Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH3:19])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1.[CH3:20][CH:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C1C=CC=CC=1>[CH3:20][CH:21]([NH:29][CH:2]([CH3:19])[CH2:3][O:4][CH:5]1[CH2:6][CH2:7][CH:8]([C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH2:9][CH2:10]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)COC1CCC(C(=O)c2ccccc2)CC1
Reactant: CC(N)Cc1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: CC(COC1CCC(C(=O)c2ccccc2)CC1)NC(C)Cc1ccccc1

Procedure:
4-(2-oxo-propoxy)-cyclohexanophenone (0.02 mole) and α-methyl-phenethylamine (0.02 mole) are then heated in benzene solution. The water formed is removed by means of a Dean-Stark apparatus.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([CH3:18])[CH2:7][CH:8]([NH:14][C:15](=[O:17])[CH3:16])[C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[Br:19]N1C(=O)CCC1=O.O>CN(C)C=O>[C:1]([O:4][CH2:5][C@H:6]([CH3:18])[CH2:7][CH:8]([NH:14][C:15](=[O:17])[CH3:16])[C:9]1[S:10][C:11]([Br:19])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC(C[C@@H](C)COC(C)=O)c1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NC(C[C@@H](C)COC(C)=O)c1ccc(Br)s1
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
(2R)-Acetylamino-2-methyl-4-(thiophen-2-yl)butyl acetate (1.81 g, 6.70 mmol) obtained in Example 47(b) was dissolved in dimethylformamide (20 ml), and N-bromosuccinimide (1.27 g, 7.11 mmol) was added thereto in an ice bath followed by stirring under a nitrogen atmosphere for 10 minutes in an ice bath and then overnight at room temperature. The reaction solution was poured into water, extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated aqueous sodium chloride solution The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=3:1-1:2) to afford the title compound (2.32 g, 99% yield).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][C:22]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH:23]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1ccc(F)c(-c2ccccn2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(F)c(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 4-fluoro-3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.68 min.; [M+H]+: 420.97 g/mol.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:24][S:25]([NH2:28])(=[O:27])=[O:26]>C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[N:3][CH:4]=2)=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cl)nc1
Reactant: CS(N)(=O)=O
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Product: CS(=O)(=O)Nc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cn1

Procedure:
100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide was reacted with methanesulfonamide and 108 μL of 2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine via Procedure F. The crude reaction was concentrated to dryness and purified by reverse phase HPLC to give pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(methylsulfonamido)nicotinamide. MS (Q1) 403 (M)+.
Reaction SMILES: CCCCCCCCCCCCCCCC([NH:18][C@@H:19]1[C:50](=[O:51])[NH:49][C@@H:48]([C@H:52]([OH:54])[CH3:53])[C:46](=[O:47])[N:45]2[C@@H:41]([CH2:42][C@@H:43]([OH:55])[CH2:44]2)[C:39](=[O:40])[NH:38][C@@H:37]([C@H:56]([OH:71])[C@@H:57]([OH:70])[C:58]2[CH:59]=[CH:60][C:61]([OH:69])=[C:62]([O:64][S:65]([OH:68])(=[O:67])=[O:66])[CH:63]=2)[C:35](=[O:36])[NH:34][C@@H:33]([C@H:72]([OH:77])[CH2:73][C:74]([NH2:76])=[O:75])[C:31](=[O:32])[N:30]2[C@@H:26]([C@@H:27]([OH:79])[C@@H:28]([CH3:78])[CH2:29]2)[C:24](=[O:25])[NH:23][C@@H:22]([OH:80])[C@H:21]([OH:81])[CH2:20]1)=O.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Na+].[Na+].ClC(Cl)(Cl)C(O)=O>>[CH3:78][C@@H:28]1[C@H:27]([OH:79])[C@H:26]2[C:24]([NH:23][C@H:22]([OH:80])[C@H:21]([OH:81])[CH2:20][C@H:19]([NH2:18])[C:50]([NH:49][C@@H:48]([C@H:52]([OH:54])[CH3:53])[C:46]([N:45]3[C@H:41]([C:39]([NH:38][C@@H:37]([C@H:56]([OH:71])[C@@H:57]([OH:70])[C:58]4[CH:59]=[CH:60][C:61]([OH:69])=[C:62]([O:64][S:65]([OH:68])(=[O:67])=[O:66])[CH:63]=4)[C:35]([NH:34][C@@H:33]([C@H:72]([OH:77])[CH2:73][C:74]([NH2:76])=[O:75])[C:31](=[O:32])[N:30]2[CH2:29]1)=[O:36])=[O:40])[CH2:42][C@@H:43]([OH:55])[CH2:44]3)=[O:47])=[O:51])=[O:25]
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@H]1C[C@@H](O)[C@H](O)NC(=O)[C@@H]2[C@@H](O)[C@@H](C)CN2C(=O)[C@H]([C@H](O)CC(N)=O)NC(=O)[C@H]([C@H](O)[C@@H](O)c2ccc(O)c(OS(=O)(=O)O)c2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]([C@@H](C)O)NC1=O
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Product: C[C@@H](O)[C@@H]1NC(=O)[C@@H](N)C[C@@H](O)[C@@H](O)NC(=O)[C@@H]2[C@@H](O)[C@@H](C)CN2C(=O)[C@H]([C@H](O)CC(N)=O)NC(=O)[C@H]([C@H](O)[C@@H](O)c2ccc(O)c(OS(=O)(=O)O)c2)NC(=O)[C@@H]2C[C@@H](O)CN2C1=O
Reaction time: 3 h

Procedure:
To 7 ml of the fermentation broth of Oidiodendron sp. No. 30084 obtained in Example 1-1 was added 1 ml of an aqueous solution (20 mg/ml) of FR901379 Substance (20 mg as FR901379 Substance; 16.7 μmol) as well as 2 ml of a buffer (0.2M sodium citrate buffer, pH 4.0), and the reaction was carried out at 30° C. for 3 hours. The reaction was then stopped by adding 0.4M trichloroacetic acid and centrifuged at low speed to remove precipitated high molecular weight protein and other impurities. The FR179642 Substance produced was subjected to HPLC and monitored at 210 nm to determine the acylase activity.
Reaction SMILES: [C:1]([NH:24][CH:25]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([OH:38])=[C:33]([CH:37]=1)[C:34]([OH:36])=[O:35])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].N[C@H:44]([C:52](O)=O)[CH2:45]C1C=CC=CC=1>>[C:1]([NH:24][CH:25]([CH2:39][C:40]1[CH:41]=[CH:52][CH:44]=[CH:45][CH:42]=1)[C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([OH:38])=[C:33]([CH:37]=1)[C:34]([OH:36])=[O:35])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(CC(C)C)C(=O)Nc1ccc(O)c(C(=O)O)c1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(Cc1ccccc1)C(=O)Nc1ccc(O)c(C(=O)O)c1

Procedure:
5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-Docosa-4,7,10,13,16,19-hexaenamido-3-phenylpropanamido)-2-hydroxybenzoic acid was prepared in a similar fashion as 5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanamido)-2-hydroxybenzoic acid, using the appropriate phenylalanine starting material. Mass calculated for C38H46N2O5=610.78. found: [M−H]+=609.3.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[C:13]=1[C:20]([O:22][CH3:23])=[O:21].Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>ClCCl>[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:13]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1cccc(CN)c1C(=O)OC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CNC(=O)OCc2ccccc2)c1C(=O)OC
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
Triethylamine (1.87 g, 18.5 mmol) was added to a stirred suspension of methyl-3-(aminomethyl)-2-(methoxycarbonyl)benzoate hydrochloride (2.0 g, 8 mmol) in dichloromethane (30 ml). The mixture was cooled in an ice bath to 4° C. Benzyl chloroformate (1.66 g, 10 mmol) was added slowly keeping the temperature between 4–7° C. After the addition was complete, the cooled mixture was stirred an additional 30 minutes and then warmed to room temperature for 4 hours. The mixture was washed with water (2×30 ml), brine (30 ml) and dried. Solvent was removed and the residue was purified by chromatography (dichloromethane/ethyl acetate 95 to 5) to give 2.1 g (76%) of the product as a solid; 1H NMR (CDCl3) δ 7.87 (d, J=7.8 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 7.36–7.26 (m, 5H), 5.41 (b, 1H), 5.09 (s, 2H), 4.36 (d, J=6.3 Hz, 2H), 3.91 (s, 3H), 3.88 (s, 3H).
Reaction SMILES: NCC1C2C(=CC=CC=2)CCN1CCCC(OCC)=O.[C:21]([NH:29][CH2:30][CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][N:32]1CCCl)(=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)CC(OCC)=O.C(O[K])CCC>C(O)(C)(C)C>[NH2:32][CH2:33][CH:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:31][CH2:30][N:29]1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(NCC1c2ccccc2CCN1CCCl)c1ccccc1
Agent: CCCCO[K]
Agent: CCOC(=O)CCCN1CCc2ccccc2C1CN
Solvent: CC(C)(C)O
Solvent: CCOC(=O)CC(=O)OCC
Product: NCC1c2ccccc2CCN1Cc1ccccc1

Procedure:
1-aminomethyl-2-(3-carbethoxypropyl)-1,2,3,4-tetrahydroisoquinoline [obtainable by reacting 1-benzamidomethyl-2-(2-chloroethyl)-1,2,3,4-tetrahydroisoquinoline with diethyl malonate in the presence of tert.--C4H9OK in tert.-butanol, saponifying, decarboxylation, and esterification]
Reaction SMILES: [CH:1]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]=[C:21]1[C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][N:22]1[CH2:39][C:40](O)=[O:41].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]([CH:14]1[CH2:19][CH2:18][N:17]([C:40](=[O:41])[CH2:39][N:22]2[CH2:23][CH2:24][CH2:25][C:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:20])[CH2:16][CH2:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-benzhydrylpiperidine (0.13 g, 0.5 mmol) in dichloromethane (10 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.16 g, 0.50 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.19 g, 1.00 mmol) and N,N-dimethylpyridin-4-amine (6 mg, 0.05 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:3) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.15-7.34 (m, 20H), 4.52-4.60 (m, 1H), 4.27 (d, J=15.7 Hz, 1H), 4.11 (d, J=15.7 Hz, 1H), 3.64-3.76 (m, 1H), 3.45-3.50 (m, 3H), 2.93-3.02 (m, 1H), 2.54-2.65 (m, 3H), 2.20-2.44 (m, 1H), 1.78-1.87 (m, 2H), 1.55-1.65 (m, 2H), 1.00-1.20 (m, 2H).
Reaction SMILES: [C:1]1([P:7]([CH2:14]S)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([NH:19][CH2:20][C:21](O)=[O:22])(=[O:18])[CH3:17].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:19]([C:16]([CH3:17])=[O:18])[CH2:20][C:21]([CH2:14][P:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:22]
Reactant: CC(=O)NCC(=O)O
Reactant: SCP(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(=O)NCC(=O)CP(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
Phosphinothiol 20 (100 mg, 0.43 mmol) and N-acetylglycine (55 mg, 0.47 mmol) were dissolved in DMF (3 mL) under Ar(g). DCC (98 mg, 0.47 mmol) was added, and the mixture was stirred for 12 h at room temperature. The DCU by-product was removed by filtration, solvent was removed under reduced pressure, and the residue was purified by chromatography as in Method A. AcGlyCH2PPh2 was isolated as a white solid in 67% yield. Spectral data. 1H NMR (CDCl3, 300 MHz) δ 7.46-7.39 (m, 4 H), 7.38-7.36 (m, 6 H), 6.44 (bs, 1 H), 4.15 (d, J=5/7 Hz, 2 H), 3.53 (d, J=3.6 Hz, 2 H), 2.02 (s, 3 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 196.13, 170.29, 136.45 (d, J=13.6 HZ), 132.62 (d, J=19.1 Hz), 129.17, 128.54 (d, J=6.7 Hz), 48.98, 25.29 (d, J-24.2 Hz), 22.84 ppm; 31P NMR (CDCl3, 121 MHz) δ −15.20 ppm; MS (ESI) m/z 331.08 (MH+—332.2, MK+—370.0).
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[CH2:7]([O:9][C:10](=[O:27])[CH2:11][N:12]1[CH2:16][C:15](=O)[C@@H:14]([NH:18][C:19]([C:21]2[S:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[O:20])[CH2:13]1)[CH3:8]>C1COCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[CH2:7]([O:9][C:10](=[O:27])[CH2:11][N:12]1[CH2:16][C:15](=[CH2:1])[C@@H:14]([NH:18][C:19]([C:21]2[S:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[O:20])[CH2:13]1)[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)CN1CC(=O)[C@@H](NC(=O)c2ccc(Cl)s2)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C1CN(CC(=O)OCC)C[C@@H]1NC(=O)c1ccc(Cl)s1
Temperature: 0 °C
Yield: 76.5 %

Procedure:
39.3 To a cooled (0° C.), stirred suspension of 44 mg potassium tert-butylate in 3 ml THF under an argon atmosphere were added 149 mg methyltriphenylphosphonium bromide. The yellow slurry was then stirred for 1 h 30, slowly warming up to room temperature. A solution of 100 mg {(S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-oxo-pyrrolidin-1-yl}-acetic acid ethyl ester in 2 ml THF was then added. The mixture was heated to reflux and stirred for 2 hrs. The mixture (dark brown slurry) was cooled to r.t., diluted with EtOAc, washed with sat. aq. NH4C1, H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel, gradient: CH2Cl2->CH2Cl2/MeOH 95:5) to give 76 mg {(R)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methylene-pyrrolidin-1-yl}-acetic acid ethyl ester (contaminated with 43 w % triphenylphosphin oxide). Amorphous gum. MS 329.0 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[Cl:1]
Reactant: Cc1ccc2ncnc(Cl)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ncnc2ccc(CBr)cc12
Temperature: 80 °C
Yield: 47.5 %

Procedure:
A flask containing 4-Chloro-6-methylquinazoline (0.91 g, 5.09 mmol), NBS (0.95 g, 5.35 mmol), benzoyl peroxide 70% (0.09 g, 0.2545 mmol) and carbon tetrachloride (25 mL) is refluxed at 80° C. for 20 h. The solution is cooled to RT, filtered and concentrated. Purification by flash chromatography (7.5% EtOAc/hexanes) yields the title compound as a white solid (0.62 g, 2.42 mmol). 1H NMR (CDCl3, 300 MHz) 9.06(s, 1H), 8.25(s, 1H), 8.07(d, 1H), 8.00(d, 1H), 4.67(s, 2H).
Reaction SMILES: CC[Mg+].[Br-].Br[C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH3:11].[O:12]=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.Cl>C1COCC1.CCOC(C)=O>[OH:12][C:13]1([C:6]2[S:7][CH:8]=[CH:9][C:10]=2[CH3:11])[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1ccsc1Br
Agent: CC[Mg+]
Agent: Cl
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccsc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.5 %

Procedure:
To a solution of EtMgBr (300 mL of 1.0M, 300 mmol) in THF (400 mL) at RT was added 2-bromo-3-methylthiophene (48.28 g, 272.7 mmol) dropwise. The mixture was stirred at RT for 72 hours. To the reaction mixture was added a solution of tert-butyl 4-oxopiperidine-1-carboxylate (54.33 g, 272.7 mmol) in THF at RT. The reaction was stirred for 3 hours and 2 N HCl was added to quench the reaction. The mixture was extracted with EtOAc and the combined organics washed with water, satd' NaHCO3 solution, and dried over MgSO4. Removal of the volatiles in vacuo gave a gummy product, to which was added EtOAc. After shaking for 10 min a white precipitate appeared, which was collected by filtration and washed with EtOAc. The filtrate was evaporated again and the precipitation step repeated to obtain additional product, which was combined with the solid previously collected to yield tert-Butyl 4-hydroxy-4-(3-methylthiophen-2-yl)piperidine-1-carboxylate (Compound 1052, 58 g, 71.5% yield; 1H NMR (300 MHz, DMSO-d6): δ 7.17 (d, J=5.0 Hz, 1H), 6.79 (d, J=5.1 Hz, 1H), 5.47 (s, 1H), 3.82 (brd, 2H), 3.09 (brs, 2H), 2.26 (s, 3H), 1.84-1.79 (m, 4H) and 1.41 (s, 9H).
Reaction SMILES: N1C=CN=C1.[C:6]([C:8]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)#[CH:7].CN(C)C=O.[CH3:20][Si:21]([CH3:24])([CH3:23])Cl>CCCCCC>[C:6]([C:8]1([O:14][Si:21]([CH3:24])([CH3:23])[CH3:20])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)#[CH:7]
Reactant: C[Si](C)(C)Cl
Reactant: C#CC1(O)CCCCC1
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C#CC1(O[Si](C)(C)C)CCCCC1
Reaction time: 0.02 h

Procedure:
A 194 g portion of imidazole and 158.2 g of 1-ethynylcyclohexan-1-ol are mixed with 500 g of dimethylformamide with cooling in an ice bath. A 152 g portion of trimethylchlorosilane is added with cooling and stirring in about one minute. The mixture is stirred for one hour and allowed to stand overnight. One liter of hexane is added. The lower layer is separated, diluted with water and extracted with hexane. The hexane layers are washed several times with water and then combined and dried over magnesium sulfate. Filtration and then evaporation of the hexane gives 198.5 g of product which is distilled giving 168 g of the desired product.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>O1CCOCC1>[CH2:25]([O:24][C:22]([CH2:21][C:17]1[CH:16]=[C:15]([NH:14][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=2)[CH:20]=[CH:19][CH:18]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)Cc1cccc(N)c1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(Nc2nc(C)ncc2C(=S)OCC)c1
Temperature: 60 °C
Yield: 95.8 %

Procedure:
A mixture of 5 g (21.5 mmol) of ethyl 4-chloro-2-methylthio-pyrimidine-5-carboxylate and 4 g (22.3 mmol) of ethyl 3-aminophenylacetate in 80 ml of 1,4-dioxan was treated with 6 ml (43 mmol) of triethylamine and then heated at 60° C. for 4 hours. The mixture was cooled and evaporated. The residue was partitioned between 120 ml of ethyl acetate and 100 ml of 2M hydrochloric acid. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 7.4 g (92%) of ethyl 4-[3-(ethoxycarbonylmethyl)phenyl]amino-2-methylthiopyrimidine-5-carboxylate as a pale orange colored oil which solidifies slowly to a white solid. [Mass spectrum (ESI) MH+ =376].
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:12])[CH:3]=1.Cl.Cl.[CH3:15][N:16]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH:21][C@@H:18]2[CH2:19][CH2:20][N:16]([CH3:15])[CH2:17]2)=[O:8])=[C:4]([F:12])[CH:3]=1
Reactant: Nc1cc(F)c(C(=O)O)cc1F
Reactant: CN1CC[C@@H](N)C1
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: CN1CC[C@@H](NC(=O)c2cc(F)c(N)cc2F)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-amino-2,5-difluoro-benzoic acid (Rare Chemicals GmbH; 450 mg, 2.6 mmol), (3R)-1-methylpyrrolidin-3-amine di Hydrochloride (Intermediate 184; 473 mg, 2.73 mmol), HATU (1.08 g 2.86 mmol) and DIPEA (2.25 mL, 13 mmol) were combined in DMF (10 mL) and stirred at room temperature for 4 hours. The solvent was evaporated and the residue dissolved in MeOH and added to an SCX-2 column (20 g), pre-wet with MeOH (2 column volumes). The column was flushed with MeOH (2 column volumes) and eluted with 2M ammonia in MeOH. Product containing fractions were combined and evaporated and the resultant material dissolved in DCM and purified on a silica column eluting with 5% 2M ammonia in MeOH/DCM. Fractions containing product were combined and evaporated to a yellow gum. Diethylether was added and re-evaporated and dried under high vacuum to yield the title compound as a yellow gum, which slowly crystallised to a cream solid (550 mg, 83%)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[CH:26]=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]3[CH3:36])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: C[C@H]1COCCN1Cc1cccc(Br)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: C[C@H]1COCCN1Cc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and (3S)-4-[(6-bromopyridin-2-yl)methyl]-3-methylmorpholine (133 mg, 0.49 mmol) as starting materials.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:17]2([C:23]([O:25][CH3:26])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N([CH2:32][CH3:33])CC)C>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([S:14]([C:17]2([C:23]([O:25][CH3:26])=[O:24])[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:33]3[CH:32]=[CH:4][CH:3]=[CH:2][CH:7]=3)=[O:24])[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)C1(S(=O)(=O)c2ccc(Oc3ccccc3)cc2)CCNCC1
Product: COC(=O)C1(S(=O)(=O)c2ccc(Oc3ccccc3)cc2)CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
1-Benzyl 4-methyl 4-((4-phenoxyphenyl)sulfonyl)piperidine-1,4-dicarboxylate was synthesized as shown in FIG. 10. A 100 ml RBF equipped with magnetic stir bar was charged with 1.1 g (2.67 mmole) 4-methyl 4-((4-phenoxyphenyl)sulfonyl)piperidine-4-carboxylate 0.73 g (2.94 mmole) Cbz-OSu, 0.8 g (8.01 mmole) triethylamine. LCMS after 1 hour showed complete reaction with M+H=510 g/mol. The reaction was partitioned between EA and satd. aq. sodium bicarbonate. The organics were washed with 10 aq. KHSO4, dried and concentrated to thick syrup that turned into white dry foam upon high vacuum drying. The product was dried overnight to afford 1.29 g (95% yield) of the Cbz ester that was used in Step 2.