Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:5]([CH:9]=[C:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])[CH:6]=[CH:7][CH:8]=1.Cl.C(=C1NC(=O)NC1=O)C1C=CC=CC=1>CO.[Zn]>[CH3:1][O:2][C:3]1[C:4]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:5]([CH2:9][CH:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C=C2NC(=O)NC2=O)c1OCc1ccccc1
Agent: Cl
Agent: O=C1NC(=O)C(=Cc2ccccc2)N1
Agent: [Zn]
Solvent: CO
Product: COc1cccc(CC2NC(=O)NC2=O)c1OCc1ccccc1
Temperature: 50 °C
Yield: 47.1 %

Procedure:
Zinc powder (40.00 g; 0.61 mole) is added to a stirred suspension of 48.00 g (0.16 mole) of the benzylidine hydantoin from Example 3 in 1,200 mL of methanol under nitrogen. Concentrated hydrochloric acid (30 mL) is added and the mixture is heated on the steam bath for 20 minutes (after 10 minutes the starting benzylidene hydantoin dissolves). Another 30 mL of concentrated hydrochloric acid is added and the mixture is heated at reflux for another 20 minutes. The cooled (50° C.) mixture is cautiously filtered and the cake washed with 100 mL of methanol. Water (500 mL) is added to the filtrate to yield 24.60 g of crystalline product; mp 202°-204° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[C:6](N)[CH:5]=1)(=[O:3])[CH3:2].[H+].[B-](F)(F)(F)[F:21]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[C:6]([F:21])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CC(=O)c1ccc(-c2ccc(F)cc2F)c(N)c1
Agent: [H+]
Product: CC(=O)c1ccc(-c2ccc(F)cc2F)c(F)c1

Procedure:
4-Acetyl-2-amino-2',4'-difluorobiphenyl prepared as described in Example 1 was subjected to the Schiemann reaction using fluoboric acid to give 4-acetyl-2,2',4'-trifluorobiphenyl, m.p. 92°-94° C. By a similar method, starting from the appropriate products of Example 1, there were obtained 4-acetyl-4'-chloro-2,2'-difluorobiphenyl, m.p. 69°-70° C. and 4-acetyl-4'-bromo-2,2'-difluorobiphenyl, m.p. 75°-76° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[N:4][C:5]([CH3:10])=[CH:6][C:7]=1[S:8][CH3:9].CN(C)C1C=CC=CC=1.[Br:31][CH2:32][C:33](Br)=[O:34].[Cl-].[NH4+]>ClCCl>[Br:31][CH2:32][C:33]([NH:1][C:2]1[C:3]([S:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])=[N:4][C:5]([CH3:10])=[CH:6][C:7]=1[S:8][CH3:9])=[O:34]
Reactant: O=C(Br)CBr
Reactant: CSc1cc(C)nc(SCCO[Si](C)(C)C(C)(C)C)c1N
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: CSc1cc(C)nc(SCCO[Si](C)(C)C(C)(C)C)c1NC(=O)CBr
Yield: 78 %

Procedure:
To a solution of 3-amino-2-(2-tert-butyldimethylsilyloxyethylthio)-6-methyl-4-methylthiopyridine (synthesized by the method disclosed in Example 30 in WO96/26925) (1.50 g, 4.35 mmol) in dichloromethane (30 ml) were added N,N-dimethylaniline (0.63 g, 5.22 mmol) and bromoacetyl bromide (1.05 g, 5.22 mmol) with ice-cooling and stirring, and the mixture was stirred at room temperature for 1 hour. The reaction solution was mixed with a saturated ammonium chloride solution and extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (silica gel 100 g, developing solvent; hexane:ethyl acetate=3:1) to provide 1.57 g (yield 78%) of 2-bromo-N-[2-(2-tert-butyldimethylsilyloxyethylthio)-6-methyl-4-methylthio-3-pyridyl]acetamide as colorless powdery crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](Cl)=[O:6].[CH3:12][C:13]1[CH:14]=[C:15]([CH:38]=[C:39]([CH3:41])[CH:40]=1)[C:16]([N:18]1[CH2:23][CH2:22][C@@H:21]([N:24]2[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]2)[CH2:20][C@@H:19]1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:17].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([O:30][CH:27]1[CH2:28][CH2:29][N:24]([C@@H:21]2[CH2:22][CH2:23][N:18]([C:16](=[O:17])[C:15]3[CH:14]=[C:13]([CH3:12])[CH:40]=[C:39]([CH3:41])[CH:38]=3)[C@@H:19]([CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:20]2)[CH2:25][CH2:26]1)=[O:6]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: Cc1cc(C)cc(C(=O)N2CC[C@@H](N3CCC(O)CC3)C[C@@H]2Cc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(C(=O)N2CC[C@@H](N3CCC(OC(=O)c4cc(Cl)cc(Cl)c4)CC3)C[C@@H]2Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.3 %

Procedure:
3,5-Dichlorobenzoyl chloride (1 g) was added to a mixture of compound 31 (2 g) and triethylamine (0.5 g) in CH2Cl2 (25 ml) and the mixture was stirred at RT for 1 hour. The mixture was washed with water. The organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and their solvent evaporated. The residue was dried, yielding 0.34 g (11.7%) of (±)-trans-1-[1-(3,5-dimethylbenzoyl)-2-(phenylmethyl)-4-piperidinyl]-4-piperidinyl 3,5-dichloro-benzoate (compound 33, mp. 83.3° C.).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:13]=[CH:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[N+:8]([C:4]1[CH:3]=[C:2]([N:11]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:13]=[CH:12]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: COC(=O)c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cn(-c2cccc([N+](=O)[O-])c2)cn1
Temperature: 120 °C
Yield: 58 %

Procedure:
A mixture of 3-fluoronitrobenzene (1.78 ml; 16.7 mmol), methyl imidazole-4-carboxylate and potassium carbonate (2.3 g; 16.7 mmol) in 10 ml NMP was heated to 120° C. in a nitrogen atmosphere overnight. The cooled mixture was poured into water (100 ml), the precipitate was filtered off, washed with water and dried to yield 6c (2.38 g; 58%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][CH:6]([O:8][CH:9]([CH:49]2[CH:53]([OH:54])[CH:52]([OH:55])[CH:51]([N:56]3[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]3=[O:63])[O:50]2)[CH:10]([C:46]([OH:48])=[O:47])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:43])[CH3:42])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])[CH:5]([O:64][CH3:65])[CH:4]1[OH:66].[CH:67](=O)[CH2:68][CH2:69][CH2:70][CH3:71].C([BH3-])#N.[Na+].Cl>CO>[O:63]=[C:57]1[NH:58][C:59](=[O:62])[CH:60]=[CH:61][N:56]1[C@@H:51]1[O:50][C@H:49]([C@H:9]([O:8][CH:6]2[C@H:5]([O:64][CH3:65])[C@@H:4]([OH:66])[C@@H:3]([CH2:2][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[O:7]2)[CH:10]([C:46]([OH:48])=[O:47])[N:11]([CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:42])[CH3:43])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:29])[CH3:30])[C:25]([OH:27])=[O:26])[C@@H:53]([OH:54])[C@H:52]1[OH:55]
Reactant: CCCCC=O
Reactant: COC1C(OC(C(NCCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C(=O)O)C2OC(n3ccc(=O)[nH]c3=O)C(O)C2O)OC(CN)C1O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCNC[C@H]1OC(O[C@H](C(C(=O)O)N(CCCCC)CCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)[C@H](OC)[C@H]1O
Reaction time: 0.08 h

Procedure:
To a solution of 50 mg (53 μmol) 16-({[5-(aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid (λmax nm in water=259) in 0.4 ml of methanol is added 9.5 mg (2.0 eq., 110 μmol) of valeraldehyde and 3.3 mg (1.0 eq., 53 μmol) of sodium cyanoborohydride. After stirring for 5 minutes, 0.04 ml of 1 N methanolic hydrochloric acid is added. The reaction mixture is then stirred for 0.5 hour (the reaction is monitored by MS). The solvent is removed under reduced pressure to give a yellow gum. The desired product is identified by LC/MS and separated by preparative HPLC to give 4.9 mg (9.0% yield) of the desired product as a white solid.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[N:6]2[CH:25]=1)=[O:2].[BH4-].[Na+]>CO.O>[OH:2][CH2:1][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[N:6]2[CH:25]=1
Reactant: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(C=O)cn23)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(CO)cn23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 75a (74.5 mg, 0.223 mmol) was suspended in MeOH (10 mL) and then NaBH4 (26.3 mg, 0.695 mmol) was added. The reaction was stirred at rt for 18 h and then diluted with water (10 mL) and filtered. The solid was collected by filtration and the filter cake was washed with water (2×10 mL). The solid was dissolved in a mixture of DCM (100 mL) and MeOH (50 mL), dried over Na2SO4, and filtered. The solvent was removed under reduced pressure to afford compound 75b. 1H-NMR (400 MHz, CD3OD+CDCl3) δ (ppm): 8.96 (d, J=2.2 Hz, 1H), 8.20 (dd, J=8.1, 2.2 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.70 (s, 1H), 7.43 (s, 1H), 4.79 (s, 2H), 4.29-4.36 (m, 4H), 3.85-3.94 (m, 4H). LCMS calcd for C17H16N6O2: 337.1 (M+H). found: 337.1.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([C:12]([OH:14])=[O:13])[CH2:7]1.[CH3:15]O>>[NH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([C:12]([O:14][CH3:15])=[O:13])[CH2:7]1
Reactant: N[C@H]1CCC[C@H](C(=O)O)C1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CCC[C@H](N)C1
Temperature: 65 °C
Yield: 90.9 %

Procedure:
Thionyl chloride (0.6 ml) was added to a solution of trans-3-amino-cyclohexane carboxylic acid (0.5 g, 2.8 mmol) in MeOH (20 ml) at 0° C. The reaction mixture was heated to 65° C. and concentrated in vacuum. The resulting residue was partitioned between saturated sodium bicarbonate (10 ml) and extracted with ethyl acetate. The combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 400 mg (90.9%) of trans-methyl 3-aminocyclohexanecarboxylate as colorless liquid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.C(O)C.[H][H]>[Pd]>[NH2:16][C:12]1[CH:11]=[C:10]([C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:9])[CH:15]=[CH:14][CH:13]=1
Reactant: [H][H]
Reactant: CN1CCN(C(=O)c2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(C(=O)c2cccc(N)c2)CC1
Yield: 80.9 %

Procedure:
(4-Methyl-piperazin-1-yl)-(3-nitro-phenyl)-methanone (2.46 g, 9.87 mmol) was dissolved in Ethanol (30.0 mL, 514 mmol) and the solution was carefully added to a Parr vessel containing 10% Palladium on Carbon (0.750 g, 56.2 mmol) under nitrogen. The mixture was then placed on a Parr hydrogenation apparatus and was allowed to shake at 55 psi until uptake of hydrogen ceased. The catalyst was then filtered to afford 1.75 g of (3-Amino-phenyl)-(4-methyl-piperazin-1-yl)-methanone without further purification. (M+H)=220.6.
Reaction SMILES: [Na].[CH:2]1([CH2:5][O:6][CH2:7][C:8](=O)[CH2:9][C:10]([O:12]CC)=O)[CH2:4][CH2:3]1.[NH2:16][C:17]([NH2:19])=[S:18].Cl>CCO>[CH:2]1([CH2:5][O:6][CH2:7][C:8]2[NH:19][C:17](=[S:18])[NH:16][C:10](=[O:12])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)CC(=O)COCC1CC1
Reactant: NC(N)=S
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=c1cc(COCC2CC2)[nH]c(=S)[nH]1
Temperature: 25 °C

Procedure:
Sodium (4.0 g, 172 mmol) was added to EtOH (80 mL) and stirred until all dissolved at 60° C. The solution was cooled down to rt and a solution of ethyl 4-(cyclopropylmethoxy)-3-oxobutanoate (15.7 g, 78.4 mmol) in EtOH (80 mL) was added, followed by thiourea (7.2 g, 94 mmol). The mixture was stirred under reflux conditions for 24 h. Hydrochloric acid (aq, 1 M) was added until pH˜4 and the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica eluting with a gradient of EtOAc and DCM to give the title compound as a solid, 15.7 g (95%).
Reaction SMILES: [CH3:1][C:2]([O:7][Si:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:9][CH3:10])([CH3:6])[C:3](=[O:5])[CH3:4].C(N(CC)CC)C.C(Cl)Cl.[Br:25]N1C(=O)CCC1=O>>[Br:25][CH2:4][C:3](=[O:5])[C:2]([CH3:1])([O:7][Si:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC[Si](CC)(CC)OC(C)(C)C(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(C)(C)C(=O)CBr
Reaction time: 0.25 h
Yield: 50 %

Procedure:
To a stirred solution of 13 (2.40 g; 10.4 mmol) and triethylamine (2.92 ml; 2.12 g; 21.0 mmol) in methylene dichloride (50 ml) triethylsilyl trifluoromethanesulfonate (2.37 ml; 2.75 g; 10.4 mmol) was added dropwise at 0° C. After 15 min. N-bromosuccinimide (2.05 g; 11.5 mmol) was added and a cooling bath was removed. After 30 min. saturated aqueous solution of NH4Cl (10 ml) and water (50 ml) was added and the mixture was extracted with methylene dichloride (3×100 ml). Organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (hexane—5% ethyl acetate/hexane) to give 1.55 g (5.25 mmol; 50% yield) of 14. 1H NMR (400 MHz, CDCl3) δ 0.64 (6H, q, J=7.9 Hz), 0.97 (9H, t, J=7.9 Hz), 1.41 (6H, s), 4.44 (2H, s); 13C NMR (101 MHz, CDCl3) δ 6.5, 7.0, 27.8, 33.6, 80.4, 206.2; MS (EI) m/z 294 and 296 ([M−Et]+, 24 and 23), 187 (45), 173 (100); exact mass calculated for C9H18O2BrSi ([M−Et]+) 265.0254. found 265.0247.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:18][CH:19]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20]1>>[CH3:18][CH:19]1[NH:20][CH2:21][CH2:22][N:23]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:24]1
Reactant: CC1CNCCN1
Reactant: Clc1nccnc1OCCOc1ccccc1
Product: CC1CN(c2nccnc2OCCOc2ccccc2)CCN1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.54 mmol; from Example 1, Step 1) and 2-methylpiperazine (250 mg, 2.5 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 138 mg (73%) of the title product. Anal. (C17H22N4O2) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[CH:7]=NCCCC)([O-:3])=[O:2].[N+:16]([CH2:19][C:20](=[O:22])[CH3:21])([O-:18])=[O:17]>C(OC(=O)C)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:19]([N+:16]([O-:18])=[O:17])[C:20](=[O:22])[CH3:21])[CH:13]=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: CC(=O)C[N+](=O)[O-]
Reactant: CCCCN=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)[N+](=O)[O-]
Reaction time: 5 h
Yield: 27.1 %

Procedure:
To a solution of 28.6 g (0.39 mole) of the butanamine in 75 mL of acetic anhydride was added 15 g of 1-nitro-2-propanone. A white precipitate formed almost at once. The mixture was warmed gently until the solid dissolved, cooled, stirred for five hours, carefully poured onto water and extracted with ether. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. After storage at 0° C. overnight, the residue had crystallized. Recrystallization of the resulting solid from dibutyl ether gave 9.3 g of 4-(3-nitrophenyl)-3-nitro-3-buten-2-one, 1H NMR 8.4 (m, 2H), 7.7 (m, 2H), 7.5 (s, 1H), 2.5 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=O.[CH2:13]([O:15][CH:16]([O:25][CH2:26][CH3:27])[C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:14].C(O)(=O)C>C1C=CC=CC=1.N1CCCCC1=O>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=1[CH:1]=[C:18]([C:17]([CH:16]([O:15][CH2:13][CH3:14])[O:25][CH2:26][CH3:27])=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:6]
Reactant: COC(=O)c1ccccc1C=O
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Agent: O=C1CCCCN1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccccc1C(=O)OC)C(=O)C(OCC)OCC
Yield: 116.3 %

Procedure:
2-(i) To a mixture of methyl 2-formylbenzoate (4.92 g), ethyl 4,4-diethoxyacetoacetate (7.2 g) and acetic acid (0.36 g) in benzene (15 ml) was added portionwise each one third portion of a solution of piperidone (306 mg) in benzene (5 ml) for each 20 minutes' interval, and the mixture was heated to reflux for 3 hours under removing off azeotropically the resulting water. After cooling, the reaction mixture was diluted with additional benzene (25 ml), washed three times with water and successively with diluted aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give reddish oil (12.7 g) of crude ethyl 2-(2-methoxycarbonylbenzyliden)-4,4-diethoxyacetoacetate which was used in the following reaction without any further purification.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[S:6](=[O:17])(=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[F:18][C:19]([F:23])([F:22])[CH2:20][OH:21].CC(C)([O-])C.[K+]>C(#N)C>[F:18][C:19]([F:23])([F:22])[CH2:20][O:21][C:2]1[CH:3]=[CH:4][C:5]2[S:6](=[O:17])(=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: OCC(F)(F)F
Reactant: O=S1(=O)c2ccccc2Oc2cc(F)ccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Product: O=S1(=O)c2ccccc2Oc2cc(OCC(F)(F)F)ccc21
Yield: 77510.2 %

Procedure:
3-Fluorophenoxathiin 10,10-dioxide (Example 47) (6.27 g, 0.025 mmol) was added to a stirred solution prepared from 1,1,1-trifluoro-2-ethanol (Aldrich) (2.64 g, 0.0264 mole), potassium tert-butoxide (Janssen) (2.96 g, 0.0264 mole) and dry acetonitrile (170 mL). The mixture was heated at reflux under nitrogen for 1 hour. The reaction was cooled, and the volatiles were removed by spin evaporation in vacuo. The residue was partitioned between dichloromethane (200 mL) and water (100 mL). The layers were separated, and the organic phase was washed with 0.1 N aqueous hydrogen chloride (75 mL), brine (75 mL) and then dried over magnesium sulfate. The dry solution was spin evaporated in vacuo to give a fluffy residue, which was recrystallized from ethanol to give 6.40 g (77% yield) of 3-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide, m.p. 167-168° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:11](=[O:18])[N:10]([CH:19]([CH3:21])[CH3:20])[CH2:9]2)=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C:30]([CH3:50])([CH3:49])[C:31]([NH:33][C@H:34]([CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:41]([CH3:48])[CH:40]=1)[C:35](O)=[O:36])=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:12]3([CH2:17][CH2:16][CH2:15][N:14]([C:35](=[O:36])[C@H:34]([NH:33][C:31](=[O:32])[C:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:24])([CH3:23])[CH3:25])([CH3:50])[CH3:49])[CH2:38][C:39]4[C:47]5[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=5)[N:41]([CH3:48])[CH:40]=4)[CH2:13]3)[C:11](=[O:18])[N:10]([CH:19]([CH3:21])[CH3:20])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)N1CC(c2ccc(F)cc2)C2(CCCNC2)C1=O
Reactant: Cn1cc(C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)N1CC(c2ccc(F)cc2)C2(CCCN(C(=O)[C@@H](Cc3cn(C)c4ccccc34)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture comprising 4-(4-fluorophenyl)-2-isopropyl-2,7-diazaspiro[4.5]decan-1-one (ASW MedChem) (243 mg, 0.744 mmol), (R)-2-(2-(tert-butoxycarbonylamino)-2-methylpropanamido)-3-(1-methyl-1H-indol-3-yl)propanoic acid (Intermediate 3D) (300 mg, 0.744 mmol) and DIPEA (0.519 ml, 2.97 mmol) in acetonitrile (3 ml) was treated with ®T3P (50% in DMF, 0.868 ml, 1.487 mmol) and stirred at RT for 19 hours. The reaction mixture was concentrated in vacuo, dissolved in EtOAc and washed with water. The organic portion was dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 2% MeOH in DCM afforded the title compound;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)=[O:16])=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2)CC1

Procedure:
4-(Tert-butoxycarbonylamino-methyl)-benzoic acid was reacted with WSCI, HOBt, triethylamine and N-methylpiperazine in dichloromethane, to obtain a crude product of [4-(4-methyl-piperazine-1-carbonyl)-benzyl]-carbamic acid tert-butyl ester, and then treated with TFA, to obtain (4-aminomethyl-phenyl)-(4-methyl-piperazin-1-yl)-methanone. Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (4-aminomethyl-phenyl)-(4-methyl-piperazin-1-yl)-methanone (159 mg) instead of 4-(4-ethyl-piperazin-1-yl)-2,6-difluoro-phenylamine used in Step D in Example 1-D-18, in the same manner as Step D in Example 1-D-18, a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid 4-(4-methyl-piperazine-1-carbonyl)-benzylamide was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-293) as a colorless powder (64 mg, 62%).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8](N)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[BrH:11].N([O-])=O.[Na+]>C(O)(=O)C.O>[Br:11][C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][N:7]=1
Reactant: Br
Reactant: CC(C)(C)c1nnc(N)s1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1nnc(Br)s1
Temperature: 65 °C

Procedure:
To a solution of crude 5-tert-butyl-1,3,4-thiadiazol-2-amine (120.8 g) in glacial acetic acid (800 ml) was added aqueous hydrobromic acid (≧40%, 218 ml) at room temperature. The resulting solution was heated to 65° C., and a solution of sodium nitrite (167 g, 2.42 mol) in water (300 ml) was added dropwise such that the internal temperature was maintained at 65˜75° C. After addition was complete, the resulting yellow solution was cooled to room temperature, poured into ice and then extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium carbonate solution until the pH was neutral, dried over magnesium sulfate, filtered and concentrated. The resulting oil was purified via flash column chromatography (ethyl acetate/petroleum ether) to obtain 2-bromo-5-tert-butyl-1,3,4-thiadiazole.