Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([C:20]2[CH:21]=[CH:22][N:23]=[C:18]([Cl:17])[N:19]=2)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)c1ccnc(Cl)n1
Temperature: 60 °C
Yield: 81.1 %

Procedure:
A stirred suspension of 1-t-butoxycarbonyl-4-[(methylamino)methyl]piperidine (3.50 g, 15.3 mmol), 2,4-dichloropyrimidine (2.74 g, 18.3 mmol) and potassium carbonate (4.15 g, 30.0 mmol) in dimethylformamide (38 mL) is heated at 60° C. for 3 hours. Excess dimethylformamide is removed in vacuo and the residue is taken into water and chloroform. The phases are separated and the aqueous phase is extracted into chloroform (×2). The combined organic extracts are dried (sodium sulfate), filtered and concentrated in vacuo. Flash column chromatography eluting with a gradient of 30% ethyl acetate-hexane to 60% ethyl acetate-hexane provides 1-t-butoxycarbonyl-4-{[(2-chloropyrimidin-4-yl)(methyl)amino]methyl}piperidine (4.23 g, 80%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:31]=[C:32]([N+:34]([O-])=O)[CH:33]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:18]=1[O:29][CH3:30])=[O:8])([O-])=O>CN(C=O)C.O.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:31]=[C:32]([NH2:34])[CH:33]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:18]=1[O:29][CH3:30])=[O:8]
Reactant: COC(=O)/C=C/c1ccc(OCCCCCCOC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)c(OC)c1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C=C/c1ccc(OCCCCCCOC(=O)c2cc(N)cc(N)c2)c(OC)c1
Yield: 62.9 %

Procedure:
5 g (9.7 mmol) of 6-{2-methoxy-4-[(1E)-3-methoxy-3-oxoprop-1-enyl]phenoxy}hexyl 3,5-dinitrobenzoate are dissolved in a mixture of 84 ml of DMF and 9 ml of water. 15.7 g (58 mmol) of ferric chloride hexahydrate are added. 6.31 g (97 mmol) of zinc powder are added portionwise within 30 min. The mixture is allowed to react for 2 hours. The reaction mixture is then partitioned between ethyl acetate and water and filtered. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Filtration of the residue on silica gel using toluene:ethyl acetate (1:3) as eluant and yielded 2.7 g (61%) of 6-{2-methoxy-4-[(1E)-3-methoxy-3-oxoprop-1-enyl]phenoxy}hexyl 3,5-diaminobenzoate as a white powder.
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@@H:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11][C@@H:10]1[NH:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([F:32])=[CH:27][CH:26]=2)=[O:22])=O)(C)(C)C.Cl.[CH3:34][N:35]1[CH2:40][CH2:39][C:38]2[N:41]=[C:42](C([O-])=O)[S:43][C:37]=2[CH2:36]1.[Li+]>O1CCOCC1>[CH2:18]([O:17][C:15]([C@H:13]1[CH2:12][CH2:11][C@H:10]([NH:20][C:21]([C:23]2[NH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][C:28]([F:32])=[CH:27][CH:26]=3)=[O:22])[C@H:9]([NH:8][C:6]([C:42]2[S:43][C:37]3[CH2:36][N:35]([CH3:34])[CH2:40][CH2:39][C:38]=3[N:41]=2)=[O:5])[CH2:14]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(F)ccc3[nH]2)[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Agent: Cl
Agent: [Li+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(F)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1

Procedure:
(1S,2R,4S)-N2-tert-Butoxycarbonyl-4-ethoxycarbonyl-N1-[(5-fluoroindol-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with a 4N dioxane solution of hydrochloric acid and then condensed with lithium 5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxylate in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2].[H-].[Na+].Cl[C:16]1[N:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:17]=1>CN(C)C=O>[OH:12][C:7]1[NH:8][C:9]2[C:5]([C:6]=1[C:16]1[CH:17]=[C:18]([O:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:19]=[CH:20][N:21]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: Clc1cc(OCCN2CCOCC2)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]c(O)c(-c3cc(OCCN4CCOCC4)ncn3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.2 %

Procedure:
To a solution of 5-cyanooxindole (411 mg, 2.60 mmol) in N,N-dimethylformamide (4 mL) was added sodium hydride (181 mg, 4.52 mmol, 60% dispersion in oil). After 10 min, a solution of 4-(2-[(6-chloropyrimidin-4-yl)oxy]ethyl )morpholine (367 mg, 1.51 mmol) in N,N-dimethylformamide (1.5 mL) was added dropwise. The mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo, and the residue was suspended in a 2 M aqueous HCl solution and washed twice with ethyl acetate. The aqueous layer was alkalized to pH 8 by adding a 45% aqueous NaOH solution. The obtained suspension was extracted twice with ethyl acetate. The combined phases were washed with brine, dried (Na2SO4) and the solvent was removed in vacuo. The crude product was purified on a silica gel column using chloroform/ethanol, (9:1), to chloroform/methanol, (8:2), as the eluent affording 172 mg (31% yield) of the title compound as a yellow solid: 1H NMR (DMSO-d6, 400 MHz) δ 10.89 (br s, 1 H), 8.62 (s, 1 H), 8.02 (s, 1 H), 7.30 (d, J=7 Hz, 1 H), 6.97 (d, J=8 Hz, 1 H), 6.83 (br s, 1 H), 4.52 (t, J=5 Hz, 2 H), 3.60 (t, J=4 Hz, 4 H), 2.77 (m, 2 H), 2.54 (m, 4 H); MS (TSP) m/z 366 (M++1).
Reaction SMILES: [CH2:1]([N:3]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[S:4]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17](=[O:18])[C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][NH:14]2)=[N:11][CH:12]=1)(=[O:6])=[O:5])[CH3:2].C[CH2:30][N:31](C(C)C)C(C)C.CN.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH2:1]([N:3]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[S:4]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17](=[O:18])[C:16]([CH2:19][C:20]([NH:31][CH3:30])=[O:22])=[CH:15][NH:14]2)=[N:11][CH:12]=1)(=[O:6])=[O:5])[CH3:2]
Reactant: CCN(c1ccccc1)S(=O)(=O)c1ccc(-n2[nH]cc(CC(=O)O)c2=O)nc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCN(c1ccccc1)S(=O)(=O)c1ccc(-n2[nH]cc(CC(=O)NC)c2=O)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.2 %

Procedure:
To a mixture of 0.28 g (0.7 mmol) of (2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)acetic acid, 0.61 mL (3.48 mmol) of DIEA and 0.8 mL (1.4 mmol) of methylamine (2N solution in THF) in 2 mL of DCM is added at 0° C. 0.33 g (1.04 mmol) of TBTU. After stirring for 3 hours at room temperature, the medium is taken up in 500 mL of DCM, washed successively with 0.1N HCl (2×40 mL), saturated NaHCO3 solution (2×40 mL) and brine (30 mL), dried over Na2SO4 and then concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a 95/5 DCM/MeOH mixture. 18 mg of 2-(2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-N-methylacetamide are obtained in the form of a brown powder.
Reaction SMILES: [CH2:1]1[O:22][C:4]([O:20]C)([C:5]2[CH:10]=[CH:9][C:8]([C:11]([N:13]3[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]3)=[O:12])=[CH:7][CH:6]=2)[O:3][CH2:2]1.O.[OH-].[Li+].Cl>C1COCC1.O>[CH2:2]1[O:3][C:4]([OH:20])([C:5]2[CH:10]=[CH:9][C:8]([C:11]([N:13]3[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]3)=[O:12])=[CH:7][CH:6]=2)[O:22][CH2:1]1
Reactant: COC1(c2ccc(C(=O)N3CCC(=O)CC3)cc2)OCCO1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCN(C(=O)c2ccc(C3(O)OCCO3)cc2)CC1
Yield: 98.1 %

Procedure:
A solution of methyl 4-(4-oxopiperidinocarbonyl)benzoate ethylene ketal (1.5 g, 4.9 mmol) and lithium hydroxide monohydrate (309 mg, 7.4 mmol) in THF/water (1:1) (50 ml) was stirred for 18 h, then acidified with dilute HCl. The product was extracted into ethyl acetate, and the extracts dried over sodium sulphate and concentrated to leave a white solid (1.4g), MS (+CI) 292 ([M+H]+), 1H NMR (CDCl3) 8.10 (2H, d, J 8.2 Hz), 7.45 (2H, d, J 8.3 Hz), 3.99 (4H, s), 3.86 (2H, br. s), 3.44 (2H, br. s), 1.81 (2H, br. s), 1.65 (2H, br. s)
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][C:16](=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:15](/[C:16](/[CH3:17])=[CH:20]/[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CC(=Cc1ccccc1)C(=O)O
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C(C)=C/c3ccccc3)nc2n(CC)c1=O
Yield: 49.8 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.00 g (10.1 mmol) of 5,6-diamino-1,3-diethyluracil and 1.80 g (11.1 mmol) of α-methylcinnamic acid. Then, the resultant crude crystals were recrystallized from ethanol/water to give 1.63 g (yield 50%) of Compound 134 as white needles.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][N:7]=1)(=[O:5])=[O:4])[CH3:2].[Cl:15][C:16]1[CH:33]=[CH:32][C:19]2[N:20]([CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:21]([CH2:23]Cl)=[N:22][C:18]=2[CH:17]=1>>[Cl:15][C:16]1[CH:33]=[CH:32][C:19]2[N:20]([CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:29])=[O:30])[C:21]([CH2:23][N:8]3[C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[N:7]3)=[N:22][C:18]=2[CH:17]=1
Reactant: CCS(=O)(=O)c1n[nH]c2ccccc12
Reactant: CS(=O)(=O)CCCn1c(CCl)nc2cc(Cl)ccc21
Product: CCS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2CCCS(C)(=O)=O)c2ccccc12

Procedure:
The title compound was prepared in analogy to Example 1-2 by using 3-(ethylsulfonyl)-1H-indazole and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole instead of 3-(methylsulfonyl)-1H-indole and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[S:19][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:6]=2[CH:5]=1.[F:20][C:21]1[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][C:22]=1[C:23]#[N:24]>>[Cl:3][C:4]1[S:19][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][N:16]([CH2:29][C:26]4[CH:27]=[CH:28][C:21]([F:20])=[C:22]([CH:25]=4)[C:23]#[N:24])[CH2:17][CH2:18]3)[C:6]=2[CH:5]=1
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Clc1cc2c(NC3CCNCC3)ncnc2s1
Agent: Cl
Product: N#Cc1cc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)ccc1F

Procedure:
The title compound was prepared (392 mg, 41%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine dihydrochloride (655 mg, 2.4 mmol) and 2-fluoro-5-formylbenzonitrile (399 mg, 2.7 mmol) by following the general procedure described for Preparation 11. 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.63 (m, 1H), 7.55 (m, 1H), 7.16 (m, 1H), 7.00 (s, 1H), 4.93 (d, 1H), 4.19 (m, 1H), 3.50 (s, 2H), 2.83 (d, 2H), 2.23 (dt, 2H), 2.10 (d, 2H), 1.59 (m, 2H); MS (ESI) m/z: Calculated for C19H18ClFN5S, 402.1; Observed: 402.2 (M++1).
Reaction SMILES: [P:1]([O:16][C:17]1[CH:22]=CC=CC=1)([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:23]([O:27][CH2:28][CH2:29][O:30]C(O)C)[CH2:24][CH2:25][CH3:26].[OH-].[Na+]>>[P:1]([O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:16][CH2:17][CH2:22][O:30][CH2:29][CH2:28][O:27][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: CCCCOCCOC(C)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCOCCOCCOP(Oc1ccccc1)Oc1ccccc1

Procedure:
248.2 g. (0.8 mol) of triphenyl phosphite and 131.2 g (0.81 mol) of 2-butoxyethoxyethanol were put into a flask of 500 ml. and 0.1 g. of sodium hydroxide was added thereto to react at 140°C. for 4 hours. The liberated phenol was distilled away by distillation under a reduced pressure (at 60°C. under 5 mm.Hg). Then the residual solution was filtered to obtain colorless transparent 2-(2-butoxyethoxy)ethyl diphenyl phosphite (Compound 9) as a filtrate.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>O1CCOCC1>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccccn1
Temperature: 150 °C

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.0 g, 5.10 mmol, Aldrich) in 1,4-dioxane (10 mL) in a sealed tube was treated with 2-bromopyridine (0.40 g, 2.50 mmol, Aldrich) and heated at 150° C. for 12 hours. The mixture was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was purified by flash chromatography (5% MeOH/CH2Cl2) to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 1.48 (m, 9H), 1.86-1.94 (m, 2H), 3.30-3.58 (m, 4H), 4.52 (brs, 0.5H), 4.67 (brs, 0.5H), 4.80 (brs, 0.5H), 4.92 (brs, 0.5H), 6.32 (d, J=9.0 Hz, 1H), 6.57 (t, J=6.0 Hz, 1H), 7.38-7.55 (m, 1H), 8.12 (d, J=6.0 Hz, 1H). MS (DCI/NH3) m/z 276 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])[CH3:2].[N+:18]([O-])([OH:20])=[O:19]>>[CH2:1]([O:3][P:4]([C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=1)([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])[CH3:2]
Reactant: CCCCCP(=O)(OCC)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Product: CCCCCP(=O)(OCC)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
Prepared analogously to Example 189b from ethyl(4-chlorophenyl)-n-pentyl-phosphinate and fuming nitric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:12][O:11]2)=[CH:4][CH:3]=1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH2:12][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)([OH:11])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C1(CCc2ccc(Cl)cc2)CO1
Solvent: CCO
Product: CC(C)(C)C(O)(CCc1ccc(Cl)cc1)Cn1cncn1
Yield: 53.3 %

Procedure:
A solution of 17.9 g (0.075 mol) of 2-(4-chlorophenyl-ethyl)-2-tert.-butyl-oxirane and 6.9 g (0.1 mol) of 1,2,4-triazole in 30 ml of ethanol was heated in a bomb tube at 150° C. for 20 hours. The reaction solution was allowed to cool and was concentrated. The residue was dissolved in ether, and the solution was washed three times with water and once with sodium chloride solution, and was dried over sodium sulphate and concentrated. The residue was subjected to chromatography over a silica gel column (eluent: dichloromethane/ethyl acetate 1:1). 12.3 g (53.2% of theory) of 1-(4-chlorophenyl)-4,4-dimethyl-3-(1,2,4-triazol-1-yl-methyl)-pentan-3-ol were obtained as a viscous oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=S)[NH2:2].NC1C=CC(C(C)C(OC)=[O:26])=CC=1>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[O:26])[NH2:2]
Reactant: COC(=O)C(C)c1ccc(N)cc1
Reactant: COC(=O)[C@@H](C)c1ccc(NC(N)=S)cc1
Product: COC(=O)C(C)c1ccc(NC(N)=O)cc1

Procedure:
Following the same procedure described for (S)-methyl 2-[4-(carbamothioylamino)phenyl]propanoate and starting from methyl 2-(4-aminophenyl)propanoate (98 mmol), after workup methyl 2-[4-(carbamoylamino)phenyl]propanoate was isolated as white solid (74%). 1H-NMR (CDCl3): δ 8.25 (bs, 1H, CSNH), 7.40 (d, 2H, J=7 Hz), 7.20 (d, 2H, J=7 Hz), 6.20 (bs, 2H, CSNH2), 3.75 (m, 1H), 3.65 (s, 3H), 1.50 (d, 3H, J=7 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[O:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[NH:32][CH2:31][CH2:30]1>>[O:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)[CH2:31][CH2:30]1
Reactant: c1ccc2c(c1)NCCO2
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: O=S(=O)(Nc1nccnc1-c1ccc(CN2CCOc3ccccc32)cc1)c1ccccc1C(F)(F)F
Yield: 65 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 3,4-dihydro-2H-1,4-benzoxazine, the title compound was isolated as a yellow solid in 65% yield (97% purity by HPLC).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].C(N(CC)CC)C.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([S:24](Cl)(=[O:26])=[O:25])=[C:19]([CH3:28])[CH:18]=1>ClCCl>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH3:28])[C:20]([S:24]([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][OH:7])(=[O:25])=[O:26])=[C:21]([CH3:23])[CH:22]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: OC[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCC[C@H]2CO)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-pyrrolidin-2-ylmethanol (2.2 g, 8.54 mmol) in dichloro-methane (20 ml) was added triethylamine (2.9 ml, 21.36 mmol) and the mixture was cooled to 0° C. Then a solution of 4-methoxy-2,6-dimethyl-benzenesulfonyl chloride (2 g, 8.547 m.mole) in dichloromethane (10 ml) was added and the mixture was stirred at room temperature for 2 h. TLC showed complete consumption of the starting material. The reaction mixture was diluted in dichloromethane and was washed with water and brine. The organic layer was dried over sodium sulfate, concentrated and purified by column chromatography.
Reaction SMILES: [CH2:1]1[CH2:6][O:5][CH:4]=[CH:3][CH2:2]1.[NH2:7][C:8]1[S:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:12]=1>CC#N.C(O)(C(F)(F)F)=O>[O:5]1[CH2:6][CH2:1][CH2:2][CH2:3][CH:4]1[NH:7][C:8]1[S:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:12]=1
Reactant: CCOC(=O)c1cnc(N)s1
Reactant: C1=COCCC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cnc(NC2CCCCO2)s1
Yield: 63.6 %

Procedure:
TFA (22 μL, 0.3 mmol) and DHP (3.9 mL, 43.5 mmol) were added to a suspension of ethyl 2-aminothiazole-5-carboxylate (5 g, 29 mmol) in CH3CN (40 mL) at RT. The resulting mixture was stirred at reflux overnight. The reaction mixture was concentrated and dissolved in AcOEt/PE and kept at 4 C overnight. The resultant white solid was filtrated and washed with PE, yielding ethyl 2-(tetrahydro-2H-pyran-2-ylamino)thiazole-5-carboxylate (4.73 g, 64%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)Cl.[CH3:12][O:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([NH:20][NH:21][C:22](=O)[CH3:23])=O)=[CH:16][CH:15]=1>ClC1C=CC=CC=1Cl>[CH3:12][O:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]2[N:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:22]([CH3:23])=[N:21][N:20]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(C(=O)NNC(C)=O)cc1
Solvent: Clc1ccccc1Cl
Solvent: ClP(Cl)Cl
Product: COc1ccc(-c2nnc(C)n2-c2ccccc2)cc1

Procedure:
Using the procedure of Step B in Example 1, 26.3 ml of aniline, 150 ml of o-dichlorobenzene, 4.65 ml of phosphorus trichloride and 10 g of N-(4-methoxybenzoyl)-N'-acetyl-hydrazine [prepared by process of J. Org., Vol. 19 (1954), p. 194-201] were reacted to obtain 7.1 g of 3-(4-methoxyphenyl)-4-phenyl-5-methyl-4H-1,2,4-triazole melting at 140°-141° C.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10](=[O:14])[CH2:11][C:12]#[N:13])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10](=[O:14])[CH:11]([C:29](=[O:30])[NH:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]#[N:13])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1cccc1C(=O)CC#N
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)Cn1cccc1C(=O)C(C#N)C(=O)Nc1ccccc1
Reaction time: 8 h

Procedure:
The solution of 2.5 g of 1-isobutyl-β-oxo-2-pyrrolpropionitrile in 30 ml of toluene and 1.6 g of triethylamine is treated with 1.6 g of phenylisocyanate while stirring. After standing overnight the mixture is filtered and the residue dissolved in 5% aqueous sodium hydroxide. The solution is filtered, acidified with 5 N hydrochloric acid and extracted with diethyl ether-ethyl acetate. The organic solution is washed with water, dried, evaporated, the residue triturated with ethanol and recrystallized from methanol, to give the 1-isobutyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile melting at 134°-136°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:22])[O:5]1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCCl>[O:22]=[C:14]1[C:13](=[C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]([CH2:3][CH2:2][O:1][S:31]([CH3:30])(=[O:33])=[O:32])[O:5]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1Nc2ccccc2C1=C1OC(CCO)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CS(=O)(=O)OCCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Temperature: 0 °C

Procedure:
To a mixture of 3-[3-(2-hydroxy-ethyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one (0.50 g, 1.71 mmol) and triethylamine (356 μμl, 2.557 mmol) in 1,2-dichloroethane (23 ml) cooled to 0° C. was added methanesulfonyl chloride (145 μl, 1.88 mmol). After 20 minutes at 0° C. the reaction was partitioned between 0.5% HCl aqueous solution and EtOAc. The organic layer was then washed with water, brine, dried with anhydrous Na2SO4 Removal of the solvent led to methanesulfonic acid 2-[3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-yl]-ethyl ester as a yellow solid (0.502 g, 79%).
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][CH:5]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[C@:22]3([C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:31])[CH2:21]2)=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C@H:20]2[C@@:22]3([C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH2:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:12])=[CH:5][CH:6]=4)[C:23]3=[O:31])[CH2:21]2)=[CH:18][CH:19]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(F)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: O=C(O)c1ccc(CN2C(=O)[C@@]3(C[C@H]3c3ccc(F)cc3)c3ccccc32)cc1

Procedure:
The title compound was prepared in analogy to Example 1 starting from 4-bromomethyl-benzoic acid methyl ester (commercially available), (1R,2S) and (1S,2R)-2-(4-fluorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C24H18FlNO3: 387, observed (M+H)+: 388.1 1H NMR (400 MHz, DMSO-d6) δppm 2.05-2.14 (m, 1 H) 2.30-2.40 (m, 1 H) 3.21 (t, 2 H) 5.09 (s, 2 H) 6.10 (d, 1 H) 6.70 (t, 1 H) 6.92 (d, 1 H) 7.07 (t, 1 H) 7.11-7.20 (m, 2 H) 7.31-7.38 (m, 2 H) 7.44 (d, 2 H) 7.93 (d, 2 H).