Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:15]1[C:16]2[N:17]([N:21]=[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[N:23]=2)[CH:18]=[CH:19][CH:20]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:37][N:34]1[CH2:35][CH2:36][N:31]([C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:22]3[N:23]=[C:16]4[C:15]([NH:14][CH2:13][CH:9]5[CH2:10][CH2:11][CH2:12][NH:8]5)=[CH:20][CH:19]=[CH:18][N:17]4[N:21]=3)=[CH:30][CH:29]=2)[CH2:32][CH2:33]1
Reactant: CN1CCN(c2ccc(Nc3nc4c(NCC5CCCN5C(=O)OC(C)(C)C)cccn4n3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(Nc3nc4c(NCC5CCCN5)cccn4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
170 c) To a solution of 2-({2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (90.0 mg, 0.178 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.0547 mL, 0.710 mmol). The mixture was stirred at room temperature for 18 hours then the volatiles were evaporated under reduced pressure. Crude N(2)-[4-(4-Methyl-piperazin-1-yl)-phenyl]-N(8)-pyrrolidin-2-ylmethyl-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine as the bis-trifluoroacetic acid salt was isolated as a red-brown resin. The residue was suspended in dichloromethane (2 mL) and triethylamine (0.148 mL, 1.06 mmol) was added. The mixture was cooled to 5° C. and methanesulfonyl chloride (0.0165 mL, 0.213 mmol) was added. The mixture was stirred for 1 hour at 5° C. then warmed to room temperature and stirred for 1 hour. The reaction mixture was poured into saturated aqueous sodium carbonate (10 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were washed with water (10 mL) then saturated aqueous sodium chloride (10 mL), dried over magnesium sulfate, filtered and evaporated to a dark resin. The residue was purified via reverse phase chromatography using a Gilson apparatus (0%→50% acetonitrile:water (w/0.1% TFA modifier)). Collected desired fractions, basified with saturated aqueous sodium carbonate and extracted with dichloromethane (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. N(8)-(1-Methanesulfonyl-pyrrolidin-2-ylmethyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was isolated as a pale yellow foam (0.033 g, 38%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.80 (d, J=6.5 Hz, 1H), 7.47 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.9 Hz, 2H), 6.71 (t, J=7.4 Hz, 1H), 6.55 (d, J=7.9 Hz, 1H), 6.52 (s, 1H), 5.09 (t, J=6.4 Hz, 1H), 4.03-3.94 (m, 1H), 3.63-3.55 (m, 1H), 3.53-3.46 (m, 1H), 3.39-3.25 (m, 2H), 3.18-3.13 (m, 4H), 2.88 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H), 2.11-1.91 (m, 4H). MS=485 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C1C(=O)N([Br:16])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Br:16])[N:3]=1
Reactant: Cc1cccc(Br)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc(Br)n1

Procedure:
A mixture of 2-bromo-6-methylpyridine (5.7 ml), NBS (8.9 g) and benzoyl peroxide (50 mg) in CCl4 (50 ml) were heated to reflux for 16 h. The reaction was filtered and the solution obtained was used without further purification in the next step. 1H NMR (400 MHz, CDCl3) δ 7.56 (1H, t, J=7.8 Hz), 7.45–7.40 (1H, m), 7.28 (1H, d, J=8.2 Hz), 4.50 (2H, s). b) (6-Bromopyridin-2-ylmethyl)dimethylamine 2-Bromo-6-bromomethyl-pyridine and NHMe2 (10 ml of 2M solution in THF) were reacted at RT for 16 h. The reaction mixture was poured into H2O, extracted into CH2Cl2 and the concentrated residue purified by column chromatography on silica, eluting with 1% MeOH/CH2Cl2 to give the title compound (440 mg). 1H NMR (400 MHz, CDCl3) δ 7.53 (1H, t, J=7.6 Hz), 7.40 (1H, d, J=7.5 Hz), 7.36 (1H, d, J=7.8 Hz), 3.57 (2H, s), 2.29 (6H, s). c) Dimethyl-{6-[3-(5-methyl-3-phenyl-isoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-α]isoindol-8-yl]pyridin-2-ylmethyl}amine Prepared in a similar manner to Example 26 using (6-bromopyridin-2-ylmethyl)-dimethylamine to give the title compound (40 mg, 39%). 1H NMR (360 MHz, CDCl3) δ 8.63 (1H, d, J=1.1 Hz), 8.13 (1H, dd, J=8.1, 1.5 Hz), 7.78 (1H, t, J=7.7 Hz), 7.67 (1H, d, J=7.7 Hz), 7.56–7.54 (2H, m), 7.47–7.34 (5H, m), 4.06 (2H, s), 3.70 (2H, s), 2.73 (3H, s), 2.37 (6H, s), m/z (ES+) 449 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:4][N:3]=1.[C:19]([Zn]C#N)#[N:20]>CN(C)C(=O)C.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>[C:11]([C:10]1[CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=[CH:16][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:19]#[N:20])[CH:7]=1)#[N:12]
Reactant: N#C[Zn]C#N
Reactant: N#Cc1cc(C=O)ccc1Oc1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: N#Cc1cc(Oc2ccc(C=O)cc2C#N)ccn1

Procedure:
To a solution of 2-((2-chloropyridin-4-yl)oxy)-5-formylbenzonitrile (400 mg, 1.55 mmol) and dicyanozinc (182 mg, 1.55 mmol) in N,N-dimethylacetamide (DMA) (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (179 mg, 0.155 mmol). The reaction mixture was sealed in a microwave vial and irradiated with a microwave using initial normal to 100° C. for 1 h and filtered.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH:17]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17][NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12]
Reactant: NCCNC(=O)c1ccccc1O
Reactant: COC(C=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(CNCCNC(=O)c1ccccc1O)OC
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of N-(2-aminoethyl)-2-hydroxybenzamide (332 mg, 1.85 mmol), dimethoxyacetaldehyde (0.475 mL, 1.85 mmol) in CH2Cl2 (10 mL) was added sodium triacetoxyboro hydrid (588 mg, 2.80 mmol). The resulting mixture was stirred overnight, then diluted with EtOAc (50 mL), washed with 10 mL of water and then brine, dried over MgSO4, and conc in vacuo to yield 441 mg (97%) of the product as a colorless oil. MS (ESI) 269 (M+H).
Reaction SMILES: C(O)C.C([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([O:27][CH3:28])[CH:19]=2)[CH2:14][C@H:13]1[F:29])C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([N:15]2[CH2:16][CH2:17][C@H:12]([NH2:11])[C@H:13]([F:29])[CH2:14]2)=[CH:19][C:20]=1[O:27][CH3:28]
Reactant: COc1cc(N2CC[C@H](NCc3ccccc3)[C@H](F)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(N2CC[C@H](N)[C@H](F)C2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Ethanol (15 ml) and ethyl acetate (3.00 ml) were added to a flask charged with (3R,4S)—N-benzyl-3-fluoro-1-(3-methoxy-4-nitrophenyl)piperidin-4-amine (INTERMEDIATE 47) (1.4 g, 3.90 mmol) and Pd/C (0.415 g, 0.39 mmol). The flask was degassed and filled with H2. The reaction was stirred at RT for 2 h under hydrogen balloon. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated under reduced pressure to give the title product (0.840 g, 90%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:20]([C:22]4([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]4)=[O:21])=[CH:15][C:14]=3[F:35])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37].CS(O[CH2:43][CH2:44][CH2:45][C:46]1([OH:49])[CH2:48][CH2:47]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:49][C:46]1([CH2:45][CH2:44][CH2:43][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:18]=[CH:17][C:16]([N:19]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=5)[C:20]([C:22]5([C:25]([NH2:27])=[O:26])[CH2:23][CH2:24]5)=[O:21])=[CH:15][C:14]=4[F:35])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:36][CH3:37])[CH2:48][CH2:47]1
Reactant: CS(=O)(=O)OCCCC1(O)CC1
Reactant: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1OCCCC1(O)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 9 by using N-(4-(7-hydroxy-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (300 mg, 0.594 mmol), 3-(1-hydroxycyclopropyl)propyl methanesulfonate (155 mg, 0.80 mmol), and Cs2CO3 (581 mg, 1.782 mmol) in 3 mL of DMA. The residue was purified by a silical gel column chromatography (6:1 (v/v) EtOAc/n-hexane). The title compound was obtained as a white solid (247 mg, 69%).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[F:35][C:36]1[CH:37]=[C:38]([OH:50])[CH:39]=[C:40]([C:42]2([O:48][CH3:49])[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH:41]=1>O>[F:35][C:36]1[CH:37]=[C:38]([CH:39]=[C:40]([C:42]2([O:48][CH3:49])[CH2:43][CH2:44][O:45][CH2:46][CH2:47]2)[CH:41]=1)[O:50][CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: NS(=O)(=O)c1ccc(-c2oc(CCl)nc2-c2ccccc2)cc1
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(c2cc(F)cc(OCc3nc(-c4ccccc4)c(-c4ccc(S(N)(=O)=O)cc4)o3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
A mixture of 4-[2-chloromethyl-4-phenyloxazol-5-yl]benzenesulfonamide (Step 3) (0.5 g, 1.4 mmol), potassium carbonate (0.4 g, 2.8 mmol), dimethylformamide (20 mL), and 3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenol [prepared as described in J. Med Chem., 35, 2600-2609 (1992)] (0.3 g, 1.4 mmol) was stirred at room temperature for 16 h. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (4×30 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The resulting crude product was purified by flash column chromatography on silica gel eluting with 50% ethyl acetate in hexanes to give 0.3 g (40%) of 4-[2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-pyran-4-yl)phenoxy]methyl]-4-phenyl-oxazol-5-yl]benzenesulfonamide as a sticky white solid: m.p. 70-80° C. 1H NMR (CDCl3/300 MHz) δ 7.92 (d, 2H, J=8.9 Hz), 7.77 (d, 2H, J=8.9 Hz) , 7.62 (m, 2H) , 7.43 (m, 3H) , 6.94 (s, 1H), 6.78 (m, 2H) 5.24 (s, 2H) , 4.82 (bs, 2H), 3.82 (m, 4H), 3.00 (s, 3H), 1.95 (m, 4H). Anal. calcd for C28H27FN2O6S: C, 62.44; H, 5.05; N, 5.20. Found: C, 62.50; H, 5.11; N, 5.24.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2[CH:17]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:15][N:14]=2)[N:10]=[CH:9]1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.C(O)C.[Pd]>[NH:8]1[CH:12]=[C:11]([C:13]2[CH:17]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:15][N:14]=2)[N:10]=[CH:9]1
Reactant: CCOC(=O)c1cc(-c2cn(Cc3ccccc3)cn2)n[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2c[nH]cn2)n[nH]1
Yield: 101.6 %

Procedure:
Ethyl 3-(1-benzyl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate (8.77 mmol, 2.6 g) was dissolved in a mixture of acetic acid (10 ml) and ethanol (190 ml). The mixture was run through H-Cube (10% Pd/C CatCart (8.77 mmol) flow 1.5 ml/min, +80° C., Full hydrogen mode). The collected fractions were combined and evaporated. The acquired solid was stirred in toluene and evaporated. This was repeated once more. 1.837 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.33 (t, 3H), 4.35 (q, 2H), 7.38 (s, 1H), 8.07 (d, 1H), 9.14 (bs, 1H), 14.44 (bs, 1H). LC-MS: [M−1]=205.0.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH:15]=[CH2:16])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:2].C(#N)C.Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>C(N(CC)CC)C>[C:1]([CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH:15]=[CH:16][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:2]
Reactant: C=CCC(CCCC#N)CCC(=O)OCC
Reactant: Brc1cccnc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CCC(CC=Cc1cccnc1)CCCC#N

Procedure:
A mixture of 1300 g of ethyl 4-(3-cyanopropyl)-6-heptenoate, 6397 ml of acetonitrile, 3190 mL of triethylamine and 920.9 g of 3-bromopyridine is degassed and then heated to reflux. Palladium II acetate catalyst (13 g) and 36.42 g of tri-o-tolylphosphine are added and the mixture is heated under reflux overnight. Additional catalyst (13 g) is added and the mixture is again heated under reflux for 7 hours. Further catalyst (6.5 g) is again added and the reaction is again heated under reflux overnight. The reaction mixture is cooled, diluted with 6 L of methylene chloride, and evaporated to dryness. The residue is partitioned between ether and water. The ether layer is separated and the aqueous layer is extracted two more times with ether. The combined ether extracts are extracted with 2×8 L of 1 N hydrochloric acid. The acid extract is cooled and made basic with 1200 ml of conc. ammonium hydroxide to pH 10, and extracted with ether (3×8 L). The ether extract is dried over sodium sulfate and evaporated to dryness to yield ethyl 4-(3-cyanopropyl)-7-(3-pyridyl)-6-heptenoate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:8][C:6]1[CH:5]=[C:4]([O:19][C:16]2[CH:17]=[CH:18][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(Cl)cc(Oc2ccc([N+](=O)[O-])cc2)n1
Temperature: 0 °C
Yield: 92.5 %

Procedure:
2-Amino-4,6-dichloropyrimidine (3.28 g, 20.0 mmol), 4-nitrophenol (2.78 g, 20.0 mmol), and potassium carbonate (4.15 g, 30.0 mmol) were heated and stirred in dimethylformamide (20 ml) at 100° C. for 3 hours. After returning the reaction solution to room temperature, it was poured into ice water (100 ml) and the precipitated crystals were filtered out, washed with water and blow-dried to obtain the title compound (4.93 g, 18.5 mmol, 92%) as colorless crystals.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH2:33][NH:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:52](I)[CH3:53]>CN(C=O)C.CCOC(C)=O>[C:24]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:22][C:21]([C:17]2[O:18][C:19]([CH3:20])=[C:15]([CH2:14][CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:41])=[C:7]([CH2:33][N:34]([CH2:52][CH3:53])[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH:8]=3)[N:16]=2)=[CH:26][CH:25]=1
Reactant: CCI
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1CNC(=O)OC(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(Cc1cc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)ccc1CCC(=O)O)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A solution of 3-[4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid methyl ester (200 mg, 0.36 mmol) in DMF (15 mL) was treated with sodium bis(trimethylsilyl)amide (132 mg, 0.719 mmol). Ethyl iodide (112 mg, 0.719 mmol) was added, and the reaction mixture was stirred overnight at room temperature under N2. The mixture was diluted with EtOAc (100 mL) and washed with brine (100 mL), then water (100 mL). The organic layer was dried (MgSO4) and concentrated to the penultimate ester as white solid (179 mg). The material was dissolved in EtOH (20 mL), treated with 5N NaOH (20 mL), and stirred at room temperature overnight. The mixture was acidified with 1N HCl (10 mL) and extracted with EtOAc (50 mL). The organics were dried (MgSO4) and concentrated to give a white solid (201 mg). MS [EI+] m/z 571 (M+H)+. Anal. Calculated for C34H38N2O6: C, 71.6; H, 6.7; N, 4.9. Found: C, 70.8; H, 6.8; N, 5.0.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1>O.[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([CH3:21])([CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(C)(C)c1ccc(O)cc1
Yield: 62.1 %

Procedure:
Under inert atmosphere, a round bottom flask was charged with ethyl 2-(4-benzyloxyphenyl)-2-methyl-propanoate (15 g, mmol) and ethyl acetate (200 mL). To above reaction mixture 2-3 drops of water was added followed by Pd/C. Reaction mixture allowed to stir and evacuated the flask until solvent begins to bubble and then carefully backfill with nitrogen gas (repeated twice). Nitrogen balloon was replaced by hydrogen bladder and flask was again evacuated and refilled with hydrogen (repeated twice). The reaction mixture thus maintained under hydrogen atmosphere was allowed to stir overnight at room temperature. The reaction mixture was filtered through cellite pad and the filtrate was concentrated under reduced pressure to afford 6.5 g of product.
Reaction SMILES: [N:1]1([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]3[C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][N:19]([C@H:28]([CH:41]4C[CH2:45][CH2:44][CH2:43][CH2:42]4)[C:29]([O:31]CC4C=CC(OC)=CC=4)=[O:30])[CH2:18]3)[CH2:12][CH2:11]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>>[N:1]1([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]3[C@@H:21]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:20][N:19]([C@H:28]([CH:41]4[CH2:42][CH2:43][CH2:44][CH2:45]4)[C:29]([OH:31])=[O:30])[CH2:18]3)[CH2:12][CH2:11]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(n4cnc5ccccc54)CC3)[C@@H](c3ccccc3)C2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H](C1CCCC1)N1C[C@H](CN2CCC(n3cnc4ccccc43)CC2)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 115.5 %

Procedure:
To 26.5 mg of α-(R)-(3-(S)-((4-benzoimidazol-1-yl-piperidin-1-yl)methyl)-4-(S)-phenyl-pyrrolidin-1-yl)- cyclohexaneacetic acid, 4-methoxy-benzyl ester (from Step D) was added 0.2 mL of anisole and 2 mL of TFA. After stirring at room temperature for 1.5 hours, concentrated under pressure. The residue was purified by flash chromatography eluting with 10% CH3OH in CH2Cl2, then 15% CH3OH/1% NH4OH in CH2Cl2 to give 24 mg of the title compound as a solid. 1H NMR (400 MHz, CDCl3): δ1.17-3.73 (m, 28H), 4.35 (m, 1H), 7.27 (m, 3H), 7.46(m, 4H), 7.55(s. 1H). 7.65(d, J=7.4 Hz, 1H), 8.17(d, J=5.0 Hz, 1H). ESI-MS 510 (M+H); HPLC A: 1.67 min.
Reaction SMILES: C([O:5][C:6](=[O:24])[CH2:7][O:8][C:9]1[C:21]([Cl:22])=[C:20]([Cl:23])[C:12]2[S:13][C:14]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:15][C:11]=2[CH:10]=1)(C)(C)C.[OH-].[Na+]>C(O)C>[Cl:22][C:21]1[C:9]([O:8][CH2:7][C:6]([OH:24])=[O:5])=[CH:10][C:11]2[CH:15]=[C:14]([C:16]([OH:19])([CH3:18])[CH3:17])[S:13][C:12]=2[C:20]=1[Cl:23]
Reactant: CC(C)(C)OC(=O)COc1cc2cc(C(C)(C)O)sc2c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(O)c1cc2cc(OCC(=O)O)c(Cl)c(Cl)c2s1
Yield: 93.4 %

Procedure:
To 8.5 g of t-butyl[[6,7-dichloro-2-(1-hydroxy-1-methylethyl)benzo[b]thien-5-yl]oxy]acetate in 200 ml of ethanol is added 150 ml of a 6N sodium hydroxide solution and the mixture is refluxed at 100° for 30 mins. The cooled mixture is concentrated in vacuo to a white slurry which is diluted with 200 ml of ice water and 200 ml of ethyl ether. With stirring and efficient cooling, the mixture is acidified with 6N hydrochloric acid. The acidic mixture is extracted with ethyl ether and the ether extracts are washed, dried over anhydrous magnesium sulfate, filtered and the solvent is removed. Recrystallization of the residue from acetone and pentane gives 6.8 g of [[6,7-dichloro-2-(1-hydroxy-1-methylethyl)benzo[b]thien-5-yl]oxy]acetic acid, mp 194°-196°.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>O>[CH2:16]([N:18]([CH2:19][CH3:20])[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH3:17]
Reactant: CCNCC
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Agent: Cl
Solvent: O
Product: CCN(CC)c1ccc(S(C)(=O)=O)cc1C(=O)O

Procedure:
3.0 g of 2-fluoro-5-methanesulfonyl-benzoic acid (CA 247569-56-8; WO200501453) was dissolved in 30 ml of diethylamine and refluxed overnight. The reaction mixture was diluted with water, acidified by addition of diluted hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and concentrated to give the title compound as a slightly brownish solid. MS (m/e): 272.1 (M+H+; 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:35][C@H:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:35][C@H:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: O=S(=O)(OC[C@H]1CCCCO1)C(F)(F)F
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Product: COc1cn(C(C[C@H]2CCCCO2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
333 mg (0.80 mmol) of tert-butyl {4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}acetate in the presence of 0.96 ml (0.96 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 426 mg (purity 70%, 1.20 mmol, 1.5 eq.) of (2R)-tetrahydro-2H-pyran-2-ylmethyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 85 mg (purity 94%, 19% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH2:31]([N:33]([CH2:38][CH3:39])[CH2:34][CH2:35][NH:36][CH3:37])[CH3:32]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:36]([CH2:35][CH2:34][N:33]([CH2:38][CH3:39])[CH2:31][CH3:32])[CH3:37])=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:29])([F:30])[F:28])[CH:3]=1
Reactant: CCN(CC)CCNC
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CCN(CC)CCN(C)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(2-diethylamino-ethyl)-methyl-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and N,N-Diethyl-N′-methyl-ethane-1,2-diamine following General Procedure B.