Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:10]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[C:14]([N:24]([C:26](=[O:44])[C:27]([C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=2)([CH3:29])[CH3:28])[CH3:25])=[CH:13][N:12]=1)C1C=CC=CC=1>CO.CN(C)C=O.[Pd]>[CH2:45]([NH:10][C:11]1[N:12]=[CH:13][C:14]([N:24]([CH3:25])[C:26](=[O:44])[C:27]([C:30]2[CH:35]=[C:34]([C:36]([F:38])([F:37])[F:39])[CH:33]=[C:32]([C:40]([F:41])([F:42])[F:43])[CH:31]=2)([CH3:29])[CH3:28])=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH:16]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: Cc1ccccc1-c1cc(N(Cc2ccccc2)C(=O)OCc2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccccc1-c1cc(NCc2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
To a solution of 973 mg (1.35 mmol) benzyl-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-carbamic acid benzyl ester in 13 ml methanol and 1 ml N,N-dimethylformamide was added 40 mg 10% palladium on activated charcoal and the mixture was hydrogenated (room temperature, 1 bar) for 1 h. Filtration of the catalyst and evaporation of the filtrate afforded 795 mg (quantitative) of the title compound as a yellow oil.
Reaction SMILES: F.F.F.C(N(CC)CC)C.C(N(CC)CC)C.[Si]([CH:35]([OH:58])[C@H:36]1[O:40][C@@H:39]([N:41]2[CH:48]=[C:47]([CH3:49])[C:45](=[O:46])[NH:44][C:42]2=[O:43])[C@H:38]([O:50][CH2:51][CH2:52][O:53][N:54]([CH3:56])[CH3:55])[C@@H:37]1[OH:57])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CO>C1COCC1.C(Cl)Cl>[CH3:55][N:54]([CH3:56])[O:53][CH2:52][CH2:51][O:50][C@@H:38]1[C@H:37]([OH:57])[C@@H:36]([CH2:35][OH:58])[O:40][C@H:39]1[N:41]1[CH:48]=[C:47]([CH3:49])[C:45](=[O:46])[NH:44][C:42]1=[O:43]
Reactant: Cc1cn([C@@H]2O[C@H](C(O)[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Agent: F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
Triethylamine trihydrofluoride (3.91 mL, 24.0 mmol) was dissolved in dry THF and triethylamine (1.67 mL, 12 mmol, dry, kept over KOH). This mixture of triethylamine-2HF was then added to 5'-tert-butyldiphenylsilyl-2'-O-[N,N-dimethylaminooxyethyl]-5-methyluridine (1.40 g, 2.4 mmol) and stirred at room temperature for 24 hrs. Reaction was monitored by TLC (5% MeOH in CH2Cl2). Solvent was removed under vacuum and the residue placed on a flash column and eluted with 10% MeOH in CH2Cl2 to get 2'-O-(dimethylaminooxyethyl)-5-methyluridine (766 mg, 92.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C@@H:9]2[C:18]3[C:13](=[C:14]([F:20])[CH:15]=[CH:16][C:17]=3[F:19])[O:12][CH2:11][C@H:10]2[CH2:21][OH:22])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[H-].[Na+].O>C1COCC1.C(OCC)(=O)C>[CH2:27]([O:26][CH2:25][CH2:24][O:22][CH2:21][CH:10]1[CH:9]([S:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:18]2[C:13](=[C:14]([F:20])[CH:15]=[CH:16][C:17]=2[F:19])[O:12][CH2:11]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OC[C@@H]1COc2c(F)ccc(F)c2[C@H]1Sc1ccc(Cl)cc1
Reactant: BrCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc(F)c2c1OCC(COCCOCc1ccccc1)C2Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans-[4-(4-chloro-phenylsulfanyl)-5,8-difluoro-chroman-3-yl]-methanol (0.6 g, 1.65 mmole) and (2-bromo-ethoxymethyl)-benzene (0.71 g, 3.3 mmole) were dissolved in 30 ml THF and NaH (0.5 g) was added. The reaction was stirred at room temperature overnight. (2-Bromo-ethoxymethyl)-benzene (0.71 g, 3.3 mmole) and NaH (0.5 g) were added and the reaction was refluxed overnight. 50 ml water and 50 ml EtOAc were added. The organic layer washed with Sat. NaCl solution (50 ml), dried over Na2SO4 and concentrated. The product was purified by column chromatography (EtOAc/Hex. from 0/100 to 25/75 in 40 minute). Yield: 0.42 g, 53%. 1H NMR (CDCl3 400 MHz δ 7.42 (d, J=8.8 Hz, 2H), 7.25-7.37 (m, 7H), 6.96 (m, 1H), 6.57 (m, 1H), 4.60 (dd, J=11.7 and 2.2 Hz, 1H), 4.52 (bs, 3H), 4.40 (t, J=11.0, 1H), 3.3-3.56 (m, 6H), 2.38 (m, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(OC(=O)C)(=O)C.[Br:18]Br.Cl.[OH-].[K+]>O.C(O)(=O)C>[Br:18][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:10]=[CH:9][C:7]=1[NH2:8]
Reactant: CC(C)c1ccc(N)cc1
Reactant: BrBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(C)c1ccc(N)c(Br)c1
Temperature: 50 °C

Procedure:
A mixture of 99 g (0.73 mol) of 4-isopropylaniline (Acros) and 300 ml of acetic acid was refluxed for 1 h; then, 75 g of acetic anhydride was added dropwise while vigorously stirring. The resulting solution was cooled to 50° C., and 37.4 ml of bromine was added dropwise, while vigorously stirring, over ca. 30 min. Then, 370 ml of 12 M HCl was added and this mixture was refluxed until a precipitate was formed. This precipitate was separated, washed with 2×150 ml of methyl-tert-butyl ether, and dried in vacuum. A mixture of the solid obtained and a solution of 112 g of KOH in 300 ml of water was stirred at 50-60° C. for 1 h. The organic layer was separated, and the aqueous layer was extracted with 2×150 ml of methyl-tert-butyl ether. The combined extract was dried over K2CO3 and evaporated to dryness. Fractional distillation gave the title product, b.p. 107-111° C./3 mm Hg. Yield 83.7 g (77%) of yellowish oil.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:18](=[O:23])[C:19]([F:22])([F:21])[F:20].[Cu][C:25]#[N:26]>CN1CCCC1=O.O.N.C(OCC)(=O)C>[F:20][C:19]([F:22])([F:21])[C:18]([N:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[CH2:11][C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[C:25]#[N:26])=[O:23]
Reactant: O=C(N1CCCCC1Cc1oc2ccccc2c1Br)C(F)(F)F
Reactant: N#C[Cu]
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1c(CC2CCCCN2C(=O)C(F)(F)F)oc2ccccc12

Procedure:
To a solution of (RS)-1-(2-3-bromo-benzofuran-2-ylmethyl-piperidin-1-yl)-2,2,2-trifluoro-ethanone, D41 (840 mg, 2.1 mmol) in N-methylpyrrolidinone (15 ml) was added copper(I)cyanide (387 mg, 4.2 mmol) and the mixture refluxed for 4.5 h. The reaction mixture was cooled sand diluted with water (100 ml), 0.880 ammonia (3 ml) and ethyl acetate (3×). The combined extracts were dried (Na2SO4) and the solvent removed in vacuo. The residual oil was redissolved in ethyl acetate (75 ml) and washed with water (4×), brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel) afforded the title compound as a solid.
Reaction SMILES: [B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+].COC1C=CC([CH:27]([C:37]2[CH:42]=CC(OC(=O)C(C)(C)C)=CC=2)[CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)C=C)=CC=1.[Cl-].[NH4+]>C(Cl)Cl>[CH2:42]1[C:32]2[C:31](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:37]1
Reactant: C=CC(c1ccccc1)C(c1ccc(OC)cc1)c1ccc(OC(=O)C(C)(C)C)cc1
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [IH2+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: c1ccc2c(c1)CCCC2
Temperature: -78 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Bis(pyridine)iodonium tetrafluoroborate (65.8 mg, 0.177 mmol) was suspended in methylene chloride (3.4 mL), and the suspension was cooled to −78° C. in a dry ice/acetone bath. A methylene chloride (1.8 mL) solution of 1-(4-methoxyphenyl)-2-phenyl-1-(4-pivaloyloxyphenyl)-3-butene (4, 56.0 mg, 0.135 mmol) was added to the suspension, and also a tribromoborane diethyl ether complex (0.015 mL, 0.118 mmol) was added stepwise three times. Thereafter, the reactant was stirred at −78° C. for 1 hour, then a saturated aqueous ammonium chloride solution (5 mL) was added thereto to stop the reaction, and the reactant was cooled to room temperature and then extracted three times with diethyl ether (10 mL). An organic layer was collected and rinsed with a saturated aqueous sodium chloride solution (10 mL), followed by drying with anhydrous sodium sulfate and concentrating. The residue was purified by thin layer chromatography to obtain the title compound as a light yellow oily substance (51.6 mg, yield 71%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)(=O)C>O1CCOCC1>[CH2:11]([N:7]1[CH:6]=[C:5]2[C:9]([CH:10]=[C:2]([Br:1])[CH:3]=[CH:4]2)=[N:8]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc2cn[nH]c2c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Brc1ccc2cn(Cc3ccccc3)nc2c1
Reaction time: 0.33 h

Procedure:
6-Bromoindazole (3.63 g, 18 mmol) was suspended in dioxane (15 mL) and benzyl bromide (2.65 mL, 22 mmol, 1.2 eq.) was added. The reaction was heated to reflux overnight, then allowed to cool to 80° C. after which point ethyl acetate (50 mL) added. The cake was broken up with a spatula and after stirring for 20 min, the solids were filtered off and washed with ethyl acetate, giving glossy white crystals of the hydrobromide salt of 2-benzyl-6-bromoindazole. These were suspended in ethyl acetate (100 mL) and shaken with saturated NaHCO3 (150 mL) until dissolution. The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were concentrated to an off-white powder which was recrystallized from 66% ethanol (40 mL). Washing with water and drying in vacuo gave 2-benzyl-6-bromoindazole (3.30 g, 62%) as shiny white plates.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13]CC)=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.[CH3:17][NH:18][O:19][CH3:20].C([Mg]Cl)(C)C.O>C1COCC1>[CH3:20][O:19][N:18]([CH3:17])[C:11]([CH:8]1[CH2:7][CH2:6][C:5]2([O:1][CH2:2][CH2:3][O:4]2)[CH2:10][CH2:9]1)=[O:13]
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)C1CCC2(CC1)OCCO2
Yield: 98.4 %

Procedure:
Ethyl 1,4-dioxaspiro[4,5]decane-8-carboxylate (6.28 g, 29.3 mmol) obtained in Step 1 was dissolved in THF, and N,O-dimethylhydroxylamine hydrochloride (4.30 g, 44.1 mmol) was added thereto, followed by stirring. In an atmosphere of argon at −30° C., a 2.0 mol/L solution of isopropylmagnesium chloride in THF (44.1 mL, 88.2 mmol) was added dropwise to the reaction mixture, followed by stirring at −5° C. for 1 hour. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford N-methoxy-N-methyl-1,4-dioxaspiro[4,5]decane-8-carboxamide (6.61 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:37])[C:25]=1[CH:26]([OH:36])[CH2:27][O:28][Si](C(C)(C)C)(C)C.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl.Cl.O1CCOCC1>C(OCC)(=O)C.CN(C=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([C:20]2[CH:21]=[N:22][CH:23]=[C:24]([F:37])[C:25]=2[CH:26]([OH:36])[CH2:27][OH:28])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OCC(O)c1c(F)cncc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cncc(F)c2C(O)CO)cc1Cl
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A 25 mL round bottom flask was charged with 2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (250 mg, 0.949 mmol), 1-(3-bromo-5-fluoro-pyridin-4-yl)-2-(tert-butyl-dimethyl-silanyloxy)-ethanol (332 mg, 0.949 mmol), 2M aqueous sodium carbonate (0.95 mL, 1.90 mmol) and DMF (5 mL). The reaction mixture was evacuated and flushed with N2 twice followed by addition of PdCl2(dppf).CH2Cl2 adduct (38.7 mg, 0.047 mmol). The reaction was stirred under N2 at 100° C. for 3 days. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water twice. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude was dissolved in DMF (5 mL) and 4M HCl solution in dioxane (2.372 mL, 9.49 mmol). The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with DCM twice. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude was purified by silica gel flash chromatography employing DCM-MeOH (9:1) to afford 2-chloro-4-[4-(1,2-dihydroxy-ethyl)-5-fluoro-pyridin-3-yl]-benzonitrile. 1H NMR (400 MHz, MeOD) δ ppm 3.72-4.03 (m, 1H), 4.80 (t, J=6.8 Hz, 1H), 7.61 (dd, J=8.0, 1.6 Hz, 1H), 7.82 (d, J=1.3 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 8.31 (s, 1H), 8.55 (d, J=2.5 Hz, 1H); HRMS: (ESI) ink 293.0488 [(M+H)+ Calcd for C14H10ClFN2O2 293.0493].
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[I:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[I:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc(I)cc2)cc1C(F)(F)F
Yield: 68.7 %

Procedure:
4-Fluoro-2-(trifluoromethyl)benzonitrile (53 g, 280.4 mmol, AK Scientific) was treated with 4-iodophenol (61.7 g, 280.4 mmol, Aldrich) and sodium carbonate (44.6 g, 420.6 mmol) in 90 mL anhydrous DMF at 100° C. for 20 hours. The reaction mixture was diluted with 250 mL water and extracted with 2×200 mL EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 4-(4-iodophenoxy)-2-(trifluoromethyl)benzonitrile as a white solid (75 g, 69%). 1H NMR (400 MHz, CDCl3): 7.80-7.72 (3 H, m), 7.36-7.32 (1 H, m), 7.17-7.10 (1 H, m), 6.89-6.82 (2 H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@@H:10]([OH:12])[CH3:11].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@@H:10]([O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](O)c1c(Cl)ccc(F)c1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](OS(C)(=O)=O)c1c(Cl)ccc(F)c1Cl
Temperature: 2.5 °C
Reaction time: 0.58 h

Procedure:
To a cooled (ice bath) solution of (S)-1-(2,6-Dichloro-3-fluorophenyl)ethanol (4.00 g, 16.3 mmol) and triethylamine (3.4 mL, 24 mmol) in toluene (20 mL) was added dropwise methanesulfonyl chloride (1.64 mL, 21.1 mmol). A white suspension formed that was stirred at 0-5° C. for 35 min. The reaction mixture was diluted with H2O (20 mL), the layers were separated, and the aqueous layer was extracted with toluene (10 mL). The combined organic layers were washed with water (2×10 mL) and concentrated under vacuum at 40-45° C. to give the title compound as colorless oil containing ≈0.2 eq. of toluene according to 1H NMR. This material was used directly in the next step. 1H NMR (CDCl3, 400 MHz): δ=7.33 (dd, J=9.0, 4.9 Hz, 1H), 7.12 (dd, J=9.0, 8.0 Hz, 1H), 6.45 (q, J=6.8 Hz, 1H), 2.91 (s, 3H), 1.84 (d, J=6.8 Hz).
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([O:13][C:14](=[O:40])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[N:20]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:21](=[O:32])[C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([C:29](O)=[O:30])=[CH:24][CH:23]=2)([CH3:12])([CH3:11])[CH3:10].CCN(C(C)C)C(C)C.[BH4-].[Na+]>ClCCl.CO>[F:39][C:36]1[CH:37]=[CH:38][C:33]([N:20]2[C:19]([CH2:18][CH2:17][CH2:16][CH2:15][C:14]([O:13][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:40])=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH2:29][OH:30])[CH:26]=3)[C:21]2=[O:32])=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)CCCCc1cc2cc(C(=O)O)ccc2c(=O)n1-c1ccc(F)cc1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)CCCCc1cc2cc(CO)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
Isobutyl chloroformate (0.285 mL, 2.184 mmol) was added to a stirred, 0° C. mixture of 3-(5-(tert-butoxy)-5-oxopentyl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinoline-6-carboxylic acid (800 mg, 1.820 mmol) and Hunig's Base (0.636 mL, 3.64 mmol) in Dichloromethane (20 mL) and the mixture was stirred at 0° C. for 3 h. The mixture was concentrated under reduced pressure with bath temp at 20° C., the residue was taken up in Dichloromethane (20 mL), NaBH4 (138 mg, 3.64 mmol) was added, the mixture was stirred at room temperature for 16 h. MeOH (10 mL) was added, and the resultant mixture was kept stirring at room temperature for 1 h. The mixture was diluted with dichloromethane (60 mL), washed with aqueous sodium hydrogen carbonate (saturated, 1×10 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane=1:1 to give tert-butyl 5-(2-(4-fluorophenyl)-6-(hydroxymethyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (650 mg, 1.528 mmol) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:14][CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:29]([O:33][C:34]([N:36]1[CH2:43][CH:42]2[O:44][CH:38]([CH2:39][NH:40][CH2:41]2)[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C([O-])([O-])=O.[K+].[K+].[Br-].[Li+]>C(#N)C>[C:29]([O:33][C:34]([N:36]1[CH2:37][CH:38]2[O:44][CH:42]([CH2:41][N:40]([CH2:15][CH2:14][N:10]([CH2:9][CH2:8][O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:28][CH:27]=3)[C:11]([NH2:13])=[O:12])[CH2:39]2)[CH2:43]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: Cc1ccc(S(=O)(=O)OCCN(CCOc2ccc(C#N)cc2)C(N)=O)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(CCN(CCOc3ccc(C#N)cc3)C(N)=O)CC(C1)O2
Temperature: 40 °C

Procedure:
A mixture of toluene-4-sulfonic acid 2-{1-[2-(4-cyanophenoxy)ethyl]-ureido}ethyl ester (15 g, 0.0372 mol, 1.0 eq.; see Preparation D above), 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (8.525 g, 0.0372 mol, 1.0 eq.; see WO 01/28992), fused K2CO3 (7.7 g, 0.0558 mol, 1.5 eq.) and lithium bromide (9.6 g, 0.1116 mol, 3.0 eq.) in dry acetonitrile (350 mL) was heated to 40° C. under N2 for 4 days. The reaction was cooled to rt, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography over silica gel, using 3% methanol and DCM as eluent, to yield the sub-title compound as a white solid. Yield: 7 g, 40.9%.
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=O)[CH:2]=[CH2:3].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([N:16]2[C:11](=[O:13])[CH:6]3[CH:5]([C:4]4([CH2:1][CH:2]=[CH2:3])[CH2:10][CH:7]3[CH:8]=[CH:9]4)[C:14]2=[O:15])=[CH:18][CH:19]=1
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Reactant: Nc1ccc(O)cc1
Product: C=CCC12C=CC(C1)C1C(=O)N(c3ccc(O)cc3)C(=O)C12
Reaction time: 1 h

Procedure:
408 g of a mixture of isomers of allylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride are heated with 238.26 g of 4-aminophenol to 200° C., the pressure is reduced to 2.7 Pa and the mixture is kept for 1 hour under these conditions. This gives 535 g of a red solid resin (87.7% of theory) having a glass transition temperature of 58° C.
Reaction SMILES: Cl.[S:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[NH:4][CH2:3]1.[N:11]([O-])=[O:12].[Na+]>CC(O)=O.O>[N:11]([N:4]1[CH:5]([C:8]([OH:10])=[O:9])[CH2:6][CH2:7][S:2][CH2:3]1)=[O:12]
Reactant: O=N[O-]
Reactant: O=C(O)C1CCSCN1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=NN1CSCCC1C(=O)O
Reaction time: 3 h

Procedure:
To a suspension of DL-tetrahydro-1,3-thiazine-4-carboxylic acid hydrochloride (48.6 g, 0.26 mol) in 666 mL of AcOH was added to the solution of 27.4 g (0.40 mol) of NaNO2 in 333 mL of water over 16 min at room temperature and stirred for 3 h. The solution was concentrated under reduced pressure. Acetone (300 mL) was added to the residue and the precipitate was filtered off. The filtrate was concentrated under reduced pressure to dryness and crude 3-nitroso[1,3]thiazinane-4-carboxylic acid was obtained as brown amorphous solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:8].C(OCC)(=O)C.[CH2:15]([O:22][C:23]([N:25]1[CH2:29][C:28](O)=[CH:27][C:26]1=[O:31])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[ClH:32]>C(O)C>[ClH:32].[CH2:15]([O:22][C:23]([N:25]1[CH2:29][C:28]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[NH2:8])=[CH:27][C:26]1=[O:31])=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: O=C1C=C(O)CN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: N[C@@H]1CCCC[C@H]1NC1=CC(=O)N(C(=O)OCc2ccccc2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
(1R,2R)-1,2-diaminocyclohexane 2294 g (20.09 mol) was dissolved in 3.1 L of ethanol to make a solution. To a 100 L glass lined reactor equipped with a stirrer, were added 26.8 L of ethyl acetate, 4635 g of 4-hydroxy-2-oxo-3-pyrroline-1-carboxylic acid benzyl ester (content: 96.2%, 19.12 mol) synthesized according to the methods of Non-Patent Reference 9 and 12.5 L of ethanol, furthermore, a previously prepared ethanol solution of (1R,2R)-1,2-diaminocyclohexane was added at 15 to 21° C. For washing, 2.2 L of ethanol was used. Next, 3.35 L of 6M hydrochloric acid (20.1 mol) was added at 19 to 25° C. For washing, 0.3 L of water was used. The reaction mixture was heated to 60° C., and reacted at the same temperature for 3 hours. While holding the temperature at approximately 60° C., 4.4 L of ethyl acetate was added, the mixture was cooled to 50° C., 2.4 g of seed crystal was added, and the solution was kept at 50° C. for one hour. While holding the temperature at approximately 50° C., 22.3 L of ethyl acetate was added over one hour, the solution was kept at 50° C. for one hour, cooling to 10° C. over 4.6 hours, and kept at 10° C. for another 10 hours. The deposited solid was separated with a centrifuge, and washed with 17.8 L of a cooled mixed solution of ethyl acetate-ethanol (volume ratio: 75:25). The obtained wet solid was dried under reduced pressure at 50° C. for 19 hours to obtain 6342 g of 4-[(1R,2R)-2-aminocyclohexylamino]-2-oxo-3-pyrroline-1-carboxylic acid benzyl ester hydrochloride.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C@@H:10]([OH:15])[C:11](OC)=[O:12])[CH:7]=[CH:8][CH:9]=1.[Cl-].[NH4+]>CO>[Cl:3][C:4]1[CH:5]=[C:6]([C@@H:10]([OH:15])[CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](O)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OC[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
At 0-5° C., sodium borohydride (2.3 g, 60.80 mmol, 2.50 equiv) was added in several batches to a solution of (R)-Methyl 2-(3-chlorophenyl)-2-hydroxyacetate (5 g, 24.92 mmol, 1.00 equiv.) in methanol (50 mL). The resulting solution was stirred at ambient temperature for about 2 hours, and then 10% ammonium chloride (20 mL) was added. The mixture was concentrated in vacuo, and extracted with ethyl acetate (3×50 mL). The organic layers were combined and concentrated in vacuo to give the title product as a colorless oil (4 g; yield=93%). 1H NMR (300 MHz, DMSO-d6) δ: 7.26-7.39 (m, 4H), 5.40 (d, J=1.5 Hz, 1H), 4.77 (t, J=5.7 Hz, 1H), 4.54 (q, J=5.7 Hz, 1H), 3.48 (m, 2H).