Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([C@@:10]23[CH2:19][C:18](=O)[CH2:17][CH2:16][C@@H:15]2[CH2:14][N:13]([CH3:21])[CH2:12][CH2:11]3)[CH:7]=[CH:8][CH:9]=1.[CH3:22]N(C)C=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:3][C:4]1[CH:5]=[C:6]([C@@:10]23[CH2:19][C:18](=[CH2:22])[CH2:17][CH2:16][C@@H:15]2[CH2:14][N:13]([CH3:21])[CH2:12][CH2:11]3)[CH:7]=[CH:8][CH:9]=1
Reactant: CN1CC[C@]2(c3cccc(O)c3)CC(=O)CC[C@@H]2C1
Reactant: CN(C)C=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=C1CC[C@@H]2CN(C)CC[C@]2(c2cccc(O)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.93 g (11 mmol) of methyl triphenylphosphonium bromide in 100 ml of absolute dimethyl formamide is treated with 1.01 g of a 50% w/w sodium hydride dispersion in oil (21 mmol) under nitrogen. The mixture is stirred for 1 hour at room temperature, and then treated with 2.59 g of octahydro-4a-(3-hydroxyphenyl)-2-methyl-cis-6(2H)-isoquinolinone. The mixture is stirred for 16 hours at 40°, and partitioned between methylene chloride and aqueous ammonium sulphate. Evaporation of the organic phase and chromatographic purification on silicagel gives the title compound.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[O:19]1[C:23]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=2)=[CH:22][N:21]=[CH:20]1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:12]=[CH:13][C:14]([CH2:17][CH3:18])=[CH:15][N:16]=3)[CH2:7][CH2:6]2)[C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([C:23]3[O:19][CH:20]=[N:21][CH:22]=3)=[N:25][CH:26]=2)[CH2:2][CH2:3]1
Reactant: CCc1cnc(N2CCC(NC3CC3)CC2)nc1
Reactant: O=C(O)c1ccc(-c2cnco2)nc1
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)nc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-amine and 6-oxazol-5-yl-nicotinic acid following a procedure analogous to that described in Example 1. LC (method 7): tR=1.02 min; Mass spectrum (ESI+): m/z=419 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH2:7]1[O:9][CH:8]1CO>C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C([O-])(=O)CCCCCCCCCCCCCCCCC.[Ca+2].C([O-])(=O)CCCCCCCCCCCCCCCCC>[C:1]([O:5][CH2:6][CH:8]1[O:9][CH2:7]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: OCC1CO1
Reactant: C=CC(=O)OC
Agent: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: [Ca+2]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=CC(=O)OCC1CO1
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To the same apparatus as described in Example 1 were added 2,150 g (25 mol) of methyl acrylate, 370 g (5 mol) of glycide, 1 g of phenothiazine as the polymerization inhibitor and 41.3 g (0.068 mol) of calcium stearate as the catalyst. The resulting mixture was heated at a temperature of 50° to 70° C. under a reduced pressure of 200 to 400 mmHg while introducing a slight amount of air to effect the reaction while distilling off the formed methanol as an azeotropic mixture with methyl acrylate. The reaction was completed in 2 hours. The formation of glycidyl acrylate was 96.5%. 575 g of glycidyl acrylate was obtained by the distillation (purity: 98.1%, yield: 89.7%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11](=[O:22])[C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH:9]=[CH:10][C:2]1=2.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].CC(O)C.Cl>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C@@H:11]([OH:22])[C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:13])[CH:9]=[CH:10][C:2]1=2
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccc2c(c1)OCCO2
Agent: CC(C)[O-]
Agent: Cl
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: C[C@H](NC(=O)OC(C)(C)C)[C@H](O)c1ccc2c(c1)OCCO2

Procedure:
The diastereoselective catalytic Meerwein-Ponndorf-Verley reduction was made by the method described by Jingjun Yin et. al. J. Org. Chem. 2006, 71, 840-843. (S)-tert-butyl 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxopropan-2-ylcarbamate (I2b) (3.76 g, 12.23 mmol), aluminium isopropoxide (0.5 g, 2.45 mmol) and 2-propanol (12 mL, 157.75 mmol) in toluene (22 mL) was stirred at +50° C. under argon for 16 hours. The reaction mixture was poured into 1M HCl (150 mL), the mixture was extracted with EtOAc (250 mL). The organic phase was washed with water (2×50 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by flash-chromatography on silica using EtOAc:Hexane (1:2) as eluent. Fractions containing product was combined. Solvent was removed by evaporation to give the desired product as a colourless solid. Yield 3.19 g (84%)
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH3:26])=[CH:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:25])[C:13]3[C:18]([O:19][C:20]=2[C:21]=1[C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=[CH:15][CH:14]=3.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[CH:32]=O>C(O)C.O>[CH3:3][C:4]([CH3:26])=[CH:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:25])[C:13]3[C:18]([O:19][C:20]=2[C:21]=1[C:22](=[O:24])[CH:23]=[CH:32][C:31]1[CH:34]=[C:35]([O:39][CH3:40])[C:36]([O:37][CH3:38])=[C:29]([O:28][CH3:27])[CH:30]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CC(=O)c1c(OCC=C(C)C)ccc2c(=O)c3ccccc3oc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C=CC(=O)c2c(OCC=C(C)C)ccc3c(=O)c4ccccc4oc23)cc(OC)c1OC
Temperature: 25 °C
Yield: 58.6 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 3-(3-methylbut -2-enyloxy)-4-acetylxanthen-9-one (2.4 g, 0.0075 mol) and 3, 4, 5-trimethoxy-benzaldehyde (1.47 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.2 g of product m.p. 153-55° C., 1H NMR (CDCl3) δ:1.69 (s, 3H); 1.72 (s, 3H); 3.85-3.91 (m, 9H); 4.73 (d, 2H, J=6.5); 5.38-5.40 (m, 1H); 6.78 (s, 2H); 7.03 (d, 1H, J=16 Hz); 7.09 (d, 1H, J=8.8 Hz); 7.23-7.42 (m, 2H); 7.27 (d, 1H J=16 Hz); 7.80-7.87; (m, 1H); 8.32 (d, 1H, J=8.8 Hz); 8.44 (d, 1H, J=8.9 Hz).
Reaction SMILES: [NH2:1][C:2]([C:18]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]2[C:19]=1[CH:20]=[CH:21][N:22]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:9]=2[N:8]=1)[C:3]([F:6])([F:5])[F:4].[C:37]([O:41][CH2:42][CH3:43])(=[O:40])[CH:38]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:16]([C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C:2]([C:18]3[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([NH:1][CH2:38][C:37]([O:41][CH2:42][CH3:43])=[O:40])[C:3]([F:6])([F:5])[F:4])=[N:8][C:9]=2[CH:15]=1)#[N:17]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(N)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Reactant: CCOC(=O)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)CNC(c1nc2cc(C#N)ccc2[nH]1)(c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C)C(F)(F)F
Temperature: 60 °C

Procedure:
To a suspension of (±)-tert-butyl 4-(1-amino-1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 139-A) (117 mg, 0.234 mmol) in DCE (2.34 mL) was added ethyl glyoxylate (50% in toluene) (93 μL, 0.468 mmol) and this was stirred at 60° C. After 5 minutes this was cooled to room temperature, then sodium triacetoxyborohydride (298 mg, 1.405 mmol) was added and this was stirred again at 60° C. After stirring overnight the reaction was quenched with sat. aq. sodium bicarbonate, extracted with EtOAc, dried with MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-50% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 586.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:59]=[CH:58][C:48]([N:49]=[S:50]([CH3:57])(=[O:56])[N:51]2[CH2:55][CH2:54][CH2:53][CH2:52]2)=[CH:47][CH:46]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:42])([CH3:43])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:45]2[CH:59]=[CH:58][C:48]([N:49]=[S:50]([CH3:57])(=[O:56])[N:51]3[CH2:55][CH2:54][CH2:53][CH2:52]3)=[CH:47][CH:46]=2)=[CH:10][CH:9]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Reactant: CS(=O)(=Nc1ccc(Br)cc1)N1CCCC1
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(-c4ccc(N=S(C)(=O)N5CCCC5)cc4)cc3)nc21

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and 4-bromo-N-[methyl-(oxo)pyrrolidin-1-yl-λ6-sulfanylidene]aniline following a procedure analogous to that described for Intermediate 3 (Step 3). LC (method 1): tR=1.16 min; Mass spectrum (ESI+): m/z=726 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([O:27]CC(F)(F)F)=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[C:12]=1[N+:22]([O-:24])=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C(N(CC)CC)C.O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([OH:27])=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[C:12]=1[N+:22]([O-:24])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(OC(F)(F)F)c1[N+](=O)[O-])C(=O)OCC(F)(F)F
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(OC(F)(F)F)c1[N+](=O)[O-])C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2,2,2-Trifluoroethyl N-(tert-butoxycarbonyl)-2-nitro-3-(trifluoromethoxy)-L-phenylalaninate (121) 2-Nitro-3-(trifluoromethoxy)-L-phenylalanine, hydrochloride salt (119) (250.6 mg, 0.758 mmol) was suspended in dioxane (3.5 mL)/water (3.5 mL) and the mixture was cooled to 0° C. Triethylamine (0.368 mL, 2.65 mmol) was added, resulting in a solution. BOC2O (199 mg, 0.910 mmol) was added and the mixture was stirred at 0° C. for 15 min, then allowed to warm to RT. After 2 h at RT, most of the dioxane was removed by evaporation under reduced pressure, and saturated aqueous ammonium chloride solution was added until the pH was lowered to −3. The mixture was diluted with EtOAc (10 mL), and the aqueous layer was extracted with EtOAc (3×15 mL). The combined extracts were dried over sodium sulfate, filtered and evaporated in vacuo to give N-(tert-butoxycarbonyl)-2-nitro-3-(trifluoromethoxy)phenylalanine (120), which was dissolved in dichloromethane (7 mL). 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (98%, 0.195 mL, 0.874 mmol), N,N-dimethylpyridin-4-amine (97%, 45.7 mg, 0.363 mmol) and 2,2,2-trifluoroethanol (99%, 0.106 mL, 1.46 mmol) were added and the resulting mixture was stirred for 18 h at RT. The reaction mixture was washed with saturated aqueous sodium chloride solution, and the aqueous layer was extracted with dichloromethane (3×5 mL). The combined organic layers were dried, filtered and concentrated in vacuo. Purification using silica gel chromatography (Gradient: 0% to 30% EtOAc in heptane) provided the product as a white solid (170.3 mg, 47% over 2 steps). LCMS m/z 475.4 (M−1). 1H NMR (400 MHz, DMSO-d6) δ 1.33 (s, 9H), 3.01-3.12 (m, 2H), 4.32-4.39 (m, 1H), 4.69-4.79 (m, 2H), 7.57-7.66 (m, 3H), 7.74 (dd, J=8.2, 8.2 Hz, 1H).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]([NH:10][NH2:11])=[O:9])C=[CH:4][CH:3]=1.[N:12]1C=CC=NC=1C(O)=O.FC1N=C(C(O)=O)C=CC=1>>[N:7]1[CH:2]=[CH:3][CH:4]=[N:12][C:6]=1[C:8]([NH:10][NH2:11])=[O:9]
Reactant: NNC(=O)c1cccc(F)n1
Reactant: O=C(O)c1ncccn1
Agent: O=C(O)c1cccc(F)n1
Product: NNC(=O)c1ncccn1

Procedure:
2-Pyrimidinecarbohydrazide was prepared in a manner analogous to that described above for 6-fluoro-2-pyridinecarbohydrazide (I23) but using pyrimidine-2-carboxylic acid (CAS [562101-38-6], commercially available e.g. from TimTec or Manchester Organics) in the place of 6-fluoro-2-pyridinecarboxylic acid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[N:6][CH:7]=1.[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:3]([NH:8][C:14]2[CH:15]=[N:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Nc1ncncc1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2ncncc2Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.5 %

Procedure:
A mixture of 5-bromopyrimidin-4-amine (344 mg, 1.977 mmol), 6-methoxypyridin-3-ylboronic acid (907 mg, 5.93 mmol), N,N-diisopropylethylamine (1.376 mL, 7.91 mmol) and anhydrous copper (II) acetate (539 mg, 2.97 mmol) in dichloromethane (2 mL) was stirred at room temperature overnight. The solid was filtered off and washed with CH2Cl2. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 50% EtOAc/hexanes to give 5-bromo-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (36 mg, 0.128 mmol, 6.48% yield). 1H NMR (300 MHz, CDCl3) δ 8.55 (s, 1H); 8.46 (s, 1H); 8.28 (s, 1H); 7.85 (dd, J=8.77, 2.48 Hz, 1H); 6.98 (s, 1H); 6.80 (d, J=8.92 Hz, 1H); 3.95 (s, 3H). m/z (ESI, +ve ion) 281.0 (M+H)+.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:8]([CH3:16])=[C:9]([C:14]#[N:15])[S:10][C:11]=1[S:12][CH3:13])=O.[C:18]1([NH:24][C:25]([NH2:27])=[NH:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C.CO>[CH3:16][C:8]1[C:7]([C:5]2[CH:4]=[CH:3][N:27]=[C:25]([NH:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:26]=2)=[C:11]([S:12][CH3:13])[S:10][C:9]=1[C:14]#[N:15]
Reactant: CSc1sc(C#N)c(C)c1C(=O)C=CN(C)C
Reactant: N=C(N)Nc1ccccc1
Solvent: CO
Solvent: CC#N
Product: CSc1sc(C#N)c(C)c1-c1ccnc(Nc2ccccc2)n1
Temperature: 25 °C

Procedure:
To a solution of 4-(3-dimethylamino-acryloyl)-3-methyl-5-methylsulfanyl-thiophene-2-carbonitrile (0.2 mmol) in acetonitrile (0.25 mL) was added N-phenyl guanidine (1 equivalent, 0.2 mmol) and the reaction heated at reflux for 24 hours. The resulting mixture was cooled to room temperature then diluted with methanol (3 mL). The resulting slurry was filtered washed with methanol to afford IIb-7.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.CCN(C(C)C)C(C)C.[C:52]1([NH2:58])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])([C:13](=[O:15])[NH:58][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)(C(=O)O)C1
Reactant: Nc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)(C(=O)Nc2ccccc2)C1
Reaction time: 0.25 h
Yield: 68.3 %

Procedure:
To a solution of 3-(benzyloxycarbonylamino-methyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (2200.00 mg; 5.81 mmol; 1.00 eq.) in DCE (40.0 ml), bis(2-oxo-1,3-oxazolidin-3-yl)phosphinic chloride (1627.95 mg; 6.40 mmol; 1.10 eq.) was added. After stirring for 15 mins. DIEA (1.25 ml; 6.98 mmol; 1.20 eq.) and phenylamine (595.55 mg; 6.40 mmol; 1.10 eq) were added. The reaction mixture was stirred overnight at RT. DCM (100 ml) was added. The solution was washed with brine, dried and concentrated to give the crude product, which was subjected for biotage for purification (20-50% EtOAc in hexane) to afford the title compound (1800 mg, 68.3%).
Reaction SMILES: CC(C)([O-])C.[K+].OC(C)(C)[CH:9]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])C)[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1>C1COCC1.C(Cl)Cl>[CH3:22][C:19]1([CH3:21])[O:18][C:17](=[O:23])[NH:16][CH:9]1[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NC(c1cccnc1)C(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1(C)OC(=O)NC1c1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.9 %

Procedure:
Potassium tert-butoxide (0.093 g, 0.826 mmol) was added to a 0° C. solution of tert-butyl (2-hydroxy-2-methyl-1-(pyridin-3-yl)propyl)carbamate (0.200 g, 0.751 mmol) in THF (5.0 mL). The ice bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to afford a yellow oil. The residual yellow oil was dissolved in DCM and passed through a Silycycle SCX column washing with MeOH and then with 7 N ammonia in MeOH. The ammonia solution was concentrated to afford 5,5-dimethyl-4-(pyridin-3-yl)oxazolidin-2-one (0.150 g, 0.780 mmol, 100% yield) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82 (s, 3H), 1.53 (s, 3H), 4.74 (s, 1H), 7.44 (ddd, J=7.90, 4.77, 0.64 Hz, 1H), 7.64-7.78 (m, 1H), 8.08 (s, 1H), 8.51 (d, J=2.35 Hz, 1H), 8.55 (dd, J=4.79, 1.66 Hz, 1H). m/z (ESI) 193 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=O.[CH:11]1([NH2:14])[CH2:13][CH2:12]1.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>ClCCl.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][NH:14][CH:11]2[CH2:13][CH2:12]2)[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: O=Cc1cc(Br)cc(Br)c1
Reactant: NC1CC1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: Brc1cc(Br)cc(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3,5-Dibromobenzaldehyde (1 eq.), cyclopropylamine (2 eq.) and magnesium sulfate (1 eq.) were stirred in dichloromethane (0.1 M) for 20 h. The insolubles were then removed via filtration through a pad of celite and washed further with dichloromethane. The filtrate was concentrated in vacuo to afford the crude imine which was then immediately re-taken up in MeOH (0.1 M). To this solution was added sodium borohydride (5 eq.) portionwise and the resulting mixture was stirred at RT for 4 h. The reaction was quenched with 1 N aq. HCl, neutralized with 1 N aq. NaOH and extracted with ether. The combined organic extracts were then washed further with water and brine, dried over MgSO4, and filtered. Concentration of the filtrate in vacuo afforded the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:4][C:3]1=[O:21].O.[ClH:23]>>[ClH:23].[NH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][N:2]([CH3:1])[C:3](=[O:21])[CH:4]=1
Reactant: Cn1ccc(CCN2C(=O)c3ccccc3C2=O)cc1=O
Agent: Cl
Solvent: O
Product: Cn1ccc(CCN)cc1=O
Yield: 85 %

Procedure:
2-(2-(1-Methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)isoindoline-1,3-dione (230 mg, 0.8 mmol) in conc. HCl (25 mL) was stirred at 95° C. for 18 hours. H2O (20 mL) was added and then extracted with ethyl acetate (3×30 mL). The aqueous was concentrated under reduce pressure to give 4-(2-aminoethyl)-1-methylpyridin-2(1H)-one hydrochloride (130 mg, 85%). LC-MS: 153 [M+H]+, tR=0.42 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:9][C:8]2[C:10]([Br:14])=[C:11]([CH3:13])[S:12][C:7]=2[CH:6]=1)=[O:4].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:9]([CH2:21][C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:25])[F:26])=[CH:24][CH:23]=2)[C:8]2[C:10]([Br:14])=[C:11]([CH3:13])[S:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2sc(C)c(Br)c2[nH]1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2sc(C)c(Br)c2n1Cc1ccc(C(F)(F)F)cc1
Yield: 114.6 %

Procedure:
A solution of 3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid methyl ester (8.3 g), 4-trifluoromethybenzyl bromide (8.4 g) and Cs2CO3 (25 g) was stirred for 14 h at room temperature. The reaction mixture was then diluted with 200 ml of 1:1 hexane/EtOAc and filtered through a pad of silica gel. The filtrate was concentrated to give 15 g of the crude title compound which was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:19]=[CH:18][C:7]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[CH:6][C:5]=1[F:20]>CCO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:19]=[CH:18][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[F:20]
Reactant: COC(=O)c1ccc(C(=O)OCc2ccccc2)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(C(=O)O)cc1F

Procedure:
A solution of the crude 2-fluoroterephthalic acid 4-benzyl ester 1-methyl ester (8, 0.14 mol) in EtOH (210 mL) and EtOAc (210 mL) is treated with 10% Pd/C (4.0 g) under hydrogen atmosphere at room temperature for 5 h. After filtration of the catalyst, the filtrate is evaporated in vacuo. Crystals are collected and washed with ether/hexane (1:1) to give 2-fluoroterephthalic acid 1-methyl ester (9) as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:19]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[CH2:20]1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:9]([N:19]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[CH2:20]1)([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCCOC(=O)C1CCN(Cc2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOC(=O)C1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
Benzylchloroformate (2.86 ml) was added to a stirred suspension of N-benzyl-3-n-butoxy carbonyl pyrrolidine (1.75 g) and sodium bicarbonate (2.52 g) in dichloromethane (30 ml). The reaction was stirred for 0.5 hours, filtered and the filtrate evaporated to give an oil. The residual oil was purified by chromatography on silica gel; elution with ethyl acetate/hexane (1/9 v/v) gave, as a pale yellow oil, N-Cbz-3-n-butoxycarbonyl pyrrolidine (1.40 g);
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(N(CC)CC)C.[P:16](Cl)(Cl)([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17]>CCOCC>[P:16]1([O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1)([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17]
Reactant: CCCCOP(=O)(Cl)Cl
Reactant: Oc1ccccc1O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCOP1(=O)Oc2ccccc2O1
Yield: 93 %

Procedure:
Pyrocatechol (0.993 g, 9.02 mM) was dissolved in 50 ml of ether and, using 1.825 g (18.04 mM) of triethylamine and 1.723 (9.02 mM) of n-butyl dichlorophosphate, the reaction was carried out at -5° C. to 0° C. and the reaction mixture treated in the same manner as in Reference Example 1. There was obtained 1.914 g (93.0% yield) of n-butyl o-phenylene phosphate as a colorless viscous oil. 1H-NMR(CDCl3) δ: 0.7~2.0(5H, m, C--CH2CH2CH3), 4.13 and 4.28(2H, each t, J=6.5 Hz, P--O--CH2), 7.10 (4H, s, ##STR64## Signals for trace amounts of ether and triethylamine were also observed.