Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[NH:10][CH2:9]1)(C)(C)C.[ClH:21].O1CCOCC1>C(Cl)Cl>[ClH:21].[ClH:21].[NH2:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[NH:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccc(C#N)cc2C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)CC(N)CN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 1C (546 mg, 2 mmol) in CH2Cl2 (5 mL) at 0° C. was added 4 M HCl in dioxane (4 mL, 16 mmol). After addition, the reaction mixture was stirred at RT for 2 h, then concentrated. The residue was stripped with ether (3×), and the resulting off-white solid dried in vacuo to afford the title compound (490 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]2[O:8][CH2:7]2)=[CH:4][CH:3]=1.[N-]=[N+]=[N-].[Na+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C@@H:6]2[O:8][CH2:7]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2CO2)cc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: Clc1ccc([C@H]2CO2)cc1

Procedure:
To 20 ml of Tris-SO4 buffer (50 mM, pH=7.3) containing 2 mM of para-chlorostyrene oxide and 1.2 mM of NaN3, 1.0 mg of purified enzyme, obtained as described in Example 1, was added. At 55% conversion, reaction was stopped and the solution was extracted with diethylether. The organic phase was analysed by chiral GC. The remaining (S)-para-chloro styrene oxide was obtained with an e.e. of higher than 99% and (R)-2-azido-1-(para-chloro-phenyl)-ethanol with an e.e. of 98%.
Reaction SMILES: [CH:1]([Si:4]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[O:5][C@H:6]([CH3:13])[CH2:7][C:8]([O:10]CC)=[O:9])([CH3:3])[CH3:2].[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[CH:17]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:14]([CH3:16])[CH3:15])[O:5][C@H:6]([CH3:13])[CH2:7][C:8]([OH:10])=[O:9])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C[C@@H](C)O[Si](C(C)C)(C(C)C)C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](O[C@H](C)CC(=O)O)(C(C)C)C(C)C

Procedure:
0.0755 mol (21.78 g) of the product from stage 1 is stirred at 60° C. for 5 days in 1.51 liters of a 0.01 molar lithium hydroxide solution in a tetrahydrofuran/water 1:1 mixture. The mixture is acidified with aqueous citric acid and the product is extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and concentrated under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([CH:28]=O)[CH:22]=2)=[O:18].[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:30]([C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)(=[O:32])=[O:31])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([CH2:28][N:44]1[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]1)[CH:22]=2)=[O:18]
Reactant: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc3ccc(C=O)cc32)cc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc3ccc(CN4CCN(C)CC4)cc32)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 86.2 %

Procedure:
2-[5-Amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazole-4-carbonyl]-1-(toluene-4-sulfonyl)-1H-indole-6-carbaldehyde (29 mg, 0.054 mmol), 1-methylpiperazine (7 μl, 0.066 mmol), and sodium triacetoxyborohydride (17 mg, 0.083 mmol) were dissolved in anhydrous dichloromethane (0.5 ml) and stirred at room temperature under a nitrogen atmosphere for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture. Then, the mixture was extracted with ethyl acetate. The organic layer was isolated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=100/15) to give [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[6-(4-methyl-piperazin-1-ylmethyl)-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone as a yellow solid (29 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)CCCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1
Yield: 20.4 %

Procedure:
Methyl 10-(4-chlorobenzenesulphonamido)decanoate (0.85 g, 0.0023 mol) was treated with 5N sodium hydroxide (15 ml) in ethanol (25 ml) at room temperature for 1 hour. The pH was adjusted to 1 with dilute hydrochloric acid and the precipitated solid was filtered off and recrystallised (isopropanol-ether) to give the title compound (0.17 g, m.p. 192°-4° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18]([F:23])[CH:19]=[CH:20]2)=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:23][C:18]1[CH:19]=[CH:20][C:21]2[C:16]([CH:17]=1)=[N:15][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1)[CH:22]=2
Reactant: C#CCCn1cc2ccc(F)cc2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCn2cc3ccc(F)cc3n2)n1
Yield: 26.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)pyridine (100 mg, 0.54 mmol) and 2-but-3-ynyl-6-fluoro-2H-indazole (93 mg, 0.49 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 40 mg (0.13 mmol, 27%) of 6-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CS(C)=O>[N:20]1([CH2:19][CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: ClCCN1CCCC1
Reactant: O=Cc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=Cc1cccc(OCCN2CCCC2)c1
Temperature: 90 °C

Procedure:
To a stirred solution of 3-hydroxybenzaldehyde (20 mmol) in DMSO (50 mL) at rt, solid Cs2CO3 (60 mmol) was added. 1-(2-chloroethyl)pyrrolidine hydrochloride (30 mmol) was added to the reaction mixture and heated to 90° C. for 9 h. After cooling to rt, the reaction was quenched by cold H2O (50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (3×50 mL) and dried (anhydrous Na2SO4). The solvent was removed in vacuo to afford crude 3-(2-pyrrolidin-1-yl-ethoxy)benzaldehyde.
Reaction SMILES: [CH2:1]([CH:7](O)[C:8]1[O:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH2:14]>>[CH2:1]([CH:7]1[CH:8]([OH:12])[CH:9]=[CH:10][C:11]1=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O
Reactant: CCCCCCC(O)c1ccco1
Product: CCCCCCC1C(=O)C=CC1O
Yield: 65 %

Procedure:
In the same apparatus as in Example 1, α-n-hexylfurfuryl alcohol (30 parts) and water (1500 parts) were charged, and the resultant mixture was stirred at 100° C., during which the pH was maintained at 4.6 to 5.0 until the starting compound was consumed. The reaction mixture was treated as in Example 1, followed by purification with chromatography to give 2-n-hexyl-3-hydroxy-4-cyclopentenone in a yield of 65 %.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[F:9].[NH:10]1[C:18]2[C:13](=[CH:14][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C(Cl)Cl>[F:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][CH:11]=[CH:12]2
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Reactant: Fc1cccc(F)c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1cccc(F)c1-c1ccc2[nH]ccc2c1
Temperature: 125 °C
Yield: 74.9 %

Procedure:
A glass microwave reaction vessel was charged with 1-bromo-2,6-difluorobenzene (1.145 mL, 7.71 mmol) and 5-indoleboronic acid pinacol ester (1.50 g, 6.17 mmol) in toluene/H2O (4:1, 15 mL) followed by dichloro(1,1-bis(diphenylphosphinoferrocene)) palladium(ii) complex with DCM (0.252 g, 0.309 mmol) and Na2CO3 (0.645 mL, 15.43 mmol). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 125° C. for 4 h, and then the mixture was diluted with DCM. The organic layer was separated, washed with water, dried over Na2SO4, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 10-15% EtOAc in Hexanes) to give 5-(2,6-difluorophenyl)-1H-indole (1.06 g, 4.62 mmol, 74.9% yield) as a light yellow oil. MS (ESI, pos. ion) m/z: 230 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3SC=CN=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.NC1C([N+]([O-])=O)=C(Cl)C(Cl)=CN=1.CN([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)C(=O)CN1CCNCC1>C(O)(C)C>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:20]([CH3:21])[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: CN(C(=O)CN1CCNCC1)c1ccccc1
Agent: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Product: CN(C(=O)CN1CCN(c2c(Cl)cnc(N)c2[N+](=O)[O-])CC1)c1ccccc1
Yield: 57 %

Procedure:
The method followed that used to prepare 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (Example 6, Steps 1 to 6), but using 2-amino-4,5-dichloro-3-nitropyridine (0.036 g, 0.17 mmol), isopropanol (4.0 ml), and N-methyl-N-phenyl-2-piperazin-1-yl-acetamide (0.056 g, 0.24 mmol). Work-up and purification as described for 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide afforded the title compound as an orange solid (0.039 g, 57%), 1H-NMR (500 Mz, DMSO-d6) 2.50 (obscured by DMSO peak, piperazine N(CH2)2), 2.96 (br s, 4H, piperazine N(CH2)2), 3.18 (s, 3H, NCH3), 6.94 (s, 2H, NH2), 7.35 (m, 3H) and 7.42 (m, 2H) (N-Ph), 8.05 (s, 1H, pyridine 6-H); LC-MS (ESI, m/z) 3.30 min—405, 407 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH:6]1([CH2:11][C@H:12]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:13]([NH:15][C:16]2[S:17][C:18]3[C:23]([N:24]=2)=[CH:22][CH:21]=[C:20]([O:25][CH3:26])[N:19]=3)=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7]1>C(Cl)Cl>[CH:6]1([CH2:11][C@H:12]([C:27]2[CH:32]=[CH:31][C:30]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:29][CH:28]=2)[C:13](=[O:14])[NH:15][C:16]2[S:17][C:18]3[C:23]([N:24]=2)=[CH:22][CH:21]=[C:20]([O:25][CH3:26])[N:19]=3)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc2nc(NC(=O)[C@H](CC3CCCC3)c3ccccc3)sc2n1
Solvent: ClCCl
Product: COc1ccc2nc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(=O)(=O)Cl)cc3)sc2n1
Temperature: 25 °C

Procedure:
Chlorosulfonic acid (20 mL) is cooled to 0° C. To this is added a solution of the title F compound, (R)-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-phenyl-propionamide (2.53 g, 6.632 mmol) in DCM (10 mL). The reaction is allowed to stir and warm to RT over 2.5 h. The reaction is then added dropwise to crushed ice (400 mL) and extracted with DCM (3×100 mL). Extracts are combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-[(R)-2-cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]benzenesulfonyl chloride as a yellow foam. Product is isolated as a 80:20 mixture of the desired para product and undesired meta product: 1H NMR (400 MHz, DMSO-D6) 1.1 (s, 2 H) 1.4 (d, J=4.8 Hz, 1 H) 1.4 (s, 1 H) 1.5 (m, 3 H) 1.7 (s, 2 H) 1.8 (d, J=13.4 Hz, 1 H) 2.1 (m, 1 H) 3.9 (s, 3 H) 4.0 (s, 1 H) 6.9 (d, J=8.6 Hz, 1 H) 7.3 (m, 2 H) 7.6 (d, J=8.1 Hz, 2 H) 8.0 (d, J=8.6 Hz, 1 H) 14.3 (s, 2 H); LC/MS 480.2 (M+1), 478.3 (M−1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12.[NH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1.[N+](C1SC=CC=1)([O-])=O>[Pd]>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[NH:16][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12
Reactant: Nc1cccs1
Reactant: CCOC(=O)c1cnc2cn[nH]c2c1Cl
Agent: [Pd]
Agent: O=[N+]([O-])c1cccs1
Product: CCOC(=O)c1cnc2cn[nH]c2c1Nc1cccs1
Yield: 10.4 %

Procedure:
Ethyl 7-chloro-1H-pyrazolo[4,3-b]pyridine-6-carboxylate (4.5 g 0.02 mole) and aminothiophene (2.0 g) [prepared from 2-nitrothiophene (supplied by Aldrich and shown by nmr to contain 15% of 3-nitrothiophene) by reduction using either H2 ; 10% Pd/C or stannous chloride] were stirred together under nitrogen for 24 hours. The ethanol was removed under reduced pressure. The resulting brown oil was purified by column chromatography on silica eluting with 5% methanol/ether to give the title compound as a beige solid (0.600 g), mp 188°-190° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][N:18]=1)[C:12](OC)=[O:13].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[F:19][C:2]([F:1])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]([CH2:12][OH:13])[CH:16]=[CH:17][N:18]=1
Reactant: COC(=O)c1ccnc(-c2ccccc2C(F)(F)F)c1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccnc(-c2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
432 mg (1.54 mmol) of the compound from Example 58A were dissolved in 10 ml of THF, and 1.08 ml (1.08 mmol) of a 1 M solution of lithium aluminum hydride in THF were added at −10° C. After the addition had ended, the mixture was stirred at RT for 2 h. For work-up, 4 ml of a saturated sodium potassium tartrate solution were added at RT, and the mixture was extracted with 15 ml of ethyl acetate. The organic phase was washed once with 10 ml of saturated sodium potassium tartrate solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. This gave 497 mg (>100% of theory) of the target compound which were reacted further without any further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH:19]([C:21]3[S:25][C:24]([C:26](O)=[O:27])=[CH:23][CH:22]=3)[CH3:20])=[CH:13][C:12]=2[CH3:29])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:31][O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH3:31][O:32][C:33](=[O:37])[CH2:34][CH2:35][NH:36][C:26]([C:24]1[S:25][C:21]([CH:19]([O:18][C:14]2[CH:13]=[C:12]([CH3:29])[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:10][CH:9]=3)=[C:16]([CH3:17])[CH:15]=2)[CH3:20])=[CH:22][CH:23]=1)=[O:27]
Reactant: COC(=O)CCN
Reactant: Cc1cc(OC(C)c2ccc(C(=O)O)s2)cc(C)c1-c1ccc(C(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CCNC(=O)c1ccc(C(C)Oc2cc(C)c(-c3ccc(C(C)(C)C)cc3)c(C)c2)s1
Yield: 71.4 %

Procedure:
To a mixture of (±)-5-[1-(4′-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carboxylic acid (0.546 g, 1.34 mmol), 3-amino-propionic acid methyl ester hydrochloride (0.204 g, 1.46 mmol), and 1-hydroxybenzotriazole hydrate (HOBt, 0.217 g, 1.60 mmol) in DMF (12.3 mL) is added N, N-diisopropylethylamine (0.70 mL, 4.01 mmol), then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 0.333 g, 1.74 mmol) and stirred overnight. The reaction mixture is poured into H2O (25 mL) and extracted with EtOAc (3×25 mL). Combined organic extracts are washed with H2O, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 75% to provide (±)-3-({5-[1-(4′-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.472 g, 71%) as a white solid. MS (ES): 492.1 [M−H]−. The racemic material is separated by chiral HPLC (column: Chiralpak OD-H 4.6×150 mm; eluent: 10:90 3A alcohol/Heptane; flow rate: 0.6 mL/min; UV absorbance wavelength: 270 nm) to provide Isomer 1 (0.180 g, 98.3% ee) and Isomer 2 (0.190 g, 96.7% ee).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]#[N:8].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[F-].[Cs+].Cl.[OH:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[C:38]([O:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH2:51][N:52]3[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]3)=[CH:45][CH:44]=1)=[C:37](B(O)O)[CH:36]=[CH:35]2>C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[OH:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[C:38]([O:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH2:51][N:52]3[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]3)=[CH:45][CH:44]=1)=[C:37]([C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]#[N:8])[CH:36]=[CH:35]2
Reactant: N#Cc1sccc1Br
Reactant: OB(O)c1ccc2cc(O)ccc2c1Oc1ccc(OCCN2CCCCC2)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CC#N
Product: N#Cc1sccc1-c1ccc2cc(O)ccc2c1Oc1ccc(OCCN2CCCCC2)cc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 10 %

Procedure:
Add 3-bromothiophene-2-carbonitrile (93 mg, 494.6 μmol), palladium (II) acetate (12 mg, 53.4 μmol), tricyclohexylphosphine (21 mg, 74.9 μmol), cesium fluoride (336 mg, 2.2 mmol) to a solution of 6-hydroxy-1-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)naphthalen-2-ylboronic acid hydrochloride (100 mg, 245.5 μmol) in ethanol (2 mL), and acetonitrile (8 mL). Purge the reaction vessel 3 times with nitrogen. Stir the mixture at 85° C. for 2 hours. Cool the mixture and filter. Wash the resulting solids with acetonitrile. Concentrate the combined filtrate and washes. Purify the residue by DOWEX ion exchange resin to obtain the crude product. Purify the crude product by Prep-HPLC to obtain the title compound (12 mg, 24.55 μmol).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])ccc1CBr
Yield: 103.8 %

Procedure:
A mixture of methyl 2-methyl-5-nitrobenzoate (2.51 g, 12.9mmol) and benzoyl peroxide (containing approx. 25% water) (164 mg, 0.51 mmol) in carbon tetrachloride (50 ml) was purged with nitrogen before removing 12 ml of the solvent by distillation. N-Bromosuccinimide (2.30 g, 12.9 mmol) was then added in small portions to the refluxing mixture under irradiation (60W) and the mixture heated at reflux for 2.5 h under nitrogen. The succinimide was removed by filtration and the filtrate evaporated in vacuo to give crude methyl 2-bromomethyl-5-nitrobenzoate (3.67 g) as a yellow oil. To this was added sodium sulphite (2.43 g, 19.3 mmol) and water (10 ml) and the mixture heated at 90° C. for 3 h. The resulting solution was allowed to cool to room temperature and the solid formed was collected, washed with cold water (2×5 ml), then diethyl ether (3×10 ml), and dried under high vacuum in the presence of phosphorus pentoxide. Two more crops were similarly collected to afford the title product (1.46 g, 38%) as a white solid. mp 290°-297° C. 1H NMR (360 MHz, D6-DMSO) δ 3.84 (3H, s), 4.34 (2H, s), 7.68 (1H, d, J=8.5 Hz),8.30 (1H, dd, J=8.5 and 2.6 Hz), 8.41 (1H, d, J=2.5 Hz). MS (FAB) 274 (M-1).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:11]3[C:12](=[O:27])[N:13]([CH3:26])[C:14]([C:23](O)=[O:24])=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)[C:10]=3[C:9]3[CH2:28][O:29][CH2:30][CH2:31][C:8]2=3)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:37])=O>O1CCCC1.CN(C=O)C>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:11]3[C:12](=[O:27])[N:13]([CH3:26])[C:14]([C:23]([Cl:37])=[O:24])=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)[C:10]=3[C:9]3[CH2:28][O:29][CH2:30][CH2:31][C:8]2=3)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(-c2c(C(=O)O)n(C)c(=O)c3c2c2c(n3Cc3ccc(F)cc3)CCOC2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(C(=O)Cl)n(C)c(=O)c3c2c2c(n3Cc3ccc(F)cc3)CCOC2)cc1
Reaction time: 0.25 h
Yield: 93 %

Procedure:
A solution of methyl 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carboxylate (0.4 g, 0.869 mmol) in Tetrahydrofuran (THF) (2.77 ml)/Methanol (2.77 ml) was treated with 2M LiOH (3.04 ml, 6.08 mmol) and heated to reflux (80° C. bath). After 18 h, the reaction mixture was cooled to ambient temperature and poured into 1M HCl. The layers were partitioned and the organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to afford 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carboxylic acid as a beige solid. A solution of 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carboxylic acid in THF (10 mL) was treated with oxalyl chloride (0.110 ml, 1.303 mmol) and 1 drop of DMF. After 15 min, the reaction mixture was concentrated in vacuo to afford 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carbonyl chloride (375 mg, 0.807 mmol, 93% yield). An ice cold solution of 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carbonyl chloride (375 mg, 0.807 mmol, 93% yield) in 1,2-DME (10 mL) was treated with NaBH4 (0.161 g, 4.34 mmol) and then warmed to ambient temperature. After 1 h, the reaction mixture was cooled to 0° C. and quenched with MeOH (1 mL) and 1M HCl (˜20 mL). EtOAc was added and the layers were partitioned and the organic layer was washed with brine, dried (MgSO4), filtered and concentrated to afford 5-(4-fluorobenzyl)-8-(hydroxymethyl)-7-methyl-9-(p-tolyl)-3,4,5,7-tetrahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridin-6(1H)-one (333 mg, 0.770 mmol, 89% yield) as a white solid. The residue was used without further purification. LCMS (m/z) ES+=433 (M+1).
Reaction SMILES: [Na].[OH:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.C[O:11][C:12](=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=1>O>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][O:2][C:12](=[O:11])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([CH3:22])[CH3:23])=[CH:16][CH:15]=2)[CH:5]=1
Reactant: OCc1cccnc1
Reactant: COC(=O)Cc1ccc(CC(C)C)cc1
Agent: [Na]
Solvent: O
Product: CC(C)Cc1ccc(CC(=O)OCc2cccnc2)cc1

Procedure:
A mixture of 0.05 g of sodium and 8 ml of 3-hydroxymethylpyridine was heated at 65°-70° C. for 10 hours. To this mixture was added 2.1 g of p-isobutylphenylacetic acid methyl ester, and the whole was heated at 95°-100° C. for 8 hours. After the reaction was complete, 100 ml of water was added. The resulting mixture was extracted with ether, and the ether layer separated was dehydrated and concentrated to leave an oily residue. This residue was distilled under reduced pressure to give 1.9 g of p-isobutylphenylacetic acid-3-pyridylmethyl ester as a colorless liquid, boiling at 142°-145° C./1 mmHg. Analysis-Calculated for C18H21NO2 : C, 76.29; H, 7.47; N, 4.94. Found: C, 76.02; H, 7.38; N, 4.79. Mass spectrum: parent ion 283 m/e.