Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:8]1[O:13][C@:12]([O:15][CH3:16])([CH3:14])[C@@:11]([O:18][CH3:19])([CH3:17])[O:10][C@H:9]1[CH2:20][OH:21])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.N1C(=O)CC[C@H]1C(O)=O.CS(C)=O>C(Cl)Cl.CC(=O)OCC>[C:1]([SiH2:5][O:6][C:7]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:8]1[O:13][C@:12]([O:15][CH3:16])([CH3:14])[C@@:11]([O:18][CH3:19])([CH3:17])[O:10][C@H:9]1[CH:20]=[O:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CO[C@]1(C)O[C@@H](CO)[C@@H](C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)O[C@@]1(C)OC
Agent: O=C1CC[C@@H](C(=O)O)N1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CO[C@]1(C)O[C@@H](C=O)[C@@H](C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)O[C@@]1(C)OC
Temperature: 0 °C
Reaction time: 4 h

Procedure:
[(2S,3S,5R,6R)-3-(tert-butyl-diphenyl-silanyloxymethyl)-5,6-dimethoxy-5,6-dimethyl-[1,4]dioxan-2-yl]-methanol (prepared from dimethyl L-tartrate according to J. Chem. Soc. Perkin 1 (1999), 1635; 9.2 g, 19.4 mmol) was dissolved in DCM (100 mL) and cooled to 0° C. DIPEA (19.9 mL, 6 eq.) was added and a solution of Pyr.SO3 complex (6.17 g, 2 eq.) in DMSO (27.5 mL, 20 eq.) was added dropwise over 20 min. The mixture was stirred at 0° C. for 4 h, diluted with DCM (200 mL) and washed several times with water. The org. phase was dried over MgSO4 and concentrated. The title aldehyde was isolated after FC (Hept/EA 2:1) as a colourless oil (8.6 g, 94% yield).
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].CN(C)C=O.C(Cl)(=O)C([Cl:31])=O>ClCCl>[CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([Cl:31])=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCOP(=O)(OCC=C)OCc1c(C)cccc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCOP(=O)(OCC=C)OCc1c(C)cccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-methylbenzoic acid (880 mg, 2.70 mmol) obtained from Example 22-(5) in dichloromethane (15 ml) was cooled to 0° C., and then N,N-dimethylformamide (15 μl) and oxalyl chloride (1.71 g, 13.5 mmol) were added thereto. After the mixture was stirred at room temperature for 30 minutes, crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-methylbenzoyl chloride was obtained according to a similar procedure to that described in Example 1-(12).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[S:9]([CH2:12][C:13](=[O:15])[CH3:14])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:33]NS(C1C=CC=CC=1)(=O)=O>C1COCC1.O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:9]([CH:12]([F:33])[C:13](=[O:15])[CH3:14])(=[O:10])=[O:11])=[CH:21][CH:20]=1
Reactant: O=S(=O)(NF)c1ccccc1
Reactant: CC(=O)CS(=O)(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)C(F)S(=O)(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a stirring solution of the methyl ketone (Example 1, 0.6 g, 1.7 mmol) in dry THF (11 mL) at 0° C., under dry nitrogen was added LiHMDS (1.0 M/THF, 2.2 mL, 1.2 mmol) and the mixture stirred for 30 minutes without warming. After this time, the resulting enolate was lowered to −78° C., whereupon a solution of N-fluorobenzenesulfonamide (0.85 g, 2.7 mmol) in dry THF (5.0 mL) was added via canula. The reaction was then stirred for 30 minutes and then at room temperature for 1 hour, and was then diluted with water and extracted with ethyl acetate. The organic layers were combined, dried on Na2SO4, and filtered to give a mixture that was purified on SiO2 with 15%–20% EtOAcHexane to give (0.075 g, the fluorinated species as a colorless oil. Anal. Calcd for C16H13Cl2F1O3S1: 0.15H2O: Calcd C, 50.85; H, 3.55; Cl, 18.76; F, 5.03; O, 13.33; S, 8.48. Found: C, 50.45; H, 3.51; S, 8.15. 1H NMR (CDCl3, 400 MHz): δ 2.1 (s, 3H), 5.2 (d, 1H, J=49.0 Hz), 5.65 (s, 1H), 7.28–7.5 (m, 4H), 7.5–7.7 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH2:9][Cl:10])=[O:6].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.O>CN(C=O)C>[Si:14]([O:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH2:9][Cl:10])=[O:6])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCCCl)c1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)OCCCl)c1

Procedure:
A solution of 10 g (50 mmol) the ester from step (a), t-butyldimethylsilyl chloride (8.25 g, 55 mmol) and imidazole (4.76 g, 70 mmol) in 100 mL of DMF was stirred under argon for 1 h. The solution was poured into 100 mL of water and extracted with ether (3×50 mL). The combined ether solutions were extracted with 20 mL of water. The organic layer was dried and evaporated giving 18 g of an oil which was purified by column chromatography using 0-2% ethyl acetate in hexane yielding 14.4 g of the product as a colorless oil (91%); 1H NMR (CDCl3) δ0.218 (s,6H), 0.995 (s,9H), 3.81 (t,2H), 4.56 (t,2H), 7.05-7.65 (m,4H). ##STR13##
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[Cl:12][C:3]1[C:2]([NH:1][S:27]([C:21]2[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:20]=2[F:19])(=[O:29])=[O:28])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: COC(=O)c1cccc(N)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1Cl
Yield: 81.6 %

Procedure:
Following a procedure analogous to Intermediate 5, Step A using methyl 3-amino-2-chlorobenzoate (39 g, 211 mmol) in DCM (200 mL) was added pyridine (51 g, 633 mmol) and 2,6-difluorobenzene-1-sulfonyl chloride (49.1 g, 232 mmol) the title compound was obtained (62 g, 81.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.87 (dd, J=1.8 Hz, 8.38 Hz, 1H), 7.72-7.79 (br, 1H), 7.56 (dd, J=1.8 Hz, 7.94 Hz, 1H), 7.45-7.53 (m, 1H), 7.28 (dd, J=7.9 Hz, 8.4 Hz, 1H), 6.95-7.01 (m, 2H), 3.89 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:13]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11][C:4]=2[NH:5][C:6]=1[C:7]([O:9]C)=[O:8].O.[OH-].[Li+].CO>C1COCC1>[Br:1][C:2]1[C:3]2[CH:13]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:11][C:4]=2[NH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1[nH]c2c(c1Br)C(CCc1ccccc1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1[nH]c2c(c1Br)C(CCc1ccccc1)CC2

Procedure:
The title compound was synthesized from methyl 3-bromo-4-phenethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (68 mg, 0.20 mmol) and lithium hydroxide monohydrate (33 mg, 0.78 mmol in 3 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by flash chromatography (Isco CombiFlash) eluting with a gradient of 0-80% EtOAc/Heptane to the title compound. 37 mg. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.68-1.80 (m, 1H), 2.08-2.22 (m, 2H), 2.55-2.71 (m, 4H), 2.71-2.83 (m, 1H), 3.00-3.08 (m, 1H), 7.10-7.16 (m, 1H), 7.17-7.28 (m, 4H); LCMS-MS (ESI+) 356.0 (M+Na); HPLC (UV=93.2%), (ELSD=100%).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[CH2:5]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([NH:21][C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=1)[O:25][CH2:26][C:27]([OH:29])=[O:28])=[O:20])=[CH:14][CH:13]=[CH:12]2)[CH2:6][CH2:7][CH3:8].C([O-])(O)=O.[Na+].CN(C=O)C>CCOC(C)=O.O>[CH2:5]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([NH:21][C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=1)[O:25][CH2:26][C:27]([O:29][CH2:2][CH2:3][OH:4])=[O:28])=[O:20])=[CH:14][CH:13]=[CH:12]2)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCc1ccc2c(C(=O)Nc3cccc(OCC(=O)O)c3)cccc2c1
Reactant: OCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1ccc2c(C(=O)Nc3cccc(OCC(=O)OCCO)c3)cccc2c1
Temperature: 70 °C
Yield: 69 %

Procedure:
2-Bromoethanol was added to a 1 dram vial containing a mixture of 2-(3-(6-butyl-1-naphthamido)phenoxy)acetic acid (27 mg, 0.07 mmol), NaHCO3 (6 mg, 0.07 mmol) and DMF (03 mL). A single drop of water from a 22 gauge needle was added and the vial was sealed under nitrogen and heated at 70° C. After several days, the mixture was cooled to room temperature and diluted with EtOAc (20 The organic mixture was and washed with water (2×5 mL) and brine (5 mL) then dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified on 4 g silica gel (100% hexanes→100% EtOAc, gradient) to afford 24 mg (69%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:2]=1.CN(C)C.ClC(OCC(C)C)=O.[N-:27]=[N+:28]=[N-:29].[Na+]>ClCCl.C(Cl)(Cl)Cl.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([C:12]([N:27]=[N+:28]=[N-:29])=[O:14])[N:11]=2)[CH:2]=1
Reactant: O=C(O)c1csc(-c2cccnc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Agent: CN(C)C
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: [N-]=[N+]=NC(=O)c1csc(-c2cccnc2)n1
Reaction time: 1 h
Yield: 40 %

Procedure:
A suspension of 2-(3-pyridyl)-thiazole-4-carboxylic acid (0.824 g, 4 mmol) in dichloromethane-chloroform (30 ml-15 ml) was treated with trimethylamine (0.75 ml, 0.5 g, 5 mmol) and then iso-butyl chloroformate (0.65 ml, 0.68 g, 5 mmol). After 1 h the mixture was evaporated to dryness and the residue suspended in THF (30 ml) and a solution of sodium azide (0.46 g, 7 mmol) in water (10 ml) was added. After 1 h, the mixture was concentrated (rotary evaporator) and partitioned between dichloromethane and brine. The organic extract was washed with half-saturated brine, dried, and evaporated. Trituration with petroleum ether, filtration, and drying in vacuo (CAUTION—no heating) afforded the title compounds as a brown solid (0.37 g, 40%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[H-].[Na+].[CH3:14][O:15][C:16](=O)[O:17]C>>[CH3:14][O:15][C:16]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[C:7]1=[O:11])=[O:17]
Reactant: COC(=O)OC
Reactant: O=C1CCc2cc(Br)ccc21
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1Cc2cc(Br)ccc2C1=O

Procedure:
Use of 5-bromo-indan-1-one (Intermediate NINETEEN-1) in a reaction with NaH and dimethylcarbonate (refer to procedures in Method EIGHTEEN) produced 5-bromo-1-oxo-indan-2-carboxylic acid methyl ester (Intermediate NINETEEN-2). A solution of 5-bromo-1-oxo-indan-2-carboxylic acid methyl ester (4.75 g, 17.7 mmol) in TFA (80 mL) at 0° C. was treated with triethylsilane (TES) (17.0 mL, 6.0 eq) and stirred for 18 h. After evaporation of the solvent, the residue was diluted with Et2O and washed with H2O (5×100 mL), sat. NaHCO3 (3×50 mL), brine (1×75 mL) and dried over MgSO4 to give crude 5-bromo-indan-2-carboxylic acid methyl ester (Intermediate NINETEEN-3). A solution of 5-bromo-indan-2-carboxylic acid methyl ester (Intermediate NINETEEN-3) in AcOH containing 20% HCl was stirred overnight. After evaporation of the solvent, the residue was dissolved in 1N NaOH. The resulting mixture was washed with Et2O (3×75 mL) after which it was acidified with HCl (aq). The solution was extracted with CH2Cl2 (3×150 mL) and the combined organic extracts was washed with H2O (3×100 mL), brine (1×75 mL), dried over MgSO4 and concentrated to give crude 5-bromo-indan-2-carboxylic acid. Use of 5-bromo-indan-2-carboxylic acid in Method EIGHTEEN produced 4-(5-bromo-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 148).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C:8](OCC)=[O:9].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[CH2:8][OH:9]
Reactant: CCOC(=O)c1ccccc1Oc1cccc(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1ccccc1Oc1cccc(F)c1

Procedure:
Ethyl 2-(3-fluorophenoxy)benzoate (37 g.) dissolved in 90 ml. of ether, was added dropwise to a suspension of lithium aluminum hydride (4.5 g.) in 350 ml of ether. The reaction mixture was heated to reflux for 6 hours to give, after work-up, 30 g. of the title compound. ##STR11##
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N+:3]=1[O-:11].[CH:12]([N:15]([CH:19]([CH3:21])[CH3:20])[CH2:16][CH2:17][NH2:18])([CH3:14])[CH3:13]>C(O)C>[CH:12]([N:15]([CH:19]([CH3:21])[CH3:20])[CH2:16][CH2:17][NH:18][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N+:3]=1[O-:11])([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Reactant: CC(C)N(CCN)C(C)C
Solvent: CCO
Product: CC(C)N(CCNc1cc([N+](=O)[O-])cc[n+]1[O-])C(C)C

Procedure:
A mixture of 2-chloro-4-nitropyridine-N-oxide (20.9 g., 0.12 mole) and 2-diisopropylaminoethylamine (34.8 g., 0.24 mole) dissolved in absolute ethanol (200 ml) is refluxed for 31/2 hours. The solvent is evaporated and the residue is extracted with hot cyclohexane several times to give upon cooling orange crystalline product (20.9 g.), m.p. 94°-97° C.
Reaction SMILES: [OH:1][CH2:2][C@@:3]([C:6]1[CH:25]=[CH:24][C:9]([C:10]([NH:12][C:13]2[N:18]=[CH:17][C:16]3[CH:19]=[CH:20][N:21]([CH2:22][CH3:23])[C:15]=3[CH:14]=2)=[O:11])=[CH:8][C:7]=1[CH3:26])([OH:5])[CH3:4].C1C(=O)N([Cl:34])C(=O)C1>CN(C)C=O.CO>[Cl:34][C:19]1[C:16]2[CH:17]=[N:18][C:13]([NH:12][C:10](=[O:11])[C:9]3[CH:24]=[CH:25][C:6]([C@:3]([OH:5])([CH3:4])[CH2:2][OH:1])=[C:7]([CH3:26])[CH:8]=3)=[CH:14][C:15]=2[N:21]([CH2:22][CH3:23])[CH:20]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCn1ccc2cnc(NC(=O)c3ccc([C@@](C)(O)CO)c(C)c3)cc21
Solvent: CO
Solvent: CN(C)C=O
Product: CCn1cc(Cl)c2cnc(NC(=O)c3ccc([C@@](C)(O)CO)c(C)c3)cc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 25.8 %

Procedure:
(R)-4-(1,2-dihydroxypropan-2-yl)-N-(1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-3-methylbenzamide (40 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (0.57 mL) to give a light yellow solution. NCS (14 mg, 0.10 mmol) was then added at room temperature. The mixture was heated mixture at 60° C.; after 3 hr, another 15 mg of NCS was added, and the reaction completed after 1 hr. The mixture was diluted with MeOH (1 ml) and then purified by preparatory HPLC (basic mode, 20-70% ACN in water). Product-containing fractions were combined, concentrated and freeze-dried to obtain the title compound as a tan colored solid (10 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (t, J=7.20 Hz, 3 H) 1.48 (s, 3 H) 2.58 (s, 3 H) 3.58-3.64 (m, 2 H) 4.19 (q, J=7.24 Hz, 2 H) 4.77 (br. s., 1 H) 4.92 (br. s., 1 H) 7.55 (d, J=8.34 Hz, 1 H) 7.68 (s, 1 H) 7.76-7.88 (m, 2 H) 8.36 (d, J=0.76 Hz, 1 H) 8.59 (d, J=1.01 Hz, 1 H) 10.58 (s, 1 H); ESI-MS: m/z 388 (M+H)+.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:25])[C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=3)[CH2:11]2)=[N:3][CH:2]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:25])[C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH:29][CH:26]4[CH2:28][CH2:27]4)=[O:21])=[CH:18][N:17]=3)[CH2:11]2)=[N:3][CH:2]=1
Reactant: NC1CC1
Reactant: CN(c1ccc(C(=O)O)cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccc(C(=O)NC2CC2)cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-6-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)amino)nicotinic acid (33.8 mg, 0.1 mmol) in DMF (2 mL) were added cyclopropylamine (5.71 mg, 0.2 mmol), DIPEA (26 mg, 0.2 mmol) and HATU (38.0 mg, 0.1 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography to give the title compound. MS (m/z): 378 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]2[N:8]([C:16](=[O:18])[CH3:17])[CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C1(P(C2CCCCC2)C2C=CC(C3C(C(C)C)=CC(C(C)C)=CC=3C(C)C)=CC=2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:22]1[CH2:23][CH2:24][N:19]([C:2]2[CH:7]=[C:6]3[N:8]([C:16](=[O:18])[CH3:17])[CH2:9][C:10]4([CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)[C:5]3=[CH:4][CH:3]=2)[CH2:20][CH2:21]1
Reactant: CC(=O)N1CC2(CCOCC2)c2ccc(Br)cc21
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccc(P(C3CCCCC3)C3CCCCC3)cc2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: CC(=O)N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21
Temperature: 110 °C

Procedure:
1-(6-Bromo-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-1-yl)ethanone (2.56 g, 8.25 mmol) was combined with morpholine (1.08 mL, 12.4 mmol), dicyclohexyl-(2′,4′,6′-triisopropylbiphenyl-4-yl)phosphine (0.118 g, 0.248 mmol), Pd2dba3 (0.256 g, 0.248 mmol), and cesium carbonate (4.03 g, 12.4 mmol) in tert-butanol (30.0 mL, 314 mmol). The reaction was purged with N2, and heated at 110° C. for 4 h. After this time the reaction was diluted with EtOAc and filtered through a Celite pad. The filtrate was concentrated in vacuo. The crude material was triturated with EtOAc/hexane to give 1-(6-morpholino-2′,3′,5′,6′-tetrahydrospiro-[indoline-3,4′-pyran]-1-yl)ethanone. Mass Spectrum (ESI) m/e=317 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH3:27][CH:28]1[CH2:33][CH:32]([NH:34][C:35]2[NH:39][CH:38]=[N:37][N:36]=2)[CH2:31][CH2:30][O:29]1>>[CH3:27][CH:28]1[CH2:33][CH:32]([N:34]2[C:17](=[O:18])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:22]([CH2:23][CH2:24][CH3:25])[N:36]3[N:37]=[CH:38][N:39]=[C:35]23)[CH2:31][CH2:30][O:29]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: CC1CC(Nc2nnc[nH]2)CCO1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOC(C)C2)c2ncnn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 55.9 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1.2 g) and N-(2-methyltetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.3 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.43 g, 56%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[S:5][C:6]=1[CH3:7].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[O:25][N:24]=[C:23]([CH3:26])[CH:22]=1>C(OCC)(=O)C>[CH3:26][C:23]1[CH:22]=[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:4]3[S:5][C:6]([CH3:7])=[C:2]([CH3:1])[N:3]=3)=[CH:9][CH:10]=2)[O:25][N:24]=1
Reactant: Cc1nc(-c2ccc(O)cc2)sc1C
Reactant: Cc1cc(CCCCCBr)on1
Solvent: CCOC(C)=O
Product: Cc1cc(CCCCCOc2ccc(-c3nc(C)c(C)s3)cc2)on1

Procedure:
3-Methyl-5-{5-[4(4,5-dimethyl-2-thiazolyl)phenoxy]pentyl}isoxazole [II; R1 and R2 =H, Het=(4,5-dimethyl-2-thiazolyl)] was prepared from 2.0 g 4-(4,5-dimethyl-2-thiazolyl)phenol and 2.3 g 5-(5-bromopentyl)-3-methylisoxazole according to the procedure of Example 1: yield 2.5 g, m.p. 96°-97° C. (yellow to orange crystals from ethyl acetate).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:21][CH:20]=1>>[NH2:14][C:9]1[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]2[O:4][C:3]([CH2:2][N:30]3[CH2:31][CH2:32][CH:27]([NH:26][CH:25]([C:22]4[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=4)[C:33]4[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)[CH2:28][CH2:29]3)([CH3:16])[CH2:7][C:6]=2[C:8]=1[CH3:15]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Reactant: COc1ccc(C(NC2CCNCC2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC2CCN(CC3(C)Cc4c(C)c(N)c(C)c(C)c4O3)CC2)c2ccc(OC)cc2)cc1
Yield: 43 %

Procedure:
Starting with 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and N-[bis(4-methoxyphenyl)methyl]-4-piperidinamine, the procedure of Example 53 was otherwise repeated to provide the title compound. Yield 43%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].S(O)(O[CH2:19][CH2:20][NH2:21])(=O)=O>O.CO.C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][C@@H:10]1[O:11][CH2:19][CH2:20][NH:21][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: NCCOS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(COC[C@H]2CNCCO2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 110.9 %

Procedure:
To a stirred mixture of (R)-2-(benzyloxymethyl)oxirane (10.0 g, 60.9 mmol) and NaOH (19.49 g, 487.2 mmol) in H2O (46 mL) and MeOH (18 mL), there was added 2-aminoethyl hydrogen sulfate (36.8 g, 255.8 mmol) in portions. After addition, the reaction mixture was stirred at 40° C. for 2 h. After cooling, the mixture was treated with NaOH (15.0 g, 375.0 mmol) then toluene (70 mL) and stirred at 65° C. overnight. The mixture was cooled, diluted with toluene (27 mL) and H2O (92 mL). The toluene layer was separated and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic layers were concentrated to give crude (R)-2-(benzyloxymethyl)morpholine (˜14 g), which was used without purification. MS m/z 208 (M+H+).
Reaction SMILES: BrCC1C=CC(C(O)=O)=CC=1.[H-].[Na+].[CH2:14]([O:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)[CH2:15]C=C>C(O)C>[CH2:14]([O:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)[CH3:15]
Reactant: C=CCCOCc1ccc(C(=O)O)cc1
Agent: O=C(O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOCc1ccc(C(=O)O)cc1

Procedure:
The reaction of ethanol and 4-Bromomethyl-benzoic acid in the presence of sodium hydride was performed as described for Compound 33 to give 4-Ethoxymethyl-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 7.89 (d, J=8.2, 2 arom.H); 7.40 (d, J=8.2, 2 arom.H); 4.50 (s, OCH2C6H4); 3.49 (q, J=6.9, CH3CH2); 1.15 (t, J=6.9, CH3CH2). 13C-NMR (100 MHz, d6-DMSO): 167.24 (—C═O); 143.88; 129.65; 129.28 (2 arom. C); 127.05 (2 arom. C); 70.95; 65.25; 15.06.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:27]=[CH:26][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:19]4[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:18]=4[O:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([CH3:30])[CH3:29]>>[CH:28]([N:31]1[CH2:36][CH2:35][N:34]([CH2:2][C:3]([NH:5][C:6]2[CH:27]=[CH:26][C:9]3[N:10]=[C:11]([NH:14][CH:15]4[C:19]5[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:18]=5[O:17][CH2:16]4)[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH2:33][CH2:32]1)([CH3:30])[CH3:29]
Reactant: CC(C)N1CCNCC1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CCl)cc3CO1)CO2
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CN4CCN(C(C)C)CC4)cc3CO1)CO2
Yield: 72.7 %

Procedure:
Prepared from rac-2-chloro-N-[2-(4-methoxy-2,3-dihydro-benzofuran-3-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 8) (50 mg, 0.129 mmol) and 1-(isopropyl)piperazine (330 mg, 2.578 mmol) according to the procedure described for Example 3 step B (here the reaction was sonicated for 2 min, which already lead to complete conversion). Obtained the title compound as a white solid (45 mg, 73%), MS (ISP) m/e=480.3 [(M+H)+].