Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]#[N:13])(=O)OCC)C.[C:14]1([C:20]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:21][CH2:22][CH2:23][N:24]2[C:28]([NH2:29])=[C:27]([CH:30]=O)[CH:26]=[N:25]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[C:12](/[CH:11]=[CH:30]/[C:27]1[CH:26]=[N:25][N:24]([CH2:23][CH2:22][O:21][C:20]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:28]=1[NH2:29])#[N:13]
Reactant: Nc1c(C=O)cnn1CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#C/C=C/c1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1N

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 3.46 g) in tetrahydrofuran (250 ml) was added dropwise diethyl(cyanomethyl)phosphonate (23.3 ml) under ice-cooling. The mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added a solution of 1-(2-triphenylmethyloxyethyl)-5-aminopyrazole-4-carbaldehyde (47.76 g) in tetrahydrofuran (250 ml) at room temperature. The mixture was stirred at room temperature for 5 hours and extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogencarbonate solution, water and brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with diisopropyl ether and dried in vacuo to give 4-[(E)-2-cyanoethenyl]-1-[2-(trityloxy)ethyl]-5-aminopyrazole (59.38 g). 1H-NMR(DMSO-d6) δ3.13 (2H, t, J=4.9 Hz), 4.15 (2H, t, J=4.9 Hz), 5.59 (1H, d, J=16.3 Hz), 6.35 (2H, s), 7.0–7.4 (15H, m), 7.47 (1H, d, J=16.3 Hz), 7.63 (1H, s)
Reaction SMILES: Cl[C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[N:3]=1.Cl.Cl.[NH2:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1.C(N(CC)CC)C.C(Cl)(Cl)Cl>CN(C)C=O.C(OCC)C.O>[NH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:2]2[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[N:3]=2)[CH2:26]1
Reactant: NC1CCNC1
Reactant: COC(=O)c1cc(F)c(Cl)nc1Nc1ccc(F)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(F)c(N2CCC(N)C2)nc1Nc1ccc(F)cc1F
Yield: 95.1 %

Procedure:
In 10 ml of N,N-dimethylformamide was suspended 1.00 g of methyl 6-chloro-2-(2,4-difluorophenylamino)-5-fluoronicotinate, and to the resulting suspension were added 750 mg of 3-aminopyrrolidine dihydrochloride, and 1.44 g of triethylamine, after which the resulting mixture was subjected to reaction at 70° C. for 30 minutes. Subsequently, to the reaction mixture were added 50 ml of chloroform and 50 ml of water, and the organic layer was separated, washed successively with 25 ml of water and 25 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 5 ml of diethyl ether, after which crystals were collected by filtration to obtain 1.10 g (yield 95.1%) of methyl 6-(3-amino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinate having a melting point of 139°-140° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([OH:16])=O)=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH:27][C:14]([C:10]2[S:9][C:8]([N:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][C:4]3=[O:17])=[N:12][C:11]=2[CH3:13])=[O:16])=[CH:21][CH:20]=1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)O
Reactant: NCCc1ccc(F)cc1
Product: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCCc1ccc(F)cc1
Yield: 69 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with 2-(4-fluorophenyl)ethanamine, the title compound was obtained as a colorless solid in 69% yield: mp 225-227° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.57 (d, J=8.0 Hz, 1H), 8.23 (t, J=5.5 Hz, 1H), 7.25-7.18 (m, 2H), 7.12-7.04 (m, 2H), 6.25 (dd, J=8.0, 2.6 Hz, 1H), 5.81 (d, J=2.5 Hz, 1H), 3.42-3.35 (m, 2H), 2.78 (t, J=7.2 Hz, 2H), 2.50 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.8, 161.9, 161.6, 159.6, 154.1, 149.6, 136.0, 132.6, 130.9, 124.0, 115.5, 104.3, 98.0, 41.2, 34.5, 17.3; MS (ES+) m/z 374.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:14]1[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N+:15]=1[O-].O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:16]1[C:17]([N+:21]([O-:23])=[O:22])=[CH:18][C:19]([CH3:20])=[C:14]([C:4]2[CH:5]=[CH:6][C:7]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:8][C:3]=2[O:2][CH3:1])[N:15]=1
Reactant: COc1cc(OC(F)(F)F)ccc1-c1c(C)cc([N+](=O)[O-])c[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc(OC(F)(F)F)ccc1-c1nc(Cl)c([N+](=O)[O-])cc1C
Temperature: 75 °C
Reaction time: 2 h

Procedure:
POCl3 (500 ml) is added to 2-(2-methoxy-4-trifluoromethoxy-phenyl)-3-methyl-5-nitro-pyridine 1-oxide (97 g, 0.3 mol) at room temperature and the mixture is stirred at 75° C. for 2 hours. The mixture is concentrated under reduced pressure. Aqueous saturated Na2CO3 is added to the residue and the mixture is extracted with EtOAc. The combined extracts are washed with brine and dried over Na2SO4. The solvent is removed under reduced pressure. The residue is purified by flash column chromatography (hexane/EtOAc 10:1) to obtain 2-chloro-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-3-nitro-pyridine. Rf (hexane/EtOAc=9:1)=0.35.
Reaction SMILES: S([O-])([O:4][CH2:5][C:6]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:7])(=O)=O.[Na+].[OH2:24]>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH2:9]([O:8][C:6]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:7])[C:5]([O:24][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:4])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCOC(C)(COS(=O)(=O)[O-])OCCCCCC
Reactant: O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCOC(=O)C(C)(OCCCCCC)OCCCCCC
Yield: 84 %

Procedure:
To a solution of methyl pyruvate 1 (10.0 g, 98.0 mmol) in toluene (100 mL) is added 1-hexanol 2 (40.1 g, 392 mmol) and p-TsOH (186 mg, 0.98 mmol). The mixture is heated to reflux for 10 hours with azeotropic removal of water from the reaction mixture. The reaction is quenched with saturated NaHCO3 (100 mL), and the reaction mixture is extracted with ethyl acetate (2×100 mL). The combined organic layers are washed with brine (100 mL) and dried over anhydrous sodium sulfate. The solvent is removed and the residue is purified by silica gel chromatography (1→10% ethyl acetate/hexane) to give hexyl 2,2-bis(hexyloxy)propanoate 3 (29.5 g, 84%) as a colorless oil: Rf (15% EtOAc/hexane)=0.53; IR (thin film, cm−1) 2956, 2930, 2860, 1746 (C═O), 1467, 1280, 1137, 1062. 1H NMR (600 MHz, CDCl3) δ 4.14 (t, J=7.2 Hz, 2H), 3.48 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 3.35 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 1.65-1.63 (m, 2H), 1.59-1.54 (m, 4H), 1.49 (s, 3H), 1.35-1.24 (m, 18H), 0.86 (t, J=7.2 Hz, 9H); 13C NMR (150 MHz, CDCl3) δ 170.2, 99.5, 65.4, 62.6, 31.7, 31.3, 29.7, 28.5, 25.8, 25.5, 22.6, 22.5, 21.9, 14.0, 13.9.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][NH:14][C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]1([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[O:20]1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][N:14]([C:19]2([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[O:20]2)[C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CONC1=O)OCc1ccccc1
Reactant: O=C1OC(Cl)(C(=O)OCc2ccc([N+](=O)[O-])cc2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CON(C2(C(=O)OCc3ccc([N+](=O)[O-])cc3)OC(=O)c3ccccc32)C1=O)OCc1ccccc1
Yield: 64.1 %

Procedure:
In 5 ml of dichloromethane were dissolved 236 mg of (4S)-4-benzyloxycarbonylamino-3-isoxazolidinone and 347 mg of Compound (98). To the solution was added, under ice-cooling, 0.14 ml of triethylamine, and the mixture was stirred for 30 minutes. The solvent was evaporated off. To the residue was added ethyl acetate, which was washed with water and an aqueous saline solution. The organic layer was dried, then the solvent was evaporated off. The residue was subjected to a column chromatography using Florisil, followed by elution with hexane--ethyl acetate (2:1→1:1) to give 350 mg of the subject Compound (99) as a pale yellow oily product.
Reaction SMILES: C(OC(=O)[NH:7][C@:8]1([C:20](=[O:25])[N:21]([O:23][CH3:24])[CH3:22])[C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:9]1[CH2:17][O:18][CH3:19])(C)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[CH3:24][O:23][N:21]([CH3:22])[C:20]([C@@:8]1([NH2:7])[C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:9]1[CH2:17][O:18][CH3:19])=[O:25]
Reactant: COC[C@@H]1[C@H](c2ccccc2)[C@]1(NC(=O)OC(C)(C)C)C(=O)N(C)OC
Agent: Cl
Solvent: C1COCCO1
Product: COC[C@@H]1[C@H](c2ccccc2)[C@]1(N)C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
[(1R*,2R*,3R*)-2-methoxymethyl-1-(methoxy-methyl-carbamoyl)-3-phenyl-cyclopropyl]-carbamic acid t-butyl ester (25 mg, 0.69 mmol) was dissolved in 4 mL of HCl in dioxane (4M). After stirring at room temperature for 1 hour, the solution was concentrated and dried under high vacuum to afford 100% of an HCl salt product.
Reaction SMILES: IC1C=CC(C2NC([C@@H](N3C(=O)[C@@H](CCC(O)=O)NC3=O)C(C)C)=NC=2)=CC=1.C1(C[C@H]2NC(=O)[N:35]([C@H:39]([C:48]3[NH:49][C:50]([C:54]4[CH:59]=[CH:58][C:57]([I:60])=[CH:56][C:55]=4[F:61])=[C:51]([CH3:53])[N:52]=3)[C@H:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH3:41])C2=O)CC1.C(O[C:68]([NH:70][C@H:71]([C:75]1[CH:80]=[CH:79][C:78]([O:81][CH2:82][C:83](=[O:87])[N:84]([CH3:86])[CH3:85])=[CH:77][CH:76]=1)[C:72]([OH:74])=O)=[O:69])(C)(C)C.ClN1C(=O)CCC1=O>>[F:61][C:55]1[CH:56]=[C:57]([I:60])[CH:58]=[CH:59][C:54]=1[C:50]1[NH:49][C:48]([C@@H:39]([N:35]2[C:72](=[O:74])[C@@H:71]([C:75]3[CH:76]=[CH:77][C:78]([O:81][CH2:82][C:83]([N:84]([CH3:85])[CH3:86])=[O:87])=[CH:79][CH:80]=3)[NH:70][C:68]2=[O:69])[C@H:40]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH3:41])=[N:52][C:51]=1[CH3:53]
Reactant: CN(C)C(=O)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: Cc1nc([C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](CC3CC3)C2=O)[nH]c1-c1ccc(I)cc1F
Agent: CC(C)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CCC(=O)O)C1=O
Agent: O=C1CCC(=O)N1Cl
Product: Cc1nc([C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc(OCC(=O)N(C)C)cc3)C2=O)[nH]c1-c1ccc(I)cc1F

Procedure:
Prepared by the same method as described in example 1 except that (i) steps A, B and C were omitted; (ii) 1-(2-fluoro-4-iodo-phenyl)-propan-1-one (prepared as described in example 13) was used in place of 1-(2-fluoro-4-iodo-phenyl)-ethanone in step 72-D; (iii) chlorination of the 5-position of the imidazole ring with N-chlorosuccinimide in step 72-F was omitted and (iv) (R)-tert-butoxycarbonylamino-(4-dimethylcarbamoylmethoxy-phenyl)-acetic acid (prepared as described in example 6) was used in place of (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid in step 72-G. HR-MS: calcd for C32H31FlN5O4 [M+H+] 696.1478. Found 696.1475.
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[CH3:13][C:14]1([CH2:22][C:23]([CH3:25])=[CH2:24])[CH2:19][CH2:18][CH2:17][CH:16]([CH3:20])[C:15]1=[O:21]>C1(C)C=CC=CC=1>[CH3:24][C:23]1([CH3:25])[CH2:22][C:14]2([CH3:13])[CH2:19][CH2:18][CH2:17][CH:16]([CH3:20])[CH:15]2[O:21]1
Reactant: C=C(C)CC1(C)CCCC(C)C1=O
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1CCCC2(C)CC(C)(C)OC12
Temperature: 100 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
A 3 L reaction flask was charged with vitride (325 g, 0.9 mol) and toluene (500 mL), heated to 100° C., fed with 2,6-dimethyl-2-(2-methyl-allyl)-cyclohexanone (200 g, 1.1 mol, obtained as detailed above) for over 2 hours, and aged for another 2 hours. After the reaction completed, the reaction mixture was cooled to room temperature, quenched with IPA (100 mL). NaOH (50%, 300 g) and water (200 mL) were then added, heated to 80° C., and aged for another hour. The reaction mixture was cooled to room temperature and more water (200 mL) was added. Layers were split to dispose the aqueous waste. The organic layer was charged back to the flask. Toluene (300 mL) was added and water was removed with a Bidwell-Sterling trap through azeotrope. The resulting mixture was cooled to 50° C. MSA (28 g, 0.3 mol) was added and the reaction mixture was heated to reflux. The consumption of the starting material was indicated after 3 hours. The resulting mixture was then cooled to room temperature and washed with saturated sodium carbonate solution (1 L) followed by brine (1 L). Distillation and fractionation provided the product 2,2,3a,7-tetramethyl-octahydro-benzofuran (125 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:27]([O:38][CH3:39])[CH:26]=1>CN(C=O)C>[C:32]([NH:31][C:29](=[O:30])[C:28]1[CH:36]=[CH:37][C:25]([CH2:24][N:11]2[C:10](=[O:13])[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:12]2)=[CH:26][C:27]=1[O:38][CH3:39])([CH3:35])([CH3:34])[CH3:33]
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1
Reactant: COc1cc(CBr)ccc1C(=O)NC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(Cn2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)ccc1C(=O)NC(C)(C)C
Temperature: 70 °C
Reaction time: 16 h

Procedure:
An amount of 70 mg (0.30 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one (preparation as per WO 2007/134862 Example 36A) was dissolved in 3 ml of DMF and admixed with 194 mg (0.59 mmol) of caesium carbonate and also 98 mg (0.33 mmol) of the compound from Example 23A. The mixture was stirred at 70° C. for 16 h. After cooling to RT, the crude mixture was freed from insoluble constituents by filtration and subjected directly to chromatographic purification [Method 8]. This gave 89 mg (66% of theory) of the target compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][O:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:17][CH:18]1[CH2:21][NH:20][CH2:19]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:13][O:14][CH3:15])[C:10]([N:20]1[CH2:21][CH:18]([F:17])[CH2:19]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: FC1CNC1
Reactant: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[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: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
A 25 mL round-bottomed flask was charged with (R)-2-tert-butoxycarbonylamino-3-methoxy-propionic acid (0.40 g, 1.82 mmol), 3-fluoroazetidine hydrochloride (204 mg, 1.82 mmol), HBTU (989 mg, 2.74 mmol), and HOBt (375 mg, 2.74 mmol). Then added DMF (3.6 mL) followed by N,N-diisopropylethylamine (1.27 mL, 7.3 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0-50% EtOAc) to afford 267 mg (53%) of [(R)-2-(3-fluoro-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: C(O)(=O)C.[CH3:5][N:6]([CH3:20])[C:7]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.[NH2:21][CH2:22][CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1>O1CCCC1.ClCCCl>[NH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([CH2:23][CH2:22][NH:21][CH:10]2[CH2:11][CH2:12][C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)([N:6]([CH3:20])[CH3:5])[CH2:8][CH2:9]2)=[CH:25]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccn2)CCC(=O)CC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)C1(c2ccccn2)CCC(NCCc2c[nH]c3ccccc23)CC1
Reaction time: 0.25 h

Procedure:
Acetic acid (0.448 ml) was added to a solution of 4-dimethylamino-4-pyridin-2-yl cyclohexanone (873 mg) and tryptamine (640 mg) in dry tetrahydrofuran (40 ml) and anhydrous 1,2-dichloroethane (10 ml) and stirred for 15 min. Following addition of sodium triacetoxyboron hydride (1.2 g) the reaction mixture was stirred for three days under argon at room temperature. To recover the product the solvent was removed in vacuo, the residue taken up in 1N sodium hydroxide solution (40 ml) and diethyl ether (40 ml), the phases separated, the aqueous phase extracted with diethyl ether (2×30 ml), the organic phases combined, dried and concentrated to low volume. The resulting raw product was separated by column chromatography on silica gel with methanol and methanol/ammonia (100:1). The non-polar diastereoisomer of N′-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-yl cyclohexane-1,4-diamine was obtained as a white solid (617 mg; mp 150–152° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][C:10](OCC(C)C)=O)=[CH:4][C:3]=1[NH:17][C:18](=[O:21])[O:19][CH3:20].[C:22]1([CH3:38])[CH:27]=CC(S(OC2CCC(C)C2)(=O)=O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:24][CH2:23][CH:22]([CH3:38])[CH2:27]2)=[CH:4][C:3]=1[NH:17][C:18](=[O:21])[O:19][CH3:20]
Reactant: COC(=O)Nc1cc(OC(=O)OCC(C)C)c(Cl)cc1F
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(C)C2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)Nc1cc(OC2CCC(C)C2)c(Cl)cc1F
Reaction time: 5 h
Yield: 75 %

Procedure:
A solution of methyl N-(2-fluoro-4-chloro-5-isobutyloxycarbonyloxyphenyl)carbamate (5.37 g, 16.8 mmol) prepared by the process as shown in Reference Example 3, 3-methylcyclopentyl p-toluenesulfonate (5.0 g, 20.2 mmol) and potassium carbonate (2.32 g, 16.8 mmol) in methanol (50 ml) was stirred for 5 hours under refluxing. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (100 ml), and the mixture was extracted with ethyl acetate (50 ml×3 times). The organic layer was dried, and the solvent was distilled off under reduced pressure to obtain methyl N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}carbamate as grey white crystals (3.81 g, 12.6 mmol, 75.2% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][CH2:12][OH:13])=[CH:5][NH:6]2.[B-][N+](C)(C)C.Cl>O1CCOCC1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([CH2:11][CH2:12][OH:13])[CH2:5][NH:6]2
Reactant: Cc1cccc2[nH]cc(CCO)c12
Agent: Cl
Agent: [B-][N+](C)(C)C
Solvent: C1COCCO1
Product: Cc1cccc2c1C(CCO)CN2
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
A mixture of 4-methyl-1H-indole (15.7 g, 0.12 mol), diethyl ether (300 mL) and tetrahydrofuran (300 mL) was stirred at room temperature. To this solution was added oxalyl chloride (22.8 g, 0.18 mol) drop wise. The resulting solution was stirred at room temperature for 16 h. Ethanol (100 mL) was added, and the mixture was stirred for 5 min. Triethylamine (100 mL) was added under cooling (20-30° C.) and then ice (200 mL) and brine (1 L). The aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The solid compound formed was stirred with diethyl ether, collected by filtration and dried in vacuo to give ethyl (4-methyl-1H-indol-3-yl)-oxo-acetate (22.5 g). This compound was dissolved in tetrahydrofuran (250 mL) and subsequently added to lithium aluminium hydride (13 g, 0.35 mol) in tetrahydrofuran (500 mL). The resulting mixture was boiled under reflux for 1 h and then quenched with water (50 mL). The mixture was filtered, and the mother liquor was concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate/heptane 50:50) and subsequently crystallised from ethyl acetate to give 2-(4-methyl-1H-indol-3-yl)ethanol (14.4 g, 85%). To a mixture of 2-(4-methyl-1H-indol-3-yl)ethanol (14.4 g, 0.08 mol), borane trimethylamine complex (64 g, 0.88 mol) and 1,4-dioxane (500 mL) was added 37% aqueous HCl (55 mL), and the resulting mixture was stirred at room temperature for 16 h. The mixture was boiled under reflux for 1.5 h. 6 M aqueous HCl (260 mL) was added, and 300 mL of 1,4-dioxane/water was removed by distillation. The aqueous phase was cooled to 20° C. and then made alkaline by the use of 28% aqueous sodium hydroxide. The aqueous phase was added brine (500 mL) and extracted with ethyl acetate. The combined organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate) to give the title compound (12.5 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.C([Li])(CC)C.C1CCCCC1.C[O:45][B:46]([O:48]C)F>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([F:10])([F:11])[F:12])=[C:6]([B:46]([OH:48])[OH:45])[CH:7]=1
Reactant: COB(F)OC
Reactant: FC(F)(F)Oc1ccc(Cl)cc1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: OB(O)c1cc(Cl)ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the 4-chloro(trifluoromethoxy)benzene (2.0 g, 10.18 mmol) in dry tetrahydrofuran (THF, 30 ml) at −78° C., was added ethylenediaminetetraacetic acid (EDTA, 1.24 g, 10.7 mmol) followed by a 1.3 M solution of sec-butyllithium in cyclohexane (7.63 ml, 10.7 mmol) and the reaction stirred for 2 hours under nitrogen. To this reaction mixture at −78° C., was then added dropwise the preformed dimethoxyfluoroborane mixture. The reaction was stirred at −78° C. for 30 minutes, warmed to room temperature for 30 minutes, and then quenched with water (10 ml). The reaction mixture was extracted with diethyl ether (4×50 ml). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. To purify, the residue was dissolved in diethyl ether (10 ml) and washed with an aqueous solution of 10% NaOH (50 ml). The aqueous layer was acidified and extracted with ethyl acetate (3×40 ml). The combined ethyl acetate extracts were dried over MgSO4 and concentrated in vacuo to afford a mixture of the title compound and its corresponding regioisomer as a white solid (0.862 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[N:1]1([CH2:6][CH2:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CC1(c2ccc(SCCCN3CCCC3)cc2)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCC1(c2ccc(SCCCN3CCCC3)cc2)CCOCC1
Yield: 91 %

Procedure:
The title compound (2.42 g, 91%) was prepared using 4-{4-[(3-pyrrolidin-1-ylpropyl)thio]phenyl}tetrahydro-2H-pyran-4-carbonitrile and lithium aluminium hydride similarly to the procedure used for intermediate 51. LRMS APCI+ m/z 335 [MH]+. Microanalysis: Found: C, 64.08; H, 8.79; N, 7.447%. C19H30N2OS.0.33DCM requires C, 64.04; H, 8.52; N, 7.73%.