Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=3)[O:12][C:11]2=[O:28])=[CH:6][CH:5]=1)#[N:3].[N:29]1C=CC=CC=1>C(N(CC)CC)C>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=3)[O:12][C:11]2=[O:28])=[CH:8][CH:9]=1)(=[NH:29])[NH2:3]
Reactant: COC(=O)Cc1ccc(OCC2CN(c3ccc(C#N)cc3)C(=O)O2)cc1
Reactant: c1ccncc1
Agent: S
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(OCC2CN(c3ccc(C(=N)N)cc3)C(=O)O2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
H2S gas is passed, at -10°, into a solution of 1.2 g of 3-p-cyanophenyl-5-(p-methoxycarbonyimethylphenoxymethyl)oxazolidin-2-one (obtainable in accordance with Example 1) in 50 ml of pyridine and 7 ml of triethylamine. The mixture is subsequently stirred at room temperature for 14 h and concentrated by evaporation; the residue is dissolved in 50 ml of acetone and treated with 9 ml of methyl iodide. After this mixture has been stirred for a further 6 h, it is filtered and the residue is washed with 5 ml of acetone and dissolved in 30 ml of methanol; 4.6 g of ammonium acetate are added to this solution, which is stirred at room temperature for 24 h. Following the customary working-up, 3-p-amidinophenyl-5-(p-methoxycarbonylmethylphenoxymethyl)oxazolidin-2-one (semihydriodide) is obtained, M.p. 151°-152°.
Reaction SMILES: Cl[C:2]1[C:9]([CH:10]2[CH2:12][CH2:11]2)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:13][CH2:14][CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[N:3]=1.[B:20]1([OH:30])[C:24]2[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:23]=2[CH2:22][O:21]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O>[CH:10]1([C:9]2[C:2]([O:29][C:27]3[CH:26]=[CH:25][C:24]4[B:20]([OH:30])[O:21][CH2:22][C:23]=4[CH:28]=3)=[N:3][C:4]([O:13][CH2:14][CH2:15][O:16][CH:17]([CH3:19])[CH3:18])=[C:5]([CH:8]=2)[C:6]#[N:7])[CH2:12][CH2:11]1
Reactant: OB1OCc2cc(O)ccc21
Reactant: CC(C)OCCOc1nc(Cl)c(C2CC2)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)OCCOc1nc(Oc2ccc3c(c2)COB3O)c(C2CC2)cc1C#N
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of 6-chloro-5-cyclopropyl-2-(2-isopropoxyethoxy)nicotinonitrile (150 mg, 0.53 mmol), benzo[c][1,2]oxaborole-1,5(3H)-diol (84 mg, 0.56 mmol) and Cs2CO3 (209 mg, 0.64 mmol) in DMSO (20 mL) was stirred at 40° C. overnight. The mixture was diluted by water, extracted by EtOAc, the separated organic layer was concentrated in vacuo and the residue was purified by column chromatography (Petroleum ether:EtOAc=10:1˜1:1) to afford 5-cyclopropyl-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-2-(2-isopropoxyethoxy)nicotinonitrile. (120 mg, 57%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 9.18 (s, 1H), 7.86 (s, 1H), 7.76 (d, J=8.0, 1H), 7.24 (d, J=2.0, 1H), 7.16 (dd, J=8.0, 2.0, 1H), 4.96 (s, 2H), 4.04 (m, 2H), 3.42 (m, 2H), 2.05 (m, 2H), 0.97 (d, J=6.0, 6H), 0.92 (m, 2H), 0.77 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[CH:6]=1)[OH:4].[CH:26]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27]1>N1C=CC=CC=1.CCOCC.O>[CH:26]1([C:30]([N:20]2[C:21]3[C:17](=[CH:16][C:15]([C:3]([OH:4])([C:5]4[C:13]5[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=5)[N:7]([CH3:14])[CH:6]=4)[C:2]([F:1])([F:24])[F:25])=[CH:23][CH:22]=3)[CH:18]=[N:19]2)=[O:31])[CH2:29][CH2:28][CH2:27]1
Reactant: Cn1cc(C(O)(c2ccc3[nH]ncc3c2)C(F)(F)F)c2ccccc21
Reactant: O=C(Cl)C1CCC1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cn1cc(C(O)(c2ccc3c(cnn3C(=O)C3CCC3)c2)C(F)(F)F)c2ccccc21
Temperature: 100 °C
Yield: 74.6 %

Procedure:
A mixture of 2,2,2-trifluoro-1-(1H-indazol-5-yl)-1-(1-methyl-1H-indol-3-yl)ethanol (0.122 mmol) and cyclobutanecarbonyl chloride (0.159 mmol) in 1 mL pyridine was heated at 100° C. for 1.5 hours, cooled to room temperature and diluted with ether and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The volatiles were removed in vacuo and the residue purified by flash silica gel chromatography using 25% ethyl acetate in hexanes. The product-rich fractions were concentrated in vacuo to afford 0.091 mmol of the title compound, m.p. 79° C.-81° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:16][C:17]1[NH:22][C:21](=[O:23])[C:20]([CH:24]([NH:26][C:27](=[O:37])[CH:28]([CH:34]([OH:36])[CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[CH3:25])=[N:19][N:18]=1.C(N(CC)CC)C>ClCCl>[C:34]([CH:28]([CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[C:27]([NH:26][CH:24]([C:20]1[C:21](=[O:23])[NH:22][C:17]([CH2:16][C:15]2[CH:38]=[CH:39][C:40]([O:41][CH3:42])=[C:13]([O:12][CH3:11])[CH:14]=2)=[N:18][N:19]=1)[CH3:25])=[O:37])(=[O:36])[CH3:35]
Reactant: C=CCCCC(C(=O)NC(C)c1nnc(Cc2ccc(OC)c(OC)c2)[nH]c1=O)C(C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=CCCCC(C(C)=O)C(=O)NC(C)c1nnc(Cc2ccc(OC)c(OC)c2)[nH]c1=O
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
100 mg (0.76 mmol) of oxalyl chloride in 5 ml of dichloromethane are treated dropwise at −70° C. with 130 mg (1.64 mmol) of dimethyl sulphoxide. The mixture is stirred at −70° C. for 30 min, then 280 mg (0.63 mmol) of N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-2-(1-hydroxyethyl)-6-heptenamide (Example 29A) are added. After a further 30 min, during which the temperature in the batch rises to about −60° C., 320 mg (3.15 mmol) of triethylamine are added and the cooling bath is then removed. If the batch temperature is warmed almost to room temperature, 10 ml of water are added and the phases are separated after stirring briefly. The dried organic phase is chromatographed in dichloromethane/methanol 50/1.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]([C:9]2[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][N:10]=2)[C:7]=1[OH:8])[CH3:2].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1>>[CH2:1]([C:3]1[CH:4]=[N:5][N:6]([C:9]2[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][N:10]=2)[C:7]=1[O:8][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=1)[CH3:2]
Reactant: OCc1ccc(F)cc1
Reactant: CCc1cnn(-c2cc(C#N)ccn2)c1O
Product: CCc1cnn(-c2cc(C#N)ccn2)c1OCc1ccc(F)cc1

Procedure:
The title compound was prepared from 2-(4-ethyl-5-hydroxypyrazol-1-yl)pyridine-4-carbonitrile and 4-fluorobenzyl alcohol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C18H15FN4O, 323; Found, 323.
Reaction SMILES: [OH2:1].[OH-].[K+].[CH3:4][C:5]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:24])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:6][C:7]#N.[CH2:25]([OH:27])C>>[CH3:4][C:5]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:24])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:6][CH2:7][C:25]([OH:27])=[O:1]
Reactant: O
Reactant: CC(=CC#N)CCCC(C)CCCC(C)CCCC(C)C
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CC(=CCC(=O)O)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Water (115 mL) and 35.5 g (0.63 mol) of potassium hydroxide were added to a solution of 77 g (0.25 mol) of 3,7,11,15-tetramethylhexadec-2-ene-1-nitrile in ethanol (345 mL). The solution was stirred for 18 hours at 80° C. The reaction mixture was concentrated, and neutralized with 3M hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated to obtain 88 g of 4,8,12,16-tetramethylheptadec-3-enoic acid as a crude product.
Reaction SMILES: [CH2:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.[CH2:14]([Li])[CH2:15][CH2:16][CH3:17].Cl[Si:20](Cl)([CH3:22])[CH3:21]>CCCCCC>[CH:10]1([Si:20]([CH:17]2[C:11]3[CH2:12][C:13]4[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=4)[C:6]=3[CH2:14][CH2:15][CH2:16]2)([CH3:22])[CH3:21])[C:11]2[CH2:12][C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH2:7][CH2:8][CH2:9]1
Reactant: [Li]CCCC
Reactant: C[Si](C)(Cl)Cl
Reactant: c1ccc2c(c1)CC1=C2CCCC1
Solvent: CCCCCC
Product: C[Si](C)(C1CCCC2=C1Cc1ccccc12)C1CCCC2=C1Cc1ccccc12

Procedure:
Following the procedure described in example 1 [step (c)], tetrahydrofluorene (17.6 mmol), butyllithium (11 ml of a solution 1.6M in hexane, 17.6 mmol) and dichlorodimethylsilane (1.07 ml, 8.81 mmol) gave a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]3[CH2:28][CH:27]([OH:29])[CH:26]=[CH:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][N:8]([CH:24]3[CH2:25][CH2:26][CH:27]([OH:29])[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: [H][H]
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1C=CC(O)C1
Agent: [Pd]
Solvent: CCO
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(O)C1

Procedure:
4-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopent-2-enol (110 mg) was hydrogenated in ethanol (20 ml) with gaseous hydrogen at atmospheric pressure using 10% palladium on charcoal (50 mg) as the catalyst. The catalyst was removed by filtration and the filtrate was evaporated to give 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentanol, as an oil. The structure was confirmed by 1H nmr and mass spectra.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:46]=[CH:47][CH:48]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[N:39]=2)[N:36]=1>CN(C)C=O.CN1CCCC1=O>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:26][C:27]1[CH:48]=[CH:47][CH:46]=[C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]4[CH2:44][CH2:45]4)=[O:42])[N:39]=3)[N:36]=2)[CH:28]=1)=[O:6]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cccc(C(F)(F)F)c1Cl
Yield: 66.6 %

Procedure:
Using 2-chloro-3-(trifluoromethyl)benzoic acid (88 mg, 0.39 mmol), oxalyl chloride (42 μL, 0.49 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.32 mmol) and N-methylpyrrolidone (4.0 mL) as starting materials and in the same manner as in Example 335, the title compound (110 mg, 68%) was obtained as a white powder.
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)S([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])(=O)=O.[CH2:22]([O:24][C:25]([C@:27]1([N:40]=[N+:41]=[N-:42])[C@H:32](O)[CH2:31][C@@H:30]2[C@H:28]1[C@@:29]2([F:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:26])[CH3:23].CCOCC>ClCCl>[CH2:22]([O:24][C:25]([C@:27]1([N:40]=[N+:41]=[N-:42])[C@H:32]([O:12][S:13]([C:16]([F:17])([F:18])[F:19])(=[O:14])=[O:15])[CH2:31][C@@H:30]2[C@H:28]1[C@@:29]2([F:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:26])[CH3:23]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OS(=O)(=O)C(F)(F)F)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Reaction time: 1.5 h

Procedure:
48 μL of pyridine and 78 μL of trifluoromethane sulfonic acid anhydride dissolved in 0.4 mL of dichloromethane were added dropwise to 120 mg of (1R,2R,3R,5R,6R)-2-azido-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 20 mL of dichloromethane at −75° C., and the mixture was stirred for 1.5 hours at ice-cooling under a nitrogen atmosphere. 24 μL of pyridine and 39 μL of trifluoromethane sulfonic acid anhydride dissolved in 0.2 mL of dichloromethane were added dropwise thereto at −75° C., and the mixture was stirred for 25 minutes at ice-cooling. 10 mL of ether was added thereto, and after the solids were filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=5:1), thereby yielding 166 mg of (1R,2R,3R,5R,6R)-2-azido-6-fluoro-3-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)=[C:10]([C:21]([OH:23])=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[C@H:10]([C:21]([OH:23])=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C(O)C1=C(c2ccc(Cl)c(F)c2)CN(Cc2ccccc2)C1
Solvent: CO
Product: O=C(O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(F)c1

Procedure:
A 2-l Hastelloy C4 autoclave was charged under argon with 1-benzyl-4-(4-chloro-3-fluoro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (30.0 g, 90.4 mmol), [Ru(OAc)2((R)-2-Furyl-MeOBIPHEP)] (275.5 mg, 0.36 mmol, S/C 250) and methanol (1.2 l). The asymmetric hydrogenation was run for 20 h at 30° C. under 40 bar of hydrogen (99.2% conversion). After the pressure was released, a sample of the white suspension was evaporated to dryness. Crude (S,S)-Id was obtained with 97.9% purity and >99.9% ee.
Reaction SMILES: Cl[C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:7].O=C1C(C(O)=O)=CC(C2C=CN=CC=2)=NN1.C(Cl)(=O)C(Cl)=O.ClC1C=CC(CN)=CC=1>C(N(CC)CC)C.CN(C)C=O.ClCCl>[Cl:25][C:23]1[CH:24]=[CH:2][C:3]([CH2:4][NH:5][C:6]([C:8]2[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH:13]=2)=[O:7])=[CH:21][CH:22]=1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Agent: NCc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cc(-c2ccncc2)n[nH]c1=O

Procedure:
Working as in example 2 for the preparation of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide, but starting with 0.3 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid, 10 cm3 of dichloromethane, 0.02 cm3 of dimethylformamide, 0.12 cm3 of oxalyl chloride, 0.19 cm3 of 4-chlorobenzylamine and 0.19 cm3 of triethylamine, 0.2 g of N-(4-chlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a cream-colored solid melting at 250° C.
Reaction SMILES: FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=[O:4].[F:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[C:30]1[O:31][C:32]2[C:38](N)=[C:37]([O:40][CH3:41])[CH:36]=[CH:35][C:33]=2[N:34]=1.[OH2:42]>C(#N)C.O>[F:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[C:30]1[O:42][C:35]2[C:36](=[O:4])[C:37]([O:40][CH3:41])=[CH:38][C:32](=[O:31])[C:33]=2[N:34]=1
Reactant: O
Reactant: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc2nc(-c3cc(F)ccc3F)oc2c1N
Solvent: CC#N
Product: COC1=CC(=O)c2nc(-c3cc(F)ccc3F)oc2C1=O
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
2.9 g (6.81 mmol; 2.2 equivalents) of bis(trifluoroacetoxy)iodo benzene dissolved in 75 ml of an acetonitrile/water mixture 4:1 is added dropwise to a solution of 0.86 g (3.10 mmol) of 2-(2,5-difluorophenyl)-6-methoxy-1,3-benzoxazol-7-amine in 30 ml of an acetonitrile/water mixture 4:1 at −5° C. After stirring for 30 minutes at −5° C., 70 ml of water is added to the reaction medium and the product formed is extracted twice with 100 ml of dichloromethane. The organic phases are combined and dried over sodium sulphate, then the solvents are evaporated off under reduced pressure. The residue is then purified by chromatography on a silica column (eluent: dichloromethane/methanol mixture 99:1) and 475 mg (yield=53%) of 2-(2,5-difluorophenyl)-6-methoxy-1,3-benzoxazole-4,7-dione is obtained in the form of a yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=O)[NH:8][C:7]2=O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:18])=O.[CH2:21]([NH2:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>O>[Cl:18][C:9]1[N:8]=[C:7]([NH:26][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1
Reactant: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)CN
Solvent: O
Product: CC(C)(C)CNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reaction time: 2 h

Procedure:
To 367 mg (1.77 mmol) of 6-nitroquinazoline-2,4 (1H,3H)-dione was added 15.13 g (98.70 mmol) of phosphorus oxychloride to effect reaction in the same manner as in Example 10. Next, to the reaction mixture was added dropwise 309 mg (3.54 mmol) of neopentylamine under ice cooling, and the resulting mixture was stirred under ice cooling for 2 hours. Water was added to the reaction mixture, and crystals thus precipitated were filtered out to obtain 2-chloro-4-neopentylamino-6-nitroquinazoline. The compound was dissolved in 2 ml of DMF, and after 1.52 g (26.65 mmol) of allylamine was added to the resulting solution, the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 210 mg (yield: 37.6%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([N:16]2[CH2:20][C@@H:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C@H:18]([N:28]([C:30](=[O:48])[C:31]([C:34]3[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=3)([CH3:33])[CH3:32])[CH3:29])[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:47][C:44]([F:45])([F:46])[C:36]1[CH:35]=[C:34]([C:31]([CH3:32])([CH3:33])[C:30]([N:28]([C@H:18]2[C@H:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:20][N:16]([C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])[CH2:17]2)[CH3:29])=[O:48])[CH:39]=[C:38]([C:40]([F:42])([F:41])[F:43])[CH:37]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)C[C@H]1c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(C(=O)N2CCNCC2)C[C@H]1c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of rac-4-[(3S,4R)-3-{[2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-(4-fluoro-phenyl)-pyrrolidine-1-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (21 mg, 0.30 mmol) in CH2Cl2 (4 ml) at RT, was added TFA (1 ml). After 1 hour, the reaction mixture was neutralized by addition of an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 to yield the title compound as a white solid.
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[N:4][N:3]=[N:2]1.C(Cl)(=O)C([Cl:13])=O.CN(C=O)C>C1C=CC=CC=1>[N:1]1([CH2:6][C:7]([Cl:13])=[O:9])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cn1cnnn1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)Cn1cnnn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-(1H-tetrazol-1-yl)acetic acid 3 (1 gm, 7.81 mmol) in benzene (20 mL) was added oxalyl chloride (1.5 g, 11.81 mmol) and a catalytic amount of DMF. The reaction mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated under vacuum and the crude acid chloride 4 obtained was used for the next step without any purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[C:13]([C:18]([NH2:20])=[O:19])[S:14][C:15]=2[S:16][CH3:17])(=[O:10])=[O:9])=[CH:4][C:3]=1Br.[C:22]1([CH3:37])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1C1C=CC=CC=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[C:13]([C:18]([NH2:20])=[O:19])[S:14][C:15]=2[S:16][CH3:17])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH3:37]
Reactant: Cc1ccccc1-c1ccccc1B(O)O
Reactant: CSc1sc(C(N)=O)cc1S(=O)(=O)c1cnc(N)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1sc(C(N)=O)cc1S(=O)(=O)c1cnc(N)c(-c2ccccc2C)c1
Yield: 32 %

Procedure:
The procedure as in Example 1: step c was followed using 4-(6-amino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid amide (25 mg, 0.06 mmol, Example 120: step a), o-tolyl phenyl boronic acid (33 mg, 0.25 mmol), Pd(PPh3)4 (14 mg, 0.01 mmol), aqueous Na2CO3 (2M, 0.4 mL), ethanol (0.4 mL) and toluene (0.8 mL). Purification by preparative SiO2 chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (7.4 mg, 32%) as a brown solid. ESI-MS (m/z): Calcd. for C18H17N3O3S3: 420.0 (M+H); found: 420.2.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1.Cl>C(#N)C.O1CCOCC1.O>[CH:18]1([NH:23][C:2]2[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[N:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1nc(NCc2ccccn2)nc(Cl)c1C
Reactant: NC1CCCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CC#N
Product: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Yield: 17.7 %

Procedure:
A solution of 4-chloro-5,6-dimethyl-N-(pyridin-2-ylmethyl)pyrimidin-2-amine (200 mg, 0.8 mmol, Step C) and cyclopentanamine (85 mg, 1 mmol) in acetonitrile (5 mL) was treated with 3.5 M hydrogen chloride in dioxane (0.2 mL), and the resultant mixture was refluxed overnight. The reaction mixture was diluted with water (50 mL), and the resultant precipitate was collected by filtration. The precipitate was purified by crystallization from ethanol (10 mL) to afford 42 mg (19%) of the titled compound as the hydrochloride salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.40-1.50 (m, 4H), 1.50-1.67 (m, 4H), 1.88 (s, 3H), 2.27 (s, 3H), 4.00-4.12 (m, 1H), 4.92 (d, J=4.57 Hz, 2H), 7.71-4.83 (m, 2H), 7.83 (d, J=8.06 Hz, 1H), 8.17-8.25 (m, 1H), 8.33-8.39 (m, 1H), 8.76 (d, J=5.10 Hz, 1H), 13.24 (bs, 1H); MS (ESI) m/z 398.5 (ESI) (M+1)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[C:8]([O:10][CH3:11])=[O:9].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[C:29]1([CH2:35][O:36][C:37]([NH:39][CH2:40][C:41](O)=[O:42])=[O:38])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:29]1([CH2:35][O:36][C:37]([NH:39][CH2:40][C:41]([N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]2[C:8]([O:10][CH3:11])=[O:9])=[O:42])=[O:38])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)[C@H]1CCCCN1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@H]1CCCCN1C(=O)CNC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 109.1 %

Procedure:
To a solution of methyl (2R)-2-piperidinecarboxylate hydrochloride (1.0 g, 5.56 mmol) and HOBt (0.90 g, 6.67 mmol) in CH2Cl2 (20 mL) was added 4-methylmorpholine (2.44 mL, 22.24 mmol), N-{[(phenylmethyl)oxy]carbonyl}glycine (1.16 g, 5.56 mmol), and EDCI (1.28 g, 6.67 mmol). After stirring overnight, the solution was washed 6 N aq. HCl (100 mL) and water (100 mL). The aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), and then dried over anhydrous MgSO4 and concentrated in vacuo to provide methyl (2R)-1-(N-{[(phenylmethyl)oxy]carbonyl}glycyl)-2-piperidinecarboxylate (2.029 g, 99%). LCMS: (M+H)+: 335.1.