Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][C:48]([N:50]([CH3:52])[CH3:51])=[O:49])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:53]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:62])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][C:48]([N:50]([CH3:52])[CH3:51])=[O:49])[CH:42]=[CH:43][N:44]=5)=[O:62])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:53]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCCC(=O)N(C)C)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCCC(=O)N(C)C)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy) phenyl]-N-[4-[[[1-[4-(dimethylamino)-4-oxobutyl]-1H-imidazol-2-yl]methyl]thio]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (400 mg) in dichloromethane (30 ml) was added a solution of 3-chloroperbenzoic acid (70%, 0.2 g) in dichloromethane (15 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica get, ethyl acetate→ethanol:ethyl acetate 1:49), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-[4-(dimethylamino)-4-oxobutyl]-1H-imidazol-2-yl]methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 421) (377 mg) as yellow amorphous.
Reaction SMILES: [C:1]([CH2:9][C:10](OCC)=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:24][CH2:25][CH3:26])(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:2]1([C:1]2[CH2:9][C:10](=[O:11])[C:19]3[C:17](=[C:16]([C:15]([O:24][CH2:25][CH3:26])=[O:23])[CH:22]=[CH:21][CH:20]=3)[N:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CCOC(=O)c1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1cccc2c1N=C(c1ccccc1)CC2=O
Yield: 39.4 %

Procedure:
A mixture of 7 grams of ethyl benzoylacetate, 6 grams of ethyl anthranilate and 0.5 gram of p-toluenesulfonic acid is dehydrated (by heating) in 300 ml of benzene for three days. Benzene is evaporated therefrom, and the resulting oil is heated at 250° to 280° C. for 0.5 hour in 20 ml of diphenyl ether. After cooling, 250 ml of n-hexane is added thereto, and crystals which separate out therefrom are collected by filtration and recrystallized from methanol to give 4.2 grams of ethyl 2-phenyl-4-quinolone-8-carboxylate, pale brown needles, melting point 218° to 219° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].B>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:5][OH:6]
Reactant: COc1ccc(C(=O)O)cc1Br
Agent: B
Solvent: C1CCOC1
Product: COc1ccc(CO)cc1Br
Temperature: 75 °C

Procedure:
To a solution of 9.8 g (42 mmol) of 3-bromo-4-methoxybenzoic acid in THF (100 mL) was added 1M solution of borane in THF (130 mL) at r.t. under nitrogen. The resulting solution was then heated at 75° C. for 30 min. The reaction mixture was then cooled to r.t. and MEOH (0.5 mL) was slowly added. The mixture was concentrated and successively treated with MEOH (0.5 mL), evaporated (2×) and finally triturated with Et2O and filtered to yield the title product as a solid, m.p.: 49°-54° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:15]([CH3:17])[CH3:16])([CH3:14])[C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[H-]>C1(C)C=CC=CC=1>[CH3:14][C:10]([N:15]([CH3:17])[CH3:16])([CH2:11][OH:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: CN(C)C(C)(Cc1ccc(Cl)c(Cl)c1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN(C)C(C)(CO)Cc1ccc(Cl)c(Cl)c1

Procedure:
1.65 to 1.75 mol of amino ester (II) are reduced in toluene with a lithium aluminium hydride-tetrahydrofuran addition complex prepared starting from 1 mol of hydride, to obtain (+/-)3-(3,4-dichlorophenyl)-2-dimethylamino-2-methylpropan-1-ol (I) or cericlamine which is optionally salified with hydrochloric acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([C:25]2[C@@H:34]3[C@@H:29]([CH2:30][CH:31]=[CH:32][CH2:33]3)[C:28](=[O:35])[N:27]([C:36]3[CH:41]=[CH:40][C:39]([C:42](N4CCN(C5C=CC=CC=5)CC4)=[O:43])=[CH:38][CH:37]=3)[N:26]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH3:24])[CH3:14]>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:42]([C:39]2[CH:40]=[CH:41][C:36]([N:27]3[N:26]=[C:25]([C:18]4[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH3:24])=[C:16]([O:15][CH2:13][CH3:14])[CH:17]=4)[C@@H:34]4[C@@H:29]([CH2:30][CH:31]=[CH:32][CH2:33]4)[C:28]3=[O:35])=[CH:37][CH:38]=2)=[O:43])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CCOc1ccc(C2=NN(c3ccc(C(=O)N4CCN(c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)N1CCN(C(=O)c2ccc(N3N=C(c4ccc(OCC)c(OCC)c4)[C@H]4CC=CC[C@H]4C3=O)cc2)CC1

Procedure:
Prepared from intermediate product A1 and 1-(ethoxycarbonyl)piperazine as described for compound 1. Cystallised from diethyl ether as the free base. M.p. 146–147° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1.O=P(Cl)(Cl)Cl.CN([CH:20]=[O:21])C>O>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([CH:20]=[O:21])=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1
Reactant: CN1CCOc2ccccc21
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CN1CCOc2cc(C=O)ccc21
Reaction time: 1.25 h
Yield: 76 %

Procedure:
4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine dissolved in 200 ul DMF under Argon. POCl3 was added under Argon. The reaction was heated and a closed vial at 90° C. for 75 min. 1 ml of NaAc in water was added and stirred while a brown oil was formed. The oil was extracted with DCM. The organic layer was washed with brine, dried and evaporated to dryness, affording 0.18 g (76%) of 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-carbaldehyde as colourless solid.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH:13]C(=O)OC(C)(C)C)(=[O:11])=[O:10]>FC(F)(F)C(O)=O>[C:1]1([CH3:21])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH2:13])(=[O:11])=[O:10]
Reactant: Cc1cc(C)c(S(=O)(=O)ONC(=O)OC(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Temperature: 0 °C

Procedure:
A solution of tert-butyl mesitylsulfonyloxycarbamate (3 g, 9.5 mmol) in trifluoroacetic acid (7 mL) was stirred at 10° C. for 40 min, then poured into ice/water (10 mL) and the resulting solid was collected by filtration. The solid was dissolved in DCM (12 mL), dried with Na2SO4, and filtered. The solution containing O-(mesitylsulfonyl)hydroxylamine was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:18]=1[CH:19]=[CH:20][C:21](O)=O>>[CH3:15][O:16][C:17]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:18]=1/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)cc3OC)nc2n(CC)c1=O
Yield: 19.7 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3diethyluracil and 2.89 g (13.9 mmol) of 2,4-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide/ethanol to give 0.92 g (yield 20%) of Compound 68 as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:50])[NH:7][C@H:8]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:9]([N:11]1[CH2:16][CH2:15]C[CH2:13][C@H:12]1[C:17](=[O:43])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][C:27]2[C:28]([C:35]3[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=3[OH:42])=[N:29][N:30]([CH2:32][CH2:33][OH:34])[CH:31]=2)=[CH:21][CH:20]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC(O)=C(C2C(C#CC3C=CC(NC(C4COCCN4)=[O:73])=CC=3)=CN(CCO)N=2)C=1.N(C(OC(C)(C)C)=O)[C@@H](C(O)=O)C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:50])[NH:7][C@H:8]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:9]([N:11]1[CH2:16][CH2:15][O:73][CH2:13][CH:12]1[C:17](=[O:43])[NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]#[C:26][C:27]2[C:28]([C:35]3[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=3[OH:42])=[N:29][N:30]([CH2:32][CH2:33][OH:34])[CH:31]=2)=[CH:23][CH:24]=1)=[O:10])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCCC[C@H]1C(=O)Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)c1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCOCC1C(=O)Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)c1ccccc1

Procedure:
Using the same procedure for the preparation of 12A, reaction of compound 17A with BOC-D-Phg-OH (11A) afforded the title compound 18A, which was purified by silica column chromatography eluting with dichloromethane/acetone (5/1, 4/1, 3/1) to give pure 18A as white powder in similar yield. 1H NMR (CDCl3, 500 MHz) δ 10.677 and 10.668 (both s, total 1H), 9.39 and 8.70 and 8.64 (all s, total 2H), 7.88 (m, 2H), 7.79 and 7.77 (both s, total 1H), 7.56 (m, 2H), 7.43 (m, 5H), 7.19 (d, 1H, J=8.5 Hz), 6.95 (d, 1H, J=8.0 Hz), 5.98 and 5.72 and 5.48 and 5.41 (all d, total 2H, J=6.5-7.5 Hz), 5.28 and 5.13 (both s, total 1H), 4.78 (d, 0.5H, J=12.0 Hz), 4.63 (m, 0.5H), 4.29 (m, 2H), 4.03 (m, 2H), 3.83 and 3.63 and 3.42 and 3.17 and 3.04 (all m, total 5H), 1.94 (s, 1H, 1.51 and 1.45 (both s, total 9H). LCMS (ESI) m/z 722.20 (MNa+), 700.21 (MH+), 644.13 (100), 600.14, 354.07. HPLC: tR=5.18 min.
Reaction SMILES: [NH2:1][C:2]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][C:5]([CH2:6][CH:7]([CH2:10][C:11](=[O:30])[N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:29])[CH2:14][CH2:13]2)[CH:8]=O)=[CH:4][C:3]=1[Cl:37].[N:38]1([CH2:43][CH2:44][CH2:45][NH:46][C:47]2[CH:48]=[N:49][CH:50]=[CH:51][C:52]=2[NH2:53])[CH2:42][CH2:41][CH2:40][CH2:39]1>>[NH2:1][C:2]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][C:5]([CH2:6][CH:7]([C:8]2[N:46]([CH2:45][CH2:44][CH2:43][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[C:47]3[CH:48]=[N:49][CH:50]=[CH:51][C:52]=3[N:53]=2)[CH2:10][C:11]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:29])[CH2:14][CH2:13]2)=[O:30])=[CH:4][C:3]=1[Cl:37]
Reactant: Nc1c(Cl)cc(CC(C=O)CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)cc1C(F)(F)F
Reactant: Nc1ccncc1NCCCN1CCCC1
Product: Nc1c(Cl)cc(CC(CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)c2nc3ccncc3n2CCCN2CCCC2)cc1C(F)(F)F
Yield: 11 %

Procedure:
The product was prepared analogously to Example 62 starting from 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butyraldehyde (Intermediate product 36) and N3-(3-pyrrolidin-1-yl-propyl)-pyridine-3,4-diamine (Intermediate product 41) at 100° C. and purified by HPLC-MS (Zorbax Bonus C18 amide-phase 5 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v). Lyophilisation of a 1 N aqueous solution of the product yielded the corresponding hydrochloride.
Reaction SMILES: CCN(CC)CC.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[C:19]([O:23][C:24]([N:26]1[CH2:29][CH2:28][C@H:27]1[CH2:30][O:31][C:32]1[CH:33]=[C:34]([C@@H:38]2[CH2:40][C@H:39]2[CH2:41][CH2:42][OH:43])[CH:35]=[N:36][CH:37]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:43][CH2:42][CH2:41][C@@H:39]2[CH2:40][C@H:38]2[C:34]2[CH:35]=[N:36][CH:37]=[C:32]([O:31][CH2:30][C@@H:27]3[CH2:28][CH2:29][N:26]3[C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH:33]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@@H]2C[C@H]2CCO)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@H]2c2cncc(OC[C@@H]3CCN3C(=O)OC(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
4-(Dimethylamino)pyridine (DMAP; 14 mg, 0.11 mmol, 0.2 equiv.), Et3N (0.24 mL, 1.7 mmol, 3.0 equiv.), and p-toluenesulfonyl chloride (164 mg, 0.86 mmol, 1.5 equiv.) were added to a stirred solution of 2-[(1S,2R)-2-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]cyclopropyl]ethanol (200 mg, 0.57 mmol) in dry CH2Cl2 (5 mL) at 0° C. The reaction mixture was stirred at room temperature overnight, then diluted with CH2Cl2 (50 mL). The organic phase was washed with aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated. The residue was purified by CC (SiO2, 60-70% EtOAc in hexane as the eluent) to give 2-[(1S,2R)-2-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]cyclopropyl]ethyl p-toluenesulfonate (175 mg, 82%), which was directly used for the next reaction.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.IC.[C:22](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:22])=[O:16])=[CH:18][CH:19]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(C2=CCC3(CC2)OCCO3)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(C2=CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
A mixture of 4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzoic acid (572 mg, 2.20 mmol), iodomethane (140 μL, 2.24 mmol), and cesium carbonate (710 mg, 2.17 mmol) in 6 mL of DMF was stirred at rt for 16 h. The mixture was diluted with H2O (10 mL) and extracted with Et2O (100 mL). The organic layer was separated, dried over MgSO4, and concentrated. Chromatography on a Biotage 40S cartridge using 3:17 v/v EtOAc/hexanes as the eluant afforded 399 mg (72%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]#[N:14].[CH2:15](N)[CH2:16][NH2:17]>>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]1[NH:17][CH2:16][CH2:15][N:14]=1
Reactant: N#CCc1cccc(C(F)(F)F)c1Cl
Reactant: NCCN
Product: FC(F)(F)c1cccc(CC2=NCCN2)c1Cl

Procedure:
2-(2-Chloro-3-trifluoromethyl-benzyl)-4,5-dihydro-1H-imidazole was prepared from (2-chloro-3-trifluoromethylphenyl)-acetonitrile and ethylene diamine in analogy to Example 19 b): white solid; MS (ISP): 262.8 ((M+H)+.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:15][C:16](=[O:21])[CH2:17][C:18](=O)[CH3:19])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][C:9]1=[O:14].[F:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[O:26][CH2:27][C:28]([NH2:30])=O.C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1(C)C(C)=CC=CC=1.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Ti+4]>[F:1][C:2]1[CH:3]=[C:4]([N:15]2[C:16](=[O:21])[CH:17]=[C:18]([CH3:19])[N:30]=[C:28]2[CH2:27][O:26][C:25]2[CH:31]=[CH:32][CH:33]=[C:23]([F:22])[CH:24]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][C:9]1=[O:14]
Reactant: NC(=O)COc1cccc(F)c1
Reactant: CC(=O)CC(=O)Nc1ccc(N2CCOCC2=O)c(F)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3=O)c(F)c2)c(COc2cccc(F)c2)n1
Temperature: 165 °C
Reaction time: 24 h
Yield: 7 %

Procedure:
A mixture of N-(3-fluoro-4-(3-oxomorpholino)phenyl)-3-oxobutanamide (0.59 g, 2.00 mmol), 2-(3-fluorophenoxy)acetamide (0.94 g, 5.56 mmol) and titanium tetraisopropanolate (4.8 mL) in xylene (10 mL) was stirred at 165° C. for 24 h. The mixture was cooled to rt and 60 mL of toluene and 60 mL of saturated NH4Cl aqueous solution were added. The resulting mixture was stirred at rt overnight and filtered and the filtrate was extracted with DCM (20 mL×4). The combined organic layers were washed with brine (30 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:2) to give the title compound as a yellow solid (0.06 g, 7%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1]1([N:4]([CH:26]2[CH2:28][CH2:27]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]([NH2:22])=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Cl[CH2:30][C:31](=O)[CH3:32]>CCO>[CH:26]1([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][CH:30]=[C:31]([CH3:32])[N:22]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:27][CH2:28]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Reactant: CC(=O)CCl
Solvent: CCO
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C)cs3)nc21
Temperature: 25 °C
Yield: 20.7 %

Procedure:
N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B, 40 mg, 0.10 mmol) and chloroacetone (62.4 mg, 0.40 mmol) in EtOH (2 ml) were heated at 80° C. for 20 min. The reaction was cooled to room temperature and the solvent removed in vacuo. Saturated NaHCO3 solution was added and the aqueous layer extracted (3×) with dichloromethane. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (dichloromethane/methanol 0-7%) to provide N,N-dicyclopropyl-6-ethyl-1-methyl-4-(4-methylthiazol-2-ylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (9 mg, 12% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[OH:22].[CH2:23]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=O)=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>O>[CH2:23]([C:31]1[CH:39]=[CH:38][C:34]([C:35]2[O:22][C:3]3[CH:4]=[CH:5][C:6]([C@H:8]4[CH2:9][CH2:10][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][CH2:13]4)=[CH:7][C:2]=3[N:1]=2)=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCc1ccc(C(=O)O)cc1
Reactant: CCCCCCCC[C@H]1CC[C@H](c2ccc(O)c(N)c2)CC1
Solvent: O
Product: CCCCCCCCc1ccc(-c2nc3cc([C@H]4CC[C@H](CCCCCCCC)CC4)ccc3o2)cc1
Temperature: 250 °C
Reaction time: 4 h

Procedure:
Step iii) In a 50 ml-round-bottomed flask, 10 g of polyphosphoric acid, 0.40 g (1.32 mM) of 2-amino-4-(trans-4-octylcyclohexyl)phenol and 0.31 g (1.32 mM) of 4-octylbenzoic acid were placed, followed by stirring for 4 hours at about 250 ° C. After the reaction, the reaction mixture was poured into water and an insoluble matter was recovered by filtration. The insoluble matter was added to 10% K2CO3 and sufficiently stirred, followed by recovery of a solid. The solid was washed with water and purified by silica gel column chromatography (eluent: toluene) to obtain 0.11 g of 2-(4-octylphenyl)-5-(trans-4-octylcyclohexyl)benzoxazole (yield: 16.7%). ##STR18##
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:28])=[C:9]([CH:11]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:5]2=[CH:4][CH:3]=1.Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:28])=[C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:36][CH2:35][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:37])=[O:24])=[CH:26][CH:27]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2ccc(Cl)nc12
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(Cl)nc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a mixture of 4-{[(5-chloro-3-methylfuro[3,2-b]pyridin-2-yl)(cyclohexyl)methyl]amino}benzoic acid (300 mg) synthesized above, β-alanine ethyl ester hydrochloride (174 mg), 1-hydroxybenzotriazole monohydrate (173 mg), triethylamine (315 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (217 mg), and the mixture was stirred at room temperature for 2.5 days. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (383 mg, quantitative) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 30 h
Yield: 62.6 %

Procedure:
1 g (6.4 mmol) of piperidine-4-carboxylic acid ethyl ester is mixed in 10 ml of absolute ethanol with 0.75 ml (6.4 mmol) of benzyl chloride and 1.52 g (11 mmol) of potassium carbonate. The batch is stirred for 30 hours at room temperature. It is then dispersed in ethyl acetate/water. The combined organic phase is washed with water, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with hexane:ethyl acetate=1:1 as an eluant. 991 mg (64% of theory) of N-benzylpiperidine-4-carboxylic acid ethyl ester is obtained.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:7][S:8]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C.C(OCC)(=O)C>[CH3:1][NH:2][S:17]([C:13]1[CH:12]=[C:11]([S:8]([NH:7][C:3]([CH3:6])([CH3:5])[CH3:4])(=[O:10])=[O:9])[CH:16]=[CH:15][CH:14]=1)(=[O:19])=[O:18]
Reactant: CN
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNS(=O)(=O)c1cccc(S(=O)(=O)NC(C)(C)C)c1
Reaction time: 2 h

Procedure:
5 ml of a 33% solution of methylamine in ethanol was added to a solution of 1.8 grams (7 mmole) of 3-tert-butylsulfamoyl-benzenesulfonyl chloride in ethyl acetate. The mixture was stirred for 2 hours. The ethyl acetate layer was separated and concentrated in vacuo. The residue was purified on silica gel eluting 5% methanol in diochloromethane to give 1.32 grams of the titled compound as a white solid.