Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.Cl.ICC([O:7][C:8]1[C:13]2[C:14](=[O:31])[C:15]3[C:27]([C:28](=[O:29])[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[C:26]1[N:17]([CH2:18][C:19]2[C:24]([CH:25]1[CH3:30])=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=3)=O>O1CCCC1>[OH:7][C:8]1[C:13]2[C:14](=[O:31])[C:15]3[C:27]([C:28](=[O:29])[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[C:26]1[N:17]([CH2:18][C:19]2[C:24]([CH:25]1[CH3:30])=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=3
Reactant: CC1c2ccccc2Cn2cc3c(c21)C(=O)c1cccc(OC(=O)CI)c1C3=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC1c2ccccc2Cn2cc3c(c21)C(=O)c1cccc(O)c1C3=O
Yield: 92.1 %

Procedure:
Water (312 ml) and concentrated hydrochloric acid (169 ml) were added to a suspension of 5,8,13,14-tetrahydro-9-[iodoacetoxy]-14-methylbenz[5,6]isoindolo[2,1-b]isoquinolin-8,13-dione (80.0 g, Intermediate 9 in GB-A-2175587) in tetrahydrofuran (1.335 L). This mixture was stirred and heated to reflux under nitrogen for 18 h and part (550 ml) of the solvent was removed by distillation at atmospheric pressure. The resulting suspension was stirred and cooled to ca. 5° for 4.5 h, and the solid was collected by filtration, washed with cold tetrahydrofuran and dried in vacuo to give the title compound (48.8 g); λmax 243 nm (MeOH), E11 1022; δ(CDCl3) 12.98 (OH, s, 1H), 5.27 (5-H, d, 16 Hz, 1H), 5.16 (5-H, d, 16 Hz, 1H), 4.98 (14-H, q, 7 Hz, 1H), 1.55 (14-CH3, d, 7 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:17]1[CH:18]=[C:19]([N:23]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:42])([F:41])[F:40])[CH:33]=2)[CH2:24][C@@H:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:20]=[CH:21][CH:22]=1.C1(C(O)=O)C2C(=CC=CC=2)C=CC=1>CN(C)C(=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:21]2[CH:20]=[C:19]([N:23]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:40])([F:41])[F:42])[CH:33]=3)[CH2:24][C@@H:25]([OH:30])[C:26]([F:27])([F:28])[F:29])[CH:18]=[CH:17][CH:22]=2)=[CH:4][C:3]=1[CH3:9]
Reactant: O[C@H](CN(Cc1cccc(OC(F)(F)F)c1)c1cccc(Br)c1)C(F)(F)F
Reactant: Cc1cc(O)ccc1F
Agent: O=C(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: Cc1cc(Oc2cccc(N(Cc3cccc(OC(F)(F)F)c3)C[C@@H](O)C(F)(F)F)c2)ccc1F
Temperature: 105 °C
Reaction time: 0.08 h
Yield: 23 %

Procedure:
A suspension of 4-fluoro-3-methylphenol (98.0 μL, 0.88 mmol) and cesium carbonate (319.5 mg, 0.98 mmol) in 1 mL of N,N-dimethylacetamide was preheated at 60° C. for 5 minutes. To this solution was added 4 mL of a stock solution containing (2R)-3-[[(3-bromophenyl)][[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (200 mg, 0.437 mmol) from EX-33B, 1-naphthoic acid (164 mg, 0.95 mmol), copper(I) trifluoromethansulfonate benzene complex (21.8 mg, 0.0434 mmol), 4 Å sieves (105 mg), and 4 mL of toluene. The reaction mixture was stirred at 105° C. for 3 weeks and 2 days. During that time, additional cesium carbonate and catalyst were added (a spatula tip of each) to the reaction three different times. The reaction was cooled to room temperature, filtered through celite, and the solvent was evaporated. The residue was purified by reverse phase HPLC eluting with 35% to 90% acetonitrile in water to afford 50.5 mg (23%) of the desired (2R)-3-[[3-(4-fluoro-3-methylphenoxy)phenyl][[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd. for C24H20F7NO3: 504.1410 [M+H]+, found: 504.1389. 1H NMR (acetone-d6) δ7.44 (t, 1H), 7.24 (d, 1H), 7.08-7.21 (m, 3H), 6.98 (t, 1H), 6.75-6.85 (m, 1H), 6.68-6.74 (m, 1H), 6.53 (d, 1H), 6.21-6.34 (m, 2H), 4.79 (t, 2H), 4.46-4.53 (m, 1H), 3.95 (dd, 1H), 2.61-2.72 (m, 1H), 2.20 (s, 3H).
Reaction SMILES: [N:1]1([C:6]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:9]=3[S:8](=[O:20])(=[O:19])[N:7]=2)[CH:5]=[CH:4]N=C1.[CH:21](N)(C)C>>[CH:5]([NH:1][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:9]=2[S:8](=[O:20])(=[O:19])[N:7]=1)([CH3:4])[CH3:21]
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)N=C(n1ccnc1)N2
Reactant: CC(C)N
Product: CC(C)NC1=NS(=O)(=O)c2cc(C(=O)O)ccc2N1

Procedure:
3-(Imidazol-1-yl)-4H-1,2,4-benzothiadiazine-7-carboxylic acid 1,1-dioxide was treated with isopropylamine according to the general procedure Method A to give the title compound; m.p. >310° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:46]=2[N:47]=[CH:48][N:49]=1)[C@@H:15]1[O:45][C@H:19]([CH2:20][O:21][C:22]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:52]([C:56]1[CH:63]=[CH:62][C:59]([CH2:60]Br)=[CH:58][CH:57]=1)([CH3:55])([CH3:54])[CH3:53]>CN(C=O)C>[C:1]([N:9]([CH2:60][C:59]1[CH:62]=[CH:63][C:56]([C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:57][CH:58]=1)[C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:46]=2[N:47]=[CH:48][N:49]=1)[C@@H:15]1[O:45][C@H:19]([CH2:20][O:21][C:22]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(N(Cc5ccc(C(C)(C)C)cc5)C(=O)c5ccccc5)ncnc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
To N6 -benzoyl-5'-O-(4,4'-dimethoxytrityl)-2'-deoxyadenosine (658 mg, 1.0 mmole) was added DMF (anhydrous, 10 ml) and evaporated to dryness. This was repeated. Fresh DMF (10 ml) was added under an Argon atmosphere. Sodium hydride (44 mg, 60% in oil, 1.1 mmole) was added and the mixture was stirred for 0.5 hour at room temperature. 4-(tert-butyl)benzyl bromide (272 mg, 1.2 mmole) was added dropwise and stirred at room temperature overnight. The solvent was removed under vacuum, and the residue was partitioned between ethyl acetate and water (20 ml each). The organic phase was washed with water (3 times, 20 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude product was purified by column chromatography on silica gel (100 g), using methylene chloride:methanol:triethylamine 96.5:3:0.5 to yield N -benzoyl-N -(p-tert-butylbenzyl)-5'-O-(4,4'-dimethoxytrityl)-2'-deoxyadenosine, (229 mg, 28.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Br.C([O-])([O-])=O.[K+].[K+].[CH3:17][O:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([N:26]2[C:31](=[O:32])[N:30](CC3C(F)=CC(F)=CC=3F)[C:29]3[CH:43]=[CH:44][CH:45]=[CH:46][C:28]=3[S:27]2(=[O:48])=[O:47])=[CH:21][C:20]=1[CH3:49]>O1CCOCC1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][N:30]1[C:29]2[CH:43]=[CH:44][CH:45]=[CH:46][C:28]=2[S:27](=[O:48])(=[O:47])[N:26]([C:22]2[CH:23]=[C:24]([CH3:25])[C:19]([O:18][CH3:17])=[C:20]([CH3:49])[CH:21]=2)[C:31]1=[O:32]
Reactant: Fc1cccc(Cl)c1CBr
Reactant: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1c(C)cc(N2C(=O)N(Cc3c(F)cccc3Cl)c3ccccc3S2(=O)=O)cc1C

Procedure:
The title compound (0.20 g, 0.42 mmol) was prepared from (IntA6) (0.35 g, 1.00 mmol), 2-chloro-6-fluorobenzyl bromide (0.34 g, 1.5 mmol) and K2CO3 (0.20 g, 1.5 mmol) in 1,4-Dioxane (10 mL) using the methods of (115).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C:17]#[N:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:19][NH:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:17]([C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][N:20]([CH3:19])[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[N:18]
Reactant: CNCCCc1ccccc1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCc1ccccc1)CCC(C#N)(c1ccccc1)c1ccccc1

Procedure:
A mixture containing 3-bromo-1-cyano-1,1-diphenyl-propane (1.5 g--see Preparation 4), 1-(N-methylamino)-3-phenylpropane (0.746 g), anhydrous potassium carbonate (1.38 g) and acetonitrile (50 ml) was heated under reflux for 48 hours and then concentrated in vacuo. Water (30 ml) was added to the residue and the mixture was extracted with dichloromethane (3×40 ml). The combined dichloromethane extracts were dried (Na2SO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with hexane containing dichloromethane (25% up to 100%) and then dichloromethane containing methanol (0% up to 4%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield, 0.93 g.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7](I)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[B:18](OC)([O:21]C)[O:19]C>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([B:18]([OH:21])[OH:19])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(Cl)c(I)c1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(Cl)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-tert-butyl-1-chloro-2-iodobenzene (0.47 g, 1.60 mmol) in dry THF (5 mL) at −78° C., n-butyl lithium (0.76 mL, 1.92 mmol, 2.5 M) was added. The solution was stirred at −78° C. for 30 min. Trimethyl borate (0.53 mL, 4.79 mmol) was added. The solution was stirred at −78° C. for 3 h. The reaction was quenched with saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc (3×15 mL). The combined EtOAc layers were dried over Na2SO4. The residue was used without further purification after evaporation of the solvent.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)=O.[C:14]1([CH2:20][C:21](=[S:23])[NH2:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.Cl.[NH4+].[OH-]>C(O)C.[Fe]>[CH2:20]([C:21]1[S:23][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=2)[N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=S)Cc1ccccc1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2csc(Cc3ccccc3)n2)cc1
Temperature: 140 °C

Procedure:
2-Bromo-1-(4-nitrophenyl)ethanone (0.5 g, 2.049 mmol) and 2-phenylethanethioamide (0.310 g, 2.049 mmol) were combined in ethanol (10 ml) in a 20 mL microwave reaction vessel and heated at 140° C. for 15 minutes. The solution was transferred to a 250 mL round bottom flask where it immediately solidified. The material was diluted with an additional ethanol (10 ml) and was heated at reflux with stirring until the solids were dissolved. Water (5.0 ml, 278 mmol), and hydrochloric acid (1 ml, 12.00 mmol) were added. Iron (0.625 g, 11.19 mmol) was added and the mixture was heated at reflux for 2 hours. The mixture was allowed to cool and 5 mL NH4OH was added. The material was filtered through a pad of diatomaceous earth and the pad was washed with 50 mL of ethyl acetate. The filtrate was washed with 100 mL of water and the aqueous phase was extracted with an additional 50 mL of ethyl acetate. The combined organic fractions were dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The material was re-dissolved in 50 mL of ethyl acetate and filtered through a ¼-inch pad of silica gel. The pad was washed with an additional 50 mL of ethyl acetate and the combined filtrate was concentrated to provide the title compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12](I)[CH:11]=[CH:10][C:9]=1[O:15][CH2:16][O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=[O:24].C(=O)([O-])[O-].[K+].[K+].N>[Cu](I)I>[CH2:1]([C:8]1[CH:13]=[C:12]([N:19]2[CH2:23][CH2:22][CH2:21][C:20]2=[O:24])[CH:11]=[CH:10][C:9]=1[O:15][CH2:16][O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCN1
Reactant: COCOc1ccc(I)cc1Cc1ccccc1
Agent: I[Cu]I
Agent: N
Agent: O=C([O-])[O-]
Product: COCOc1ccc(N2CCCC2=O)cc1Cc1ccccc1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
A mixture of 560 mg of 2-benzyl-1-methoxymethyloxy-4-iodobenzene (Production Example 4), 5 ml of 2-pyrrolidone, 90 mg of copper iodide (I), and 400 mg of anhydrous potassium carbonate was heated under stirring under nitrogen atmosphere on an oil bath at 140° C. for 8 hours. Aqueous ammonia was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Then it was successively washed with water and brine, dried over anhydrous magnesium sulfate and then evaporated, to give 505 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=O)[C:7]([CH3:16])=[CH:6]2)#[N:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][NH2:30])=O)[CH:22]=1>>[CH3:16][C:7]1[N:8]([CH2:12][C:13]2[O:15][C:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)=[N:29][N:30]=2)[C:9]2[C:5]([CH:6]=1)=[C:4]([C:17]([F:19])([F:18])[F:20])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=2
Reactant: NNC(=O)c1cccnc1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=O)O
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nnc(-c2cccnc2)o1

Procedure:
Synthesized as described in Example 35C using [5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and 3-pyridinecarbohydrazide: 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.78 (d, J=4.9 Hz, 1H), 8.27 (d, J=7.8 Hz, 1H), 8.08 (d, J=8.5 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.60 (dd, J=7.8 and 4.9 Hz, 1H), 6.65 (s, 1H), 6.00 (s, 2H), 2.57 (s, 3H); MS (ES) m/z 384 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Cl:6][C:7]1[C:12]2[CH2:13][NH:14][CH2:15][CH2:16][S:17][C:11]=2[CH:10]=[CH:9][CH:8]=1.Cl.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[C:12]2[CH2:13][N:14]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:15][CH2:16][S:17][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Clc1cccc2c1CNCCS2
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N1CCSc2cccc(Cl)c2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of propionyl chloride (0.92 g) in dichloromethane (10 ml) was added dropwise at room temperature to a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.99 g, prepared in a similar manner to its hydrochloride, Example 1 above) and triethylamine (1.01 g) in dichloromethane (50 ml). The reaction mixture was stirred at room temperature for 30 minutes, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane as eluent gave 6-chloro-4-propionyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from hexane. Yield 1.14 g (m.p. 55°-57° C.).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]1[CH2:22][CH2:23][CH2:24][CH:25]([NH:26][CH3:27])[C:17]1=[C:16]2[CH3:28].O>O1CCCC1>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]1[CH2:22][CH2:23][CH2:24][CH:25]([N:26]([CH3:27])[CH:1]=[O:3])[C:17]1=[C:16]2[CH3:28]
Reactant: O=CO
Reactant: CNC1CCCn2c1c(C)c1cc(OC)ccc12
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)c(C)c1n2CCCC1N(C)C=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of formic acid (3.05 g, 66.3 mmol) and acetic anhydride (5.4 g, 55 mmol) was heated at 60° C. for 4 hours. A solution of 6,7,8,9-tetrahydro-2-methoxy-N,10-dimethylpyrido[1,2-a]indol-9-amine (2 g, 8.2 mmol, described in Example 27) in dry tetrahydrofuran (20 mL) was added upon cooling to the resultant mixed anhydride. The reaction mixture was stirred at 25° C. overnight, poured into water (40 mL), and extracted with ether (3×40 mL). The combined extracts were washed successively with 5% hydrochloric acid (50 mL), 5% aqueous sodium bicarbonate (60 mL), and water (80 mL). The ethereal solution was dried over MgSO4, filtered, and evaporated to afford 2.1 g (95%) of the title formamide as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][CH:3]=1.Cl.[N:11](OCCC(C)C)=[O:12]>C(O)C>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[N:11]=[O:12]
Reactant: Nc1ccnn1CCO
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CCO
Product: Nc1c(N=O)cnn1CCO
Temperature: 25 °C
Reaction time: 17 h
Yield: 51.3 %

Procedure:
To a solution of 5-amino-1-(2-hydroxyethyl)pyrazole (6.35 g) in a mixed solvent of ethanol (25 ml) and concentrated hydrochloric acid (0.035 ml) was added dropwise isoamyl nitrite (7.03 g). The mixture was stirred at room temperature for 17 hours. The crystalline residue was collected by filtration and dried in vacuo to give 5-amino-1-(2-hydroxyethyl)-4-nitrosopyrazole (4.0 g) as a solid.
Reaction SMILES: Cl.[C:2]1([CH3:29])[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][CH2:11][C:12]([NH:14][C:15]1[NH:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-])=O)[N:19]=1)=[O:13]>C(O)C.[Fe]>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:15]([NH:14][C:12](=[O:13])[CH2:11][O:10][C:3]2[C:2]([CH3:29])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=2[CH3:9])[NH:16][CH:17]=1
Reactant: Cc1cc(C)c(OCC(=O)Nc2nc(-c3ccccc3[N+](=O)[O-])c[nH]2)c(C)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)c(OCC(=O)Nc2nc(-c3ccccc3N)c[nH]2)c(C)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
Iron powder (1.0 g) was suspended in 50% aqueous ethanol solution (100 mL), 12 mol/L hydrochloric acid (1.0 mL) was added thereto, and the mixture was stirred for 30 minutes at 70° C. To the mixture was added 2-(mesityloxy)-N-[4-(2-nitrophenyl)-1H-imidazol-2-yl]acetamide (Compound 18) (875 mg, 2.3 mmol) obtained in Example 18, and the mixture was stirred for 1 hour at 70° C. The mixture was left to cool, and then the insoluble materials were removed by filtration, and then the filtrate was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then distilled under reduced pressure. The resulting residue was separated by silica gel column (0 to 3% methanol/chloroform), and the resulting crystals were dispersed in diethyl ether, collected by filtration and dried to give 520 mg of the title compound (yield 65%) expressed by the following formula (Ex. 19).
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH:4]=1.C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=1>>[Br:26][C:23]1[CH:22]=[CH:21][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:5]3[CH:4]=[C:3]([OH:2])[N:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[N:6]=3)=[CH:19][CH:18]=2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccc(Br)cc3)cc2)nn1-c1ccccn1
Agent: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Product: Oc1cc(-c2ccc(-c3ccc(Br)cc3)cc2)nn1-c1ccccn1
Yield: 87 %

Procedure:
The title compound was prepared in the same manner as in Example D-1, except that an equimolar amount of Compound 45 of Example C-19 was used in place of Compound 27 of Example C-1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.[NH2:23][NH2:24]>O1CCOCC1>[NH:23]([C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1)[NH2:24]
Reactant: NN
Reactant: Clc1cc(N2CCOCC2)nc(OCCN2CCOCC2)n1
Solvent: C1COCCO1
Product: NNc1cc(N2CCOCC2)nc(OCCN2CCOCC2)n1
Yield: 102.8 %

Procedure:
4-[2-(4-Chloro-6-(morpholin-4-yl)-pyrimidin-2-yloxy)-ethyl]-morpholine (2.0 g; 6 mmol) was dissolved in dioxane (100 mL) and hydrazine (2 mL; 60 mmol) was added. The solution was heated to reflux for one hour, at which point the solvent was evaporated. The solid was dissolved in dichloromethane (100 mL) and washed with 10% sodium carbonate (10 mL). The organic layer was dried over magnesium sulfate and evaporated to give 4-[2-(4-Hydrazino-6-(morpholin-4-yl)-pyrimidin-2-yloxy)-ethyl]-morpholine (2.0 g)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:12]=[C:11]([C:13]([OH:15])=O)[N:10]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[N:9]=1.C(N(CC)CC)C.[Br:30][C:31]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[C:32]=1[NH2:33]>CN(C)C=O.C(Cl)Cl.CN(C)C1C=CN=CC=1.C(=O)=O>[Br:30][C:31]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[C:32]=1[NH:33][C:13]([C:11]1[N:10]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[N:9]=[C:8]([Br:7])[CH:12]=1)=[O:15]
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: Nc1c(F)cc(F)cc1Br
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1c(F)cc(F)cc1Br)c1cc(Br)nn1-c1ncccc1Cl
Reaction time: 0.17 h

Procedure:
Oxalyl chloride (0.043 mL, 0.5 mmol) was added to a mixture of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the product of Step D) (200 mg, 0.66 mmol) and two drops of N,N-dimethylformamide (DMF) in 30 mL of methylene chloride at room temperature and the reaction was stirred for 10 minutes. After this time a catalytic amount of 4-(dimethylamino)pyridine was added, followed by dropwise addition of a mixture of triethylamine (184 mL, 1.4 mmol) and 2-bromo-4,6-difluoroaniline in 10 mL of methylene chloride. The reaction was stirred overnight and then concentrated to near dryness. Chromatography on silica gel with hexane/ethyl acetate gradient as eluent (9:1 to 1:1) afforded an oil. The oil was then cooled in dry ice and triturated with ether/hexane to provide the title compound (0.22 g), a compound of the present invention, as a solid melting at 138-139° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20](N1CCN(C2N=CC(C3C=CC(F)=CC=3)=CN=2)CC1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[Cl:45][C:46]1[CH:47]=[C:48]([C:53]2[CH:54]=[N:55][C:56]([N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)=[N:57][CH:58]=2)[CH:49]=[CH:50][C:51]=1[Cl:52].C([C@@H]1COC(=O)N1C(=O)[C@H](CS(Cl)(=O)=O)C(C)C)C1C=CC=CC=1>>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20]([N:62]1[CH2:61][CH2:60][N:59]([C:56]2[N:57]=[CH:58][C:53]([C:48]3[CH:49]=[CH:50][C:51]([Cl:52])=[C:46]([Cl:45])[CH:47]=3)=[CH:54][N:55]=2)[CH2:64][CH2:63]1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2cnc(N3CCNCC3)nc2)cc1Cl
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(Cl)c(Cl)c3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 39 %

Procedure:
Prepared according to the method for the preparation of 4-(R)-benzyl-3-(2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methyl-butyryl)oxazolidin-2-one, from 5-(3,4-dichlorophenyl)-2-piperazin-1-yl-pyrimidine, dihydrochloride (0.52 g) and 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3 methylbutyryl)oxazolidin-2-one (0.67 g), to yield the title compound as a white solid (0.51 g, 39%).