Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](CCOS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.[NH:28]1CCC[C@@H]1CO>O1CCOCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[NH2:28]
Reactant: OC[C@H]1CCCN1
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Solvent: C1COCCO1
Product: Nc1cc2ccccc2[nH]1
Yield: 168.1 %

Procedure:
5-(2-Methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.350 g, 0.900 mmol, 1 eq, Example 56, Step D) was suspended in dioxane (20 mL) under Ar. (R)-2-Pyrrolidine methanol (0.272 g, 2.700 mmol, 3 eq) was added. The reaction mixture was stirred and heated to reflux for 18 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.200 g (57%) of the indole-amine was obtained as a white solid. This was converted to the .HCl salt. LC/MS (ESI+) 393 (M+1); Anal. Calcd for C24H28N2O3.1HCl.1.25H2O: C, 63.85; H, 7.03; N, 6.20; Found: C, 63.68; H, 6.81; N, 6.20.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][N:24]=[CH:23]2.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][N:24]=[CH:23]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1ccc2ncncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2ncncc2c1
Reaction time: 0.08 h
Yield: 23.9 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (163 mg, 0.723 mmol) in dichloromethane (4 mL) was added pyridine (140 μL, 1.72 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-aminoquinazoline [21] (100 mg, 0.689 mmol) was added. The resulting mixture was stirred for 4 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a pale yellow solid (55 mg, 24%), single spot at Rf 0.56 (ethyl acetate). mp>270° C. (appeared to decompose at about 150° C.), HPLC purity 98% (tR 2.06 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 9.28 (1H, s), 9.25 (1H, s), 7.98 (1H, d, J=4.4 Hz), 7.95 (1H, d, J=5.2 Hz), 7.59-7.53 (3H, m), 7.25-7.20 (1H, m), 2.76 (3H, s). LCMS: 332.11 (M−). FAB-MS (MH+, C15H12ClN3O2S): calcd 334.0417, found 334.0420.
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH3:13])[C:7](=[O:9])[CH:8]=1.[OH-].[NH4+:15]>>[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][N:15]=1
Reactant: [NH4+]
Reactant: CCCOc1coc(CO)cc1=O
Agent: [OH-]
Product: CCCOc1cnc(CO)cc1O
Temperature: 90 °C

Procedure:
A mixture of 2-hydroxymethyl-5-propoxy-pyran-4-one (30.0 g, 0.163 mole), 150 mL ammonium hydroxide is stirred and heated in a sealed vessel at 90° C. for 2 hours. The reaction mixture is cooled, evaporated to dryness in-vacuo, taken up in 15% methanol in chloroform and passed thru a pad of magnesol and silica gel eluting with the same solvent. The eluate is evaporated, treated with acetone, filtered, washed with acetone and air dried to give a-grey solid, 8.03 g, (80%), m.p. 159-60° C.; MS (ES+): m/z 184.3 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:35]=[CH:34][S:33][CH:32]=2)[CH:26]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[C:8][C:9]([C:15]([F:18])([F:17])[F:16])([OH:14])[C:10]([F:13])([F:12])[F:11])[CH3:2].[H-].[Na+].S(OC)(O[CH3:42])(=O)=O>CN(C)C=O>[CH2:1]([N:3]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:35]=[CH:34][S:33][CH:32]=2)[CH:26]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[C:8][C:9]([C:15]([F:18])([F:17])[F:16])([O:14][CH3:42])[C:10]([F:11])([F:12])[F:13])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCN(C/C=C/C#CC(O)(C(F)(F)F)C(F)(F)F)CCOCCOc1cccc(-c2ccsc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C/C=C/C#CC(OC)(C(F)(F)F)C(F)(F)F)CCOCCOc1cccc(-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
159 mg of (E)-ethyl-N-(7,7,7-trifluoro-6-trifluoromethyl-6-hydroxy-2-hepten-4-ynyl)-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine was dissolved in 2 ml of dimethylformamide, and 24 mg of 60% oily sodium hydride was added. The mixture was stirred at room temperature for 10 minutes. To this solution was added 60 μl of dimethyl sulfate, and then the mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and ethyl acetate and water were added to the residue to extract it. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the solvent was evaporated. The residue was purified by silica gel column chromatography [methylene chloride/methanol=70/1] to give 24 mg (yield 15%) of the captioned compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([N+:17]([O-])=O)=[CH:10][CH:9]=3)[CH2:6]1.[H][H]>CCO.C(Cl)Cl.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([NH2:17])=[CH:10][CH:9]=3)[CH2:6]1
Reactant: [H][H]
Reactant: COCCN1CC2CC(C1)c1cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: COCCN1CC2CC(C1)c1cc(N)ccc12
Yield: 142 %

Procedure:
10-(2-Methoxy-ethyl)-4-nitro-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (75 mg, 0.30 mmol) in 8 ml EtOH and 2 ml methylene chloride in a Parr bottle was treated with 50 mg 10% Pd/C and subjected to hydrogen (g) at 40 psi for 2 h. The suspension was filtered and the solvent removed under reduced pressure to yield 10-(2-methoxy-ethyl)-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (99 mg, 85%). LC/MS (ESI+): 233 (M+H)
Reaction SMILES: S([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][C:23]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:22]2=[O:32])=[CH:12]1)(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][C:23]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:22]2=[O:32])=[CH:12]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CN3CCCC4(CCNCC4)C3=O)c3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C1N(Cc2c[nH]c3ccccc23)CCCC12CCNCC2
Yield: 97.8 %

Procedure:
The mixture of 2-((1-tosyl-1H-indol-3-yl)methyl)-2,9-diazaspiro[5.5]undecan-1-one (15 g, 23 mmol) and Cs2CO3 (45 g, 139 mmol) in methanol (170 ml) was heated under reflux for 2.5 h. The solution was diluted with water, the pH adjusted to 7 with a saturated aqueous potassium carbonate solution and the aqueous phase extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 6.69 g (99%) of the title compound as a beige foam which was not further purified. [1H NMR (400 MHz, DMSO-d6) ♀ ppm 10.91 (br. s., 1H), 7.48-7.55 (m, 1H), 7.32 (d, J=8.2 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.04 (t, J=7.6 Hz, 1H), 6.88-6.96 (m, 1H), 4.60 (s, 2H), 3.10 (t, J=6.1 Hz, 2H), 2.71-2.89 (m, 2H), 2.51-2.69 (m, 2H), 2.01 (s, 3H), 1.54-1.73 (m, 4H), 1.25-1.38 (m, 2H); LCMS RtC=2.44 min, [M+H]+=298.2].
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:10]=[C:11](Cl)[C:12]2[S:17][C:16]([NH2:18])=[N:15][C:13]=2[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:29][NH:30][C@@H:31]([CH2:36][OH:37])[CH2:32][CH:33]([CH3:35])[CH3:34]>CN1C(=O)CCC1>[NH2:18][C:16]1[S:17][C:12]2[C:11]([N:30]([CH3:29])[C@H:31]([CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:36][OH:37])=[N:10][C:9]([S:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:14][C:13]=2[N:15]=1
Reactant: CN[C@@H](CO)CC(C)C
Reactant: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](CO)N(C)c1nc(SCc2ccccc2)nc2nc(N)sc12
Temperature: 110 °C
Reaction time: 48 h
Yield: 72.4 %

Procedure:
5-(Benzylthio)-7-chloro[1,3]thiazolo[4,5-d]pyrimidin-2-amine (1.5 g, 4.86 mmol), DIPEA (691 mg, 5.35 mmol) and (R)—N-methylleucinol (956 mg, 7.29 mmol) were mixed in NMP (7.5 mL). The resulting solution was stirred at 110° C. under a nitrogen atmosphere for 2 days. After cooling to room temperature the reaction mixture was poured onto ice. The resulting yellow precipitate was collected by filtration, washed with water and dried in vacuo. The crude product was purified by flash column chromatography on silica (DCM:EtOAc 50:50 to 0:100) to give 1.42 g (72% yield) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:19]1[CH:24]=[C:23]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])[C:22]([F:38])=[CH:21][C:20]=1[N+:39]([O-:41])=[O:40]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:19]1[CH:24]=[C:23]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])[C:22]([F:38])=[CH:21][C:20]=1[N+:39]([O-:41])=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Reactant: Oc1cccc(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(OCc4ccccc4)c3)c([N+](=O)[O-])cc2F)c1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52.9 %

Procedure:
A mixture of 1.71 g of 3-benzyloxyphenol and 4.0 ml of N,N-dimethylformamide was added dropwise into a mixture of 0.34 g of sodium hydride and 8.5 ml of N,N-dimethylformamide while cooling with ice, and the mixture was stirred for 20 minutes. A mixture of 3.0 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene (described later, produced in Intermediate Production Example 4) and 7.0 ml of N,N-dimethylformamide was added dropwise at the same temperature, and stirred for 1 hour. This reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed once with 1N hydrochloric acid and once with saturated saline, and dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 2.4 g of 2-(3-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)#[N:33].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:38]3[CH:39]=[C:34]([CH:35]=[CH:36][CH:37]=3)[C:32]#[N:33])[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1cccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)c1
Yield: 20 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (20%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:13][CH:14]1[CH2:19][NH:18][CH:17]([CH3:20])[CH2:16][NH:15]1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:15]2[CH2:16][CH:17]([CH3:20])[NH:18][CH2:19][CH:14]2[CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1CNC(C)CN1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)C(C)CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3,4-dichlorobenzene-1-sulfonyl chloride (840 mg, 3.42 mmol) and 2,5-dimethylpiperazine (1.171 g, 10.26 mmol) in anhydrous dichloromethane (5 mL) was added diisopropylethylamine (1.2 mL, 6.84 mmol). The mixture was stirred overnight at room temperature. Reaction was complete as determined by TLC. The reaction mixture was diluted with dichloromethane, washed with water and dried over MgSO4. After solvent evaporation crude product was treated with ethyl acetate/hexanes. Solid impurity was filtered of and the filtrate was concentrated to afford 1-(3,4-dichlorophenylsulfonyl)-2,5-dimethylpiperazine in quantitative yield. It was carried to the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O.[NH2:19][CH:20]1[CH:27]2[CH2:28][C:23]3([CH2:30][OH:31])[CH2:24][CH:25]([CH2:29][CH:21]1[CH2:22]3)[CH2:26]2>>[OH:31][CH2:30][C:23]12[CH2:22][CH:21]3[CH2:29][CH:25]([CH2:26][CH:27]([CH:20]3[NH:19][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[C:10]([O:9][CH2:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH:11]=3)[CH2:28]1)[CH2:24]2
Reactant: NC1C2CC3CC1CC(CO)(C3)C2
Reactant: O=C(O)c1cccc(OCCc2ccccn2)c1
Product: O=C(NC1C2CC3CC1CC(CO)(C3)C2)c1cccc(OCCc2ccccn2)c1

Procedure:
Prepared from 3-(2-pyridin-2-yl-ethoxy)-benzoic acid and 4-amino-1-hydroxymethyladamantane to give the title compound as a mixture of two isomers. 1H NMR (400 MHz, CDCl3) δ: 8.88 (t, 1H), 8.28 (q, 1H), 7.84 (d, 1H), 7.75 (q, 1H), 7.32 (q, 2H), 7.23-7.29 (m, 1H), 6.93-7.04 (m, 1H), 6.44-6.51 (m, 1H), 4.44 (q, 2H), 4.14-4.22 (m, 1H), 3.61 (q, 2H), 3.27 (s, 1H), 2.10-2.24 (m, 2H), 1.98-2.09 (m, 2H), 1.55-1.94 (m, 8H), 1.45-1.54 (m, 1H), 1.40 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CN=C1.[C:17]([Si:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)Cl)([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C.CCOCC>[C:17]([Si:21]([O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1ccc([N+](=O)[O-])cc1)(c1ccccc1)c1ccccc1
Reaction time: 5 h

Procedure:
To a stirred solution of 4-nitrobenzyl alcohol, 12, (1.00 g, 6.50 mmol), and imidazole (0.97 g, 14.1 mmol) in DMF (10.0 ml), was added tert-butyl-diphenyl-chlorosilane (1.98 g, 7.20 mmol) over 10 min under N2 at room temperature. The reaction mixture was stirred for an additional 5 h, diluted with Et2O (75 ml), washed with H2O (5×15 ml), dried (MgSO4) and evaporated to dryness under vacuum. An oil was obtained which crystallised on standing and was recrystallised to a solid from EtOH (70%); yield: 2.36 g (93%). vmax /cm-1 (film): 2931, 2857 (CH2, asym., sym.), 1521, 1345 (NO2); 1H-NMR, dH : 1.06(9H, s, t-Bu), 4.92 (2H, s, CH2), 7.42-7.46 (5H, m, Ph), 7.63-7.65 (7H, m, Ph+Harom2+6), 8.23 (2H, d, J=8.23, Harom3+5); MS, (EI), (391.54); m/z: 334 (M - t-Bu, 100), 288 (M - t-Bu - NO2, 10), 256 (M - t-Bu - Ph, 20), 199 (Ph2SiOH+, 100); C23H25NO3Si.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6]([OH:8])=O)[CH3:2].O1CCCC1.[F:16][C:17]([F:21])([F:20])[CH2:18][NH2:19].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>Cl>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6]([NH:19][CH2:18][C:17]([F:21])([F:20])[F:16])=[O:8])[CH3:2]
Reactant: NCC(F)(F)F
Reactant: CCOC(=O)C(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
To a solution of 1.56 g (10.6 mmol) methyl-malonic acid monoethyl ester in 20 ml of tetrahydrofuran 1.06 g (10.6 mmol) of 2,2,2-trifluoroethylamine, 2.05 g (10.6 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 1.44 g (10.6 mmol) of 1-hydroxybenzotrizole hydrate and 2.75 g (21.2 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. The mixture was poured onto 0.5 N HCl (50 ml) and afterwards extracted with dichloromethane (three times 50 ml). The combined organic layers were extracted with 0.5 N aqueous NaHCO3 solution, dried (MgSO4) and evaporated on the rotary evaporator. The residue was purified by column filtration (hexane/ethyl acetate=2:1) to yield 1.48 g (61%) of the title compound as white crystalline solid.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH2:21][OH:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:23][C:24]1([NH2:28])[CH2:27][O:26][CH2:25]1>>[CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:28][C:24]3([CH3:23])[CH2:27][O:26][CH2:25]3)=[O:18])=[CH:14][N:13]=2)=[C:8]([CH2:21][OH:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1(N)COC1
Reactant: CCCCc1noc(CO)c1COc1ccc(C(=O)O)cn1
Product: CCCCc1noc(CO)c1COc1ccc(C(=O)NC2(C)COC2)cn1
Yield: 48 %

Procedure:
As described in example 52g, 6-[3-butyl-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (49 mg, 0.16 mmol) was converted, using 3-methyl 3-oxetanamine instead of cyclobutylamine, to the title compound (29 mg, 48%) which was obtained as a colorless oil. MS: m/e=376.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:6][O:7][N+:8]([O-:10])=[O:9])[C:3](Cl)=[O:4].[C:12]([CH:15]1[CH2:19][S:18][CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:16]1)([OH:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[C:12]([CH:15]1[CH2:19][S:18][CH:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:16]1[C:3](=[O:4])[C:2]([CH3:11])([CH3:1])[CH2:6][O:7][N+:8]([O-:10])=[O:9])([OH:14])=[O:13]
Reactant: O=C(O)C1CSC(c2ccccc2)N1
Reactant: CC(C)(CO[N+](=O)[O-])C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO[N+](=O)[O-])C(=O)N1C(C(=O)O)CSC1c1ccccc1
Reaction time: 0.75 h
Yield: 38 %

Procedure:
A solution of 5.2 g of 2,2-dimethyl-3-nitroxypropanoyl chloride in 100 ml of tetrahydrofuran was added at 0° C. under nitrogen to a solution of 6.0 g of 4-carboxy-2-phenylthiazolidine and 4.0 g of potassium carbonate in a mixture of 50 ml of tetrahydrofuran and 150 ml of water. After stirring the resulting solution for 45 minutes the mixture was concentrated under reduced pressure to about 150 ml and then acidified to pH=2 with citric acid. The resulting mixture was extracted with diethyl ether and the organic phase was dried over sodium sulphate and evaporated. The residue was purified by chromatography (silica, petroleum ether 60-80: ethyl acetate: acetic acid/8:8:1). Yield 38%. Empirical formula C15H18N2O6S. Molecular weight 354. Melting point 35°-38° C. TLC system: petroleum ether 60-80: ethyl acetate: acetic acid/4:4:1. Rf 0.50.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]3[C:18]4[C:23]([CH2:24][CH2:25][C:14]=23)=[CH:22][C:21]([CH:26]2[CH2:28][O:27]2)=[CH:20][CH:19]=4)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[NH:29]1[CH2:34][CH2:33][CH2:32][C@H:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:30]1>CC(O)C.O1CCOCC1.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]3[C:18]4[C:23]([CH2:24][CH2:25][C:14]=23)=[CH:22][C:21]([CH:26]([OH:27])[CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][C@H:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:30]2)=[CH:20][CH:19]=4)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2onc3c2CCc2cc(C4CO4)ccc2-3)cc1OCC
Reactant: CCOC(=O)[C@H]1CCCNC1
Agent: CN(C)c1ccncc1
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CCOC(=O)[C@H]1CCCN(CC(O)c2ccc3c(c2)CCc2c-3noc2-c2ccc(OCC)c(OCC)c2)C1
Temperature: 60 °C
Yield: 26.4 %

Procedure:
To 3-(3,4-diethoxyphenyl)-7-(oxiran-2-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 81A, 0.08 g, 0.212 mmol) in a mixture of 2-propanol (1 mL) and dioxane (1.000 mL) was added DMAP (5.18 mg, 0.042 mmol) followed by (S)-ethyl piperidine-3-carboxylate (0.033 mL, 0.212 mmol) at room temperature. The reaction mixture was heated at 60° C. (oil bath temp.) for 26 h, concentrated under reduced pressure, and purified by column chromatography using an ISCO setup (12 g, RediSep® silica gel column). The desired fractions were collected and concentrated to yield (0.03 g, 0.056 mmol, 26.5% yield) of the product as a diastereomeric mixture. The individual diastereomers were separated using a CHIRALCE1® OJ-H column under SFC conditions (25% MeOH with 0.1% diethylamine in CO2). Isomer 1 (7.7 mgs), retention time on chiral HPLC, 4.39 min; Isomer 2 (9 mgs), retention time on chiral HPLC, 6.15 min. The absolute stereochemistry at the carbon anchoring the secondary alcohol, of Isomer 1 and Isomer 2 was not determined.
Reaction SMILES: [CH:1]#[C:2][CH3:3].[Cl:4][C:5]1[CH:6]=[C:7](I)[C:8]([NH2:11])=[N:9][CH:10]=1.C(N(CC)CC)C>C1COCC1.[Cu]I>[Cl:4][C:5]1[CH:6]=[C:7]([C:1]#[C:2][CH3:3])[C:8]([NH2:11])=[N:9][CH:10]=1
Reactant: C#CC
Reactant: Nc1ncc(Cl)cc1I
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC#Cc1cc(Cl)cnc1N
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
Propyne (35 g, 0.87 mol) was condensed into a pre-weighed flask cooled to ca. −40° C. containing THF (100 mL). The solution was added via cannula to a cooled (0-5° C.), degassed mixture of 5-chloro-3-iodo-pyridin-2-ylamine (81.4 g, 0.32 mol), bis(triphenylphosphine)dichloropalladium(0) (4.49 g, 6.4 mmol), copper (I) iodide (1.46 g, 7.67 mmol) and triethylamine (97.3 g, 134 mL, 0.98 mol) in THF (900 mL). The mixture was stirred at 0-5° C. for 30 minutes then for a further 30 minutes at ambient temperature. The solid was removed by filtration and the cake washed with THF. The filtrate was diluted with ethyl acetate and extracted with 2M hydrochloric acid (×3). The combined acid extract was washed with diethyl ether and then made basic by careful addition of potassium carbonate then extracted with diethyl ether (×3). The combined organic layer was dried (Na2SO4), filtered and evaporated to afford the title compound as a brown solid (53.8 g, quantitative yield). LCMS (Method B): RT=3.55 min, M+H+=167/169. 1H NMR (300 MHz, CDCl3): 7.92 (d, J=2.5 Hz, 1H), 7.42 (d, J=2.5 Hz, 1H), 5.00 (s, 2H), 2.10 (s, 3H).