Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[NH3:18].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: N
Reactant: O=C(O)c1c(O)cccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1c(O)cccc1F
Temperature: 0 °C
Reaction time: 20 h
Yield: 51.5 %

Procedure:
2-Fluoro-6-hydoxybenzoic acid (20.0 g, 0.128 mol) and oxalyl chloride (22.3 ml, 0.256 mol) were dissolved in ethyl acetate (300 ml) together with N,N-dimethylformamide (DMF) (2 drops) and the mixture was stirred under an atmosphere of nitrogen for 20 h. The solvent was removed by distillation under reduced pressure leaving the crude acid chloride which was redissolved in ethyl acetate (300 ml) and cooled to 0° C. Concentrated aqueous ammonia (d 0.88, 50 ml) was added dropwise and the mixture was stirred for a further 2 h. The mixture was poured into aqueous sodium bicarbonate solution. The organic phase was separated and the aqueous phase extracted with ethyl acetate (2×200 ml). The combined organic phases were dried (MgSO4) and concentrated leaving the crude compound (10.2 g, 51.5%). Mass spectrum (-ve CI)m /z 154 (M+ -H) .
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[C:12]([O:16][C:17]([N:19]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:20]1[C:21]([C:27]([O:29][CH3:30])=[O:28])=[N:22][C:23](Br)=[CH:24][N:25]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>[Cu]Br.C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1.O>[C:12]([O:16][C:17]([N:19]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:20]1[C:21]([C:27]([O:29][CH3:30])=[O:28])=[N:22][C:23]([N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:24][N:25]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: C1CCNC1
Reactant: COC(=O)c1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(N2CCCC2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.5 %

Procedure:
A pre-dried flask was charged with copper(I) bromide (0.35 mg, 2.89 μmol), (R)-(+)-1,1′-bi-2-naphthol (1.66 mg, 5.78 μmol) and cesium carbonate (113 mg, 347 μmol) under argon atmosphere. DMF (0.5 ml), methyl 3-(bis(tert-butoxycarbonyl)amino)-6-bromopyrazine-2-carboxylate (50 mg, 116 μmol) and pyrrolidine (14.3 μl, 174 μmol) were added and the reaction mixture was stirred at r.t. for 1.5 h. The reaction mixture was poured into water (10 ml) and extracted with ethyl acetate. The combined organic layer was washed with brine, dried, evaporated and purified by silica gel chromatography using a heptane/ethyl acetate gradient to yield the product as yellow solid (37 mg, 68%).
Reaction SMILES: [F:1][CH:2]1[CH2:5][NH:4][CH2:3]1.[CH3:6][N:7]1[C:11]([C:12](=[O:29])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[N:18]([N:20]=[C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[N:22]=3)[CH:19]=2)=[C:10]([C:30](O)=[O:31])[CH:9]=[N:8]1>>[N:23]1([C:21]2[N:22]=[C:17]3[CH:16]=[CH:15][C:14]([NH:13][C:12]([C:11]4[N:7]([CH3:6])[N:8]=[CH:9][C:10]=4[C:30]([N:4]4[CH2:5][CH:2]([F:1])[CH2:3]4)=[O:31])=[O:29])=[CH:19][N:18]3[N:20]=2)[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Reactant: FC1CNC1
Product: Cn1ncc(C(=O)N2CC(F)C2)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1

Procedure:
Using 3-fluoro-azetidine and 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. Off-white solid (150 mg, 76%). MS: m/z=429 (M+H+).
Reaction SMILES: C1([Se][C@@H:8]2[C@H:12]3[O:13][CH2:14][CH2:15][C@@:11]3([C:16]([N:18]3[CH2:27][CH2:26][C:25]4[N:24]=[CH:23][C:22]([C:28]([F:31])([F:30])[F:29])=[CH:21][C:20]=4[CH2:19]3)=[O:17])[CH2:10][C@@H:9]2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])C=CC=CC=1.C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[F:31][C:28]([F:29])([F:30])[C:22]1[CH:23]=[N:24][C:25]2[CH2:26][CH2:27][N:18]([C:16]([C@:11]34[CH2:10][C@H:9]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:38])[CH3:36])[CH2:8][C@H:12]3[O:13][CH2:14][CH2:15]4)=[O:17])[CH2:19][C:20]=2[CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@]2(C(=O)N3CCc4ncc(C(F)(F)F)cc4C3)CCO[C@@H]2[C@H]1[Se]c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reaction time: 3 h

Procedure:
To a solution of the product of Step E (1.51 g, 2.67 mmol, 1 eq), tris(trimethylsilyl)silane (1.72 mL, 5.34 mmol, 2 eq) and AIBN (438 mg, 2.67 mmol, 1 eq) in benzene (20 mL) was warmed to 80° C. under Ar. After 3 hrs, the solution was concentrated. Purification by chromatography (80 g column) eluting with 50 to 100% EtOAc/heptane afforded the title compound of Step F. 1H NMR (CHLOROFORM-d) δ: 8.72 (br. s., 1H), 7.71 (br. s., 1H), 4.97-5.09 (m, 1H), 4.70-4.91 (m, 2H), 4.56-4.69 (m, 1H), 4.28 (br. s., 1H), 3.80-4.07 (m, 3H), 3.71 (q, J=7.3 Hz, 1H), 3.13 (br. s., 2H), 2.07-2.53 (m, 4H), 1.81 (br. s., 1H), 1.61-1.72 (m, 1H), 1.40 (s, 9H). Calculated for C22H28F3N3O4: 478.2 (M+23). found: 478.2.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:24]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:35])[NH:29]2)[CH2:10][NH:11][C:12]([CH3:23])([CH3:22])[CH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:36]([C:39]1[S:43][CH:42]=[C:41]([C:44]([N:46]2[CH2:51][C:50]3([CH2:56][CH2:55][NH:54][CH2:53][CH2:52]3)[O:49][CH2:48][CH2:47]2)=[O:45])[CH:40]=1)([CH3:38])[CH3:37]>>[Si:1]([O:8][C@H:9]([C:24]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:35])[NH:29]2)[CH2:10][NH:11][C:12]([CH3:23])([CH3:22])[CH2:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:16]([CH2:17][N:54]2[CH2:53][CH2:52][C:50]3([O:49][CH2:48][CH2:47][N:46]([C:44]([C:41]4[CH:40]=[C:39]([CH:36]([CH3:38])[CH3:37])[S:43][CH:42]=4)=[O:45])[CH2:51]3)[CH2:56][CH2:55]2)[CH:15]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: CC(C)(Cc1cccc(C=O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Product: CC(C)c1cc(C(=O)N2CCOC3(CCN(Cc4cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4)CC3)C2)cs1

Procedure:
The subtitled compound was prepared using a similar method to that described in Example 14, step b) using (R)-3-(2-(2-(tert-butyldimethylsilyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino)-2-methylpropyl)benzaldehyde (0.32 g) (Example 275, step h) and (5-isopropylthiophen-3-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (0.21 g) (Example 275, step i)). The crude product was purified by flash silica chromatography, 8% methanol in dichloromethane with 1% 880 aqueous ammonia. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.31 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.C[Mg]Br.[CH2:20]1COC[CH2:21]1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]([OH:16])[CH2:20][CH3:21])=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ccc(C=O)nc2)c1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOC(C)=O
Product: CCC(O)c1ccc(-c2cccc(OC)c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of 5-(3-methoxyphenyl)picolinaldehyde (0.75 g, 3.5 mmol), in THF (7 mL) was added methyl magnesium bromide (0.17 g, 8.8 mmol) under nitrogen at −40° C./ The reaction was brought to rt and then stirred at rt for 2 h. The contents were diluted with ethyl acetate (150 mL), quenched with ammonium chloride solution (100 mL), the organic layer washed with brine solution (2×100 mL), the layers separated, the organic layer was dried over sodium sulphate and distilled off to get the crude product. The compound was purified by flash chromatography (100-200 microns; 15% ethyl acetate in hexane) to give 1-(5-(3-methoxyphenyl)pyridin-2-yl)propan-1-ol (450 mg, 53% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.73 (s, 1H), 8.04 (d, 1H), 7.52 (d, 1H), 7.38 (t, 1H), 7.26 (s, 1H), 7.23 (d, 1H), 6.95 (d, 1H), 5.28 (d, 1H), 4.54 (q, 1H), 3.81 (s, 3H), 1.7 (m, 1H), 1.8 (m, 1H), 0.86 (t, 3H); LC-MS m/z calcd for [M+H]+ 244.13. found 244.0.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:40])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[N:24]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:23]3=[O:36])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][C:5]2=O.Cl.[NH2:42][OH:43].N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CO>[OH:1][C:2]1[C:3]([CH3:40])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[N:24]([CH2:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[C:23]3=[O:36])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][C:5]2=[N:42][OH:43]
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC(C)(COc1ccc(CC3SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)C(=NO)CC(C)(COc1ccc(CC3SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Reaction time: 48 h

Procedure:
A mixture of 0.5 g of t-butyl α-{5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3yl}acetate (prepared as described in Example 49), 0.25 g of hydroxylamine hydrochloride, 0.25 g of pyridine and 5 ml of methanol was allowed to stand t 25°-30° C. for 2 days. Ethyl acetate and an aqueous solution of potassium carbonate were added to the mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography (eluted with a 9:1 by volume mixture of benzene and ethyl acetate) to obtain the title compound.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])=[CH:11][C:10]1=[O:23])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[Cl:21][C:17]1[C:16]([F:22])=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:24])=[O:2])[C:10](=[O:23])[CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(Cl)c2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(Cl)c2F)=CC1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.2 %

Procedure:
A mixture of (S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.87 g, 2.46 mmol) in tetrahydrofuran (15 mL) and water (5 mL) was treated with lithium hydroxide monohydrate (0.12 g, 2.85 mmol). The reaction was stirred at 25° C. for 2.5 h. At this time, the reaction was diluted with water (75 mL) and extracted with diethyl ether (1×75 mL). The aqueous layer was acidified with a 2N aqueous hydrochloric acid solution and then extracted with ethyl acetate (3×50 mL). The combined organics were dried over magnesium sulfate, filtered, rinsed with ethyl acetate and concentrated in vacuo to afford (S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.75 g, 90%) as a light orange solid: HR-ES-MS m/z calculated for C16H17NO4FCl [M+H]+ 342.0903, observed 342.0904; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.5 Hz, 3H), 0.93 (d, J=6.5 Hz, 3H), 1.35-1.56 (m, 1H), 1.56-1.70 (m, 1H), 1.72-1.86 (m, 1H), 4.19 (d, J=18.2 Hz, 1H), 4.29 (d, J=18.2 Hz, 1H), 4.63 (dd, J=11.5, 4.3 Hz, 1H), 5.05 (s, 1H), 7.33 (td, J=8.3, 1.4 Hz, 1H), 7.49-7.55 (m, 1H), 7.57 (ddd, J=8.3, 6.8, 1.4 Hz, 1H), 12.92 (br. s., 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[CH3:13][N:14](C)[CH2:15]CCN=C=NCC.CNC.CCO>ClCCCl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:14]([CH3:15])[CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: CNC
Agent: Cl
Solvent: CCO
Solvent: ClCCCl
Product: CN(C)C(=O)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.6 %

Procedure:
A suspension of 4-aminophenylacetic acid (5 g, 30 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (6.9 g, 36 mmol), and dimethylamine (6.5 mol of a 5.6M solution in EtOH 36 mmol) in 1,2, DCE was stirred at room temperature for 4 h. Silica was added, the suspension evaporated and residue loaded onto silica plug column, eluting with DCM:MeOH/98:2). The title compound (2.6 g, 45%) was isolated as an orange solid. 1H MNR (400 MHz, CDCl3) δ2.94 (3H, s), δ2.98 (3H, s), 3.60 (2H, s), 6.64 (2H, d, J=8.3 Hz), 7.03 (2H, d, 8.2 Hz). MS (CI)+179 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[NH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]1=[S:24].[H-].[Na+].O>CN(C=O)C>[CH3:17][C:12]1[C:11]([O:10][C:4]2[C:5]([C:8]#[N:9])=[N:6][CH:7]=[C:2]([S:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)[CH:3]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: Cc1ncccc1Oc1cc(Br)cnc1C#N
Reactant: S=c1cccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1C#N
Temperature: 0 °C
Reaction time: 18 h
Yield: 96.9 %

Procedure:
5-Bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (56.9 g, 196 mmol) and pyridine-2(1H)-thione (22.9 g, 206 mmol) were dissolved in DMF (400 mL) and cooled to 0° C. NaH (4.94 g, 206 mmol) was added portionwise and warmed to ambient temperature. The reaction was stirred for 18 hours and then poured into 2.5 L of water and stirred for 30 minutes The solids were filtered to provide 3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (60.8 g, 190 mmol, 96.8% yield).
Reaction SMILES: [CH3:1]O.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([S-:17])=[S:16])[CH2:11][CH2:10]1.[Na+].CI>O>[CH3:24][O:23][C:19]1[CH:18]=[C:7]([CH:6]=[C:5]([O:4][CH3:3])[C:20]=1[O:21][CH3:22])[CH2:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]([S:17][CH3:1])=[S:16])[CH2:13][CH2:14]1
Reactant: COc1cc(CN2CCN(C(=S)[S-])CC2)cc(OC)c1OC
Reactant: CO
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1cc(CN2CCN(C(=S)SC)CC2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To 70 ml of methanol containing 6.67 g of sodium 4-(3,4,5-trimethoxybenzyl)piperazinecarbodithioate was dropwise added under chilling with ice 20 ml of methanol solution containing 2.6 g of methyl iodide for 20 min. The resulting mixture was further stirred for 3 hours under chilling with ice. The reaction solution was placed under reduced pressure to distill off the solvent, leaving a residue. The residue was dissolved in water, and then extracted with chloroform. The chloroform portion was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. Thus obtained crude product was purified by silica gel chromatography to give 3.7 g of the desired compound as a pale yellow crystalline product.
Reaction SMILES: Cl.[C:2]1([CH:8]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.NC[C:33](O)=[O:34].C1(C(C2C=CC=CC=2)=[N+]=[N-])C=CC=CC=1.C(Cl)(Cl)=O>O1CCOCC1.C1(C)C=CC=CC=1>[N:18]([CH2:17][C:16]([O:15][CH:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:19])=[C:33]=[O:34]
Reactant: NCC(=O)OC(c1ccccc1)c1ccccc1
Reactant: NCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C(Cl)Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=C=NCC(=O)OC(c1ccccc1)c1ccccc1

Procedure:
A suspension of 20 g. of glycine diphenylmethyl ester hydrochloride (prepared by reacting glycine tosylate and diphenyldiazomethane in dioxane followed by conversion to the hydrochloride salt) in 300 ml. of toluene is heated to boiling with stirring. At the boiling temperature, a strong stream of phosgene is passed through the suspension for three hours. The isocyanatoacetic acid, diphenylmethyl ester is then isolated by distillation; b.p.0.01 160°-170°.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7]1)=[O:5])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[I:30][CH2:31]I>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1([CH2:31][I:30])[CH2:10][CH2:9][N:8]([C:11](=[O:19])[C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: ICI
Reactant: CCOC(=O)C1CCN(C(=O)c2ccc(F)cc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(F)cc2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a stirred solution of 1-(4-fluoro-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (4.20 g, 15.8 mmol) (see Preparation 3) in tetrahydrofuran (50 mL) at −78° C. under a nitrogen atmosphere, was added lithium bis(trimethylsilyl)amide (19.0 mL of a 1.0M solution in tetrahydrofuran, 19.0 mmol). The resulting mixture was stirred at −78° C. for 30 minutes and then diiodomethane was added (1.40 mL, 17.4 mmol). The mixture was allowed to warm to room temperature and stir for a further 16 hours. The mixture was quenched with 10% aqueous citric acid (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organics were washed with brine (100 mL), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified using silica gel column chromatography, using a gradient eluent of 30% ethyl acetate in heptane to 50% ethyl acetate in heptane to afford the title compound as a colourless oil (4.2 g, 65%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH:12]1([CH:15]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:16][CH2:17][OH:18])[CH2:14][CH2:13]1>C(Cl)Cl.C(OCC)C>[CH:12]1([CH:15]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:16][CH:17]=[O:18])[CH2:14][CH2:13]1
Reactant: OCCC(c1ccc(Cl)cc1)C1CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCC(c1ccc(Cl)cc1)C1CC1
Yield: 24 %

Procedure:
A mixture of 6.5 grams (0.03 mole) of pyridinium chlorochromate in 25 ml of methylene chloride was stirred, and a solution of 2.1 grams (0.03 mole) of 3-cyclopropyl-3-(4-chlorophenyl)propan-1-ol in 5 ml of methylene chloride was quickly added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for one hour. The reaction mixture was then diluted with 100 ml of diethyl ether, and this mixture was filtered through a pad of activated magnesium silicate. The filtrate was concentrated under reduced pressure, yielding 1.5 grams of 3-cyclopropyl-3-(4-chlorophenyl)propionaldehyde.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:10][C:11]1[C:16]([F:17])=[C:15]([CH:18]=O)[CH:14]=[CH:13][N:12]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[Cl:10][C:11]1[C:16]([F:17])=[C:15]([CH2:18][N:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2)[CH:14]=[CH:13][N:12]=1
Reactant: O=Cc1ccnc(Cl)c1F
Reactant: CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(=O)N1CCN(Cc2ccnc(Cl)c2F)CC1

Procedure:
1-Acetylpiperazine (0.164 g, 1.28 mmol) was dissolved in 5 mL DCE and the resulting solution was added to 2-chloro-3-fluoro-pyridine-4-carbaldehyde (14-2, 0.170 g, 1.07 mmol). NaBH(OAc)3 (0.248 g, 1.17 mmol) was added followed by the addition of 0.100 mL of HOAc. After 45 min the reaction was quenched with sat NaHCOC3 (aq). The mixture was extracted 3× with DCM, and the organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (10 g column, DCM (for 4 min) gradient to 95:5 DCM/MeOH (over 8 min)), desired comes off shortly after 95:5 is attained (13 min) affording good separation from close peak preceeding desired. Afforded pure titled compound. 1H NMR (CDCl3) δ 8.18 (d, 1H, J=4.9 Hz), 7.38 (t, 1H, J=4.6 Hz), 3.66 (m, 4H), 3.50-3.48 (m, 2H), 2.50-2.46 (m, 4H), 2.09 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][C@@H:6]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[O:7][C@H:8]2[CH2:14][NH:15][CH:16]=[O:17].[Cl:24][C:25]1[CH:38]=[CH:37][C:28]([C:29]([NH:31][CH:32]([CH3:36])[CH2:33][CH:34]=O)=[O:30])=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:31][CH:32]([CH3:36])[CH2:33][CH2:34][N:21]2[CH2:20][CH2:19][CH:18]([C@@H:6]3[CH2:5][C:4]4[C:9](=[CH:10][CH:11]=[C:12]([CH3:13])[C:3]=4[O:2][CH3:1])[C@H:8]([CH2:14][NH:15][CH:16]=[O:17])[O:7]3)[CH2:23][CH2:22]2)=[O:30])=[CH:37][CH:38]=1
Reactant: COc1c(C)ccc2c1C[C@@H](C1CCNCC1)O[C@H]2CNC=O
Reactant: CC(CC=O)NC(=O)c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(C)ccc2c1C[C@@H](C1CCN(CCC(C)NC(=O)c3ccc(Cl)cc3)CC1)O[C@H]2CNC=O

Procedure:
Stir a suspension of N-((1R,3S)-5-methoxy-6-methyl-3-(4-piperidinyl)-1-isochromanylmethyl)formamide (1.0 mmol) with 4-Chloro-N-(1-methyl-3-oxo-propyl)-benzamide (3.0 mmol) and sodium triacetoxyborohydride (3.0 mmol) in dichloromethane (5 mL) at room temperature overnight. Apply the reaction mixture directly to a 5 g SCX column and elute and concentrate the appropriate fractions to obtain the title compound. Use the compound directly for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[O:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[O:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CN2CCN(C(=O)Nc3ccc(F)c(Cl)c3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(F)c(Cl)c1)N1CCN(C[C@H]2CNCCO2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of tert-butyl (2S)-2-[(4-{[(3-chloro-4-fluorophenyl)amino]carbonyl}piperazin-1-yl)methyl]morpholine-4-carboxylate (9.867 g, 21.6 mmol) in dichloromethane (100 ml) was added TFA (100 ml). The reaction was allowed to stir at ambient temperature for 2 hours. The solvents were then removed in vacuo, residue partitioned between DCM and 2M NaOH, extracted twice and the combined organics dried (Na2SO4), filtered and evaporated to dryness to give the product as an off white solid (7.69 g, 21.6 mmol, 100%).