlorosulfanyl)methanone (5.03 g, 38.40 mmol, 1.99 equiv), toluene (30 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction progress was monitored by GCMS/TLC/LCMS (ethyl acetate/petroleum ether=1:20). The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether. This resulted in 3.8 g (92%) of 5-(4-chlorophenyl)-2H-1,3,4-oxathiazol-2-one as a white solid.