Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22](O)=[O:23])=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C@H:34]([NH:40][C:41](=[O:52])[CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O.O>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C@H:34]([NH:40][C:41](=[O:52])[CH2:42][CH2:43][C:44]4[CH:45]=[CH:46][C:47]([O:50][CH3:51])=[CH:48][CH:49]=4)[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=3)=[O:23])=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc2oc(C(=O)O)cc2c1
Reactant: CCOC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)CCc1ccc(OC)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(NC(=O)c2cc3cc(C(=N)NC(=O)OCc4ccccc4)ccc3o2)cc1)NC(=O)CCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.2 %

Procedure:
5-(Benzyloxycarbonylamidino)-2-benzofurancarboxylic acid (151mg, 0.447 mmol) and ethyl (S)-3-(4-aminophenyl)-2-[3-(4-methoxyphenyl)-propionylamino]propionate (165 mg, 0.445 mmol) were dissolved in N,N-dimethylformamide (10 ml), and PyBOP (benzotriazol-1-yl-oxy-tris(pyrrolidino) phosphonium hexafluorophosphate) (225 mg, 0.490 mmol) and N-methylmorpholine (0.05 ml, 0.455 mmol) were added. The mixture was stirred at room temperature for 15 hours. Water (20 ml) was added to the reaction mixture, and the resulting precipitate was collected by filtration and washed with water to give 271mg of ethyl (S)-3-[4-[[5-(benzyloxycarbonylamidino)-2-benzofuranyl]carbonylamino]phenyl]-2-[3-(4-methoxyphenyl)propionylamino]propionate as a colorless solid (88%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]([C:8]1[CH:17]=[C:16]2[C:12](=[CH:13][CH:14]=[C:15]2[CH3:18])[C:11]([CH:19]([CH3:23])[CH2:20][CH2:21][OH:22])=[CH:10][CH:9]=1)([CH3:7])[CH3:6].N1C=CC=CC=1>ClCCl>[C:1]([O:22][CH2:21][CH2:20][CH:19]([C:11]1[C:12]2[C:16](=[CH:17][C:8]([CH:5]([CH3:7])[CH3:6])=[CH:9][CH:10]=1)[C:15]([CH3:18])=[CH:14][CH:13]=2)[CH3:23])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1ccc2c(C(C)CCO)ccc(C(C)C)cc1-2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCCC(C)c1ccc(C(C)C)cc2c(C)ccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.8 g (0.063 mol) of acetyl chloride in 20 ml of dichloromethane were added dropwise at 0° C. to a solution of 12.1 g (0.05 mol) of 3-(7-isopropyl-1-methylazulen-4-yl)butanol and 7.9 g (0.1 mol) of pyridine in 100 ml of dichloromethane, and the mixture was stirred at room temperature for 1 hour. It was then extracted with 30 ml of 2N hydrochloric acid, and the organic phase was washed neutral and dried over sodium sulfate. The residue remaining behind after evaporating off the solvent was chromatographed (silica gel; 9:1 v/v petroleum ether/ethyl acetate). This gave 12.6 g (89%) of the acetate as a highly viscous blue oil. Physical data: IR (KBr): 2959, 2929 (CH); 1741 (C=O); 1555, 1463, 1436, 1387, 1365, 1241, 1047 cm-1. 1H-NMR (CDCl2): δ=1.38 (d, 6H); 2.05 (s, 3H); 2.16 (cm, 2H); 2.68 (s, 3H); 3.08 (cm, 1H); 2.22 (cm, 2H); 4.18 (cm, 2H); 6.95 (d, 1H); 7.30 (d, 1H); 7.40 (d, 1H); 7.64 (d, 1H); 8.18 (s, 1H) ppm. 13C-NMR (CDCl3); δ=1286; 20.85; 24.72 (2C); 30.17; 34.53; 38.28; 64.22; 112.19; 124.41; 125.46; 133.30; 135.13; 136.39; 136.59; 137.28; 140.04; 147.55; 170.90 ppm. MS: m/e=284.4 (C19H24O2+, 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:10]([Si:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)Cl)([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>C(Cl)Cl>[C:10]([Si:14]([O:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1cc(F)cc(F)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1cc(F)cc(F)c1)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
To a well stirred ice cooled solution of 3,5-difluorophenol (30.0 g) in CH2Cl2 (500 ml) under N2 were added tert-butyldiphenylchlorosilane (63.4 g) and imidazole (17.3 g). The reaction mixture was stirred 15 min before removing the cooling bath. After 3.5 h the reaction was stopped by washing 1 N HCl sol. (2×300 ml and 1×200 ml), sat. aq. Na2CO3 sol. (200 ml) and brine (200 ml). The aqueous layers were extracted with more CH2Cl2 (200 ml). After drying (MgSO4) the solvent was evaporated to obtain 84.8 g (100%) of tert-butyl-(3,5-difluoro-phenoxy)-diphenyl-silane. Colorless oil. MS 368.1 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([Cl:9])[CH:3]=1.[C:10](Cl)(Cl)=[S:11]>O1CCCC1.C(=O)([O-])O.[Na+]>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:10]=[S:11])=[C:4]([Cl:9])[CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(Br)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: S=C=Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture of 4-bromo-2-chloroaniline (30.0 g, 0.145 mol) in tetrahydrofuran (150 mL) and aqueous saturated sodium hydrogen carbonate (150 mL) was added thiophosgene (13.3 mL, 0.174 mol) at 0° C. The reaction mixture was stirred at room temperature for 1 hr. The mixture was extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with cold-n-hexane to give the title compound as a colorless solid (25.51 g, 0.103 mol, 71%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:25])(=[O:24])[CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CN(P(N(C)C)(N(C)C)=O)C.[C:37](=[O:39])=[O:38]>C1COCC1>[CH2:15]([CH:14]([C:37]([OH:39])=[O:38])[C:13]([OH:25])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23]
Reactant: CCCCCCCCC=CC(=O)O
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCCCCCCCC(C(=O)O)C(=O)O
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
An oven-dried 500 mL 2-neck flask equipped with magnetic stirbar and addition funnel was charged with diisopropylamine (12.8 mL, 91.1 mmol) and THF (180 mL) under nitrogen. The solution was chilled to −25° C. in a dry ice/water/ethanol bath, and n-butyllithium (34 mL of a 2.65 M solution in hexanes, 89.0 mmol) was added dropwise via addition funnel. The solution was stirred for 30 min, after which a degassed solution of undecenoic acid (8.0 g, 43.4 mmol) in THF (44 mL) was added dropwise via addition funnel, causing the solution to become turbid. HMPA (8 mL, 43.4 mmol) was added via addition funnel. The cooling bath was then removed to allow the solution to warm to room temperature over 30 min, during which time the solution turned clear and yellow. The solution was cooled again to −25° C. A second 500 mL 2-neck flask under N2(g) purge was charged with CO2(s) (200 g, 4.5 mol) and chilled to −25° C. The enolate solution was cannula transferred onto the CO2(s) under N2(g) purge, causing the solution to become clear and colorless. The solution was stirred at −25° C. for 30 minutes then the cooling bath was removed and stirring continued at 22° C. overnight, during which time the reaction gelled. The reaction was quenched by the addition of 10% HCl (aq) (100 mL), causing two layers to form. This biphasic mixture was transferred to a reparatory funnel, and the organic layer was collected and the aqueous layer was extracted with ether (3×75 mL). The combined organic layers were then washed successively with 2M HCl (aq) (3×50 mL), water (75 mL), saturated NaCl (aq) (75 mL), and then dried over anhydrous MgSO4 (s). The solvent was removed on a rotary evaporator to yield 9.5 g of white solid. The crude product was recrystallized from heptane to yield white crystals. Yield: 9.07 g (92% yield). 1H NMR (300 MHz, DMSO-d6, 22° C.): δ (ppm) 12.62 (s, 2H, CH(COOH)2), 5.78 (ddt, JH—H3=17.0, 10.3, 6.8 Hz, 1H, CH2═CHCH2), 4.98 (ddt, JH—H3=17.2, 1.6 Hz, JH—H32.2 Hz, 1H, CH2═CHCH2), 4.93 (ddt, JH—H3=10.2, 1.2 Hz, JH—H2=2.3 Hz, 1H, CH2═CHCH2), 3.17 (t, JH—H3=7.5 Hz, 1H, CH(COOH)2), 2.00 (dt, JH—H3=7.0, 6.8 Hz, 2H, CH2═CHCH2), 1.73-1.63 (m, 2H, CH2CH(COOH)2), 1.40-1.16 (m, 10H, CH2═CHCH2(CH2)5CH2CH(COOH)2). 13C NMR (75 MHz, DMSO-d6, 22° C.): δ (ppm) 170.90, 138.82, 114.64, 51.60, 33.18, 28.69, 28.64, 28.41, 28.24, 26.79. ESI-MS: calcd. for C12H20O4Na [M+Na]+251.1, found 251.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCCCC1.ClC(OC)=O.Cl.[CH3:32][O:33][NH:34][CH3:35]>C(Cl)Cl>[CH3:32][O:33][N:34]([CH3:35])[C:16]([C@@H:13]1[CH2:12][CH2:11][C@H:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:15][CH2:14]1)=[O:18]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: CNOC
Agent: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCCCC1
Product: CON(C)C(=O)[C@H]1CC[C@@H](CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of cis-4-{[(tert-butoxycarbonyl)amino]methyl}-cyclohexanecarboxylic acid (18.53 g, 72.0 mmol) and N-methylpiperidine (21.9 ml, 17.8 g, 180 mmol) in methylene chloride (360 ml) under nitrogen cooled in an ice-bath was adde dropwise methyl chloroformate (6.13 ml, 7.48 g, 79.2 mmol). The solution was stirred 15 minutes with cooling, and O,N-dimethylhydroxylamine hydrochloride (8.43 g, 86.4 mmol) was added. The mixture was stirred 18 hours while warming from ice-bath temperature to ambient temperature. The mixture was washed with 10% citric acid solution (100 ml), saturated sodium carbonate solution (100 ml), water (100 ml), and brine (100 ml), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give crude product (15.30 g, 71%) as a yellow oil. The crude product was purified by flash column chromatography on silica gel, eluting with a gradient of 50:50 to 75:25 ethyl acetate/hexane to give tert-butyl [(cis-4-{[methoxy(methyl)amino]carbonyl}cyclohexyl)methyl]carbamate (13.76 g, 64%) as a pale yellow oil. 1H NMR (CDCl3) 4.61 (1H, br s), 3.68 (3H, s), 3.17 (3H, s), 3.11 (2H, t, J 6.5 Hz), 2.79 (1H, m), 1.75 (3H, m), 1.68-1.52 (6H, m), 1.44 (9H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])[CH:9]=[N:10][C:5]2=[C:4]([O:23]C)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:22][C:13]1[C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:8]1[C:6]2=[N:7][C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:3][C:4]([OH:23])=[C:5]2[N:10]=[CH:9]1
Reactant: C1COCCN1
Reactant: COc1cc(Cl)nc2c1ncn2Cc1cccc(C(F)(F)F)c1C
Product: Cc1c(Cn2cnc3c(O)cc(N4CCOCC4)nc32)cccc1C(F)(F)F
Reaction time: 3 h

Procedure:
5-chloro-7-(methyloxy)-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (45 mg, 0.126 mmol) was suspended in 1.5 mL of morpholine in a microwave vial and the mixture was irradiated in a microwave oven at 130° C. for 45 min, then for additional 3 h, another 3 h and then additional 12 h. Product is slowly forming (as observed by LC/MS) going through the formation of the 7-hydroxy derivative first. The mixture was then irradiated for 3 h at 200° C., to provide complete conversion to the desired product. An additional aliquot of 5-chloro-7-(methyloxy)-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (60 mg, 0.169 mmol) was suspended in morpholine (1.5 mL) and irradiated in a microwave oven at 200° C. for 3 h. The reaction was not completed, so it was irradiated again in the microwave at 200° C. for 150 min. The two reaction mixtures were combined and diluted with water and 1 N HCl was added to pH 4-5. The precipitate formed was collected by filtration, washed with water and dried. The solid was dissolved in DMSO and purified by Reverse phase-HPLC (25 to 80% AcCN in water plus 0.1% TFA). Two peaks closely eluted on the HPLC and were isolated for the product. The slower retention time peak presented 2% impurity so it was kept separated. The collected fractions were neutralized by the addition of NaHCO3 sat sol and the solvent volume was reduced to ½-⅓ of the original. The precipitates were collected washed with water and dried in a vacuum oven at 45° C. for 5 h to give 3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(4-morpholinyl)-3H-imidazo[4,5-b]pyridin-7-ol (21 mg, 0.052 mmol, 17.77% yield) which was submitted for testing, and the less pure sample of 3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(4-morpholinyl)-3H-imidazo[4,5-b]pyridin-7-ol (18 mg, 0.046 mmol, 15.54% yield), which was stored as is. MS (ES+) m/e 393 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (br. s., 1H), 7.99 (s, 1H), 7.62 (d, J=8.08 Hz, 1H), 7.34 (t, J=7.83 Hz, 1H), 7.26 (d, J=7.58 Hz, 1H), 6.07 (s, 1H), 5.41 (s, 2H), 3.57-3.76 (m, 4H), 3.24-3.40 (m, 4H), (CH3 peak under DMSO peak).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].C(OC(=O)C)(=O)C.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[CH3:1][C:2]1[CH:10]=[C:9]([N+:20]([O-:22])=[O:21])[C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12]
Reactant: Cc1ccc(O)c2c1CCC2=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])c(O)c2c1CCC2=O

Procedure:
Into a solution of 25.6 g of 4-methyl-7-hydroxy-1-indanone in 250 ml of acetic acid was added 19.4 ml of acetic anhydride and a solution of 15.4 ml of concentrated nitric acid in 50 ml of acetic acid gradually. The reaction mixture was concentrated to drynsss, and the residue was washed with ether to obtain 25.7 g of 4-methyl-6-nitro-7-hydroxy-1-indanone.
Reaction SMILES: [Cl:1][CH:2]([CH3:7])[C:3]([NH:5][OH:6])=[NH:4].C(N(CC)CC)C.[CH3:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=O>C(Cl)Cl>[Cl:1][CH:2]([C:3]1[N:4]=[C:15]([C:16]2[CH:17]=[C:18]([CH3:19])[CH:22]=[CH:23][CH:24]=2)[O:6][N:5]=1)[CH3:7]
Reactant: CC(Cl)C(=N)NO
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(-c2nc(C(C)Cl)no2)c1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
2-Chloro-N-hydroxy-propionamidine (218 mg, 1.78 mmol) and triethylamine (0.677 ml, 4.86 mmol) were added to 3-methyl-benzoyl chloride (250 mg, 1.62 mmol) in DCM (10.0 ml) at 0° C. and the resulting mixture was stirred for 20 min. The solution was concentrated and DMF (20 ml) was added to the residue and heated at 120° C. for 20 min. The product was purified by flash chromatography using 10-20% EA in hex. affording 0.250 g (59% yield over 2 steps) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[O:10][CH2:9]CO[C:6]=2[C:5]([CH3:12])=[CH:4][CH:3]=1.CC1C=CC(C)=[C:16]([OH:17])C=1O.C(=O)([O-])[O-].[K+].[K+].BrC(Br)C>C(O)CO.CCOCC>[CH3:12][C:5]1[C:6]2[CH2:16][O:17][CH2:9][O:10][C:11]=2[C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(C)c2c1OCCO2
Reactant: Cc1ccc(C)c(O)c1O
Agent: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CCOCC
Product: Cc1ccc(C)c2c1COCO2
Temperature: 120 °C

Procedure:
5,8-Dimethyl-1,4-benzodioxane. To a stirred solution of 3 g of 3,6-dimethylcatechol and 6.15 g of potassium carbonate in 35 mL of ethylene glycol is added 3.74 mL of dibromoethane. A reflux condenser is attached and the mixture heated in an oil bath to 120° C. for 4 hours. The mixture is allowed to cool to room temperature and then is distributed between 100 mL of saturated potassium carbonate solution and 200 mL of ether. The ether layer is dried over magnesium sulfate and concentrated under reduced pressure to yield a red liquid, which is purified by chromatography on silica gel to afford 2.90 g of 5,8-dimethyl-1,3-benzodioxane as a light yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[ClH:19].[CH3:20][CH:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)[CH3:22].C(N(CC)CC)C.C([BH3-])#N.[Na+]>C(O)C>[ClH:19].[CH3:37][O:36][C:30]1[CH:29]=[C:28]([CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH:21]([CH3:22])[CH3:20])[CH:14]2[CH2:13][CH2:12][C:11]([C:17]#[N:18])([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:16][CH2:15]2)[CH:33]=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: COc1ccc(CCCCNC(C)C)cc1OC
Reactant: COc1ccc(C2(C#N)CCCCC2)cc1OC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(CCCCN(C(C)C)C2CCC(C#N)(c3ccc(OC)c(OC)c3)CC2)cc1OC

Procedure:
A solution of 4-(3,4-dimethoxyphenyl)-4-cyanocyclohexane (5 mmol), N-(1-methylethyl)-4-(3,4-dimethoxyphenyl) butylamine hydrochloride (5 mmol), triethylamine (6 mmol) and sodium cyanoborohydride (6 mmol) in 25 ml ethanol was stirred at 25° C. for 72 hours and worked up and recrystallized. ##STR8##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23](=[O:31])[CH2:24][N:25]1[C:29]([CH3:30])=[CH:28][CH:27]=[N:26]1)[CH3:21].[C:32](O)(=O)C.C=O>C(O)C>[CH2:20]([O:22][C:23](=[O:31])[CH2:24][N:25]1[C:29]([CH3:30])=[C:28]([CH2:32][N:17]2[CH2:16][CH2:15][N:14]([C:9]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:13][CH:12]=[CH:11][N:10]=3)[CH2:19][CH2:18]2)[CH:27]=[N:26]1)[CH3:21]
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: CCOC(=O)Cn1nccc1C
Reactant: CC(=O)O
Agent: C=O
Solvent: CCO
Product: CCOC(=O)Cn1ncc(CN2CCN(c3nccnc3-c3ccc(F)cc3)CC2)c1C
Temperature: 120 °C
Yield: 16.3 %

Procedure:
Combine 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.500 g, 1.94 mmol) with (5-methyl-pyrazol-1-yl)-acetic acid ethyl ester (0.416 g, 2.48 mmol) in ethanol (8 mL). Add acetic acid (801 μL, 14 mmol) and a 37% aqueous solution of formaldehyde (401 μL). Heat in microwave at 120° C. for 5 hr. Add acetic acid (801 μL, 14 mmol) and a 37% aqueous solution of formaldehyde (401 μL). Heat in microwave at 120° C. for 3 hr. Concentrate, add ethyl acetate and saturated aqueous sodium bicarbonate solution. Separate organic layer. Extract aqueous layer twice with ethyl acetate, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate:hexanes then 10:90 methanol:ethyl acetate) to give {4-[3′-(4-fluoro-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-ylmethyl]-5-methyl-pyrazol-1-yl}-acetic acid ethyl ester (139 mg, 16%). MS (ES): m/z=439 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=O.CN(C)CCN>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:25][CH2:26][CH2:27][N:23]([CH3:24])[CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCN
Solvent: ClCCl
Product: CN(C)CCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stream of nitrogen was bubbled through a stirred suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.50 g, 0.0157 mole), 1,1'-carbonyldiimidazole (2.54 g, 0.0157 mole) and anhydrous methylene chloride (100 ml ) for 2 hrs at room temperature. A solution of N,N-dimethylethylenediamine (1.50 g, 0.0170 mole) in 10 ml of methylene chloride was added dropwise and the reaction mixture was stirred overnight at room temperature. The methylene chloride was washed with water (2×30 ml), 5% sodium hydroxide (2×30 ml), water (30 ml), dried over sodium sulfate and concentrated. The residue (4.5 g) was recrystallized from isopropyl alcohol to give 3.5 g (62%) of white flakes, mp 195°-196.5 ° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]2[S:19][C:18]([C:20]3([O:24][CH2:25][O:26][CH3:27])[CH2:23][CH2:22][CH2:21]3)=[N:17][CH:16]=2)=[C:4]2[CH:10]=[C:9](/[C:11](=[N:13]/[OH:14])/[NH2:12])[NH:8][C:5]2=[N:6][CH:7]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH2:38][CH:37]([C:41](O)=[O:42])[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[NH2:12]/[C:11](=[N:13]\[O:14][C:41]([CH:37]1[CH2:38][CH2:39][CH2:40][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:36]1)=[O:42])/[C:9]1[NH:8][C:5]2=[N:6][CH:7]=[C:2]([Cl:1])[C:3]([C:15]3[S:19][C:18]([C:20]4([O:24][CH2:25][O:26][CH3:27])[CH2:23][CH2:22][CH2:21]4)=[N:17][CH:16]=3)=[C:4]2[CH:10]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(/C(N)=N/O)cc34)s2)CCC1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(/C(N)=N/OC(=O)C5CCCN(C(=O)OC(C)(C)C)C5)cc34)s2)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of Example 22B (0.09 g, 0.221 mmol), 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (0.056 g, 0.243 mmol), N-methylmorpholine (0.085 mL, 0.772 mmol), and 1-hydroxybenzotriazole hydrate (0.017 g, 0.110 mmol) in N,N-dimethylformamide (2.5 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.063 g, 0.331 mmol), and the reaction was stirred at ambient temperature for 3 hours. The reaction was treated with water (15 mL), and the resulting suspension was stirred for 10 minutes and filtered. The solid collected was washed with water and dried under vacuum. The crude material was purified by flash chromatography on silica gel, eluting with a gradient of from 0% to 40% ethyl acetate in hexane, to provide the title compound. MS ESI(+) m/z 619.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(=[O:14])[CH:11]([CH3:13])[CH3:12]>>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH:4][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12]
Reactant: Cc1ccc(Br)c(N)c1
Reactant: CC(C)C(=O)Cl
Product: Cc1ccc(Br)c(NC(=O)C(C)C)c1

Procedure:
Analogously to Example 18e, 12.20 g of 2-bromo-5-methylaniline are reacted with 7.77 ml of isobutyryl chloride. The title compound is obtained as a white solid. Rt=4.29.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][CH2:22]O)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:29]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>O1CCCC1>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][CH2:22][I:29])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: II
Reactant: CS(=O)(=O)Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCO)CS3)cc2c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCI)CS3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
2-[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol (178 mg, 0.42 mmol) prepared in Example 99 was dissolved in tetrahydrofuran (10 mL). Iodine (161 mg, 0.63 mmol), triphenylphosphine (166 mg, 0.63 mmol) and imidazole (86 mg, 1.23 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. The reaction was quenched by water, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (120 mg, Yield 54%).