Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[F:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:35]([O:37][CH3:38])=[O:36]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:26][C:20]1[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:19]=1[C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:35]([O:37][CH3:38])=[O:36])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(F)c2F)C1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCO[C@@H](c1cccc(F)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(2,3-difluorophenyl)methyl)piperidine-1-carboxylate (195 mg, 0.402 mmol), DMAP (25.8 mg, 0.201 mmol) and Et3N (0.18 mL) in dry CH2Cl2 at 0° C. was added methyl chloroformate (189 mg, 2.013 mmol), the mixture was allowed to warm to rt and stirred overnight. The mixture was concentrated in vacuo to give the crude product (R)-tert-butyl 3-((R)-(2,3-difluorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (168 mg, 98%), which was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.21 (m, 3H), 4.57 (m, 1H), 4.44 (d, 1H), 4.08 (m, 1H), 3.82 (m, 1H), 3.53 (s, 3H), 3.29 (d, 2H), 2.93 (m, 2H), 1.79 (m, 1H), 1.63 (m, 1H), 1.43 (s, 9H), 1.34 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[C:38](O)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.Cl.C(N=C=NCCCN(C)C)C.Cl>C(#N)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([NH:37][C:38](=[O:45])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:36])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1c(-c2c(S(N)(=O)=O)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1c(-c2c(S(=O)(=O)NC(=O)c3ccccc3)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
(+)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide (prepared in Example 209) (46 mg) was dissolved in acetonitrile (1 ml) and thereto were added benzoic acid (13 mg), 4-dimethylaminopyridine (21 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (25 mg) and the resulting mixture was stirred for three hours at room temperature. To the reaction solution were added 1N hydrochloric acid (20 ml) and ethyl acetate (30 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with 1N hydrochloric acid (20 ml) and saturated saline (30 ml) successively, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford N-(1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-4-ylsulfonyl)benzamide (51 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Cl:21][C:22]1[CH:23]=[C:24]([O:31][CH2:32][CH2:33][NH:34][CH3:35])[CH:25]=[C:26]([Cl:30])[C:27]=1[O:28][CH3:29]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:34]([CH3:35])[CH2:33][CH2:32][O:31][C:24]3[CH:25]=[C:26]([Cl:30])[C:27]([O:28][CH3:29])=[C:22]([Cl:21])[CH:23]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNCCOc1cc(Cl)c(OC)c(Cl)c1
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCOc1cc(Cl)c(OC)c(Cl)c1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane, N-[2-(3,5-dichloro-4-methoxy-phenyloxy)-ethyl]-methylamine and triethylamine analogously to Example 6.
Reaction SMILES: C([O:3][C:4](=O)[C:5](=[O:22])[CH2:6][C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[O:20][CH3:21])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)C.[F:24][C:25]([Si](C)(C)C)([F:27])[F:26].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1.C(OC)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:19][C:15]1[C:14]([O:20][CH3:21])=[C:13]([C:7]2([CH2:6][C:5]([OH:22])([C:25]([F:27])([F:26])[F:24])[CH:4]=[O:3])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:18]=[CH:17][CH:16]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC1(c2cccc(Cl)c2OC)CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1c(Cl)cccc1C1(CC(O)(C=O)C(F)(F)F)CCCCC1
Reaction time: 8 h
Yield: 34.5 %

Procedure:
7.07 g (20.87 mmol) of ethyl-3-[1-(3-chloro-2-methoxyphenyl)-cyclohexyl]-2-oxopropionate is dissolved in 33 ml of tetrahydrofuran and mixed with 3.56 g (25.04 mmol) of (trifluoromethyl)-trimethylsilane. After 51.1 mg of tetrabutylammonium fluoride is added, the batch is stirred overnight. The reaction mixture is diluted with methyl tert-butyl ether, washed once with water and then with brine. After conventional working-up, the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). The isolated 5.71 g (60.4%) of the product is mixed in 70 ml of tetrahydrofuran with 3.98 g (12.61 mmol) of tetrabutylammonium fluoride and stirred for one hour at room temperature. After the reaction mixture is mixed with water, it is extracted with methyl tert-butyl ether. After conventional working-up, the residue is chromatographed on a Flashmaster. 2.63 g (51.1%) of the desired compound: ethyl-2-[1-(3-chloro-2-methoxyphenyl)-cyclohexylmethyl]-3,3,3-trifluoro-2-hydroxypropionate is isolated.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[O:25]=[C:26]1[N:31]([CH2:32][C:33]([NH:35][NH2:36])=[O:34])[CH2:30][CH2:29][O:28][CH2:27]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C1COCC1.O>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:36][NH:35][C:33](=[O:34])[CH2:32][N:31]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:25])=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:1])[F:23])[CH:8]=1
Reactant: NNC(=O)CN1CCOCC1=O
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNC(=O)CN1CCOCC1=O
Reaction time: 1 h
Yield: 8.7 %

Procedure:
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.400 g, 1.14 mmol) was dissolved in THF (4 mL) and 2-(3-oxomorpholino)acetohydrazide (0.295 g, 1.71 mmol) was added. T3P (1.09 g, 1.71 mmol) was added dropwise followed by DIPEA (220.80 mg, 1.71 mmol) at −60° C. and the reaction mixture was stirred for 1 h. The reaction mixture was transferred into 25 mL iced-water and extracted with EtOAc (2×25 mL) Combined organic layers was washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give the crude product which was purified by chromatography (0-4% MeOH/CH2Cl2) to give 0.05 g of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(2-(3-oxomorpholino)acetyl)acrylohydrazide (Yield: 8%). 1H NMR (400 MHz, DMSO-d6) δ 10.33 (bs, 2H), 9.63 (s, 1H), 8.57 (s, 2H), 8.30 (s, 1H), 7.50-7.52 (d, J=8 Hz, 1H)), 6.01-6.03 (d, J=8 Hz, 1H), 4.08-4.12 (m, 4H), 3.85-3.87 (m, 2H), 3.41-3.44 (m, 2H). LCMS m/z 507.13 [M+H]+, tR 1.950 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([N:8]=[C:9]=S)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl.Cl.[NH2:21][CH2:22][C@@:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([NH:8][C:9]2[O:31][C@:23]3([CH2:22][N:21]=2)[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]3)=[N:6][CH:7]=1
Reactant: Cc1cc(N=C=S)ncc1Cl
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(NC2=NC[C@@]3(CN4CCC3CC4)O2)ncc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
To 5-chloro-2-isothiocyanato-4-methylpyridine (0.37 g, 2.0 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (0.7 mL, 5.0 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (from Step B of Example 17) (0.47 g, 2.0 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with N,N-dimethylformamide (20 mL) and N,N′-diisopropylcarbodiimide (0.94 mL, 6.0 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated to yield the crude product. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)—N-(5-chloro-4-methylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.19 g, 0.61 mmol, 30.3% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.79 (s, 1 H), 8.08-8.15 (m, 2 H), 6.78 (s, 1 H), 3.82 (d, J=8.55 Hz, 2 H), 3.55 (d, J=10.38 Hz, 2 H), 2.93-3.02 (m, 5 H), 2.71-2.80 (m, 5 H), 2.66 (t, J=7.63 Hz, 4 H), 2.23-2.29 (m, 7 H), 1.94-2.02 (m, 2 H), 1.92 (s, 1 H), 1.86 (s, 2 H), 1.53-1.62 (m, 5 H), 1.41-1.49 (m, J=12.55, 9.88, 7.02, 2.29 Hz, 2 H). MS (LC/MS) R.T.=0.72; [M+H]+=307.1.
Reaction SMILES: N1([C:7]2[C:8]([C:13]([NH:15][C@H:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[NH:21][C:22]3[CH:27]=[N:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=3)=[O:14])=NC=CC=2)CCCCC1.Cl.FC(F)(F)C1N=CC(N[C@H]2CCC[C@@H]2N)=NC=1.[Cl:50][C:51]1[CH:52]=[CH:53][C:54]([N:60]2[N:64]=[CH:63][CH:62]=[N:61]2)=C(C=1)C(O)=O>>[Cl:50][C:51]1[CH:52]=[CH:53][C:54]([N:60]2[N:64]=[CH:63][CH:62]=[N:61]2)=[C:8]([CH:7]=1)[C:13]([NH:15][C@H:16]1[CH2:20][CH2:19][CH2:18][C@@H:17]1[NH:21][C:22]1[CH:27]=[N:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][N:23]=1)=[O:14]
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ncccc1N1CCCCC1
Reactant: O=C(O)c1cc(Cl)ccc1-n1nccn1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cc(Cl)ccc1-n1nccn1

Procedure:
Prepared according to the procedure for 3-(piperidin-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]pyridine-2-carboxamide (Example 51) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 500 mg, 1.77 mmol) and 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 38a; CAS number 1293284-54-4; 396 mg, 1.77 mmol) except this was purified only by column chromatography (silica, 40-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:14]([C:16]3[C:17]([O:35][CH3:36])=[C:18]([CH:24]4[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)[C:19]([CH3:23])=[C:20]([Cl:22])[CH:21]=3)[CH3:15])[N:9]=[C:10]([CH:11]([F:13])[F:12])[C:3]=12.[ClH:37].O1CCOCC1>ClCCl>[ClH:22].[ClH:37].[NH:26]1[CH2:25][CH:24]([C:18]2[C:17]([O:35][CH3:36])=[C:16]([CH:14]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([CH:11]([F:12])[F:13])=[N:9]3)[CH3:15])[CH:21]=[C:20]([Cl:22])[C:19]=2[CH3:23])[CH2:27]1
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a mixture of tert-butyl 3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate (30 mg, 0.057 mmol) in dichloromethane (0.2 mL) was added 4.0 M hydrogen chloride in 1,4-dioxane (0.10 mL, 0.40 mmol). The resulting mixture was stirred for 3 h at room temperature and then concentrated. The residue was dried in vacuo to give 27 mg (100%) of the product as a salt. LCMS calculated for C19H22ClF2N6O (M+H)+: m/z=423.1; Found: 423.0.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23]#[N:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:25]>O=[Pt]=O.C(O)(C)C>[ClH:25].[ClH:25].[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3([CH2:23][NH2:24])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:15][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#CC1(c2ccc(OCCCN3CCCCC3)cc2)CCOCC1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(C)O
Product: NCC1(c2ccc(OCCCN3CCCCC3)cc2)CCOCC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile (1.45 g, 4.4 mmol), isopropanol (12 mL), concentrated HCl (350 μL), and PtO2 (115 mg) was stirred and hydrogenated to 50° C. overnight at atmospheric pressure. The mixture was filtrated over diatomaceous earth and concentrated. The residue was dissolved in DCM/MeOH mixture and washed with NaOH (1M). The organic layers were dried over Na2SO4, filtered and concentrated, purified by flash chromatography (10 g silica gel, DCM/MeOH (10% NH3)) to provide the title compound as free base (0.650 g, 44.5%). This was then converted to the dihydrochloride salt. 1H NMR (400 MHz, DMSO-D6) δ 10.66 (bs, 1H), 7.74 (bs, 3H), 7.32 (d, 2H), 6.97 (d, 2H), 4.07 (t, 2H), 3.73-3.65 (m, 2H), 3.47-3.28 (m, 4H), 3.18-3.10 (m, 2H), 2.98-2.81 (m, 4H), 2.25-2.16 (m, 2H), 2.14-2.06 (m, 2H), 1.90-1.67 (m, 7H), 1.44-1.31 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-2].[O-2].[O-2].[Cr+6].S(=O)(=O)(O)O.[Cr:26]([OH:30])([OH:29])(=[O:28])=[O:27]>CC(C)=O.O>[Cr:26]([OH:30])([OH:29])(=[O:28])=[O:27].[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: O=[Cr](=O)(O)O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Temperature: 25 °C
Yield: 76 %

Procedure:
Commercial (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid (30 g, 0.13 mol) was dissolved in acetone (1500 ml). A mechanical stirrer was placed in the flask and the solution stirred vigorously. A freshly made solution of 8N chromic acid was prepared by dissolving chromium trioxide (66.7 g, 0.667 mol) in water (40 ml), adding concentrated sulphuric acid (53.3 ml) and adding enough water to bring the solution volume to 115 ml. The 8N chromic acid solution (115 ml) was then added dropwise over a period of 30 minutes with continued vigorous stirring, the reaction's exotherm being maintained at the optimal temperature of 25° C. by the use of an ice bath. After the complete addition of the chromic acid, the reaction mixture was stirred for a further 15 minutes—maintaining the optimal temperature of 25° C. The reaction mixture was then quenched by the addition of methanol (20 ml). Exotherm controlled by the use of an ice bath and, if necessary, direct addition of a small amount of crushed ice to the reaction mixture itself. The reaction mixture was filtered through a Celite pad and then concentrated in vacuo. The resulting acidic solution was then extracted with ethyl acetate (3×300 ml) and the combined organic layers washed with brine (2×100 ml). Organics then dried with magnesium sulfate and concentrated in vacuo. Crude product recrystallised from ethyl acetate to give the white crystalline product, (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (22.55 g, 76%). The antipodal intermediate, (2R)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid, was made according to the same protocol, starting from commercial (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C@@H:7]([C@H:9]([C@@H:11]([C@@H:13]([CH2:15][OH:16])[OH:14])[OH:12])[OH:10])[OH:8])[CH2:2][CH2:3][CH3:4].Cl>O>[CH2:1]([NH:5][CH2:6][C@@H:7]1[O:8][C@:13]([OH:14])([CH2:15][OH:16])[C@@H:11]([OH:12])[C@@H:9]1[OH:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Cl
Solvent: O
Product: CCCCNC[C@@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O
Temperature: 15 °C
Reaction time: 23 h
Yield: 83 %

Procedure:
A reaction solution is prepared by adding 91 gm N-n-butylglucamine to 580 ml of water in a 1-L bioreactor. The suspension is adjusted to about pH 5 (with concentrated HCl) and cooled to about 15° C. A total of 24 gm (wet weight) of washed G. oxydans cell paste is added and the reaction mixture is agitated (500 rpm) and aerated (0.5 vvm) while controlling the temperature at 15° C. and pH at 5. After 23 hours, the HPLC assay indicates that over 99% of the substrate has converted for a 83% yield of 6-n-butylamino-6-deoxy-α-L-sorbofuranose.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:22])[CH3:21])[CH:17]=2)[N:12]=[C:11]([CH3:23])[CH:10]=1>C1(C)C=CC=CC=1>[CH3:5][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:22])[CH3:21])[CH:17]=2)[N:12]=[C:11]([CH3:23])[CH:10]=1
Reactant: COS(=O)(=O)OC
Reactant: CC(=O)Nc1ccc2nc(C)cc(O)c2c1
Solvent: Cc1ccccc1
Product: COc1cc(C)nc2ccc(NC(C)=O)cc12
Temperature: 25 °C

Procedure:
Dimethyl sulfate (294 g, 2.33 mol) was charged to a suspension of hydroxyquinoline 4 (287 g, 1.33 mol) in toluene (1.5 L) and the mixture was refluxed for 6 h. After cooling to ambient temperature, the resulting dark yellow solids were collected by filtration and washed with toluene. The dry solid was dissolved in water (2.5 L) and the pH adjusted to 14 using 35% aqueous NaOH (290 g). The resulting tan precipitate was collected by filtration, washed with copious amounts of water and dried in vacuo at 60° C. to give methoxyquinoline 5 as light tan solid (259 g, 85% yield); 1H NMR (DMSO) δ 10.18 (s, 1H), 8.46 (s, 1H), 7.76 (m, 2H), 6.84 (s 1H), 3.99 (s, 3H), 2.55 (s, 3H), 2.09 (s, 3H); 13C NMR (DMSO) δ 168.36, 160.99, 158.07, 144.86, 135.87, 128.27, 122.78, 119.26, 108.80, 101.20, 55.69, 25.08, 23.97.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].C([O-])([O-])=O.[Cs+].[Cs+].C([O:17][CH:18]=[CH:19][C:20](OCC)=O)C.Cl>CN(C=O)C.O>[OH:17][C:18]1[CH:19]=[CH:20][N:6]2[N:5]=[CH:4][C:3]([C:7]#[N:8])=[C:2]2[N:1]=1
Reactant: N#Cc1cn[nH]c1N
Reactant: CCOC=CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cnn2ccc(O)nc12
Temperature: 100 °C
Yield: 96.7 %

Procedure:
To a mixture of 5-amino-1H-pyrazole-4-carbonitrile (2.70 g, 25.0 mmol) and Cs2CO3 (16.3 g, 50.0 mmol) in dry DMF (70 mL) was added ethyl 3-ethoxyacrylate (5.41 g, 37.5 mmol) and the mixture was heated at 100° C. for 4 hours. The mixture was cooled to ambient temperature and the resultant slurry was poured into deionized H2O (150 mL). The resulting aqueous solution was cooled on an ice bath and concentrated HCl was added slowly with mixing to pH=3.5. The resulting precipitate was collected, washed with H2O followed by Et2O. The solid was dried in vacuum to afford the product as a light beige powder (3.87 g, 97%). MS (apci) m/z=159.0 (M−1).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][CH:11]([CH2:13]O)[OH:12].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1.C(OC(C)C)(C)C>[OH:12][CH:11]1[CH2:10][O:9][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][CH2:13]1
Reactant: OCC(O)CO
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: OC1COC(c2ccccc2)OC1
Reaction time: 8 h

Procedure:
To a solution of benzaldehyde (150.0 g, 1.41 mol) in toluene, glycerol (160.0 g, 1.74 mol) was added followed by 4-methylbenzenesulfonic acid (1.0 g) and the mixture was vigorously stirred under reflux with a Dean-Stark water separator. The refluxing was continued until no more water separated in the condenser (6-8 h). The clear solution was treated with 4N NaOH until basic and the organic layer was washed with water (5×100 mL) followed by saturated sodium chloride solution and then dried over anhydrous sodium sulfate. Concentration of the organic layer resulted in an oil which was dissolved in hot isopropylether and then left in the freezer overnight. The colorless solid was filtered and washed with isopropylether to yield the title product as a colorless solid. Yield: 55.0 g (22%). m.p. 83°-84° C. [Lit. m.p. 83°-84° C.; J. S. Briamacombe, A. B. Foster and M. Stacey, Chem. & Ind., 1958, 122814 9]. 1H NMR (CDCl3) ε 3.1 (d, 1H, --OH), 3.7 (d, 1H Ar--CH), 4.3 (m, 4H, O--CH2), 5.6 (s, 1H, O--CH--O) and 7.4 (m, 5H, Ar--H). M/e: [M+H]+ =181.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10]C)[C:3]=1C#N.C[Mg]I.[CH2:15]([O:17][CH2:18][CH3:19])C.Cl>>[F:1][C:2]1[CH:9]=[CH:8][CH:19]=[C:18]([O:17][CH3:15])[C:3]=1[C:6](=[O:10])[CH3:7]
Reactant: COc1cccc(F)c1C#N
Reactant: CCOCC
Agent: C[Mg]I
Agent: Cl
Product: COc1cccc(F)c1C(C)=O
Temperature: 25 °C
Yield: 663.4 %

Procedure:
A mixture of 2-fluoro-6-methoxybenzonitrile (15.94 g, 105.5 mmol) and a solution of methyl magnesium iodide in diethyl ether (3 M, 46.0 cm3, 137 mmol) was heated to 100° C. for 18 h. Upon cooling to room temperature, aqueous hydrochloric acid (3 M, 94 cm3) was added and the mixture was heated to reflux to for 4 h. When the reaction had cooled to room temperature the organic layer was separated and the aqueous phase was extracted with ethyl acetate (100 cm3). The combined organic extracts were washed with brine (100 cm3) before being dried (Na2SO4). The solvent was removed in vacuo to afford the title compound as an oil (117.7 g, 100%).