Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:6]([CH3:11])[CH:7]1[CH2:10][O:9][CH2:8]1)([CH3:5])[CH:3]=O.N1CCCC1.[Si](Cl)(C)(C)C.[NH2:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([CH2:46][C@@H:47]3[CH2:51][CH2:50][CH2:49][N:48]3[C:52](=[O:56])[CH2:53][C:54]#[N:55])[N:30]=[C:31]([C:32]3[CH:37]=[CH:36][C:35]([O:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:34][C:33]=3[F:45])[C:24]=12>C(Cl)Cl.CCOC(C)=O>[NH2:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([CH2:46][C@@H:47]3[CH2:51][CH2:50][CH2:49][N:48]3[C:52]([C:53](=[CH:3][C:2]([CH3:1])([N:6]([CH3:11])[CH:7]3[CH2:10][O:9][CH2:8]3)[CH3:5])[C:54]#[N:55])=[O:56])[N:30]=[C:31]([C:32]3[CH:37]=[CH:36][C:35]([O:38][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[CH:34][C:33]=3[F:45])[C:24]=12
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: CN(C1COC1)C(C)(C)C=O
Agent: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCNC1
Product: CN(C1COC1)C(C)(C)C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.8 %

Procedure:
To a solution of 2-methyl-2-[methyl(oxetan-3-yl)amino]propanal (100.0 mg, 0.6400 mmol) in DCM (5 mL), was added pyrrolidine (0.06 mL, 0.760 mmol). The reaction mixture was cooled to 0° C., followed by addition of TMS-Cl (0.06 mL, 0.51 mmol, the ice bath was removed and reaction mixture was stirred for 10 minutes before adding 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (60 mg, 0.13 mmol). The mixture was stirred for 50 minutes and the reaction was deemed finished by checking progress through TLC and LC-MS. The reaction mixture was washed by 15 ml Sat.Na2HCO3 and the layers separated. The aq. layer was extracted with CH2Cl2 and the combined organic layer was washed with brine, dried over Na2SO4, filtered, and the solvent removed. The residue was loaded on silica gel column and purified by [MeOH:CH2Cl2(1:4)]: EtOAc 20%, 30% to get pure product 2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-[methyl(oxetan-3-yl)amino]pent-2-enenitrile (61.8 mg, 0.1012 mmol, 79.5% yield) as off white solid. LC-MS (ES, m/z): 612 [M+H]
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31]Br)[CH2:26][C@@H:25]2[CH3:34])=[C:20]([CH:35]=[CH:36][CH3:37])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1C2C=C(C3(C)NC(=O)NC3=O)C=CC=2CC1.[CH3:55][CH:56]([O:58][C:59]1[CH:60]=[CH:61][C:62]([C:65]2([CH3:72])[NH:69][C:68](=[O:70])[NH:67][C:66]2=[O:71])=[N:63][CH:64]=1)[CH3:57]>>[CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31][N:67]3[C:66](=[O:71])[C:65]([C:62]4[CH:61]=[CH:60][C:59]([O:58][CH:56]([CH3:55])[CH3:57])=[CH:64][N:63]=4)([CH3:72])[NH:69][C:68]3=[O:70])[CH2:26][C@@H:25]2[CH3:34])=[C:20]([CH:35]=[CH:36][CH3:37])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)C[C@@H]1C
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)nc1
Agent: CC1(c2ccc3c(c2)OCC3)NC(=O)NC1=O
Product: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc(OC(C)C)cn3)C2=O)C[C@@H]1C

Procedure:
(S)-1-(4-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-2-(prop-1-en-1-yl)phenyl}-3-methylpiperazin-1-yl)-2-bromoethanone, 5-(2,3-dihydrobenzofuran-6-yl)-5-methylimidazolidine-2,4-dione and 5-[5-(1-methylethoxy)pyridin-2-yl]-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Example 14-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])[CH3:3].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:33][C:34](=[NH:53])[C:35]1[CH:52]=[CH:51][C:38]2[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43][C:37]=2[CH:36]=1>CN(C=O)C>[CH3:3][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[O:11][N:33]=[C:34]([C:35]3[CH:52]=[CH:51][C:38]4[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH2:42][CH2:43][C:37]=4[CH:36]=3)[N:53]=2)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(=N)NO)cc2CC1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.3 %

Procedure:
4-[(1-Methylethyl)oxy]-3-(trifluoromethyl)benzoic acid (Preparation 39) (744 mg, 3.00 mmol), HOBT (446 mg, 3.30 mmol) and EDC (630 mg, 3.30 mmol) were stirred in DMF (28 ml) under argon for 20 minutes. 1,1-dimethylethyl 7-[(hydroxyamino)(imino)methyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 41) (915 mg, 3.00 mmol) was added and the mixture stirred at room temperature for 2 hrs before it was heated to 80° C. for 20 hrs. The reaction mixture was partitioned between EtOAc and water and the organic layer washed with aqueous sodium bicarbonate before it was dried in the usual manner and evaporated. The residue was purified by Biotage Horizon, reverse phase cartridge, eluting with 5-100% acetonitrile in water to give the title compound (749 mg, 1.45 mmol). δH (d6DMSO, 400 MHz): 8.40 (1H, dd), 8.31 (1H, d), 7.89 (1H, br.s), 7.86 (1H, dd), 7.58 (1H, d), 7.37 (1H, d), 4.98 (1H, septet), 3.54-3.46 (4H, m), 3.00-2.92 (4H, m), 1.41 (9H, s), 1.36 (6H, d).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[S:18][CH:17]=[C:16](Br)[C:11]=2[N:12]=[C:13]([Cl:15])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1(NC2CCCCC2)CCCC[CH2:21]1.C([Si](C)(C)C)#C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([NH:8][C:9]1[C:10]2[S:18][CH:17]=[C:16]([C:20]#[CH:21])[C:11]=2[N:12]=[C:13]([Cl:15])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: Clc1nc(NCc2ccccc2)c2scc(Br)c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CC#N
Product: C#Cc1csc2c(NCc3ccccc3)nc(Cl)nc12
Temperature: 80 °C
Reaction time: 14 h
Yield: 68.7 %

Procedure:
N-Benzyl-7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-amine (310 mg, 0.874 mmol) was dissolved in acetonitrile (4 mL) and then bis(triphenylphosphine)palladium(II) dichloride (15 mg, 0.022 mmol), CuI (6 mg, 0.350 mmol), dicyclohexylamine (0.19 mL, 0.96 mmol) and ethynyltrimethylsilane (0.24 mL, 1.75 mmol) were added. After flowing nitrogen gas for 15 minutes, the reaction mixture was stirred at 80° C. for 14 hours. After cooling to room temperature, the reaction mixture was filtered with celite and washed with ethyl acetate (50 mL). The filtrate was washed with brine and concentrated by drying with MgSO4. Without purification, the resultant compound was dissolved in anhydrous tetrahydrofuran (5 mL) and then 1.0 M tetrabutylammonium fluoride dissolved in tetrahydrofuran (4.4 mL, 4.4 mmol) was added thereto. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated. Purification of the mixture by silica gel chromatography (ethyl acetate/hexane: 2/8→3/7) yielded the target compound (180 mg, 68% yield).
Reaction SMILES: [CH2:1]([S:8][CH:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:18][C:19]1[CH:20]=[N:21][C:22](=[O:25])[NH:23][CH:24]=1.C(N(CC)CC)C.C(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([S:8][CH:9]([N:23]1[CH:24]=[C:19]([Cl:18])[CH:20]=[N:21][C:22]1=[O:25])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(SCc1ccccc1)c1ccccc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1ncc(Cl)cn1C(SCc1ccccc1)c1ccccc1

Procedure:
α-Chlorobenzyl benzyl sulphide (see R. H. Mitchell, Tetrahedron Letters 44, 4395 (1973) (4 mmol) in CH2Cl2 (10 ml) was added dropwise over a period of 5 minutes at 0° C. to a mixture of 5-chloropyrimidin-2-one hydrochloride (4 mmol) and triethylamine (8 mmol) in CH2Cl2 (30 ml). The mixture was stirred for 3 hours at room temperature and 1/2 hour at 40° C. before chloroform (20 ml) was added and the solution washed with water (3 times). The dried (MgSO4) solution was evaporated, ether added to the crude product and the insoluble product collected. Yield 0.35 g (26%), m.p. 118° C. 1H-NMR (CDCl3): δ(CH2) 7.12 (--CH--), 7.27 (Ph), 7.33 (Ph), 8.12 (H-4, d, J 3 Hz)), 8.30 (H-6, d, J 3 Hz).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([NH:16]C=O)[C:6]([SH:15])([CH3:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])C.Cl.[Cl:21]CCl.CO>C(O)(=O)C>[ClH:21].[NH2:16][CH:5]([C:6]([SH:15])([CH3:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:4]([OH:19])=[O:3]
Reactant: ClCCl
Reactant: CCCCCCCC(C)(S)C(NC=O)C(=O)OCC
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CCCCCCCC(C)(S)C(N)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
16.7 g of 2-formylamino-3-mercapto-3-methyldecanoic acid ethyl ester as a 6:4 threo/erythro mixture (product 6) were added at room temperature to 606 ml of 6N hydrochloric acid and then stirred for 24 hours under reflux (TLC check: dichloromethane:methanol:glacial acetic acid 35:5:3). After cooling to room temperature the reaction mixture was stirred further while cooling with ice. The precipitated white solid was suction filtered, washed with ether and then dried in vacuo. 13.3 g (94.9% of theory) of rac-2-amino-3-mercapto-3-methyldecanoic acid hydrochloride were thus obtained as a 6:4 threo/erythro mixture (compound 6; product 1).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>C1COCC1>[Cl:25][C:26]1[CH:27]=[C:28]([C:29](=[O:30])[CH2:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=3)[O:5][C:4](=[O:14])[CH:3]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: Cc1cc(=O)oc2ccc(C#N)cc12
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2oc(=O)cc(CC(=O)c3cccc(Cl)c3)c2c1
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-2-oxo-2H-chromene-6-carbonitrile (180 mg, 0.92 mmol) in dry THF (33 mL) at −20° C. was added drop wise 1.0 M LiHMDS solution in THF (1.6 mL). After 30 minutes 3-chlorobenzoylchloride (200 mg) was added into the reaction mixture and the reaction mixture was stirred for 1 hour. The reaction mixture was then quenched with saturated aqueous ammonium chloride (15 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and dried over sodium sulfate, then concentrated and purified on silica gel eluted with 30%-60% ethyl acetate in hexanes to yield 4-[2-(3-chloro-phenyl)-2-oxo-ethyl]-2-oxo-2H-chromene-6-carbonitrile as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8](C(COC)=O)[CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[C:6]([CH3:20])[CH:5]=[CH:4][CH:3]=1.CC1C=CC=C(C)C=1N.BrC(C)C([O-])=O.C(=O)([O-])O.[Na+]>>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH3:20])[C:7]=1[NH:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10]
Reactant: COCC(=O)N(c1c(C)cccc1C)C(C)C(=O)OC
Agent: CC(Br)C(=O)[O-]
Agent: Cc1cccc(C)c1N
Agent: O=C([O-])O
Product: COC(=O)C(C)Nc1c(C)cccc1C

Procedure:
The preparation of metalaxyl is published in the CH-PS 607,888, according to which 2,6-dimethylaniline is first reacted with methyl DL-α-bromopropionate in the presence of sodium hydrogen carbonate as acid binding agent, then methyl N-(2,6-dimethylphenyl)-DL-alaninate thus obtained is acylated with methoxyacetyl chloride to give metalaxyl.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:7]([CH:19]=[CH:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:25])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(F)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(F)c1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3-fluorophenyl)-5-(pent-1-enyl)pyridine (Example 127) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): δ 0.79 (t, J=7.0 Hz, 3 H), 1.10-1.35 (m, 18 H), 2.28 (m, 2 H), 3.24 (m, 1 H), 3.42 (m, 1 H), 4.33 (s, 2 H), 6.96 (m, 2 H), 7.12 (m, 1 H), 7.40 (m, 1 H). mp 117-118° C. Rf=0.36 (10% ethyl acetate/n-hexane).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[CH2:12]O)=[CH:6][CH:5]=1)=[O:3].N1C=CC=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O.O.[N:33]1([CH:39]2[C:49]3[C:44](=[N:45][CH:46]=[CH:47][CH:48]=3)[CH2:43][CH2:42][C:41]3[CH:50]=[CH:51][CH:52]=[CH:53][C:40]2=3)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[CH2:12][N:36]2[CH2:37][CH2:38][N:33]([CH:39]3[C:49]4[C:44](=[N:45][CH:46]=[CH:47][CH:48]=4)[CH2:43][CH2:42][C:41]4[CH:50]=[CH:51][CH:52]=[CH:53][C:40]3=4)[CH2:34][CH2:35]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CS(=O)c1ccc(/C=C/CO)cc1
Reactant: c1ccc2c(c1)CCc1ncccc1C2N1CCNCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)c1ccc(/C=C/CN2CCN(C3c4ccccc4CCc4ncccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.5 %

Procedure:
1.96 g of (E)-3-(4-methylsulfinylphenyl)allyl alcohol was dissolved in 40 ml of methylene chloride. To the solution were added 1.34 g of 4-N,N-dimethylamino)pyridine and 2.19 g of p-toluenesulfonyl chloride with ice-cooling. The mixture was stirred for 4 hours at room temperature. To the reaction mixture were added 1.32 g of triethylamine and 3.15 g of 5-(piperazin- 1-yl)-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine dihydrate. The mixture was stirred for 5 hours at room temperature. The reaction mixture was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: chloroform/methanol=35/1) to obtain 2.31 g of 5-[4-{(E)-3-(4-methylsulfinylphenyl)allyl}piperazin-1-yl]-10,11-dihydro-5H-benzo-[4,5]cyclohepta[1,2-b]pyridine. It was recrystallized from isopropyl alcohol to obtain 1.85 g of colorless crystals having a melting point of 166°-168° C.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([CH3:9])=[C:7]([C:10]#[CH:11])[N:6]=[C:5]2[CH3:12])[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:19]=[C:18](I)[CH:17]=[CH:16][N:15]=1>>[Cl:13][C:14]1[CH:19]=[C:18]([C:11]#[C:10][C:7]2[N:6]=[C:5]([CH3:12])[N:4]([CH:1]3[CH2:3][CH2:2]3)[C:8]=2[CH3:9])[CH:17]=[CH:16][N:15]=1
Reactant: C#Cc1nc(C)n(C2CC2)c1C
Reactant: Clc1cc(I)ccn1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)c(C)n1C1CC1

Procedure:
The title compound, MS: m/e=272.0 (M+H+), was prepared in accordance with the general method of example A, step 1 from 1-cyclopropyl-4-ethynyl-2,5-dimethyl-1H-imidazole and 2-chloro-4-iodo-pyridine.
Reaction SMILES: Cl[C:2]1[C:3](=[O:17])[N:4]([CH2:15][CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>CN(C=O)C>[CH2:15]([N:4]1[C:3](=[O:17])[C:2]([NH:28][C:27]2[CH:26]=[CH:25][C:24]([N:21]3[CH2:22][CH2:23][O:18][CH2:19][CH2:20]3)=[CH:30][CH:29]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])[CH3:16]
Reactant: CCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CN(C)C=O
Product: CCN1C(=O)C(Nc2ccc(N3CCOCC3)cc2)=C(c2ccccc2)S1(=O)=O
Yield: 29 %

Procedure:
A solution of 4-chloro-2-ethyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.217 g, 0.80 mmol) and 4-morpholinoaniline (0.285 g, 1.60 mmol) in DMF (2.0 mL) was heated at 110° C. for 15 mins in a microwave reactor. The mixture was purified by preparative HPLC (C8 50×250, 0.1M NH4OAc/MeCN, gradient) which gave impure product. Repurification was done by preparative HPLC (C8 50×250, 0.1M NMR OAc/MeCN, 50% MeCN isocratic) to give the title compound (0.096 g, 29%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.22-7.16 (m 1H), 7.12-7.09 (m, 4H), 6.62-6.57 (m 2H), 6.52-6.48 (m, 2H), 3.84 (q, 2H), 3.81-3.78 (m, 4H), 2.99-2.95 (m, 4H), 1.47 (t 3H); 13C NMR (500 MHz, CDCl3): δ 159.4, 149.2, 131.5, 129.5, 128.9, 128.4, 128.1, 125.1, 123.6, 115.6, 109.8, 66.9, 49.7, 35.6, 14.0; Mass Spectrum: M−H+ 414.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:11]([OH:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1(C)[CH:29]=CC=C[CH:25]=1>>[C:1]([N:9]1[C@@H:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:17][C:24]1([CH3:29])[CH3:25])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(O)C(NC(=O)c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Product: CCOC(=O)[C@@H]1OC(C)(C)N(C(=O)c2ccccc2)[C@H]1c1ccccc1
Yield: 93 %

Procedure:
[R-(R*,S*)]-β-(Benzoylamino)-α-hydroxybenzenepropanoic acid, ethyl ester (2.200 mg) was suspended in toluene (250 ml) and the flask equipped with a Dean-Stark trap. After heating to reflux, the compound dissolved. 40 ml of toluene were distilled off, PPTS (120 mg) and 2-methoxypropene (3.5 ml) were added, and distillation was continued. Further additions of 2-methoxypropene (2 ml, and then 1 ml) and toluene (50 ml, and then another 50 ml) were made, and the distillate periodically discarded. Purification on HPLC (hexane/ethyl acetate, 3:1) gave 2.3 g (93%) of the title product in a mixture with other reaction products. (Product characteristics consistent with structure of Example 1.)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5]([OH:7])=O.[CH3:29][NH:30][CH2:31][CH2:32][OH:33]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:22]1)[N:14]=2)[C:5]([N:30]([CH2:31][CH2:32][OH:33])[CH3:29])=[O:7]
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: CNCCO
Product: CN(CCO)C(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
The title compound was synthesized using the procedure described in Example 105 above, with 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzoic acid (98 mg, 0.251 mmol) and 2-(methylamino)ethanol (24 μl, 0.301 mmol). MS (ESI) m/z: Calculated: 447.1; Observed: 448.1 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>>[O:29]1[CH2:28][CH:27]1[CH2:25][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: Cc1cc(C(F)(F)F)nc(-c2ccc(O)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(C(F)(F)F)nc(-c2ccc(OCC3CO3)cc2)n1
Reaction time: 1.5 h

Procedure:
The mixture of 17.0 g of 2-(4-hydroxyphenyl)-4-methyl-6-(trifluoromethyl)-pyrimidine, 23.1 g of potassium carbonate and 135 ml of epichlorohydrin is stirred at a temperature of 130° for 1.5 hours, then filtered with suction while hot; the filter residue is subsequently washed with methylene chloride and the filtrate is evaporated to dryness under reduced pressure. The residue is recrystallised from isopropanol and yields 2-[4-(2,3-epoxypropoxy)-phenyl]-4-methyl-6-(trifluoromethyl)pyrimidine having a melting point of 97°-99°.
Reaction SMILES: O[NH:2][C@H:3]([C:16](N)=[O:17])[CH2:4][CH2:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(Cl)(Cl)=[O:20]>C1COCC1>[NH2:2][C@H:3]([C:16]([OH:17])=[O:20])[CH2:4][CH2:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)Cl
Reactant: NC(=O)[C@H](CCC(=O)OCc1ccccc1)NO
Solvent: C1CCOC1
Product: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Temperature: 50 °C
Yield: 99.7 %

Procedure:
HO-Glu(Bzl)-NH2 (30.0 g, 126.0 mmol) was suspended in 300 mL of anhydrous THF and heated to 50° C. Phosgene (20% in toluene) (81.3 mL, 164.6 mmol) was added to the amino acid suspension by syringe, and the amino acid dissolved over the course of approx. 30 minutes, forming a clear solution. The solution was concentrated by rotory evaporation, dissolved in ˜150 mL of anhydrous THF, and transferred to an Erlenmeyer flask. Hexane was added and the product was allowed to crystallize overnight. The NCA was isolated by filtration and dried in vacuo. 29.8 g (90% yield) of Glu(Bzl) NCA was isolated as a white, crystalline solid. 1H NMR (CDCl3) δ 7.36 (5H), 6.22 (1H), 5.14 (2H), 4.35 (1H), 2.61 (2H), 2.29 (1H), 2.14 (1H) ppm.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.[CH3:17]O>C(OCC)C>[CH3:17][O:15][C:14](=[O:16])[CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Br:6])[CH:8]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COC(=O)Cc1cccc(Br)c1
Temperature: 25 °C

Procedure:
Concentrated sulphuric acid (588 μL) was added to a solution of 3-bromophenyl acetic acid (10 g, 46.5 mmol) in methanol (100 mL). The mixture was refluxed for 1.5 h and then cooled to ambient temperature and evaporated under reduced pressure to afford a residue. The residue was redissolved in diethyl ether (500 mL), washed with water (2×100 mL), brine (100 mL), dried (MgSO4) and then evaporated under reduced pressure to afford 3-bromophenyl acetic acid methyl ester (10.65 g). The 3-bromophenyl acetic acid methyl ester was dissolved in toluene (17 mL) then phenyl boronic acid (6.8 g, 55.69 mmol) added, followed by a aqueous solution of sodium carbonate (93 mL, 2M) and tetrakis(triphenylphosphine)palladium (1.6 g, 1.41 mmol). The mixture was stirred overnight then cooled to ambient temperature and an aqueous solution of saturated ammonium chloride (100 mL) added. The mixture was extracted with ethyl acetate (2×200 mL), died (Na2SO4) and evaporated under reduced pressure to afford a residue. Flash chromatography of the residue over silica (200 g) using ethyl acetate:heptane (3:48) as the eluent gave biphenyl-3-yl acetic acid methyl ester, yield 10.5 g, (99%), TLC (single UV spot, Rf=0.24, 10% ethyl acetate in heptane), analytical HPLC Rt=19.55 min, HPLC-MS (single main UV peak with Rt=9.35 min, 227.1 [M+H]+).