Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([NH:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[N:19]=[C:6]2[N:5]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:4]=1[CH3:39])#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])[N:19]=[C:6]2[N:5]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH:30]=2)[C:4]=1[CH3:39])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NCC(=O)OC(C)(C)C)nc2N1c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NCC(=O)O)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 0.75 h

Procedure:
Under an atmosphere of argon protective gas, tert-butyl N-{(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}glycinate (18.0 mg, 34 μmol) was dissolved in dry dichloromethane (3.1 ml). At room temperature, trifluoroacetic acid (1.6 ml) was added, and the mixture was stirred for 45 min. More trifluoroacetic acid (2 ml) was then added, and the mixture was stirred for a further 30 min. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (15.2 mg, 94% of theory).
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:10]1([OH:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.[OH-].[K+]>CCOCC>[C:10]1([O:20][CH2:6][CH:7]([OH:9])[CH2:8][NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cccc2ccccc12
Reactant: CC(C)(C)N1CC(O)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)(C)NCC(O)COc1cccc2ccccc12
Temperature: 160 °C

Procedure:
To a mixture of 6.5 parts of 1-(tert.-butyl)-3-azetidinol and 7.9 parts of α-naphthol 0.2 part of potassium hydroxide was added, and the mixture was heated at 160° C. for 24 hours. The reaction mixture was cooled and then dissolved in 100 parts of ether. The solution was washed twice with 50 parts of 2 N-sodium hydroxide aqueous solution and extracted three times with 50 parts of 2 N-hydrochloric acid aqueous solution. The extract was washed with 50 parts of ether and made alkaline by addition of 2 N-sodium hydroxide aqueous solution. Extraction was conducted three times with 50 parts of benzene, and the extract was dried over anhydrous sodium sulfate. Then benzene was distilled off and the residue was solidified by drying under reduced pressure. The solid residue was subjected to distillation under reduced pressure. As a result, 5 parts of 1-(α-naphthoxy)-3-(tert.-butylamino)-2-propanol boiling at 175°-180° C. under 1.5 mm Hg were obtained. A part of the product was dissolved in 5 parts of anhydrous ether and the product was converted to a hydrochloride by adding a hydrochloric acid gas to the resulting ether solution. The hydrochloride was recrystallized twice from a mixed solvent of ethyl acetate and ether. As a result, 1-(α-naphthoxy)-3-(tert.-butylamino)-2-propanol hydrochloride having a melting point of 182°-184° C. was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:8]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1>>[CH3:22][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:24]3[C:33]4[C:28](=[CH:29][C:30]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]=[CH:26][N:25]=3)=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:8]=1
Reactant: COc1cc(O)ccc1CC(=O)Nc1ccc(N(C)C)cn1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Product: COCCOc1cc2ncnc(Oc3ccc(CC(=O)Nc4ccc(N(C)C)cn4)c(OC)c3)c2cc1OC
Yield: 74 %

Procedure:
Using an analogous procedure to that described in Example 15, N-(5-dimethylaminopyridin-2-yl)-2-(4-hydroxy-2-methoxyphenyl)acetamide was reacted with 4-chloro-7-(2-methoxyethoxy)-6-methoxyquinazoline. There was thus obtained the title compound in 74% yield; 1H NMR: (CDCl3) 2.93 (s, 6H), 3.5 (s, 3H), 3.75 (s, 2H), 3.88-3.93 (m, 2H), 3.91 (s, 3H), 4.05 (s, 3H), 4.32-4.38 (m, 2H), 6.86 (s, 1H), 6.87 (m, 1H), 7.10 (m, 1H), 7.33 (s, 1H), 7.4 (d, 1H), 7.53 (d, 1H), 7.73 (d, 1H), 8.09 (d, 1H), 8.18 (br s, 1H), 8.63 (s, 1H); Mass Spectrum: M+H+ 534.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[OH:18].[H-].[Na+].Br[CH2:22][CH2:23][OH:24]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[O:18][CH2:22][CH2:23][OH:24]
Reactant: CCc1ccc(Cc2cc(Br)c(O)cc2Cl)cc1
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc(Cc2cc(Br)c(OCCO)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a solution of 2-bromo-5-chloro-4-(4-ethylbenzyl)phenol (AT) (3.26 g, 10 mmol) in anhydrous DMF (15 mL), NaH (0.72 g, 30 mmol) was added in portions. The reaction mixture was stirred for 2 h at room temperature, and then 2-bromoethanol (3.75 g, 30 mmol) was added dropwise, and the reaction mixture was heated to 45° C. overnight. TLC showed the reaction was complete. The reaction was quenched with the saturated NH4Cl, the mixture was extracted with EtOAc, and then washed with water and brine. After drying with anhydrous Na2SO4 the organic portion was filtered and concentrated. The residue was purified by flash chromatography to give AU as an oil (3.00 g, yield 81%). 1H-NMR (CDCl3, 300 MHz) δ 7.32 (s, 1H), 7.13 (m, 4H), 6.94 (s, 1H), 4.11 (m, 2H), 3.57-3.99 (m, 4H), 2.64 (q, J=7.5 Hz, 2H), 1.22 (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@H:13]([C:15]3[O:22][NH:29][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(F)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 52.6 %

Procedure:
Trans-methyl 2-(3,4-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (502 mg, 1.36 mmol) (from example 23, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. Sodium hydroxide (0.358 mL, 1.36 mmol) dissolved in water (0.500 mL) was added and the reaction stirred at −40° C. for 20 min. Hydroxylamine (0.083 mL, 1.36 mmol) was added and stirring continued for 3.5 h at −40° C. The reaction mixture was then added to a prewarmed 80° C. solution of hydrogen chloride (7.02 mL, 42.13 mmol) and stirred for 20 min. The solvent was evaporated in vacuo. DCM (50 mL) and water (50 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (50 mL). The combined organic phase were dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 20-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Trans-methyl 2-(3,4-difluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (242 mg, 52.6%) was isolated as a white solid. 1H NMR (600 MHz, CDCl3) δ 1.60-1.72 (m, 1H), 1.94 (d, 1H), 1.98-2.07 (m, 1H), 2.60 (d, 1H), 2.78-2.94 (m, 2H), 3.77 (s, 3H), 4.25 (s, 1H), 5.51-5.71 (m, 2H), 6.94-6.99 (m, 1H), 7.02-7.09 (m, 1H), 7.17 (dd, 1H). MS m/z 337 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]3[B:11]([OH:14])[O:12][CH2:13][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[OH:14][B:11]1[C:10]2[CH:15]=[CH:16][C:7]([O:6][C:5]3[CH:17]=[CH:18][C:2]([NH:1][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:3][CH:4]=3)=[CH:8][C:9]=2[CH2:13][O:12]1
Reactant: Nc1ccc(Oc2ccc3c(c2)COB3O)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 20 mL scintillation vial containing 5-(4-amino-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (50 mg, 0.21 mmol, 1.0 eq.) in DCM (3.0 mL) was added Et3N (35 μL, 0.25 mmol, 1.2 eq.), followed by methanesulfonyl chloride (18 μL, 0.31 mmol, 1.1 eq.). The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenyl]-methanesulfonamide as a white solid. LCMS (m/z) 342 (M+23); 1H NMR (DMSO-d6) δ: 9.72 (s, 1H), 7.65-7.79 (m, 1H), 7.21-7.26 (m, 2H), 7.01-7.05 (m, 2H), 6.91-6.94 (m, 1H), 6.89-6.91 (m, 1H), 4.88 (s, 2H), 2.94 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[C:32]([NH2:38])=[C:31]([CH3:39])[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:38][C:32]1[C:33]([N+:35]([O-:37])=[O:36])=[CH:34][C:29]([O:28][C:24]2[N:25]=[CH:26][N:27]=[C:22]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:23]=2)=[CH:30][C:31]=1[CH3:39]
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc([N+](=O)[O-])c1N
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c(N)c([N+](=O)[O-])c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
496 mg (1.80 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 480 mg (1.71 mmol) 4-(6-chloro-pyrimidin-4-yloxy)-2-methyl-6-nitro-phenylamine and 0.697 mL (4.00 mmol) DIPEA were combined in 10.0 mL DMF and stirred overnight at RT. The reaction mixture was added to ice water, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[N:24][CH:25]=2)(=[O:19])=[O:18])[CH:5]=[CH:6][C:7]=1B1OC(C)(C)C(C)(C)O1.Cl[C:28]1[N:33]=[CH:32][C:31]([C:34]([OH:43])([C:39]([F:42])([F:41])[F:40])[C:35]([F:38])([F:37])[F:36])=[CH:30][N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[NH2:26][C:23]1[N:24]=[CH:25][C:20]([S:17]([C:4]2[CH:5]=[CH:6][C:7]([C:28]3[N:29]=[CH:30][C:31]([C:34]([OH:43])([C:35]([F:36])([F:37])[F:38])[C:39]([F:41])([F:42])[F:40])=[CH:32][N:33]=3)=[C:2]([CH3:1])[CH:3]=2)(=[O:18])=[O:19])=[CH:21][CH:22]=1
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(S(=O)(=O)c2ccc(N)nc2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(S(=O)(=O)c2ccc(N)nc2)ccc1-c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Temperature: 100 °C
Yield: 25.3 %

Procedure:
A glass microwave reaction vessel was charged with 5-((3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-2-pyridinamine (278 mg, 0.74 mmol), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (139 mg, 0.49 mmol, Intermediate D), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (20 mg, 0.025 mmol, Strem Chemical Inc, Newburyport, Mass.), cesium carbonate (484 mg, 1.49 mmol, Sigma-Aldrich, St. Louis, Mo.), DME (1.2 mL), and water (0.1 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 45 min. The organic layer was taken and the solvent was removed under vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of DCM to 2% 2M NH3.MeOH in DCM, to provide 2-(2-(4-((6-amino-3-pyridinyl)sulfonyl)-2-methylphenyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (61 mg) as an off-white solid.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.Br[C:31]1[N:32]=[C:33]([CH2:56][CH3:57])[C:34]([NH:39][C@H:40]2[C@@H:44]([OH:45])[CH2:43][N:42]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:41]2)=[N:35][C:36]=1[CH2:37][CH3:38].[Cl:58][C:59]1[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=1B(O)O>>[Cl:58][C:59]1[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=1[C:31]1[N:32]=[C:33]([CH2:56][CH3:57])[C:34]([NH:39][C@H:40]2[C@@H:44]([OH:45])[CH2:43][N:42]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:41]2)=[N:35][C:36]=1[CH2:37][CH3:38]
Reactant: CCc1nc(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2O)c(CC)nc1Br
Reactant: COc1ccc(B(O)O)c(Cl)c1
Agent: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting benzyl(3R,4S)-3-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate and 2-chloro-4-methoxy phenyl boronic acid, and making non-critical variations provided the title compound as a oil: 1H NMR (DMSO-d6) δ) 1.06, 2.35, 2.67, 3.51, 3.57, 3.62, 3.82, 4.35, 4.46, 5.08, 5.42, 5.95, 6.98, 7.11, 7.24, 7.38; IR (diffuse reflectance) 2968, 2351 (w), 2339 (w), 2063 (w), 1951 (w), 1700 (s,b), 1681 (s), 1568 (s), 1482 (s), 1428 (s,b), 1422 (s), 1397, 1359 (s), 1287, 1229, cm−1 HRMS (FAB) calcd for C27H31ClN4O4+H 511.2112, found 511.2115.
Reaction SMILES: [C:1]([C:3]1([C:6]([OH:8])=O)[CH2:5][CH2:4]1)#[N:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:43]([O:45][C:46]1[CH:51]=[CH:50][C:49]([CH:52]2[CH2:57][CH2:56][N:55]([C:58]3[CH:63]=[CH:62][C:61]([C@@H:64]([NH2:66])[CH3:65])=[CH:60][CH:59]=3)[CH2:54][CH2:53]2)=[CH:48][CH:47]=1)[CH3:44]>CN(C=O)C>[CH2:43]([O:45][C:46]1[CH:47]=[CH:48][C:49]([CH:52]2[CH2:53][CH2:54][N:55]([C:58]3[CH:59]=[CH:60][C:61]([C@@H:64]([NH:66][C:6]([C:3]4([C:1]#[N:2])[CH2:5][CH2:4]4)=[O:8])[CH3:65])=[CH:62][CH:63]=3)[CH2:56][CH2:57]2)=[CH:50][CH:51]=1)[CH3:44]
Reactant: N#CC1(C(=O)O)CC1
Reactant: CCOc1ccc(C2CCN(c3ccc([C@H](C)N)cc3)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc(C2CCN(c3ccc([C@H](C)NC(=O)C4(C#N)CC4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 14 mg (0.13 mmol) 1-cyano-cyclopropanecarboxylic acid in 1 mL DMF are added 52 μL (0.30 mmol) DIPEA and 49 mg (0.13 mmol) HATU. The mixture is stirred for 10 min at rt. Subsequently a mixture of 36 mg (0.10 mmol) (S)-1-{4-[4-(4-ethoxy-phenyl)-piperidin-1-yl]-phenyl}-ethylamine hydrochloride (XII.1) in 1 mL DMF is added and stirring is continued for 6 h at rt. The crude mixture is directly purified by HPLC (Sunfire, narrow gradients, water (+0.1% TFA)/methanol) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:25])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:16](=[O:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Cl)c1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)Oc1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
To a solution of 3-chlorophenol (1, 50.1 g, 0.3 mol), triethylamine (TEA, 85 mL), and CH2Cl2 (500 mL) at 23° C. was added hydrocinnamoyl chloride (2, 31 mL, 0.3 mol) over 5 minutes. After 30 minutes, the reaction mixture was concentrated in vacuo. The crude slurry was then dissolved in 10:1 hexanes:EtOAc (300 mL) and washed with 1 N NaOH (100 mL) and brine (100 mL). The organic layer was dried (MgSO4) and filtered through a plug of silica gel (10:1 hexanes:EtOAc rinse). The eluent was concentrated to afford 78 g of a slightly yellow oil, which was used without any further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][CH:4]=1)=[O:2].[CH:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CCCCCCC.CCOC(C)=O>[C:20]([C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][CH:7]=1)#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C=O)cc2)cc1
Reactant: C#CCCCCC
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCCC#Cc1ccc(C=O)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-formyl-phenyl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 9:1; yield (60 mg, 70%); 1H NMR δ (CDCl3): 10.02 (s, 1H), 7.8 (d, J=8.65 Hz, 2H), 7.53 (d, J=8.62 Hz, 2H), 2.45 (t, J=7.22 Hz, 2H), 1.62 (p, J=7.11 Hz, 2H), 1.48-1.3 (m, 4H), 0.93 (t, J=7.20 Hz, 3H); LCMS m/z: 200
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Cl[CH2:14][C:15]1[C:16]([CH3:21])=[N:17][O:18][C:19]=1[CH3:20].[CH3:22][C:23]1[N:24]=[C:25]([N:38]2[C:42](=[O:43])[NH:41][N:40]=[CH:39]2)[S:26][C:27]=1[C:28]([NH:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:29]>>[CH3:21][C:16]1[C:15]([CH2:14][N:41]2[C:42](=[O:43])[N:38]([C:25]3[S:26][C:27]([C:28]([NH:30][CH2:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)=[O:29])=[C:23]([CH3:22])[N:24]=3)[CH:39]=[N:40]2)=[C:19]([CH3:20])[O:18][N:17]=1
Reactant: Cc1noc(C)c1CCl
Reactant: Cc1nc(-n2cn[nH]c2=O)sc1C(=O)NCc1cccnc1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: Cc1nc(-n2cnn(Cc3c(C)noc3C)c2=O)sc1C(=O)NCc1cccnc1
Yield: 45 %

Procedure:
Following the procedure as described in Example 19, making variation as required to replace 4-(trifluoromethyl)benzyl bromide with 4-(chloromethyl)-3,5-dimethylisoxazole to react with 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 45% yield: mp 233-234° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.74 (br s, 1H), 8.60 (br s, 1H), 8.22 (s, 1H), 7.87-7.80 (m, 1H), 7.52-7.31 (m, 1H), 6.51 (t, J=5.8 Hz, 1H), 4.74 (s, 2H), 4.64 (d, J=5.8 Hz, 2H), 2.64 (s, 3H), 2.48 (s, 3H), 2.32 (s, 3H); MS (ES+) m/z 426.1 (M+1).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:16])[C:8](=[O:9])[C:7]2[C:10]([CH3:15])=[CH:11][C:12]([CH3:14])=[CH:13][C:6]=2[O:5]1.C([O-])(=O)C.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.C(#N)C>[Br:1][C:11]1[C:12]([CH3:14])=[CH:13][C:6]2[O:5][C:4]([CH3:16])([CH3:3])[C:8](=[O:9])[C:7]=2[C:10]=1[CH3:15]
Reactant: BrBr
Reactant: Cc1cc(C)c2c(c1)OC(C)(C)C2=O
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc2c(c(C)c1Br)C(=O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
Bromine (8.7 mL, 169 mmol) was added to a mixture of acetonitrile (200 mL) containing 2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one (30.7 g, 161 mmol) synthesized in Reference Example 118 and sodium acetate (14.5 g, 177 mmol), and the mixture was stirred at room temperature for 2 hours. After that, the reaction solution was poured into 5% sodium sulfite aqueous solution, and extraction was performed using ethyl acetate. The extract was washed with water and saturated saline, and dried using anhydrous magnesium sulfate. After that, the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 50:1-9/1), and crystallization was performed using methanol to give 26.2 g of the title compound (yield: 61%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[SH:11].[H-].[Na+].Br[CH:15]([CH2:19][CH3:20])[C:16]([OH:18])=[O:17].Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[S:11][CH:15]([CH2:19][CH3:20])[C:16]([OH:18])=[O:17]
Reactant: CCC(Br)C(=O)O
Reactant: COc1ccc(S)c(Cl)c1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(Sc1ccc(OC)c(Cl)c1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of 4.4 g of 2,3-dichloro-4-methoxythiophenol in 30 ml of anhydrous dimethylformamide is added 1.2 g of sodium hydride in small portions. The mixture is stirred at room temperature until gas evolution subsides (20-30 minutes) and 3.34 g of α-bromobutyric acid in 10 ml of dimethylformamide is added. After stirring at room temperature for 1 hour, the mixture is diluted with water and acidified with conc. hydrochloric acid. The white crystalline solid is filtered, air dried and recrystallized from acetone-hexane to give 5.32 g of α-(2,3-dichloro-4-methoxyphenylthio)butyric acid as granular crystals, mp 143°-145°.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[C:14]1([S:20]([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([Cl:11])[C:10]=3[C:2]([Br:1])=[CH:3]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a slurry of the product from Method K (4.1 g/0.018 mol) in DMF (15 mL) and cooled to 0° C. was added 1.0 g (0.025 mol) of 60% sodium hydride in mineral oil and the resulting mixture stirred at 0° C. for 15 minutes. Benzenesulfonyl chloride (3.2 g/0.018 mol) was added, the reaction mixture warmed to room temperature and stirred for 2 hours. Water was then added (15 mL) and the resulting solid removed by filtration and dried in vacuo affording 5.9 grams (89%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=1[NH2:13].CC([O-])(C)C.[Na+].O(CCCC)CCCC>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:13][C:12]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=2[CH3:10])=[CH:3][CH:4]=1
Reactant: COc1ccc(Cl)cc1
Reactant: Cc1ccc(C)c(N)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: COc1ccc(Nc2cc(C)ccc2C)cc1
Temperature: 110 °C
Yield: 96.8 %

Procedure:
Following general procedure E, a mixture of 4-chloroanisole (123 μL, 1.0 mmol), 2,5-dimethylaniline (149 μL, 1.2 mmol), NaOt-Bu (115 mg, 1.2 mmol), 10 (0.08 mg, 0.01 mol %), 1 (0.05 mg, 0.01 mol %), and Bu2O (1 mL) was heated to 110° C. for 1 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 0-30% EtOAc/hexanes) to provide the title compound as a white solid (220 mg, 97%), mp 40-41° C. 1H NMR (300 MHz, CDCl3) δ: 7.11 (m, 3H), 6.96 (m, 3H), 6.75 (d, J=7.5 Hz, 1H), 5.27 (s, 1H), 3.88 (s, 3H), 2.33 (s, 3H), 2.30 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 155.3, 143.5, 136.8, 136.7, 131.0, 122.7, 122.5, 121.1, 116.2, 115.0, 55.9, 21.7, 17.7 ppm. IR (neat, cm−1): 3400, 2921, 1579, 1511, 1463, 1292, 1241, 1037, 828, 800. Anal. Calcd. for C15H17NO: C, 79.26; H, 7.54. Found: C, 79.11; H, 7.59.