Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10](O)[CH2:11][C:5]=2[CH:4]=1.[Cl-:21].[Ca+2].[Cl-].Cl>C1C=CC=CC=1>[Cl:21][CH:10]1[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7][C:6]2[CH:17]=[CH:18][C:3]([C:2]([F:20])([F:19])[F:1])=[CH:4][C:5]=2[CH2:11]1
Reactant: [Cl-]
Reactant: OC1Cc2cc(C(F)(F)F)ccc2Sc2ccccc21
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: FC(F)(F)c1ccc2c(c1)CC(Cl)c1ccccc1S2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
11.4 g of 10,11-dihydro-2-trifluoromethyl-dibenzo[b,f]thiepin-10-ol, 100 ml of benzene and 4 g of calcium chloride are saturated with hydrochloric acid gas for 2 hours at 15° C and subsequently stirred at room temperature for 3 hours. The mixture is filtered and concentrated under reduced pressure. There is obtained 10-chloro-10,11-dihydro-2-trifluoromethyl-dibenzo[b,f]thiepin in the form of yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH2:9].N1C=CC=CC=1O[C:17](=[S:25])OC1C=CC=CN=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]=[C:17]=[S:25]
Reactant: Nc1c(F)cccc1Cl
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: C1CCOC1
Product: Fc1cccc(Cl)c1N=C=S
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-6-fluoro-phenylamine (400 mg, 2.8 mmol), thiocarbonic acid O,O-dipyridin-2-yl ester (650 mg, 2.8 mmol) and TEA (840 μL, 6.0 mmol) in 5 mL THF was stirred overnight at 50° C. The mixture was heated to 65° C. and stirred for further 5 h. The mixture was concentrated i.vac. The residue was purified by chromatography on HPLC (C-18 Symmetry, eluent gradient: water+0.15% HCOOH+15-100% acetonitrile).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[C:23]1([C:29]2[C:38]([CH:39]([OH:50])[C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=3)=[C:37]([CH:51]([CH3:53])[CH3:52])[CH:36]=[C:35]3[C:30]=2[C:31](=[O:56])[CH2:32][C:33]([CH3:55])([CH3:54])[O:34]3)[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1>ClCCl>[C:23]1([C:29]2[C:38]([C:39](=[O:50])[C:40]3[CH:41]=[CH:42][C:43]([C:46]([F:48])([F:49])[F:47])=[CH:44][CH:45]=3)=[C:37]([CH:51]([CH3:52])[CH3:53])[CH:36]=[C:35]3[C:30]=2[C:31](=[O:56])[CH2:32][C:33]([CH3:54])([CH3:55])[O:34]3)[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: CC(C)c1cc2c(c(C3=CCCCC3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)c1cc2c(c(C3=CCCCC3)c1C(=O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reaction time: 4 h

Procedure:
At 0° C., 153 mg (360 μmol) of 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-one are added to a solution of 85 mg (180 μmol) of 5-cyclohex-1-en-1-yl-6-{hydroxy[4-(trifluoromethyl)phenyl]-methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 35A) in 4 ml of dichloromethane, and the mixture is stirred at this temperature for 4 h. The mixture is then diluted with dichloromethane and washed three times with 1 M aqueous sodium hydroxide solution. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure, and the residue is purified by column chromatography on silica gel (mobile phase: gradient cyclohexane→cyclohexane/dichloromethane/ethyl acetate 20:20:0.5).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:25])=[C:11]([C:14]3[C:15]([O:23][CH3:24])=[N:16][C:17]([N:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=3)[CH:12]=2)[NH:7][CH:6]=1)=[O:4].O1CCCC1.[OH-].[Na+].Cl>C(OCC)(=O)C.CC(C)=O.CO>[Cl:25][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([C:3]([OH:4])=[O:2])=[CH:6][NH:7]2)=[CH:12][C:11]=1[C:14]1[C:15]([O:23][CH3:24])=[N:16][C:17]([N:20]([CH3:21])[CH3:22])=[CH:18][CH:19]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(N(C)C)nc3OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1nc(N(C)C)ccc1-c1cc2c(C(=O)O)c[nH]c2cc1Cl
Reaction time: 60 h
Yield: 178 %

Procedure:
To a solution of Intermediate 6-chloro-5-(6-dimethylamino-2-methoxy-pyridin-3-yl)-1H-indole-3-carboxylic acid methyl ester (45.0 g, 130 mmol) in 1:1 tetrahydrofuran:methanol (1250 mL) at 50° C. was added 2 N NaOH (1250 mL). After 60 h, the reaction was cooled to <5° C. and with stirring, 6 N HCl (417 mL) was added dropwise until pH 6-7. The solution was divided in half and each was diluted with ethyl acetate (1.5 L) and the layers separated. The aqueous layers were back extracted with ethyl acetate (2×600 mL). All organics were combined and washed with sat. aq. NH4Cl (1 L) and brine (1 L), and dried over MgSO4, filtered and concentrated in vacuo to give crude material. Several batches of crude material were combined (117 g) and acetone (3.5 L) was added. This was refluxed to dissolve all solids and then partially concentrated to ˜1.5 L and slowly cooled to lead to solids crashing out. These solids were suspended in heptanes (˜500 mL) and stirred at 80° C. for 48 h. Solids were collected by filtration and suction dried for 15 h to afford desired product (80.0 g) as a solid. 1H NMR (DMSO-d6, 400 MHz) δ=12.03 (br. s., 1 H) 11.86 (br. s., 1 H) 8.04 (d, J=2.73 Hz, 1 H) 7.83 (s, 1 H) 7.55 (s, 1 H) 7.32 (d, J=8.20 Hz, 1 H) 6.21 (d, J=8.20 Hz, 1 H) 3.76 (s, 3 H) 3.07 (s, 6 H); MS (ES+) 346.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[C:19](Br)=[CH:18][S:17][CH:16]=2)[N:12]([S:21]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:30])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[C:19]([C:31]#[N:32])=[CH:18][S:17][CH:16]=2)[N:12]([S:21]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CN(Cc1cc(-c2cscc2Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CN(Cc1cc(-c2cscc2C#N)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 71 %

Procedure:
To a solution (5 mL) of tert-butyl{[5-(4-bromo-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (470 mg) in N,N-dimethylformamide were added zinc cyanide (215 mg) and tetrakis(triphenylphosphine)palladium (212 mg) and the mixture was sufficiently degassed. The mixture was stirred with heating at 120° C. for 18 hr and cooled to room temperature. Water and ethyl acetate were added and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:1) to give the title compound as a pale-yellow oil (yield 297 mg, 71%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].C([Li])CCC.[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH:28]=[O:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1>[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH:28]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[Cl:8])[OH:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1ccccc1Br
Reactant: O=CCC1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(CC1CCN(Cc2ccccc2)CC1)c1ccccc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
After dissolving 1.75 ml of 1-bromo-2-chlorobenzene in 30 ml of tetrahydrofuran, the solution was cooled to −78° C. Next, 5.31 ml of n-butyllithium (2.6 M, n-hexane solution) was added dropwise thereto while stirring and after 1 hour, a solution of 2.50 g of 1-benzylpiperidine-4-acetaldehyde in tetrahydrofuran (10 ml) was added and stirring was continued for 1 hour. After adding water to the reaction solution, the temperature was raised to room temperature and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 2-(1-benzylpiperidin-4-yl)-1-(2-chlorophenyl)ethanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][NH:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:32][C:33]([F:37])([F:36])[CH2:34]I.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:19]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[CH:18][N:17]([CH2:34][C:33]([F:37])([F:36])[F:32])[N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)CI
Reactant: c1ccc(COc2ccc(-c3n[nH]cc3-c3ccncc3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2)n1
Temperature: 60 °C

Procedure:
To a solution of 4-[3-(4-Benzyloxy-phenyl)-1H-pyrazol-4-yl]-pyridine (0.42 g) in dimethyl formamide (7 ml) was added cesium carbonate (0.65 g) and 1,1,1-Trifluoro-2-iodo-ethane (0.29 ml). The reaction mixture was heated at 60° C. for 24 h, poured into water and extracted 3× with dichloromethane. Purification via biotage MPLC chromatography, eluting with 5% methanol/0.5% ammonium hydroxide/70% ethyl acetate/hexane provided the title compound. MS: (M+H m/z=410.0).
Reaction SMILES: [Br:1][C:2]1[C:11]([I:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13]P(=O)(OCC)OCC)=[CH:7]2.[H-].[Na+].[CH:24]([C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[C:29]([O:31][CH3:32])=[O:30])=O>C1COCC1>[Br:1][C:2]1[C:11]([I:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](/[CH:13]=[CH:24]/[C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[C:29]([O:31][CH3:32])=[O:30])=[CH:7]2
Reactant: CCOP(=O)(Cc1ccc2c(Br)c(I)ccc2c1)OCC
Reactant: COC(=O)c1cccc(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(/C=C/c2ccc3c(Br)c(I)ccc3c2)c1
Reaction time: 1 h

Procedure:
To a solution of diethyl (5-bromo-6-iodo-2-naphthyl)methylphosphonate (250 mg) from step 5 in THF (5 mL) at 0° C. was added NaH (60% in mineral oil, 17 mg). The reaction mixture was stirred for 1 hour upon which methyl 3-formylbenzoate (85 mg) was added and stirring continued for 1 h at rt. The mixture was quenched with a saturated solution of NH4Cl, extracted with EtOAc, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography eluting with 5% EtOAc/hexanes to afford the titled product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:17]=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][C:21]=1O.BrC1C=C([N+]([O-])=O)C=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[Br:15][C:16]1[CH:17]=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][C:21]=1[O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=[N+]([O-])c1cccc(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2Br)CC1
Temperature: 25 °C
Reaction time: 11.5 h
Yield: 88.6 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (2.7 g), 3-bromo-4-hydroxynitrobenzene (1.9 g) [which was prepared from 3-bromonitrobenzene according to the method described in J. Org. Chem., 63 4199 (1998)] and triphenylphosphine (4.4 g) in dichloromethane (50 ml) was added dropwise diethyl azodicarboxylate (2.7 ml) and the mixture was stirred at room temperature for 11.5 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=2/1 as an eluant to give the desired compound (3.1 g, yield 91%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([S:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)(=[O:17])=[O:16])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[Cl:24]N1C(=O)CCC1=O>ClCCCl.CO>[Cl:24][C:10]1[C:5]2[N:6]([C:2]([CH3:1])=[N:3][N:4]=2)[C:7]2[CH:13]=[C:12]([CH3:14])[N:11]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:8]=2[CH:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc2c(ccc3nnc(C)n32)n1S(=O)(=O)c1ccccc1
Solvent: CO
Solvent: ClCCCl
Product: Cc1cc2c(cc(Cl)c3nnc(C)n32)n1S(=O)(=O)c1ccccc1
Temperature: 60 °C

Procedure:
A suspension of 1,7-dimethyl-6-(phenylsulfonyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (2.0 g, 6.1 mmol, from Step 4) and N-chlorosuccinimide (0.91 g, 6.8 mmol, Aldrich) in 1,2-dichloroethane (40 mL) was heated at 60° C. overnight. Flash chromatography, eluting with a gradient from 0-5% MeOH/DCM (0.5% NH4OH), afforded an orange solid which was refluxed in 10 mL MeOH for 15 minutes. The product was isolated by filtration. Yield: (2.2 g, 80%). 1H NMR (500 MHz, d6-DMSO) δ 8.23 (s, 1H), 8.01-7.96 (m, 2H), 7.80-7.74 (m, 1H), 7.68-7.61 (m, 2H), 7.22 (s, 1H), 2.86 (s, 3H), 2.62 (s, 3H); LCMS (M+H)+: 361.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]([CH2:7][CH2:8][CH3:9])[CH2:5][OH:6].Cl[CH2:11][C:12](OCC)=[O:13].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH2:7]([C@@H:4]1[NH:3][C:12](=[O:13])[CH2:11][O:6][CH2:5]1)[CH2:8][CH3:9]
Reactant: CCOC(=O)CCl
Reactant: CCC[C@H](N)CO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CCC[C@H]1COCC(=O)N1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To an ice cold, stirred suspension of NaH (60% in oil, 1.9 g, 46.0 mmol) in toluene (62 mL) was added dropwise a solution of (S)-2-aminopentan-1-ol (2.1 g, 20.0 mmol) in toluene (44 mL). After the addition was completed, the reaction mixture was warmed to room temperature and a solution of ethyl chloroacetate (2.7 g, 22.0 mmol) in toluene (12 mL) was added in a dropwise manner. The resulting mixture was then stirred at reflux for 20 h, cooled to room temperature, and solid ammonium chloride (2.5 g, 46.0 mmol) was added to the reaction. The mixture was stirred for 20 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 98:2 CH2Cl2/CH3OH to 95:5 CH2Cl2/CH3OH) to give (S)-5-propylmorpholin-3-one (2.2 g, 76%) as a yellow oil. To ice-cold THF (10 mL) was added lithium aluminum hydride (1.0 M solution in THF, 30 mL, 30 mmol). Once the addition was complete, a solution of (S)-5-propylmorpholin-3-one (2.2 g, 15 mmol) in THF (10 mL) was added dropwise over 20 min. Once the addition was completed, the ice bath was removed and the reaction mixture stirred at reflux for 20 h. The reaction was cooled in an ice-bath and to this was slowly added H2O (1.2 mL), then 15% aqueous solution of sodium hydroxide (1.2 mL), and then H2O (1.2 mL). The resulting mixture was stirred at room temperature for 1.5 h and then filtered washing the solid with EtOAc (50 mL). The filtrate was concentrated at room temperature under reduced pressure to provide (S)-3-propylmorpholine (1.9 g, 98%) as a light yellow oil. 1H NMR and MS consistent.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:12]([C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)C1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (22.17 g, 0.176 mol) in CH2Cl2 (200 mL) was added dropwise a solution of DMSO (20.59 g, 0.264 mol) in CH2Cl2 (50 mL) at −78° C. The mixture was stirred for 0.5 hrs at this temperature. A solution of (S)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (M6) (11.8 g, 58.7 mmol) in CH2Cl2 (50 mL) was added dropwise to the reaction mixture at −78° C. The mixture continued to stir for 1 hr at that temperature. Et3N (29.7 g, 0.294 mol) was added at −78° C. The resultant mixture was warmed to room temperature and stirred for 3 hrs. The mixture was poured into saturated aqueous NaHCO3 and shaken. The organic layer was separated, washed twice with water, dried and evaporated to give a residue, which was purified by column chromatography (P.E./EtOAc 5:1) to give (S)-tert-butyl 3-formylpyrrolidine-1-carboxylate (M7). 1H NMR (CDCl3, 300 MHz): δ 9.68 (d, J=1.8 Hz, 1H), 3.67-3.68 (m, 1H), 3.51-3.55 (m, 1H), 3.35-3.40 (m, 2H), 2.99-3.04 (m, 1H), 2.04-2.18 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:17])[CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.[C:18]([O:22][C:23](=[O:39])[NH:24]/[C:25](/N1C=CC=N1)=[N:26]/[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C(Cl)Cl>[C:29]([O:28][C:27](=[O:33])[NH:26]/[C:25](/[NH:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:17])[CH3:16])[CH2:10]2)=[CH:7][CH:8]=1)=[N:24]/[C:23](=[O:39])[O:22][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(=O)N[C@@H]1CCN(c2ccc(N)cc2)C1
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)n1cccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H]1CCN(c2ccc(N/C(=N\C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)C1

Procedure:
N-[(3R)-1-(4-aminophenyl)pyrrolidin-3-yl]acetamide mono hydrochloride (Method 44, 3.31 g, 15 mmol), di-tert-butyl[(Z)-1H-pyrazol-1-ylmethylylidene]biscarbamate (5.91 g, 15 mmol) and triethylamine (4.17 ml, 30 mmol) in DCM (50 ml) were heated at 40° C. for 18 hours. After evaporation under reduced pressure, chromatography on silica gel with ethyl acetate/isohexane (50:50 to 100) gave di-tert-butyl[(E)-({4-[(3R)-3-(acetylamino)pyrrolidin-1-yl]phenyl}amino)methylylidene]biscarbamate, which was dissolved in DCM (80 ml) and treated with TFA (15 ml) at ambient temperature for 18 hours under nitrogen. After evaporation under reduced pressure, the residue was dissolved in MeOH (20 ml) and diluted with ether. The title compound was collected by filtration as an off white solid (1.79 g, 30% over two steps). NMR: 1.80 (s, 3H), 1.81-1.93 (m, 1H), 2.10-2.27 (m, 1H), 2.99-3.06 (m, 1H), 3.19-3.51 (m, 3H), 4.27-4.39 (m, 1H), 6.52 (d, 2H), 7.03 (d, 2H), 7.16 (s, 3H), 8.10 (d, 1H), 9.36 (s, 1H).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[C:5]([NH:17][CH3:18])=[C:6]([C:14]([NH2:16])=[O:15])[S:7][C:8]=1[C:9]1[CH:10]=[N:11][NH:12][CH:13]=1.C([O-])(O)=O.[Na+].[C:24]1(=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CC1C=CC(S(O)(=O)=O)=CC=1.[O-]S([O-])(=O)=O.[Mg+2]>CN(C=O)C.CCOC(C)=O>[Br:3][C:4]1[C:5]2[N:17]([CH3:18])[C:24]3([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[NH:16][C:14](=[O:15])[C:6]=2[S:7][C:8]=1[C:9]1[CH:10]=[N:11][NH:12][CH:13]=1
Reactant: O=C1CCCCC1
Reactant: CNc1c(C(N)=O)sc(-c2cn[nH]c2)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1c2c(sc(-c3cn[nH]c3)c2Br)C(=O)NC12CCCCC2
Yield: 45.4 %

Procedure:
A mixture of 4-bromo-3-(methylamino)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide dihydrochloride (90 mg, 0.267 mmol), saturated aqueous NaHCO3 (50 mL) and EtOAc (50 mL) was shaken well. The organic layer was collected, dried over MgSO4, filtered and concentrated under reduced pressure. This residue was mixed with cyclohexanone (2.00 mL, 19.3 mmol), PTSA (93 mg, 0.491 mmol), MgSO4 (64.2 mg, 0.533 mmol) and DMF (2 mL). This mixture was stirred at 80° C. for 4 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with 3:1 EtOAc/THF (100 mL), and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc) to afford a white solid. This solid was triturated with EtOAc, and the precipitate was collected by filtration to afford the title compound (46.2 mg, 46%) as a white solid:
Reaction SMILES: [BH4-].[Na+].[C:3]([NH:6][CH:7]([CH2:13][C:14]1[S:18][CH:17]=[N:16][CH:15]=1)[C:8](OCC)=[O:9])(=[O:5])[CH3:4]>C(O)C>[OH:9][CH2:8][CH:7]([NH:6][C:3](=[O:5])[CH3:4])[CH2:13][C:14]1[S:18][CH:17]=[N:16][CH:15]=1
Reactant: CCOC(=O)C(Cc1cncs1)NC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)NC(CO)Cc1cncs1
Temperature: 20 °C
Reaction time: 18 h
Yield: 63.5 %

Procedure:
0.4 g of sodium borohydride is added to a solution of 1.2 g of ethyl (2RS)-2-acetylamino-3-(5-thiazolyl)propanoate in 20 cm3 of ethanol, followed by stirring under an inert atmosphere at a temperature in the region of 20° C. After 18 hours, a further 0.1 g of sodium borohydride is added and the mixture is then stirred for 24 hours at a temperature in the region of 20° C. The reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The residue is taken up in 10 cm3 of water and extracted with 3 times 30 cm3 of ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The residue is chromatographed under an argon pressure of 60 kPa on a column of silica gel (particle size 40-63μ; diameter 3.5 cm; height 31 cm), eluting with 100 cm3 it of dichloromethane, 600 cm3 of a dichloromethane/methanol mixture (98/2 by volume), 500 cm3 of a dichloromethane/-methanol mixture (96/4 by volume) and 1 dm3 of a dichloromethane/methanol mixture (90/10 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions. 0.63 g of N-[(1RS)-1-hydroxymethyl-2-(5-thiazolyl)-ethyl]acetamide is obtained in the form of a yellow oil [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1.80 (s: 3H); 2.85 (dd, J=15 and 9 Hz: 1H); 3.16 (dd, J=15 and 5 Hz: 1H); from 3.25 to 3.45 (mt: 2H); 3.87 (mt: 1H); 4.85 (mt: 1H); 7.65 (s: 1H); 7.79 (d, J=8.5 Hz: 1H); 8.91 (s: 1H)].
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[NH2:26]>CCOC(C)=O>[CH3:33][O:32][C:28]1[CH:27]=[C:25]([NH:26][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:10]=3)[N:3]=2)[CH:24]=[C:23]([O:22][CH3:21])[C:29]=1[O:30][CH3:31]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Clc1cncc(Oc2cccc(-c3ccccc3)c2)n1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3cccc(-c4ccccc4)c3)n2)cc(OC)c1OC
Yield: 78 %

Procedure:
Using Method EE (reaction time: 4 hours) with 2-chloro-6-[(3-phenyl)-phenyl-oxy]-pyrazine (100 mg, 0.35 mmol) and 3,4,5-trimethoxyaniline (84 mg, 0.46 mmol), and purification by column chromatography (AcOEt), the title compound was obtained (117 mg). Yield: 78%.