Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:28][C@@H:29]([C@@H:31]4[CH2:35][C:34](=[O:36])[NH:33][CH2:32]4)[CH3:30])=[N:10][C:11]([C:13]4[CH:18]=[C:17]5[NH:19][C:20](=[O:27])[C:21]6([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]6)[C:16]5=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.FC(F)(F)S(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O>CN(C=O)C>[CH:1]1([N:4]2[C:8]3[C:9]([O:28][C@@H:29]([C@@H:31]4[CH2:35][C:34](=[O:36])[NH:33][CH2:32]4)[CH3:30])=[N:10][C:11]([C:13]4[CH:18]=[C:17]5[NH:19][C:20](=[O:27])[C:21]6([CH2:22][CH2:23][N:24]([CH2:43][C:44]([F:47])([F:46])[F:45])[CH2:25][CH2:26]6)[C:16]5=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C[C@@H](Oc1nc(-c2ccc3c(c2)NC(=O)C32CCNCC2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H](Oc1nc(-c2ccc3c(c2)NC(=O)C32CCN(CC(F)(F)F)CC2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)spiro[indoline-3,4′-piperidin]-2-one: 3.78 (94 mg, 0.19 mmol) in DMF was added TEA (117 mg, 1.1 mmol), then followed by the addition of 2,2,2-trifluoroethyl trifluoromethanesulfonate (45 mg, 0.19 mmol). Reaction mixture was stirred at r.t. overnight, and LC-MS showed reaction was complete. The reaction mixture was filtered and purified by prep HPLC (MeCN:water gradient, TFA modified) to provide 6-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(2,2,2-trifluoroethyl)spiro[indoline-3,4′-piperidin]-2-one: 3.80 as its TFA salt.
Reaction SMILES: [CH2:1]([C:3]1(O)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH2:14]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[CH:21]2)[CH3:15]>>[CH2:14]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:15]
Reactant: CCc1cccc2cc[nH]c12
Reactant: CCC1(O)CCc2cc(F)ccc21
Product: CCc1cccc2c(C3(CC)CCc4cc(F)ccc43)c[nH]c12

Procedure:
Utilizing 1-ethyl-5-fluoro-indan-1-ol and 7-ethylindole, the title compound is prepared as in example 1. 104 mg (58%). LC-MS m/z 308.1 (M++1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH:9]=[CH:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:22][CH2:23][CH2:24][CH2:25][C:26](O)=[O:27])=[CH:17][CH:16]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH:9]=[CH:10][CH2:11][NH:12][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]([C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)[C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCC=CCN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC=CCNC(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of (4-amino-but-2-enyl)-carbamic acid tert-butyl ester (1.0 g, 5.36 mmol) in dry CH2Cl2 (40 ml) was added 6,6-bis-(4-fluorophenyl)-hexanoic acid (1.62 g, 5.36 mmol) under nitrogen. To the reaction was added EDC (2.04 g, 10.72 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate:water (10:1) (150 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (30 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (15:1) to give the desired product in 70% yield.
Reaction SMILES: Br[C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[CH3:16][O:17][C:18](=[O:32])[C:19]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[CH2:20].CC(N=NC(C#N)(C)C)(C#N)C.[SnH](CCCC)(CCCC)CCCC>C1C=CC=CC=1>[CH2:25]([O:24][C:22]([NH:21][CH:19]([CH2:20][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C:18]([O:17][CH3:16])=[O:32])=[O:23])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCCC[C@H]1Br
Reactant: C=C(NC(=O)OCc1ccccc1)C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: COC(=O)C(C[C@@H]1CCCC[C@H]1O[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 0.08 h
Yield: 39.1 %

Procedure:
A benzene solution of ((1R*,2R*)-2-bromocyclohexyloxy)(tert-butyl)dimethylsilane (17.8 g, 0.061 mol), 2-benzyloxycarbonylamino-acrylic acid methyl ester (8 g, 0.037 mol), AIBN (1.22 g, 0.019 mol) was heated to reflux. After 5 minutes, n-Bu3SnH (19.8 mL, 0.074 mol) was added. The resulting mixture was then stirred at reflux for 14 hours. Solvent was removed under reduced pressure, the residue was purified by column chromatography to give methyl 2-(benzyloxycarbonylamino)-3-((1S*,2R*)-2-(tert-butyldimethylsilyloxy)cyclohexyl)propanoate (6.5 g, 24%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[C:26](=O)[C:27](OC)=[O:28])#[N:16].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[C:26]1[C:27](=[O:28])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2)#[N:16]
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2ccc(C#N)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5ccc(C#N)cc45)C(=O)NC3=O)c21
Temperature: 50 °C
Yield: 10.1 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (296 mg, 1.57 mmol) and methyl 2-(5-cyano-1H-indol-3-yl)oxoacetate (356 mg, 1.56 mmol) in DMF (6.5 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (4.8 mL, 4.8 mmol) dropwise over 20 min at 4° C. under N2. The resulting dark red solution was heated up to 50° C. for 6 h. The mixture was cooled to 4° C. and quenched with 1.0 N hydrochloric acid (10 mL) and poured into EtOAc (100 mL). The organic layer was separated, washed with saturated NaHCO3 (60 mL), saturated NaCl (60 mL), dried (MgSO4), and concentrated to a red solid. Filtration from a slurry in CH2Cl2 (15 mL) afforded the first batch of the title compound (58 mg, 7.4%) as a red crystalline solid, mp 220° C. dec. Tritration of the concentrated filtrate with Et2O (8.0 mL) afforded a second batch of the title compound (288 mg, 36.9%). 1H NMR (DMSO-d6) δ 8.09 (s, 1H), 7.68 (m, 1H), 7.51 (m, 1H), 7.28–7.19 (m, 2H), 7.09–6.92 (m, 2H), 6.47 (m, 2H), 3.60 (s, 3H). MS (ESI): m/z=367 [C22H14N4O2+H]+
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH:11]=[O:12].C1(C)C=CC=CC=1.[OH-:20].[Na+].OO>O>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:9])[F:10])[C:3]=1[C:11]([OH:20])=[O:12]
Reactant: [OH-]
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Agent: OO
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1nc(C(F)F)c(C(=O)O)c1Cl
Temperature: 50 °C
Reaction time: 7 h
Yield: 49 %

Procedure:
In a 500 mL flask, 6.0 g (31 mmol) of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde are added to 30 mL of toluene. A solution of 2.4 g (62 mmol) of sodium hydroxide in 6 ml of water is added to the reaction mixture, followed by 103 mL of a 30% solution of hydrogen peroxide in water, whilst keeping the temperature below 37° C. After the end of the addition, the reaction mixture is stirred at 50° C. for 7 hours. Once the reaction mixture is back to room temperature, the two phases are separated and the organic phase is extracted with 100 mL of water. The combined aqueous phases are acidified to pH 2 with aqueous hydrochloric acid. The resulting white precipitate is filtered, washed twice with 20 mL of water, and dried to yield 3.2 g of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 3.78 (s, 3H); 7.12 (t, 1H, JHF=53.60 Hz); 13.19 (s, 1H); IR (KBr): 1688 cm−1 (C═O); 2200-3200 cm−1 broad (hydrogen bond).
Reaction SMILES: C[O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH3:14])=[C:8]2[C:4]=1[CH2:5][C:6]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]2=[O:15].Br.O>C(O)(=O)C>[CH3:22][C:6]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]2[C:8](=[C:9]([CH3:14])[CH:10]=[C:11]([O:12][CH3:13])[C:3]=2[OH:2])[C:7]1=[O:15]
Reactant: COc1cc(C)c2c(c1OC)CC(C)(c1ccccc1)C2=O
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C)c2c(c1O)CC(C)(c1ccccc1)C2=O

Procedure:
141.7 g (0.478 mole) of the 2,3-dihydro-4,5-dimethoxy-2,7-dimethyl-2-phenyl-1H-inden-1-one obtained according to Example 2(d) are boiled under slight reflux for 45 minutes with a mixture of 275 ml of aqueous 48% strength hydrobromic acid, 475 ml of glacial acetic acid and 72 ml of 33% strength hydrogen bromide in glacial acetic acid and then the reaction mixture is poured into 3000 ml of a mixture of ice and water. The product so obtained is extracted twice with ether and the ethereal phases are washed once with water, once with dilute sodium bicarbonate solution, and twice with water again. The ethereal phases are dried over sodium sulphate, filtered, and concentrated to dryness by evaporation in vacuo in a rotary evaporator. The crude residue of 135 g of brown crystals is dissolved warm in 250 ml of ethyl acetate and filtered. Subsequently, 500 ml of petroleum ether having a boiling range of 40°-60° are added. On leaving to stand, the product crystallises out and can be filtered and dried. In this manner 2,3-dihydro-2,7-dimethyl-4-hydroxy-5-methoxy-2-phenyl-1H-inden-1-one having a melting point of 136°-139° is obtained.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Cl:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20].[Na+].[Cl-]>CN(C)C=O>[Cl:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: OCCOCCCl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOCCCl
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Imidazole (17.8 g, 261 mmol) was dissolved in dimethylformamide (100 ml) and t-butyldimethylsilyl chloride (36.3 g, 241 mmol) was added and stirred. 2-(2-chloroethoxy)ethanol (25.0 g, 200 mmol) was added dropwise over 1 hour under cooling with ice, and the mixture was stirred for 1 further hour, left standing overnight at room temperature, and then poured into saturated aqueous NaCl (500 ml). The resulting mixture was extracted twice with ether. The extract was washed twice with saturated aqueous NaCl, and dried over MgSO4. Then the solvent was removed in vacuo, giving 1-chloro-2-(2-t-butyldimethylsilyloxyethoxy)ethane (47.8 g, yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=NOC)[CH:6]([C:11](=O)[CH3:12])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2].Cl.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[NH:27][NH2:28]>C(O)(=O)C.COCCO>[CH2:1]([O:3][C:4]([C:5]1[N:27]([C:21]2[C:20]([Cl:19])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:26])[N:28]=[C:11]([CH3:12])[C:6]=1[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:17])[CH3:2]
Reactant: NNc1c(Cl)cccc1Cl
Reactant: CCOC(=O)C(=NOC)C(CC(C)C)C(C)=O
Agent: Cl
Solvent: COCCO
Solvent: CC(=O)O
Product: CCOC(=O)c1c(CC(C)C)c(C)nn1-c1c(Cl)cccc1Cl
Temperature: 105 °C
Reaction time: 3 h

Procedure:
A mixture of 3-acetyl-2-methoxyimino-5-methyl-hexanoic acid ethyl ester (1 g, 4.1 mmol), 2,6-dichlorophenylhydrazine hydrochloride (1.76 g, 8.2 mmol) in glacial acetic acid (10 mL) and 2-methoxy-ethanol (5 mL) is stirred at 105° C. for 3 hours. The reaction is concentrated and the residue is partitioned between EtOAc and 1N HCl. The organic layer is concentrated and purified by column chromatography (0-20% EtOAc in hexanes) to give the title product as an oil, 1.1 g (76%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH:6]([S:8]([CH:11]=[CH2:12])(=[O:10])=[O:9])=[CH2:7]>>[O:9]=[S:8]1(=[O:10])[CH2:11][CH2:12][N:1]([CH2:2][CH2:3][CH2:4][OH:5])[CH2:7][CH2:6]1
Reactant: NCCCO
Reactant: C=CS(=O)(=O)C=C
Product: O=S1(=O)CCN(CCCO)CC1
Temperature: 110 °C
Yield: 49.3 %

Procedure:
A mixture of 3-amino-1-propanol (650;1, 8.4 mmol) and vinyl sulphone (1 g, 8.4 mmol) was heated at 110° C. for 45 minutes. The mixture was allowed to cool and was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 3-(1,1-dioxothiomorpholino)-1-propanol (800 mg, 90%).
Reaction SMILES: [C:1]([C:3]([C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH:13]=[CH:12][C:11]=1[O:24][CH3:25])(C)[C:4]([O:6]CC)=[O:5])#N.[OH-].[K+]>O.C(O)C>[CH3:25][O:24][C:11]1[CH:12]=[CH:13][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:15][C:10]=1[CH:3]([CH3:1])[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(C)(C#N)c1cc(Oc2ccccc2Cl)ccc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Oc2ccccc2Cl)cc1C(C)C(=O)O
Yield: 68.2 %

Procedure:
A mixture of ethyl 2-cyano-2-[2-methoxy-5-(2-chlorophenoxy)phenyl]propionate (5.5 g) and potassium hydroxide (4.3 g) in water 40 ml and ethanol (80 ml) was treated in a similar manner to that of Example 14-(7) to give oily 2-[2-methoxy-5-(2-chlorophenoxy)phenyl]propionic acid (3.2 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:22][CH2:21][C:11]2([O:19][C:18]3[CH:17]=[N:16][NH:15][C:14]=3[C:13](=[O:20])[CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][CH:24](O)[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>O1CCCC1>[CH2:1]([N:8]1[CH2:22][CH2:21][C:11]2([O:19][C:18]3[CH:17]=[N:16][N:15]([CH:24]([CH3:25])[CH3:23])[C:14]=3[C:13](=[O:20])[CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC2(CCN(Cc3ccccc3)CC2)Oc2cn[nH]c21
Reactant: CC(C)O
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)n1ncc2c1C(=O)CC1(CCN(Cc3ccccc3)CC1)O2
Temperature: 25 °C
Reaction time: 120 h
Yield: 39.6 %

Procedure:
1-Benzyl-1′H-spiro[piperidine-4,5′-pyrano[3,2-c]pyrazol]-7′(6′H)-one (204 mg, 0.67 mmol) was dissolved in 10 mL tetrahydrofuran. 2-propanol (0.11 mL, 1.37 mmol) and polymer supported triphenylphosphine (0.5 g, 3 mmol/g loading) were added followed by addition of DBAD (322 mg, 1.37 mmol) and stirred at ambient temperature for 5 days. Filtered off polymer supported triphenyl phosphine and washed filtercake with 100 mL ethyl acetate. The filtrate was concentrated and the resultant yellow oil was treated with 10 mL 4N HCl/dioxane. The mixture was stirred 1 h at ambient temperature. The volatiles were removed under reduced pressure. The resultant sludge was partitioned between 50 mL sat aq. sodium bicarbonate and 50 mL ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed (30-100% ethyl acetate/heptane gradient, 10 g silica) to yield 90 mg (35%) of 1-benzyl-1′-isopropyl-1′H-spiro[piperidine-4,5′-pyrano[3,2-c]pyrazol]-7′(6′H)-one as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.30 (m, 3H), 7.24 (m, 2H), 7.18 (s, 1H), 5.14 (spt, 1H), 3.52 (s, 2H), 2.60 (m, 4H), 2.41 (td, J=11.6, 2.5 Hz, 2H), 2.06 (d, J=12.5 Hz, 2H), 1.71 (m, 2H), 1.44 (m, 6H): m/z (M+1)=340.5.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[NH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:20]([O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27](F)=[CH:26][C:25]=1[O:31][CH2:32][O:33][CH3:34])[CH3:21].O>CN(C)C=O>[CH2:20]([O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27]([N:5]2[C:6]3[C:11](=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=3)[C:3]([C:1]#[N:2])=[CH:4]2)=[CH:26][C:25]=1[O:31][CH2:32][O:33][CH3:34])[CH3:21]
Reactant: CCOC(=O)c1ccc(F)cc1OCOC
Reactant: N#Cc1c[nH]c2cc(F)c(F)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(F)c(F)cc32)cc1OCOC
Temperature: 75 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
To a solution of 3-cyano-5,6-difluoroindole (0.25 g) in N,N-dimethylformamide (10 mL) were added cesium carbonate (0.91 g), 4-fluoro-2-methoxymethoxybenzoic acid ethyl ester (0.32 g), and this mixture was stirred at 75° C. overnight. This reaction mixture was poured into water, and this resulting mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=10/90-75/25) to give the title compound (0.12 g).
Reaction SMILES: Cl.[NH:2]1[CH2:13][S:12][CH2:11][C@H:3]1[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].C(N(CC)CC)C.[CH2:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH:22]1[CH2:30][CH2:31][C:32](O)=[O:33].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21][CH:22]1[CH2:30][CH2:31][C:32]([CH:11]1[S:12][CH2:13][NH:2][C@@H:3]1[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])=[O:33]
Reactant: O=C(O)CCC1Cc2ccccc2C1
Reactant: O=C([C@@H]1CSCN1)N1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCC1Cc2ccccc2C1)C1SCN[C@@H]1C(=O)N1CCCC1
Reaction time: 0.17 h
Yield: 71.2 %

Procedure:
0.89 g of 1-L-thioprolylpyrrolidine hydrochloride was suspended in 20 ml of methylene chloride. To the suspension were added 0.40 g of triethylamine and 0.76 g of 3-(indan-2-yl)propionic acid under ice-cooling with stirring. After 10 minutes, 0.92 g of WSC.HCl was added to the mixture under ice-cooling while stirring. The mixture was sirred for 16 hours at room temperature. The reaction mixture was washed with diluted hydrochloric acid, water, and saturated sodium hydrogen carbonate in this order. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was recrystallized from ethyl acetate/isopropyl ether to produce 1.02 g of 1-{3-[3-(indan-2-yl)proprionyl]-L-thioprolyl]pyrrolidine as colorless crystals (yield: 71%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[C:18](Cl)(=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:18](=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1cccc([N+](=O)[O-])c1
Reaction time: 18 h
Yield: 95.5 %

Procedure:
To 2.0 g (14.5 mmol) of 3-nitroaniline and 4.5 ml (32 mmol) of triethylamine in 60 ml of methylene chloride stirred at room temperature was added 5.4 ml (16 mmol) of octadecanoyl chloride in 10 ml of methylene chloride. The reaction mixture was kept at room temperature for 18 hours and then was washed with 1N HCl, dried and concentrated at reduced pressure to a solid. Recrystallization from methanol gave 5.6 g (95% yield, mp 75°-76°) of N-(3-nitrophenyl) octadecanamide.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][NH:11][C:12]1[S:16][N:15]=[C:14]([CH3:17])[N:13]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:17][C:14]1[N:13]=[C:12]([N:11]([CH3:10])[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[S:16][N:15]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CNc1nc(C)ns1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1nsc(N(C)C(=O)C2CCCCC2)n1

Procedure:
Cyclohexane carboxylic acid chloride (9.92 g, 0.068 mol) was added slowly to a solution of 5-methylamino-3-methyl-1,2,4-thiadiazole (7.0 g, 0.054 mol) in dry benzene containing triethylamine (6.87 g, 0.068 mol) and the mixture heated under reflux for 11/2 hours, cooled and washed with 2N hydrochloric acid, saturated solution sodium hydrogen carbonate and water; dried over magnesium sulphate, filtered and evaporated down to yield yellow oil which crystallised upon standing. This was recrystallised twice from petroleum ether 60°-80° C. to yield off-white crystals of N-(3-methyl-1,2,4-thiadiazol-5-yl)-N-methylcyclohexane carboxamide. Yield 8.23 g, (63.8%), m.p. 96° C.
Reaction SMILES: BrC1C(N2CCN(CC3C=NC=CC=3)CC2)=C2N=C(C3C=CC(CN)=CC=3)NC2=NC=1.[Cl:32][C:33]1[C:34]([N:62]2[CH2:67][CH2:66][N:65]([CH2:68][C:69]3[CH:70]=[N:71][CH:72]=[N:73][CH:74]=3)[CH2:64][CH2:63]2)=[C:35]2[N:41]=[C:40]([C:42]3[CH:61]=[CH:60][C:45]([CH2:46][N:47]4[CH2:52][CH2:51][N:50](C(OC(C)(C)C)=O)[CH2:49][CH2:48]4)=[CH:44][CH:43]=3)[NH:39][C:36]2=[N:37][CH:38]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:32][C:33]1[C:34]([N:62]2[CH2:63][CH2:64][N:65]([CH2:68][C:69]3[CH:70]=[N:71][CH:72]=[N:73][CH:74]=3)[CH2:66][CH2:67]2)=[C:35]2[N:41]=[C:40]([C:42]3[CH:61]=[CH:60][C:45]([CH2:46][N:47]4[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]4)=[CH:44][CH:43]=3)[NH:39][C:36]2=[N:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3nc4c(N5CCN(Cc6cncnc6)CC5)c(Cl)cnc4[nH]3)cc2)CC1
Agent: NCc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cnc2[nH]c(-c3ccc(CN4CCNCC4)cc3)nc2c1N1CCN(Cc2cncnc2)CC1
Yield: 55.6 %

Procedure:
This was prepared using the same procedure as for (4-(6-bromo-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)methanamine, but here using tert-butyl 4-(4-(6-chloro-7-(4-(pyrimidin-5-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzyl)piperazine-1-carboxylate (15 mg, 0.025 mmol), TFA (0.2 mL) and CH2Cl2 (1 mL). The same purification procedure gave the desired product (7 mg, 56%) as a pale yellow solid; δH (500 MHz, DMSO-d6) 2.32 (s, br, 4H, piperazine N(CH2)2), 2.64 (s, br, 4H, piperazine N(CH2)2), 2.72 (t, J=4.6 Hz, 4H, piperazine N(CH2)2), 3.50 (s, 2H, NCH2), 3.64 (s, 2H, NCH2), 3.70 (t, J=4.5 Hz, 4H, piperazine N(CH2)2), 7.45 (d, J=8.2 Hz, 2H, phenyl H-3 & H-5), 8.11 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.12 (d, J=8.3 Hz, 2H, phenyl H-2 & H-6), 8.80 (s, 2H, pyrimidine H-4 & H-6), 9.12 (s, 1H, pyrimidine H-2);
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[NH2:32][CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:32][CH:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[O:31])=[CH:5][N:6]=4)[CH:14]=3)=[C:19]([C:20]([F:22])([F:21])[F:23])[O:18][N:17]=2)=[CH:29][CH:28]=1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(Cl)cc4)noc3C(F)(F)F)c2)nc1
Product: O=C(NC1CCOCC1)c1ccc(-n2cnc(-c3c(-c4ccc(Cl)cc4)noc3C(F)(F)F)c2)nc1
Yield: 78 %

Procedure:
As described for Example 48b, 6-{4-[3-(4-chloro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-nicotinic acid methyl ester (100 mg, 0.23 mmol), was converted, using 4-aminotetrahydropyran instead of cyclopropanemethylamine, to the title compound (90 mg, 78%) which was obtained as a light yellow solid. MS: m/e=516.4 [M−H]−.