Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH2:7][CH2:8][CH3:9])[NH2:6].[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[C:20]([F:22])[CH:21]=1)[CH2:18][C:17](=O)[CH2:16][CH2:15]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:10])[CH:5]([NH:6][CH:17]1[CH2:16][CH2:15][C:14]2[C:19](=[C:20]([F:22])[CH:21]=[C:12]([F:11])[CH:13]=2)[CH2:18]1)[CH2:7][CH2:8][CH3:9]
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Reactant: CCC[C@H](N)C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine L-norvaline methyl ester-hydrochloride (1 equiv) with 6,8-difluoro-3,4-dihydro-1H-naphthalen-2-one (1 equiv) in methylene chloride and stir 30 min. and add sodium triacetoxy borohydride (1.1 equiv) and stir at rt overnight. The reaction is quenched with aqueous sodium bicarbonate, extracted with methylene chloride, dried, and concentrated. The resultant material is purified by silica gel chromatography to afford the separated diastereomers of 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid methyl ester: Diastereomer 1; 13C NMR (100 MHz, CDCl3) 14.0, 19.4, 27.7, 28.2, 29.5, 29.6, 36.3, 51.1, 58.7, 100.7, 100.9, 101.2, 110.5, 110.7, 110.8, 118.5, 118.6, 141.1, 159.7, 159.8, 162.1, 176.7; MS m/z 298.3 (M+1). Diastereomer 2; Diagnostic 13C NMR (100 MHz, CDCl3) 14.0, 19.3, 28.3, 28.4, 28.5, 30.3, 36.4, 51.1, 52.0, 58.5, 100.7, 100.9, 101.2, 110.5, 110.7, 176.8; MS m/z 298.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[H][H]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: [H][H]
Solvent: CCO
Product: COc1cc(F)ccc1N
Yield: 99.6 %

Procedure:
Paladium/carbon(Pd/C, 5%, 0.5 g) was added to a solution of 4-fluoro-2-methoxynitrobenzene (1.65 g, 9.6 mmol) in ethanol, which was then stirred for 1 hour under 30 psi of hydrogen pressure. The reaction mixture was filtered to remove paladium/carbon, and concentrated to give 1.35 g of the titled compound. (Yield 100%)
Reaction SMILES: [C@@H:1]1([O:11][CH2:12][CH2:13][NH:14][C:15](=[O:32])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][C@@H:27]([C:29]([OH:31])=[O:30])[NH2:28])=[O:21])[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].O=C1CCC(=O)N1[O:40][C:41](=O)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:51]([O:50][C:48](=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][C:41]([NH:28][C@H:27]([C:29]([OH:31])=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][C:15]([NH:14][CH2:13][CH2:12][O:11][C@@H:1]1[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1[OH:3])=[O:32])=[O:40])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CCCCC(=O)NCCCC[C@H](N)C(=O)O)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: O=C(CCCCCCC(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1O[C@@H](OCCNC(=O)CCCCC(=O)NCCCC[C@H](NC(=O)CCCCCCC(=O)OCc2ccccc2)C(=O)O)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N6-[6-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)-6-oxohexanoyl]-L-lysine (310 mg, 0.669 mmol) in DMF (20 mL) at 0° C. was added benzyl 8-[(2,5-dioxopyrrolidin-1-yl)oxy]-8-oxooctanoate (242 mg, 0.669 mmol), followed by the addition of DIPEA (0.117 ml, 0.669 mmol). The reaction was warmed to 25° C. and stirred at this temp for 18 hr. The reaction mixture was concentrated, and the residue was purified by flash chromatography on C18 reverse phase silica gel, eluting with 0-30% CAN in water, to give the title compound. UPLC Method B: m/e=710.423 [M+1]; Rt=4.59 min.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH:15]([NH2:19])([CH2:17][CH3:18])[CH3:16]>CCCCCC>[CH:15]([NH:19][SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12])([CH2:17][CH3:18])[CH3:16]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Reactant: CCC(C)N
Solvent: CCCCCC
Product: CCC(C)N[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 92 %

Procedure:
In an argon atmosphere, 5.23 g (22.4 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 30 mL of hexane and after adding 3.30 g (45.1 mmol) of sec-butylamine, the mixture was stirred at room temperature for 14 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 98° C./3.5×102 Pa) to obtain 2-sec-butylamino-1,3-di-tert-butyl-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NHsBu) as a pale yellow liquid (yielded amount: 5.56 g, yield: 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[CH3:12][N:13]1[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:18][C:15]2[CH:16]=[CH:17][N:13]([CH3:12])[N:14]=2)=[S:10])[CH:7]=1
Reactant: Cn1ccc(N)n1
Reactant: Cc1ccc(Cl)cc1N=C=S
Product: Cc1ccc(Cl)cc1NC(=S)Nc1ccn(C)n1
Yield: 94.2 %

Procedure:
Prepared using Method A from 4.73 g (27.5 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 2.5 g (25.7 mmol) of 1-methyl-3-aminopyrazole to give 6.8 g of title compound as a white solid (95% yield, m.p. 217-218° C.)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([NH2:9])=O)=[CH:3][CH:2]=1.C1([C:13]2[N:17](C)[C:16]([CH:19]=[O:20])=[CH:15]N=2)CC1>>[CH3:13][N:17]1[C:16]([CH:19]=[O:20])=[CH:15][N:9]=[C:7]1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: Cn1c(C=O)cnc1C1CC1
Reactant: NC(=O)c1ccncc1
Product: Cn1c(C=O)cnc1-c1ccncc1

Procedure:
3-Methyl-2-pyridin-4-yl-3H-imidazole-4-carbaldehyde was prepared from pyridine-4-carboxamide in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: [ClH:1].N1CCC(C2C=CC(C#N)=CC=2)CC1.[CH:16]1[N:17]=[CH:18][N:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][C:20]=12.C(C1C=CC(C2CCN(C(OC(C)(C)C)=O)CC2)=CC=1)#N>>[ClH:1].[NH:28]1[CH2:27][CH2:26][CH:25]([C:22]2[CH:23]=[CH:24][N:19]3[CH:18]=[N:17][CH:16]=[C:20]3[CH:21]=2)[CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccn3cncc3c2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: Cl
Agent: N#Cc1ccc(C2CCNCC2)cc1
Product: c1cn2cncc2cc1C1CCNCC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 1.2, except tert-butyl 4-(imidazo[1,5-a]pyridin-7-yl)piperidine-1-carboxylate (compound 39.4) was used in place of tert-butyl 4-(4-cyanophenyl)piperidine-1-carboxylate (compound 1.1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)Cl>[Br:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc(F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: Fc1cc(CBr)ccn1
Temperature: 25 °C
Yield: 21.1 %

Procedure:
A solution of 2-fluoro-4-methylpyridine (0.5 g) in chloroform (50 ml) was treated with N-bromosuccinimide (1.35 g) and azobisisobutyronitrile (0.25 g). The mixture was heated at reflux for 30 hours, cooled to room temperature and washed with water (30 ml). The chloroform solution was evaporated and the resulting brown oil purified by flash chromatography on silica eluting initially with a mixture of ethyl acetate and pentane (1:9, v/v) then with a mixture of ethyl acetate and pentane (15:85, v/v). Fractions homogenous in the required product were combined and evaporated affording the title compound (0.18 g) as a yellow oil.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6]CC)=[O:5].O.[OH-].[Na+]>CC(C)=O>[NH2:1][C@H:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CC(N)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: N[C@@H](CC(=O)O)c1ccccc1

Procedure:
9.2 mmol of the racemic compound ethyl rac-3-amino-3-phenylpropionate (1.79 g) are taken up in 50 ml of a solvent mixture composed of 25 ml of water and 25 ml of acetone as organic solvent. The solution is set to a pH of 8.2 by means of automatic pH adjustment through adding 1 M sodium hydroxide solution (obtained from Merck). On reaching a reaction temperature of 20° C., 200 mg of lipase PS (Pseudomonas cepacia; obtained through Amano Enzymes, Inc.) are added to start the reaction. After a reaction time of 3, 5 and 24 hours, the conversion rate of the (S)-3-amino-3-phenylpropionic acid formed is determined. A conversion of 1.8% after 3 hours, 2.0% after 5 hours and 5.5% after 24 hours is determined. The value of the enantioselectivity was not determined because of the unsatisfactory course of the reaction in view of the low conversion. The conversion is determined by means of HPLC.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:9])([CH3:8])[CH:5]([OH:7])[CH3:6].[Cl:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:10][C:11]1[CH:16]=[C:15]([O:7][CH:5]([CH3:6])[C:4]([CH3:9])([CH3:8])[CH3:3])[N:14]=[CH:13][N:12]=1
Reactant: CC(O)C(C)(C)C
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(Oc1cc(Cl)ncn1)C(C)(C)C
Reaction time: 0.17 h

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.11 g of sodium hydride (60% in oil), to which 0.5 ml of tetrahydrofuran containing 0.23 g of 3,3-dimethyl-2-butanol dissolved therein was added dropwise at room temperature, followed by stirring for 10 minutes. To this was added dropwise 0.5 ml of tetrahydrofuran containing 0.3 g of 4,6-dichloropyrimidine dissolved therein, followed by stirring at the same temperature for 6 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.24 g of 4-chloro-6-(1,2,2-trimethylpropyloxy)pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl.CN(C)[CH2:15][CH2:16]CN=C=N.O.ON1C2C=CC=CC=2N=N1.C(O)C>CN(C)C=O.O>[F:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][CH2:15][CH3:16])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(F)ccc1O
Reactant: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(F)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
5-Fluoro-2-hydroxybenzoic acid (344 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg), 1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 5-fluorosalicylate (191 mg, yield 28%).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[C:10]([NH2:15])[CH:11]=[C:12]([Cl:14])[CH:13]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]([NH:15][C:16](=[O:18])[CH3:17])[CH:11]=[C:12]([Cl:14])[CH:13]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
200 ml of pyridine are added dropwise to 100 g of 3,5-dichlorophenylamine in 3000 ml of chloroform, followed by addition of 90 ml of acetic anhydride. The reaction mixture is stirred for 12 hours at room temperature. The solvents are evaporated off under reduced pressure and the residue obtained is recrystallized from 1000 ml of ethyl acetate; m.p.=182° C.
Reaction SMILES: Cl[C:2]1([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:7](=[O:8])[CH2:6][CH2:5][CH2:4]C1=O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[C:20]([CH2:19][CH2:18][CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][C:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH:4]=1)([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CCCc1ccccc1CC1(Cl)C(=O)CCCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COC(=O)CCCc1ccccc1CC1=CCCC1=O
Yield: 141.2 %

Procedure:
A mixture of 10 g (0.026 mol) of 2-chloro-2-[2-(3-carbomethoxypropyl)benzyl]-1,3-cyclohexanedione, VIIIb and 18.5 g (0.175 mol) of anhydrous Na2CO3 was refluxed in 200 ml xylene for 2 hours. Filtration and evaporation gave a brown oil (10 g). Evaporative distillation at 175° C./0.2 mm gave 6 g of a pale yellow oil. This was chromatographed on silica gel and eluted with 7:3 v:v CCl4 :acetone. Like fractions were combined to give 4.1 g of the keto ester IXb as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:24])[CH:18]([C:19]([O:21][CH3:22])=[O:20])[CH:17](O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.CS(Cl)(=O)=O.N12CCCN=C1CCCCC2>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:24])[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)C1C(O)c2ccccc2OC1(C)c1ccc(Cl)c(Cl)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C1=Cc2ccccc2OC1(C)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.3 %

Procedure:
A solution of crude methyl 2-(3,4-dichlorophenyl)-4-hydroxy-2-methylchroman-3-carboxylate (100 mg, 272 μmol) in dichloromethane (2.0 mL) was stirred on an ice bath and treated with triethylamine (76 μL, 545 μmol), then dropwise with methanesulfonyl chloride (23 μL, 300 μmol). After stirring for 1.5 h, the solution was warmed to rt. After stirring at rt for 6 h, the solution was diluted with dichloromethane, washed with 1.0 M aqueous HCl, dried over sodium sulfate and concentrated under vacuum. The resulting residue was dissolved in benzene (2.0 mL), treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (55 μL, 408 μmol) and stirred at rt for 25 min. After this time, the resulting mixture was heated to 60° C. where it stirred for 5.25 h. After this time, the solution was cooled to rt, diluted with ethyl acetate, washed with water, 1.0 M aqueous HCl, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate and then concentrated under vacuum to yield a residue. The residue was purified by rotary TLC (silica gel, 92:8 hexane-ethyl acetate) to provide racemic methyl 2-(3,4-dichlorophenyl)-2-methyl-2H-chromene-3-carboxylate as a colorless gum (44 mg, 46%). 1H NMR (400 MHz, CDCl3) δ ppm 2.02 (s, 3 H) 3.73 (s, 3 H) 6.82 (d, J=8.1 Hz, 1 H) 6.92 (dt, J=7.6, 1.0 Hz, 1 H) 7.15 (dd, J=7.6, 1.5 Hz, 1 H) 7.25 (dt, J=7.9, 1.5 Hz, 1 H) 7.37 (m, 2 H) 7.58 (s, 1 H) 7.61 (t, J=1.5 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[C:10]([CH:11]=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:20]([Mg]Br)#[CH:21].C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[C:10]([CH:11]([OH:12])[C:20]#[CH:21])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2nn3c(Cl)cccc3c2C=O)c1
Reactant: C#C[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(O)c1c(-c2cccc(C)c2)nn2c(Cl)cccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 105.2 %

Procedure:
To a cold (−78° C.) suspension of 7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (10.38 g, 36.2 mmol) in tetrahydrofuran (80 mL) was added ethynylmagnesium bromide (87 mL, 0.5 M in tetrahydrofuran, 43.4 mmol) dropwise. The reaction mixture was stirred at −78° C. for 1 hour, then at 0° C. for 2 hours. The resultant solution was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and brine and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1 hexanes:ethyl acetate to 7:3 hexanes:ethyl acetate) provided 1-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (11.3 g, 77%) as a yellow foam. 1H NMR (CDCl3) δ 8.03 (d, 1H), 7.60 (s, 1H), 7.54 (d, 1H), 7.37 (t, 1H), 7.26 (d, 1H), 7.17 (dd, 1H), 6.98 (d, 1H), 2.67 (s, 1H), 2.43 (s, 3H), 2.38 (s, 1H); MS m/z297 (M+1).
Reaction SMILES: Br[C:2]1[S:6][C:5]2[C:7](=[O:17])[CH2:8][CH:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[C:4]3[CH:3]=[C:2]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:6][C:5]=3[C:7](=[O:17])[CH2:8]2)=[CH:11][CH:12]=1
Reactant: O=C1CC(c2ccc(Cl)cc2)c2cc(Br)sc21
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C1CC(c2ccc(Cl)cc2)c2cc(N3CCOCC3)sc21
Temperature: 140 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
To a 10-20 mL microwave vial was added a solution of 2-bromo-4-(4-chlorophenyl)-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one (0.150 g, 0.458 mmol) and morpholine (0.120 mL, 1.374 mmol) in anhydrous 1,4-dioxane (8.00 mL, 102.5 mmol) and degassed under nitrogen for 10 min. Cesium carbonate (0.694 g, 2.130 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.080 g, 0.137 mmol) was added followed by tris(dibenzylideneacetone)dipalladium(0) (0.042 g, 0.046 mmol). The reaction mixture was sealed and heated via microwave to 140° C. and allowed to stir for 1 hour. The reaction was cooled to ambient temperature and quenched by the addition of a solution of saturated aqueous solution of sodium bicarbonate (10.0 mL) and extracted with EtOAc (10.0 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was dry loaded onto silica gel and then purified using an ISCO (12 g cartridge, gradient hexanes to 100% EtOAc over 30 min) to afford the title compound (0.088 g, 49%) as a brown oil. LC/MS (AA) ES+ 334, 336. 1H NMR (dmso-d6, 400 MHz): δ 7.38 (d, 2H), 7.19 (d, 2H), 6.04 (s, 1H), 4.48 (dd, 1H), 3.69-3.68 (m, 4H), 3.27-3.19 (m, 6H).
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8](O)=[O:9])=[O:4].Cl.[F:38][C:39]1([F:43])[CH2:42][NH:41][CH2:40]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:38][C:39]1([F:43])[CH2:42][N:41]([C:8](=[O:9])[CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH:2]([OH:1])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:21]=[C:20]([C:22]4[O:26][N:25]=[C:24]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:23]=4[C:33]([F:35])([F:34])[F:36])[O:19][N:18]=3)=[CH:15][CH:16]=2)[CH2:40]1
Reactant: FC1(F)CNC1
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCCC(=O)N1CC(F)(F)C1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 13.1 %

Procedure:
(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Int-V, 25 mg, 0.050 mmol), 3,3-difluoroazetidine-HCl (6.45 mg, 0.050 mmol), 4-methylmorpholine (20.13 mg, 0.199 mmol), and HATU (24.60 mg, 0.065 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=10.6 min) to provide (R/S)-N-(3-(3,3-difluoroazetidin-1-yl)-3-oxopropyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (5 mg, 6.53 μmol, 13.12% yield): LCMS=578.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14-8.24 (2 H, m), 7.51-7.74 (7 H, m), 5.11 (1 H, s), 4.49 (2 H, td, J=11.77, 7.04 Hz), 4.29 (2 H, t, J=12.21 Hz), 3.45-3.58 (2 H, m), 2.38-2.52 (2 H, m); HPLC peak RT=9.4 min (Method A).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[N:18][C:17]=2[CH:34]=1.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(Cl)Cl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([CH:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]3)=[N:18][C:17]=2[CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(-n5cnnn5)cc4F)ccc3o2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cc(-n2cnnn2)ccc1-c1ccc2oc(C3CCNCC3)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl 4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate (250 mg, 0.54 mmol) dissolved in DCM (15 ml) and added Trifluoroacetic acid (1 ml). This mixture was stirred at rt for 2 h. DCM removed from the reaction mixture to obtain 5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoro acetate (260 mg). 5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (150 mg, 0.31 mmol) was dissolved in DMF (2.6 ml) and added N,N-Carbonyl diimidazole (101 mg, 0.63 mmol) and stirred at rt for 1 h. To this mixture added 2-butanol (46 mg, 0.63 mmol) and TEA (0.13 ml, 0.94 mmol) and stirred at 60° C. for overnight. Work up (EtOAc/H2O) and purification of the crude by combiflash with gradient mixture of ethyl acetate and petether (1:1) as eluent afforded the titled compound (30 mg) as an off-white solid. M.P.: 118-122° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 9.03 (s, 1H), 7.88 (s, 1H), 7.72-7.58 (m, 4H), 7.55-7.50 (m, 1H), 4.82-4.73 (m, 1H), 4.21 (d, J 12.7, 2H), 3.24-3.13 (m, 1H), 3.06 (t, J 11.6, 2H), 2.19 (d, J 10.9, 2H), 2.00-1.88 (m, 2H), 1.69-1.50 (m, 2H), 1.24 (d, J 6.2, 3H), 0.92 (t, J 7.4, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:11][C:12]([NH:14][CH3:15])=O)[CH:8]=2)[CH:3]=[CH:2]1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:11][CH2:12][NH:14][CH3:15])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CNC(=O)CC(c1cccc(Cl)c1)c1ccc2cc[nH]c2c1
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNCCC(c1cccc(Cl)c1)c1ccc2cc[nH]c2c1

Procedure:
[3-(1H-Indol-6-yl)-3-(3-chloro-phenyl)-propyl]-methyl-amine XLII was prepared as a hydrochloride salt (190 mg, 83% yield) from 3-(1H-indol-6-yl)-3-(3-chloro-phenyl)-N-methyl-propionamide, using the procedure described above for [3-(1H-indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (see Example 4). MS (M+H)=299.