Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:37]=[CH:36][C:11]([CH2:12][NH:13][C:14](=[O:35])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][C:23]4[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][C:27]([C:33]#[N:34])=[CH:26][C:24]=4[N:25]=3)=[CH:17][CH:16]=2)=[CH:10][CH:9]=1.[F:38][C:39]([F:52])([F:51])[C:40]1[CH:45]=[CH:44][C:43]([CH:46]2[CH2:50][CH2:49][NH:48][CH2:47]2)=[CH:42][CH:41]=1.CC(C)=O>C1(C)C=CC=CC=1>[C:33]([C:27]1[CH:28]=[C:29]([CH:30]([CH3:32])[CH3:31])[C:23]2[O:22][C:21]([C:18]3[CH:19]=[CH:20][C:15]([C:14]([NH:13][CH2:12][C:11]4[CH:36]=[CH:37][C:8]([N:48]5[CH2:49][CH2:50][CH:46]([C:43]6[CH:44]=[CH:45][C:40]([C:39]([F:38])([F:51])[F:52])=[CH:41][CH:42]=6)[CH2:47]5)=[CH:9][CH:10]=4)=[O:35])=[CH:16][CH:17]=3)=[N:25][C:24]=2[CH:26]=1)#[N:34]
Reactant: FC(F)(F)c1ccc(C2CCNC2)cc1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCc4ccc(Br)cc4)cc3)oc12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCc4ccc(N5CCC(c6ccc(C(F)(F)F)cc6)C5)cc4)cc3)oc12
Temperature: 150 °C
Yield: 52 %

Procedure:
Sodium tert-butoxide (10 mg), N-(4-bromobenzyl)-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzamide (24 mg, EXAMPLE 1), and 3-[4-(trifluoromethyl)phenyl]pyrrolidine (31 mg) were dissolved in toluene (5.0 mL). To this mixture was added bispalladiumtribenzylidene acetone (10 mg) and 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine) (12 mg). The mixture was heated to 150° C. for 25 min in a microwave reactor. Upon cooling, the mixture was then concentrated in vacuo, taken up in dichloromethane, and purified via flash chromatography on a Biotage Horizon, 40 M column, eluting with 1 column volume of 100% hexanes, followed by a linear gradient of ethyl acetate in hexanes from 0 to 100% over 10 column volumes, followed by 4 column volumes of 100% ethyl acetate to provide the title compound (16 mg, 53%). Mass spectrum (ESI) 609.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.31 (d, J=8.5 Hz, 2H), 7.95 (d, J=8.5 Hz, 2H), 7.94 (s, 1H), 7.59 (d, J=8.0 Hz, 2H), 7.51 (s, 1H), 7.39 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 6.60 (d, J=8.4 Hz, 2H), 6.33 (t, J=4.0 Hz, 1H), 4.59 (d, J=5.3 Hz, 2H), 3.75 (t, J=8.4 Hz, 1H), 3.57 (m, 5H), 2.47 (m, 1H), 2.15 (m, 1H), 1.46 (d, J=6.9, 6H).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([CH2:10][Cl:11])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C>[ClH:11].[C:1]([C:5]1[O:9][C:8]([CH2:10][S:14][C:13]([NH2:15])=[NH2+:12])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cnc(CCl)o1
Reactant: NC(N)=S
Solvent: CCO
Product: CC(C)(C)c1cnc(CSC(N)=[NH2+])o1
Product: Cl
Temperature: 25 °C
Yield: 92.7 %

Procedure:
The title compound of Example 6 (1.77 g, 10.2 mmol, 1.02 eq) was combined with thiourea (0.76 g, 9.98 mmol, 1 eq) under N2 in 10 mL of absolute ethanol. The reaction was heated at reflux for 1.5 hours. The mixture was cooled to room temperature and concentrated in vacuo. Trituration of the resulting crude material with t-butyl methyl ether provided 2.32 g (93%) of the title compound. HPLC R.T.=2.05 min (Phenomenex Inc., 5 μm C18 column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm); 1H NMR (d6-DMSO): δ 9.48 (s, 3H), 6.85 (s, 1H), 4.73 (s, 2H), 1.24 (s, 9H).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[C:8]([CH2:12]O)=[CH:9][S:10][CH:11]=1>C(Cl)Cl>[Br:2][CH2:12][C:8]1[C:7]([O:6][CH3:5])=[CH:11][S:10][CH:9]=1
Reactant: BrP(Br)Br
Reactant: COc1cscc1CO
Solvent: ClCCl
Product: COc1cscc1CBr
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 96.6 %

Procedure:
To a solution of phosphorous tribromide (271 mg, 1.00 mmol) in CH2Cl2 (1.5 mL) cooled to 0° C. was added a solution of the above alcohol (144 mg, 1.00 mmol) in CH2Cl2 (1.5 mL) and the solution was stirred at 0° C. for 5 minutes to give 3-bromomethyl-4-methoxy-thiophene as an oil (200 mg, 97%) after work-up.
Reaction SMILES: C(O[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=2)[NH:8][C:7]=1[NH2:17])=[O:5])C.[CH:18]([O-])=O.[NH4+:21]>C(N)=O>[OH:5][C:4]1[C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=3)[NH:8][C:7]=2[N:17]=[CH:18][N:21]=1
Reactant: CCOC(=O)c1c(N)[nH]c2cc(C#N)ccc12
Reactant: O=C[O-]
Reactant: [NH4+]
Solvent: NC=O
Product: N#Cc1ccc2c(c1)[nH]c1ncnc(O)c12
Temperature: 25 °C
Yield: 42.8 %

Procedure:
A solution of 2-amino-6-cyano-1H-indole-3-carboxylic acid ethyl ester (750 mg, 3.3 mmol) and ammonium formate (193 mg, 3.3 mmol) in 4 mL formamide was heated to 175° C. overnight. The reaction mixture was allowed to cool to room temperature then poured onto water. The resulting precipitate was collected by filtration to give 297 mg of the title compound as a black solid. 1H NMR (DMSO) δ 12.7 (1H, s, br), 12.5 (1H, s, br), 8.23 (1H, d, J=4), 8.10 (1H, d, J=8.1), 7.93 (1H, s), 7.61 (1H, dd, J=8.1, 1.4); LC-MS (1) Rt 1.12 min; m/z (ES−) 209.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C.[NH2:38][C@@H:39]([C:41]([OH:43])=[O:42])[CH3:40]>ClCCl.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:16]=[CH:15][C:13]([NH:14][C:18]([NH:38][C@@H:39]([C:41]([OH:43])=[O:42])[CH3:40])=[O:20])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[C@@H](N)C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(Oc2ccc(F)c(Cl)c2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H](NC(=O)Nc1ccc(Oc2ccc(F)c(Cl)c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 302.4 %

Procedure:
To a solution of 4-[(3-chloro-4-fluorophenyl)oxy]aniline (Intermediate 8, 237 mg) and triphosgene (99 mg, 0.33 mmol) in 15 mL of dichloromethane was added DIPEA (155 mg, 1.2 mmol) and the mixture was stirred at room temperature for 2 hours. Then the solvent was evaporated to give a residue. The residue was dissolved in 5 mL of THF and was transferred to a mixture of DIPEA (65 mg, 0.5 mmol, Acros) and D-Alanine (89 mg, 1 mmol) in 5 mL of THF. The whole reaction mixture was stirred at room temperature for 16 hours. Removal of the solvent afforded the title compound (352 mg) which was directly used in the next step.
Reaction SMILES: O.[NH2:2][NH2:3].C([O:8][CH2:9][CH3:10])(=O)CO.[CH2:11]([N:13]=[C:14]=[S:15])[CH3:12].[OH-].[Na+].Cl>C(O)C>[CH2:11]([N:13]1[C:14]([SH:15])=[N:3][N:2]=[C:10]1[CH2:9][OH:8])[CH3:12]
Reactant: NN
Reactant: CCOC(=O)CO
Reactant: CCN=C=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCn1c(S)nnc1CO
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.6 %

Procedure:
To a solution of hydrazine monohydrate (10.0 g) in ethanol (100 ml), ethyl glycolate (20.8 g) was slowly added dropwise with keeping the reaction temperature under 10° C. at room temperature. The mixture was stirred for 5 hours at room temperature, and ethyl isothiocyanate (17.42 g) was slowly added dropwise to the mixture with keeping the reaction temperature under 10° C. The mixture was stirred for 18 hours at 40° C., cooled to room temperature, and ice-water (50 ml) was added to the mixture. The mixture was stirred for 15 miuntes, 5N aqueous solution of sodium hydroxide (40 ml) was added to the mixture, and the mixture was stirred for 4 hours at 60° C. Concentrated hydrochloric acid was added dropwise to the solution at 0° C. to adjust pH to 6, and the precipitated crystals were removed by filtration. The mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with water, to give 4-ethyl-3-hydroxymethyl-5-mercapto-4H-1,2,4-triazole (7.5 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:7][CH2:6][C:3]2([C:2]([F:9])([F:8])[F:1])[CH2:5][CH2:4]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: OCC1(C(F)(F)F)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
Treat a solution of (1-(trifluoromethyl)cyclopropyl)methanol (7 g, 50 mmol) and p-toluenesulfonyl chloride (10.4 g, 55 mmol) in DCM (100 mL) with TEA (10 g, 100 mmol) and 4-dimethylaminopyridine (DMAP) (0.6 g, 5 mmol) and stir at RT overnight. Wash successively with 2 M HCl, satd. NaHCO3, and brine, dry over Na2SO4 and concentrate to give the title compound (12 g, 81%). 1H NMR (400 MHz, DMSO-d6): δ 7.79 (d, J=8.0 Hz, 2H), 7.50 (d, J=8.0 Hz, 2H), 4.13 (s, 2H), 2.43 (s, 3H), 1.08-1.05 (m, 2H), 0.96-0.94 (m, 2H).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[O:13]([CH2:20][C:21]([NH:23][CH:24]1[C:55](=[O:56])[N:26]2[C:27]([C:39]([O:41][CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])=[C:28](OS(C(F)(F)F)(=O)=O)[CH2:29][S:30][C@H:25]12)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[O:13]([CH2:20][C:21]([NH:23][CH:24]1[C:55](=[O:56])[N:26]2[C:27]([C:39]([O:41][CH:42]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)=[O:40])=[C:28]([S:1][C:2]3[S:3][C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=3)[CH2:29][S:30][C@H:25]12)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Sc1nc2ccccc2s1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(=O)(=O)C(F)(F)F)CS[C@H]12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3nc4ccccc4s3)CS[C@H]12
Temperature: -20 °C
Reaction time: 16 h

Procedure:
To a solution of 2-mercaptobenzothiazole (0.26 g. 1.54 mmol) in dry tetrahydrofuran (5.0 ml) at -78° C. was added sodium hydride (98%) (0.0369 g. 1.54 mmol). followed by diphenylmethyl 7-phenoxyacetamido-3-(trifluoromethylsulfonyloxy)-3-cephem-4-carboxylate (1.0 gm, 1.54 mmol). The reaction was warmed up to -20° C. and stirred for 16 hours before quenching in 0.5 N solution of hydrochloric acid (5 ml). The aqueous layer was extracted with dichloromethane (3×5 ml), dried (magnesium sulfate) and evaporated in vacuo to give the title compound as an oil which was purified by flash chromatography (silica, 40% ethylacetate in haxanes); yield isolated 0.7 g (70%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.C(N(CC)CC)C.ClC(Cl)(O[C:23](=[O:29])OC(Cl)(Cl)Cl)Cl.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>C(Cl)Cl>[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]1[CH2:43][CH2:42][N:41]([C:23]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[S:9][C:8]([CH3:10])=[N:7][C:6]=3[CH:11]=2)=[O:29])[CH2:40][CH2:39]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Cc1nc2cc(N)ccc2s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2cc(NC(=O)N3CCN(c4ccccc4F)CC3)ccc2s1
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a stirred solution of 5-amino-2-methylbenzothiazole (100 mg, 0.61 mmol) and triethylamine (170 ul, 1.22 mmol) in DCM (5 ml) at 0° C. under an argon atmosphere was added triphosgene (60 mg, 0.2 mmol). The mixture was warmed to room temp. and stirred for 1 h. 4-(2-Fluorophenyl)piperazine (110 mg, 0.61 mmol) was added and the reaction was stirred at room temp. overnight. The solvent was removed in vacuo and the residue purified by chromatography eluting with a 0-100% EtOAc/petroleum ether gradient to give the title compound as a pale yellow solid (69 mg). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.82 (d, 1H), 7.71 (d, 1H), 7.53 (dd, 1H), 6.92-7.10 (m, 4H), 6.65 (s, 1H), 3.69 (m, 2H), 3.13 (m, 2H), 2.81 (s, 3H). MS(ES): MH+ 371, M−H+ 369.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[CH:26][S:27][CH:28]=3)=[C:18]([Cl:29])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:30][C@@H:31]1[CH2:36][CH2:35][O:34][C:32]1=[O:33]>>[Cl:29][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][CH2:3][CH2:2][NH:1][C:32](=[O:33])[C@H:31]([OH:30])[CH2:36][CH2:35][OH:34])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[N:25]=[CH:26][S:27][CH:28]=1
Reactant: NCCOc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12
Reactant: O=C1OCC[C@H]1O
Product: O=C(NCCOc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12)[C@H](O)CCO
Yield: 69 %

Procedure:
The procedure described in Example 63 was repeated using 5-(2-aminoethoxy)-N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]quinazolin-4-amine and (R)-(+)-α-hydroxy-γ-butyrolactone to give the title compound in 69% yield; NMR spectrum (DMSO-d6 400 MHz) 1.44-1.55 (m, 1H), 1.73-1.85 (m, 1H), 3.41-3.52 (m, 2H), 3.65-3.77 (m, 2H), 3.93-4.02 (m, 1H), 4.31-4.48 (m, 3H), 5.38 (s, 2H), 5.50 (d, 1H), 7.17 (d, 1H), 7.33 (t, 2H), (7.60 (dd, 1H), 7.74 (t, 1H), 7.83 (s, 1H), 8.02 (s, 1H), 8.20 (t, 1H), 8.48 (s, 1H), 9.17 (s, 1H), 9.85 (s, 1H); Mass spectrum MH+ 529.9.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:8]2[CH2:15][C:14](=[O:16])[NH:13][C:9]=2[N:10]=[CH:11][N:12]=1.CN(C)CCN(C)C.Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:28]=1[CH2:36]Br>>[Cl:6][C:7]1[C:8]2[C:15]3([CH2:36][C:28]4[C:27](=[CH:32][CH:31]=[C:30]([N+:33]([O-:35])=[O:34])[CH:29]=4)[CH2:26]3)[C:14](=[O:16])[NH:13][C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Product: O=C1Nc2ncnc(Cl)c2C12Cc1ccc([N+](=O)[O-])cc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Butyllithium (2.5 M in hexanes, 0.29 ml, 0.74 mmol) was added to a stirred solution of 4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one from Step B (50 mg, 0.295 mmol) at −78° C. in THY (30 mL). After complete addition of butyllithium, N,N,N′,N′-tetramethylethane-1,2-diamine (0.31 mL, 0.77 mmol) was added. After 1 h at −78° C., 1,2-bis(bromomethyl)-4-nitrobenzene (91 mg, 0.295 mmol, described in Intermediate 2) was added and the reaction warmed to ambient temperature. After 8 h, the reaction was quenched with H2O and the mixture was partitioned between EtOAc and H2O. The aqueous solution was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=317 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:22]([O-])=O)=[C:7]([CH:21]=1)[NH:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]2[N:14]=[C:15]([S:17][CH3:18])[O:16][C:12]=2[CH:11]=1.CC(O)=O.CO>C(Cl)Cl.[Zn]>[CH3:1][O:2][C:3]1[CH:21]=[C:7]([NH:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]3[N:14]=[C:15]([S:17][CH3:18])[O:16][C:12]=3[CH:11]=2)[C:6]([NH2:22])=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(NCc2ccc3nc(SC)oc3c2)c1
Agent: [Zn]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(N)c(NCc2ccc3nc(SC)oc3c2)c1
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a stirred solution of 5-methoxy-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline (1.05 g, 3.05 mmol), HOAc (3.6 mL) and methanol (3.6 mL) in DCM (40 mL) at 0° C. was added zinc dust (1.98 g, 30.5 mmol) portionwise. After stirring for 2 h, the mixture was filtered. The filtrate was washed with aq NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure to give 5-methoxy-N1-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamine as a light yellow solid (920 mg, 95.7%). 1H NMR (300 MHz, DMSO-d6) δ 7.55-7.60 (m, 2H), 7.35 (d, J=7.8 Hz, 1H), 6.47 (d, J=8.1 Hz, 1H), 5.93-5.99 (m, 2H), 5.32 (t, 1H), 4.38 (d, J=5.7 Hz, 2H), 4.13 (s, 2H), 3.50 (s, 3H), 2.74 (s, 3H). LCMS (ESI) m/z 316 (M+H)+.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH3:5].C([Li])CCC.[CH3:11][C:12]([CH3:23])([CH2:21][F:22])[C:13](=[O:20])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1>O1CCCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3]>[CH3:11][C:12]([CH3:23])([C:13]([OH:20])([C:1]#[C:2][CH2:3][CH2:4][CH3:5])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[CH2:21][F:22]
Reactant: C#CCCC
Reactant: CC(C)(CF)C(=O)Cn1cncn1
Agent: Cl[Ti+3]
Agent: CC(C)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC#CC(O)(Cn1cncn1)C(C)(C)CF
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.2 %

Procedure:
To a stirred solution of pent-1-yne (1.5 g, 22 mmol) in dry tetrahydrofuran (40 ml) was added n-butyl lithium (9 ml of 2.6M, 23 mmol) at -78° C. under a nitrogen atmosphere followed by chlorotitanium tri-isopropoxide (22 ml of 1M, 20 mmol). After 15 minutes, a solution of 3,3-dimethyl-4-fluoro-1-(1,2,4-triazol-1-yl)butan-2-one (prepared as in DE 2,820,361) (4.0 g, 22 mmol) in dry tetrahydrofuran (20 ml) was added dropwise. Upon complete addition the mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was then poured onto ice and extracted with ether (2×250 ml). The ethereal solution was washed with saturated brine solution then dried over anhydrous magnesium sulphate and the solvent removed. The resulting yellow oil was chromatographed (silica gel, petrol/diethyl ether elution) to give a yellow gum (2.8 g).
Reaction SMILES: C([Li])CCC.C1(C)C=CC(S([CH:15]([N+:23]#[C-:24])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)(=O)=O)=CC=1.[Br-].[Li+].[N:28]1[CH:33]=[CH:32][C:31]([CH:34]=[CH:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:30][CH:29]=1>CCCCCC.O1CCCC1>[CH2:39]([O:38][C:36]([C:35]1[C:34]([C:31]2[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=2)=[C:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[NH:23][CH:24]=1)=[O:37])[CH3:40]
Reactant: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C=Cc1ccncc1
Agent: [Br-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
36 ml (54.7 mmol) of a 1.53 N solution of butyllithium in hexane were added to 240 ml of tetrahydrofuran. A solution of 15.90 g (54.7 mmol) of α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile in 120 ml of tetrahydrofuran was then added to the resulting solution at −45° C., followed by stirring of the resulting mixture for 10 minutes at the same temperature. At the end of this time, 25.00 g (273 mmol) of 95% lithium bromide were added, the resulting mixture was stirred for 30 minutes and then a solution of 8.73 g (49.2 mmol) of ethyl 3-(4-pyridyl)acrylate in 120 ml of tetrahydrofuran was added. The resulting mixture was stirred at the same temperature for 1 hour and then the cooling bath was removed and the mixture was stirred at room temperature for a further 1 hour. At the end of this time, 500 ml of water were added and the resulting mixture was extracted with ethyl acetate. The organic extract was washed with water and then dried over anhydrous sodium sulfate, after which it was concentrated by evaporation under reduced pressure to afford a solid. The solid was washed with diethyl ether to give 13.61 g (yield 89%) of the title compound as a pale yellow powder.
Reaction SMILES: C[C:2]1[C:3]([OH:16])=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:7]=1.C(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:25](O)C.Cl>O.CCOCC>[CH3:25][C:9](=[CH:10][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:8]([C:6]1[CH:7]=[CH:2][C:3]([OH:16])=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=1)=[O:11]
Reactant: CCC(=O)c1cc(C)c(O)c(CC(=O)O)c1
Reactant: O=Cc1ccccc1
Reactant: CCO
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CC(=Cc1ccccc1)C(=O)c1ccc(O)c(CC(=O)O)c1

Procedure:
11 g of methyl 5-propanoyl-2-hydroxy-benzeneacetic acid, 10,6 g of benzaldehyde, 150 ml of ethanol and 50 ml of ether saturated with hydrogen chloride are refluxed for 5 days. The solution is poured on to water and extracted with ethyl acetate. The ethyl acetate is evaporated and the residue is hydrolyzed in sodium hydroxide solution. The pH is adjusted to 7 and the solution is washed with ethyl acetate. The aqueous phase is acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate is evaporated, the residue is leached with dichloroethane and recrystallized from 2-butanone/1,2-dichloroethane. NMR spectrum and elemental analysis data are consistent with the structure of the title compound. Melting point 192° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][N:26]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][N:26]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccc(-c4ccccc4)cn3)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCc3ccc(-c4ccccc4)cn3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[4-(5-phenyl-2-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (700 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(5-phenyl-2-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (620 mg, yield: 94%). This was recrystallized from acetone-hexane. Melting point: 127–128° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[N:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]>C(O)(C)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)[CH2:27][C:28]([OH:33])([C:29]([F:32])([F:31])[F:30])[N:20]=2)[N:3]=1
Reactant: Cc1cccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)n1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1cccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)n1
Yield: 20.7 %

Procedure:
To a mixture of the amidine of Step 1 (4.9 g, 16.95 mmol) and sodium bicarbonate (2.85 g, 33.9 mmol) in isopropanol (300 ml), 3-bromo-1,1,1-trifluoroacetone (2.65 ml, 25.4 mmol) was added. After heating at 80–85° C. for 24 hours, the reaction mixture was cooled and filtered. The residue was washed with methylene chloride and the combined organic fractions were dried over sodium sulfate, filtered and concentrated. The crude mixture (9 g) was purified by chromatography (silica gel, ethyl acetate/isopropanol/ammonium hydroxide 95/5/0.5) to give 2-methyl-6-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine (1.4 g, 21%) as a white solid: Anal. Calc'd. for C17H16N3SO3F3: C, 51.12; H, 4.02; N, 10.52. Found: C, 51.43; H, 3.96; N, 10.06.