Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(Cl)Cl.[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].C(OC(=O)[NH:18][C:19](=[NH:57])[C:20]1[S:21][C:22]([S:55][CH3:56])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=3[NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][NH:46][S:47]([C:50]([F:53])([F:52])[F:51])(=[O:49])=[O:48])[CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:24]=1)(C)(C)C>>[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].[C:19]([C:20]1[S:21][C:22]([S:55][CH3:56])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=3[NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][NH:46][S:47]([C:50]([F:52])([F:53])[F:51])(=[O:48])=[O:49])[CH:31]=[CH:32][CH:33]=2)(=[O:26])=[O:27])[CH:24]=1)(=[NH:18])[NH2:57]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCNS(=O)(=O)C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCNS(=O)(=O)C(F)(F)F)c1
Reaction time: 1 h
Yield: 54 %

Procedure:
A solution of dichloromethane/trifluoroacetic acid (1/1) [2 mL] was added to (imino-{5-methylsulfanyl-4-[6′-methyl-2′-(4-trifluoromethanesulfonylaminobutyrylamino)-biphenyl-3-sulfonyl]-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester (0.020 g, 0.027 mmol) [example 212, step c] at room temperature and stirred for 1 hour. The reaction mixture was evaporated and purified via reverse-phase HPLC [acetonitrile/water (0.01% TFA)] to give the title compound (0.009 g, 54%) as a solid. 1H-NMR (MeOD): δ 8.29 (s, 1H), 8.03 (md, 1H, J=8.4 Hz), 7.87 (m, 1H), 7.68 (t, 1H, J=7.6 Hz), 7.53 (md, 1H, J=7.6 Hz), 7.34 (t, 1H, J=7.6 Hz), 7.28 (d, 1H, J=7.2 Hz), 7.19 (d, 1H, J=7.2 Hz), 2.98 (m, 2H), 2.72 (s, 3H), 2.06 (s, 3H), 2.05 (t, 2H, J=7.6 Hz), 1.48 (m, 2H). ESI-MS (m/z): Calcd. for C24H25F3N4O5S4: 634.07; found: 635.1.
Reaction SMILES: [Br:1][C:2]1([Br:18])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([N+:14]([O-])=O)=[CH:9][C:8]=1[CH3:17].C(O)(=O)C>[Fe].O>[Br:1][C:2]1([Br:18])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[C:8]([CH3:17])=[CH:9][C:10]([NH2:14])=[C:11]([CH3:13])[CH:12]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1OCC1CC1(Br)Br
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(OCC2CC2(Br)Br)c(C)cc1N
Temperature: 80 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
A mixture of 0.37 g of 1-[(2,2-dibromocyclopropyl)methoxy]-2,5-dimethyl-4-nitrobenzene, 0.29 g of iron powder, 20 mL of acetic acid and 5 mL of water was stirred at 80° C. for 1 hour. The reaction mixture was cooled to around room temperature, and then concentrated under reduced pressure. The resulting residue was converted into basic with an aqueous 1 N sodium hydroxide solution, then ethyl acetate was added, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water, and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 0.19 g of 4-[(2,2-dibromocyclopropyl)methoxy]-2,5-dimethylphenylamine
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[CH:10][C:11]3[O:15]C=[N:13][C:12]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:17].O>CCO.C(Cl)Cl>[ClH:17].[NH2:13][C:12]1[CH:16]=[C:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:9]=[CH:10][C:11]=1[OH:15]
Reactant: c1ccc(Sc2ccc3ocnc3c2)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: Nc1cc(Sc2ccccc2)ccc1O
Reaction time: 2 h

Procedure:
A solution of 5-(phenylthio)benzo[d]oxazole (1.04 g, 4.6 mmol) and conc. HCl (0.97 mL, 11 mmol) under nitrogen in 4.6 mL EtOH in a 50 mL rbf fitted with a water-cooled reflux condensor was placed in a 100° C. bath. After 2 h, the mixture was cooled, concentrated in vacuo and dried to give a yellow solid. The material was sonicated in 10 mL DCM, filtered, rinsing with DCM, and dried to give 2-amino-4-(phenylthio)phenol hydrochloride as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.72 (s, 1H), 8.75 (br. s., 1H), 7.28-7.35 (m, 2H), 7.12-7.25 (m, 5H), 6.99 (d, J=8.0 Hz, 1H), 4.32 (br. s., 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.S(=O)(=O)(O)N.[CH2:26]([N:28]([CH2:31][CH2:32][CH2:33][CH2:34]N)[CH2:29][CH3:30])[CH3:27]>>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:10]1[C:9]([NH2:20])=[N:8][C:6]2[N:7]=[C:2]([NH:1][CH2:34][CH2:33][CH2:32][CH2:31][N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])[N:3]=[CH:4][C:5]=2[CH:11]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: CCN(CC)CCCCN
Agent: NS(=O)(=O)O
Product: CCN(CC)CCCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Temperature: 150 °C

Procedure:
A mixture of 2,7-diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine (40 g) from Example 1, sulfamic acid (25.4 g) and diethylaminobutylamine (205 mL) was heated to approximately 150° C. for 28 hours. The reaction temperature was lowered to 50° C., and excess diethylaminobutylamine was removed in vacuo. After cooling to 25° C., the residue was suspended in water. The aqueous solution was made alkaline with a solution of saturated sodium bicarbonate and extracted with dichloromethane several times. The dichloromethane layers were combined, washed several times, first with a saturated solution of sodium bicarbonate then a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was washed repeatedly with diethyl ether and then crystallized from ethyl acetate. The recrystallized product was further purified by column chromatography, eluting first with ethyl acetate:methyl alcohol:triethylamine (85:14:1) followed by ethyl acetate:ethyl alcohol:triethylamine (9:2:1) to afford 36.2 g of the title compound 6-(2,6-dichlorophenyl)-N2 -(4-diethylamino-butyl)-pyrido[2,3-d]pyrimidine-2,7-diamine, CIMS (1% NH3 in CH4): 461=M+ +C2H5, 433=M+ +H (Base), 417, 403, 360.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[F:10].[C:11]([Cu])#[N:12].CN1CCCC1=O>C(Cl)Cl>[F:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[C:11]#[N:12]
Reactant: N#C[Cu]
Reactant: COc1ccc(F)c(Cl)c1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COc1ccc(F)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-Chloro-1-fluoro-4-methoxy-benzene (10.4 grams, 65.0 mmole), CuCN (6.4 grams, 71.0 mmole) and N-methylpyrrolidinone (100 ml) was refluxed for 18 hours. An additional 2.3 g CuCN was added, and the mixture was refluxed for 40 hours. The mixture was poured into 300 ml ice water and stirred for 10 minutes. This was poured into 100 ml methylene chloride and the layers were separated. The mixture was washed with water, dried over MgSO4, filtered, and concentrated to a solid (2.8 g). MW 137.12; MS (m/e) 137(M+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[C:13]1(B(O)O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:21]3[C:22]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:18]=[CH:19][CH:20]=3)[CH:3]=[CH:4][CH:5]=2)[C:9]1=[O:11]
Reactant: CC1Cc2cccc(Cl)c2C1=O
Reactant: OB(O)c1cccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: OCCO
Product: CC1Cc2cccc(-c3cccc4ccccc34)c2C1=O
Temperature: 125 °C
Reaction time: 5 h
Yield: 81.7 %

Procedure:
Using a method similar to Example 15c), 2.5 g (13.84 mmol) of (1), 2.86 g (16.6 mmol) of naphthylboronic acid and 3.66 g (34.6 mmol) of sodium carbonate were placed in 41 ml of ethylene glycol/8.3 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. After addition of 1 mg (0.0046 mmol) of palladium acetate and 10.4 mg (0.0184 mmol) of TMSPP, the reaction mixture was stirred for 5 hours at 125° C. The aqueous phase was extracted twice with 50 ml each time of ether, the combined ether phases were washed with 40 ml of water and 40 ml of saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave 3.08 g of (16) as solid.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)(=O)C.[OH-].[Na+].Cl>CO>[Cl:25][C:20]1[CH:19]=[C:18]([NH:17][C:8]2[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([OH:4])[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
To a suspension of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl acetate (2.51 g) and methanol (50 mL) was added 5 mol/L NaOH (5.00 mL) at room temperature. The reaction mixture was stirred at room temperature for 6 h, and was adjusted to pH 5 with 0.1 N HCl (aq). The mixture was filtered to give the title compound as a solid (1.99 g, 90.00%).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([NH2:6])=[C:4]([F:11])[CH:3]=1.[N:12]([O-])=O.[Na+]>Cl.O>[Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([NH:6][NH2:12])=[C:4]([F:11])[CH:3]=1
Reactant: O=N[O-]
Reactant: COc1cc(N)c(F)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(NN)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
A stirred solution of 48.0 g (0.27 mole) of 4-chloro-2-fluoro-5-methoxyaniline in 500 mL of concentrated hydrochloric acid was cooled to -5° C. and 23.5 g (0.34 mole) of sodium nitrite in 100 mL of water was added dropwise. After complete addition, the reaction mixture was stirred at 0° C. for one hour. A second solution of 154.0 g (0.68 mole) of stannous chloride in 225 mL of concentrated hydrochloric acid was cooled to 0° C., and the cold diazonium solution prepared above was added to it slowly. After complete addition, the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was filtered to collect a solid. This solid was dissolved in an aqueous 50% sodium hydroxide solution, and the solution extracted with toluene. The toluene extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 22.4 g of 4-chloro-2-fluoro-5-methoxyphenylhydrazine as a solid.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:22][C:23]1[N:24]=[N:25][N:26]([CH2:28][C:29]([O:31]CC)=[O:30])[N:27]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO.C(OC(C)C)(C)C>O1CCCC1>[C:3]([NH:22][C:23]1[N:24]=[N:25][N:26]([CH2:28][C:29]([OH:31])=[O:30])[N:27]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cn1nnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cn1nnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To an aqueous solution (27 ml) of sodium hydroxide (2.1 g) were added ethyl 2-(5-tritylamino-2H -tetrazol-2-yl)acetate (14.2 g), methanol (50 ml) and tetrahydrofuran (100 ml), and the mixture was stirred at 40° C. for 2 hours. After the organic solvent was removed by evaporation, to the residue were added water (50 ml) and ethyl acetate (50 ml), followed by separating out the aqueous layer. Thereto was added ethyl acetate (100 ml) and then adjusted to pH 1.5 with 10% hydrochloric acid. The aqueous solution was washed with an aqueous sodium chloride (50 ml) and dried over magnesium sulfate. Removal of the solvent gave a residue, which was pulverized with diisopropyl ether to obtain 2-(5-tritylamino-2H-tetrazol-2-yl)acetic acid (9.0 g).
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[OH:31][C:32]1[CH:45]=[CH:44][C:35]([CH:36]([NH2:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:34][CH:33]=1>>[OH:31][C:32]1[CH:33]=[CH:34][C:35]([CH:36]([NH:43][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:44][CH:45]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: NC(c1ccccc1)c1ccc(O)cc1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccc(O)cc1
Yield: 83 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 4-hydroxybenzhydrylamine (prepared as described in Preparation 13) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 83%.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:19])[N:3]=1)=[C:11]([F:16])[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=3.[F:20][C:21]1[C:22]([CH3:30])=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>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>[F:16][C:11]1[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=[C:7]2[C:12]=1[N:13]=[C:14]([CH3:15])[C:5]1[N:6]2[C:2]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[C:22]=2[CH3:30])=[N:3][C:4]=1[CH3:19]
Reactant: Cc1c(F)cccc1B(O)O
Reactant: COc1cc(F)c2nc(C)c3c(C)nc(Br)n3c2c1
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: [K+]
Product: COc1cc(F)c2nc(C)c3c(C)nc(-c4cccc(F)c4C)n3c2c1
Yield: 42.4 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 6A (65 mg, 0.2 mmol), 3-fluoro-2-methylphenylboronic acid (46 mg, 0.3 mmol), K2CO3 (82 mg, 0.6 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol) provided the coupling product as an off-white powder (30 mg, 43% yield). EIMS 354.1 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([CH3:12])([CH3:11])[O:6][CH:7]([CH3:10])[CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:22]([O:26][C:27](=[O:30])[CH2:28]Br)([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C>[C:22]([O:26][C:27](=[O:30])[CH2:28][NH:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:12])[CH3:11])[CH3:10])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(CN)O[Si](C)(C)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(CNCC(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 16 h

Procedure:
2-(tert-Butyl-dimethyl-silanyloxy)-propylamine (6.0 g, 31.6 mmol) was dissolved in DMF (60 mL). Diisopropylethylamine (5.5 mL, 31.6 mmol) and bromo-acetic acid tert-butyl ester (3.6 g, 18.6 mmol) was added. The reaction mixture was stirred at 50° C. for 16 h. The mixture was evaporated onto silica gel and and purified by column chromatography using a gradient, starting eluting with ethyl acetate/heptane 20:80 up to ethyl acetate/heptane 80:20. The product was isolated as an oil. Yield: 4.0 g, 71%.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].[NH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16].[C:24](OCC)(OCC)(OCC)[CH3:25]>CO>[ClH:1].[C:7]1([NH:6][C:4]([CH2:3][NH:2][C:24](=[N:13][CH2:14][C:15](=[O:16])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:25])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NCC(=O)Nc1ccccc1
Agent: Cl
Solvent: CO
Product: CC(=NCC(=O)Nc1ccccc1)NCC(=O)Nc1ccccc1
Yield: 20.1 %

Procedure:
0.82 Grams (4.13 millimoles) of 2-aminoacetanilide hydrochloride, 0.77 g (4.13 millimoles) of 2-aminoacetanilide (free base) were dissolved in 1.4 milliliters of hot methanol. To this solution was added 0.76 milliliters (0.67 g, 4.13 millimoles) of triethyl orthoacetate. The mixture was heated gently for five minutes. The reaction mixture was cooled and the reaction product precipitated by addition of diethyl ether. The supernatant liquid was decanted, and the precipitate was triturated with ether and collected on a filter. The product was recrystallized from ethanol, and dried to yield about 300 milligrams of N,N'-bis[phenylcarbamylmethyl]acetamidine hydrochloride.
Reaction SMILES: CCO[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:16][CH:17]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=2[O:19][CH2:18]1.[OH-].[Na+]>O>[CH3:16][CH:17]1[N:22]2[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11](=[O:13])[C:23]3[CH:24]=[C:25]([CH3:27])[CH:26]=[C:20]([C:21]=32)[O:19][CH2:18]1
Reactant: Cc1ccc2c(c1)OCC(C)N2
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1cn2c3c(cc(C)cc3c1=O)OCC2C
Temperature: 130 °C

Procedure:
Diethyl ethoxymethylene malonate (19.8 g., 0.092 mole) is added to 3,4-dihydro-3,7-dimethyl-2H-1,4-benzoxazine (15.0 g., 0.092 mole) and the solution is heated at 110° to 120° C. for three hours. Polyphosphoric acid (100 g.) is added and the solution is gradually heated to 130° C. with occasional stirring. The solution is heated at 140° to 150° C. for one additional hour. The hot solution is poured into 300 ml. water with stirring, then neutralized with forty percent sodium hydroxide solution. The solid which precipitates is separated by filtration and washed with water. Recrystallization from ethanol gives ethyl 2,3-dihydro-3,9-dimethyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate, m.p. 195°-197° C.
Reaction SMILES: B(F)(F)F.CCOCC.[NH2:10][C@H:11]([C:22]([NH2:24])=O)[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1.CSC.B.[OH-].[Na+]>O.O1CCCC1>[NH2:24][CH2:22][CH:11]([NH2:10])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1
Reactant: NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: B
Agent: FB(F)F
Agent: [Na+]
Solvent: CSC
Solvent: O
Solvent: C1CCOC1
Product: NCC(N)Cc1c[nH]c2ccccc12

Procedure:
Boron trifluoride etherate (12.3 ml, 0.1 mmole) was added to a tetrahydrofuran (24.4 ml) solution of tryptophan amide (20.3 g, 0.1 mole) at room temperature with stirring. At reflux with constant stirring, borane methylsulfide (32.25 ml, 0.34 mole) was added dropwise. The reaction was heated at reflux with stirring for five hours. A tetrahydrofuran:water mixture (26 ml, 1:1) was carefully added dropwise. A sodium hydroxide solution (160 ml, 5N) was added and the mixture heated at reflux with stirring for sixteen hours.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>C1COCC1.ClCCl>[CH2:27]([O:14][CH:13]1[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CC1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CC1OCc1ccccc1
Reaction time: 1 h
Yield: 26.1 %

Procedure:
To a solution of benzyl rac-(3R,4R)-3-[(tert-butoxycarbonyl)amino]-4-hydroxypyrrolidine-1-carboxylate (600 mg, 1.8 mmol; prepared according to WO2004/050024A2) in THF (8 mL) cooled to 0° C. was added NaH (216 mg, 5.4 mmol [60%]) and the reaction mixture stirred for 1 hour. Benzyl bromide (430 μL, 3.57 mmol) was added and the reaction mixture was allowed to stir at room temperature overnight. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an additional portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography to afford benzyl rac-(3R,4R)-3-(benzyloxy)-4-[(tert-butoxycarbonyl)amino]pyrrolidine-1-carboxylate (200 mg, 26%). To the product was added 4N HCl (in dioxane, 5 mL) and the mixture was stirred 2 hours. All volatiles were removed, and the salt was dissolved in DMF (5 mL), to which was added {[3-(trifluoromethyl)benzoyl]amino}acetic acid (174 mg, 0.705 mmol), HATU (268 mg, 0.705 mmol), diisopropylethylamine (246 μL, 1.41 mmol) and HOBt (95 mg, 0.705 mmol) and the mixture was allowed to stir overnight. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography to afford benzyl rac-(3R,4R)-3-(benzyloxy)-4-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>ClCCl>[Cl:24][CH2:25][C:26]([N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)=[O:27]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a mixture of 1-[4-(trifluoromethyl)phenyl]piperazine (600 mg, 2.61 mmol) and triethylamine (660 mg, 6.52 mmol) in dichloromethane (20 ml) was added 2-chloroacetyl chloride (380 mg, 3.36 mmol) dropwise at 0° C. The resulting solution was stirred for 1 hour at room temperature. The reaction mixture was then quenched by water (80 ml) and extracted with dichloromethane (3×30 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using 1%-10% ethyl acetate in petroleum ether to afford 2-chloro-1-[4-[4-(trifluoromethyl)phenyl]piperazin-1-yl]ethan-1-one as a white solid (479 mg, 60%). (ES, m/z): [M+H]+ 307.1; 1H NMR (300 MHz, CDCl3): δ 7.52 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.7 Hz, 2H), 4.12 (s, 1H), 3.81 (t, J=5.1 Hz, 2H), 3.72 (t, J=5.1 Hz, 2H), 3.36 (t, J=5.1 Hz, 2H), 3.30 (t, J=5.1 Hz, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[OH:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][N:27]=1>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:6]2[C:7]3[CH2:8][CH2:9][N:32]([C:29]4[CH:30]=[CH:31][C:26]([OH:25])=[N:27][CH:28]=4)[C:2]=3[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:5]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Reactant: Nc1ccc(O)nc1
Product: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc(O)nc2)c1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 2-hydroxy-pyridin-5-ylamine, the desired compound was obtained.