Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:32]I>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][O:29][CH3:32])=[CH:26][CH:27]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(CO)cc3)c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-tert-butoxycarbonyl-7-chloro-6-(4-hydroxymethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (133 mg, 0.306 mmol) in anhydrous DMF (2 mL) under nitrogen, add sodium hydride (60% dispersion, 13-15 mg, 0.375 mmol) at ambient temperature and continue sting for 30 min. Add methyl iodide (80 □L, 1.28 mmol). After 15 min, dilute with water, extract three times with EtOAc, dry over anhydrous MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (15:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(4-methoxymethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a clear oil, which crystallizes on standing to a white solid (87 mg, 63%), along with recovered starting material (22 mg, 17%). Use a method similar to the General Procedure 1-4 to give the title compound as a white solid. MS (ES+) m/z: 348 (M+H−Boc)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C@H:13]1[CH2:18][NH:17][C@H:16]([CH3:19])[CH2:15][N:14]1[C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23].C(N(CC)CC)C>CCOC(C)=O>[CH3:12][C@H:13]1[CH2:18][N:17]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C@H:16]([CH3:19])[CH2:15][N:14]1[C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:23])[F:24]
Reactant: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1S(=O)(=O)c1ccc(F)cc1
Yield: 56 %

Procedure:
A solution of 4-fluorobenzene sulphonyl chloride (234 mg, 1.2 mmol) in EtOAc (10 ml) was added to a stirred mixture of (R)-[(2S,5R)-2-methyl-5-methyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperazine] (J. Med. Chem., 1999, 42, 2741-2746) (254 mg, 1.0 mmol) and triethylamine (0.17 ml, 1.2 mmol) in EtOAc (15 ml). The resultant mixture was stirred at ambient temperature for 2 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was recrystallized from EtOAc/hexane to give the title compound as a solid (230 mg, 0.56 mmol). Mp: 174-175° C.; NMR: 0.95 (d, 3H), 1.25 (d, 3H), 1.75 (s, 3H), 3.25 (dd, 1H), 3.35 (d, 1H), 3.5 (dd, 1H), 4.15 (m, 2H), 4.3 (s, 1H), 4.75 (s, 1H), 7.2 (d, 2H), 7.8 (d, 2H); m/z 411.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:20]#[N:21])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:5]([CH2:11]Br)[C:6]=1[C:7]([F:10])([F:9])[F:8].[NH:22]1[CH:26]=[CH:25][NH:24][C:23]1=[S:27]>C(O)(C)C>[BrH:1].[Br:1][C:2]1[C:3]([C:20]#[N:21])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:5]([CH2:11][S:27][C:23]2[NH:22][CH:26]=[CH:25][N:24]=2)[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: S=c1[nH]cc[nH]1
Reactant: N#Cc1c(Br)c(C(F)(F)F)n(CBr)c1-c1ccc(Cl)cc1
Solvent: CC(C)O
Product: Br
Product: N#Cc1c(Br)c(C(F)(F)F)n(CSc2ncc[nH]2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of 4-bromo-1-(bromomethyl)-2-(p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (0.88 g, 0.002 mol) and 4-imidazoline-2-thione (0.23 g, 0.002 mol) in isopropanol is heated at reflux temperature for 3 hours, cooled to room temperature and filtered. The filtercake is washed with isopropanol and air-dried to give the title product as a white solid, 0.81 g (75% yield), mp 221°-223° C.(dec).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[H-].[Na+].[CH2:9]([CH:11]1[O:13][CH2:12]1)Br>O1CCCC1>[CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][O:5][CH2:9][CH:11]1[O:13][CH2:12]1
Reactant: BrCC1CO1
Reactant: CC(C)=CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCOCC1CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,3-dimethylallyl alcohol (17.3 g, 20.5 mL, 0.2 mol) in dry tetrahydrofuran (THF) (200 mL) was added sodium hydride (4.8 g, 0.2 mol) in portions and the mixture was stirred at room temperature for 1 hr. Epibromohydrin (27.4 g, 17.12 mL, 0.2 mol) was added dropwise and the reaction mixture was stirred at room temperature for 24 hrs. THF was removed on a rotary evaporator and the residue was taken up in ether and filtered. The ether solution was concentrated on a rotary evaporator and the brown oil obtained was distilled under vacuum. bp: 93°-94° C./10 mm. Yield: 17.2 g (60.5%). 1H NMR (CDCl3) ε 1.68 and 1.75 (s, 6H, CH3), 2.61 and 2.88 (dd, 2H, oxirane CH2), 3.17 (m, 1H, oxirane CH), 3.38 and 3.7 (m, 2H, CH2OCH2CH), 4.05 (m, 2H, CH2OCH2CH), 5.35 (m, 1H, >C=CH).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([S:23][C:24]4[CH:44]=[CH:43][C:27]5[N:28]=[C:29]([NH:31][C:32]([NH:34][CH2:35][CH2:36][N:37]6[CH2:42][CH2:41][O:40][CH2:39][CH2:38]6)=[O:33])[S:30][C:26]=5[CH:25]=4)=[N:21][N:22]=3)[N:19]=2)=[CH:10][CH:9]=1.I([O-])(=O)(=O)=[O:46].[Na+]>O.C(O)(=O)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([S:23][C:24]4[CH:44]=[CH:43][C:27]5[N:28]=[C:29]([NH:31][C:32]([NH:34][CH2:35][CH2:36][N+:37]6([O-:46])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]6)=[O:33])[S:30][C:26]=5[CH:25]=4)=[N:21][N:22]=3)[N:19]=2)=[CH:10][CH:9]=1
Reactant: O=C(NCCN1CCOCC1)Nc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: O=C(NCC[N+]1([O-])CCOCC1)Nc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1
Temperature: 20 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
116 mg of periodate of sodium in 0.5 cm3 of water are added to a mixture of 200 mg of 1-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea in 5 cm3 of acetic acid at 20° C. After an overnight period, the precipitate is filtered off. The white powder obtained is a mixture containing oxidized product and starting product. This mixture is taken up in 10 cm3 of acetic acid with 155 mg of sodium periodate dissolved in 1 cm3 of water. The mixture is left to stir overnight at 20° C. The precipitate is then filtered off and then washed successively with diisopropyl ether and with diethyl ether. 155 mg of white powder of 1-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)-3-[2-(4-oxidomorpholin-4-yl)ethyl]urea are obtained, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.C1C(=O)N([I:17])C(=O)C1>>[Cl:8][C:6]1[C:5]([I:17])=[C:4]([CH3:9])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(Cl)nc(N)n1
Product: Cc1nc(N)nc(Cl)c1I

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 10 g (70 mmol) 2-amino-4-chloro-6-methylpyrimidine and 16 g NIS (70 mmol). Yield: 18 g (95%). The crude product is used in next steps without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][PH:11](=[O:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:17][C@H:18]([C:26]([NH:28][C@H:29]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:13]([O:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:27])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:15])[CH3:14]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCO[PH](=O)CCCCc1ccccc1
Agent: Cl
Product: CCOP(=O)(CCCCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1

Procedure:
(4-Phenylbutyl)phosphinic acid, ethyl ester is reacted with L-phenylalanyl-L-leucine, phenylmethyl ester, hydrochloride according to the procedure of Example 1(c) to yield N-[N-[ethoxy(4-phenylbutyl)phosphinyl]-L-phenylalanyl]-L-leucine, phenylmethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(OC([NH:70][CH:71]1[CH2:75][CH2:74][NH:73][CH2:72]1)=O)(C)(C)C.FC(F)(F)C(O)=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:73]1[CH2:74][CH2:75][CH:71]([NH2:70])[CH2:72]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCC(N)C3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 3-tert.-butyloxycarbonylamino-pyrrolidine in DMSO at ambient temperature and subsequent treatment with trifluoroacetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(O)(=O)C.ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[Na+].[Cl-]>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:1][C:2]2[CH:7]=[N:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(=O)Nc1ccc(N)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(=O)Nc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cn1
Reaction time: 16 h
Yield: 20 %

Procedure:
A mixture of N-(5-amino-pyridin-2-yl)-acetamide (2.05 g, 13.55 mmol, 1.0 equiv; commercially available) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.70 g, 13.55 mmol, 1.0 equiv; commercially available) in conc. acetic acid (0.78 mL, 0.81 g, 13.55 mmol, 1.0 equiv) and dichloroethane (50 mL) was stirred at rt for 4 h. Sodium triacetoxyborohydride (3.45 g, 16.26 mmol, 1.2 equiv) was added in one portion and the reaction mixture stirred for an additional time period of 16 h. To the reaction mixture was added a sat. solution of NaCl (2×50 mL) and the crude extracted with ethyl acetate (3×100 mL). The combined organic phases were washed over a sat. solution of Na2CO3 (50 mL), dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with silica column chromatography eluting with a gradient of dichloromethane/methanol (50:1→12:1). Recrystallization from diethylether provided 0.91 g (20%) of the title compound in 90% purity according to 1H NMR. 1H NMR (400 MHz, DMSO): δ 1.12-1.28 (m, 2H), 1.40 (s, 9H), 1.86 (d, J=12.3 Hz, 2H), 2.00 (s, 3H), 2.90 (br s, 2H), 3.39 (d, J=9.1 Hz, 1H), 3.86 (d, J=12.8 Hz, 2H), 5.48 (d, J=8.4 Hz, 1H), 7.00 (d, J=8.9 Hz, 1H), 7.69 (d, J=2.7 Hz, 1H), 7.77 (d, J=8.9 Hz, 1H), 10.01 (s, 1H). MS (ESI): 335.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=O)[CH2:11][C:5]=2[CH:4]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>O.C([BH3-])#N.[Na+].C(O)(=O)C>[CH2:15]([NH:22][CH:10]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)CC(=O)CCC2
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (3.6 g), benzylamine (2.5 ml), and acetic acid (27 ml) in water bath was added portionwise sodium cyanoborohydride (0.49 g), and the mixture was stirred at ambient temperature for 5 hours. Additional benzylamine (2.5 ml) and sodium cyanoborohydride (0.10 g) were added to the mixture, and stirring was continued for an additional 2 hours. The reaction mixture was made alkaline (pH>8) with 10% sodium hydroxide (150 ml), and extracted once with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution; n-hexane-ethyl acetate; 3:1 to 2:1 to 1:1) to give N-benzyl-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-amine (4.8 g) as an oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH3:14])[CH:8]=1.CN(C)[CH:17]=[O:18]>O1CCCC1>[CH2:13]([C:9]1[CH:8]=[C:7]([CH2:17][OH:18])[CH:12]=[CH:11][CH:10]=1)[CH3:14]
Reactant: CCc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cccc(CO)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (34 ml of a 2.5M solution in hexanes) was added to a solution of 1-bromo-3-ethylbenzene (15 g) in tetrahydrofuran at -78° C. After 1 hour dimethylformamide (15 ml) was added. The mixture was stirred at -78° C. for 1 hour and allowed to warm to room temperature. The mixture was quenched with aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. The residue was dissolved in methanol (250 ml) and treated with sodium borohydride (1.51 g) portionwise. The mixture was stirred at room temperature for 16 hours, quenched with 2M HCl (100 ml) and stirred for 4 hours. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and 2M HCl. The organic phase was dried (MgSO4), evaporated and the residue purified by chromatography eluting with 5-10% ethyl acetate in isohexane. Yield 7.6 g.
Reaction SMILES: Cl[Ti:2](Cl)(Cl)Cl.[C:6]1([C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9])[OH:7]>C1(C)C(C)=CC=CC=1>[C:6]1([C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[O-:9])[O-:7].[Ti+4:2].[C:6]1([C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[O-:9])[O-:7]
Reactant: Cl[Ti](Cl)(Cl)Cl
Reactant: Oc1ccccc1O
Solvent: Cc1ccccc1C
Product: [O-]c1ccccc1[O-]
Product: [Ti+4]
Yield: 66.9 %

Procedure:
A mixture of freshly distilled TiCl4 (11 g, 58 mmol) and pyrocatechol (13.7 g, 0.124 mol) was refluxed in 80 mL of xylene during 20 hours. The resulting dark-brown solid was filtered, washed by xylene and dried under vacuum. Titanium catecholate (10.24 g, 66%) was isolated. This salt (2.3 g, 8.7 mmol), pyrocatechol (82.5 g, 0.749 mol), xylene (80 mL) and isobutylene (150 mL) were heated in autoclave during 1.5 hours at 140° C. The solvent was removed and the residue was distilled under vacuum (b.p. −140-145° C., ˜1 mm Hg; m.p. 96-96.5° C.). Yield: 157.4 g (95%). (Also see “Organic Chemistry of Free Radicals”, Moscow, Khimia, 1979, p. 134.)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][C:14]([F:17])([F:16])[F:15])[C:7]([OH:9])=O)([O-])=O.C(Cl)(=O)C(Cl)=O.[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][C:14]([F:17])([F:16])[F:15])[C:7]([NH:29][C:28]1[CH:30]=[CH:31][C:25]([F:24])=[CH:26][CH:27]=1)=[O:9]
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1ccc(OC(F)(F)F)c([N+](=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Product: Nc1cc(C(=O)Nc2ccc(F)cc2)ccc1OC(F)(F)F
Yield: 88.5 %

Procedure:
Prepared according to the procedure described for Example 1 using 3-nitro-4-trifluoromethoxybenzoic acid from Step A (5.1 g, 20.5 mmol), oxalyl chloride (2.1 mL, 20.5 mmol), and 4-fluoroaniline (Aldrich. Milwaukee, Wis.) (4.6 g, 41.1 mmol) to afford the product (5.7 g); m.p. 139-140° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:3]=1.Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C.[CH3:33][NH:34][C:35]([C:37]1[CH:42]=[C:41]([O:43][C:44]2[CH:49]=[CH:48][C:47]([NH2:50])=[C:46]([F:51])[CH:45]=2)[CH:40]=[CH:39][N:38]=1)=[O:36]>C1COCC1.CN(C=O)C>[CH3:33][NH:34][C:35]([C:37]1[CH:42]=[C:41]([O:43][C:44]2[CH:49]=[CH:48][C:47]([NH:50][C:13]([NH:1][C:2]3[CH:3]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:5]=[CH:6][N:7]=3)=[O:15])=[C:46]([F:51])[CH:45]=2)[CH:40]=[CH:39][N:38]=1)=[O:36]
Reactant: CC(C)(C)c1cc(N)ncn1
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)ncn3)c(F)c2)ccn1
Temperature: 70 °C
Yield: 63.9 %

Procedure:
A solution of 6-amino-4-t-butylpyrimidine (20.0 mg; 0.13 mmol), triphosgene (14.52 mg; 0.05 mmol) and diisopropylethylamine (20.51 mg; 0.16 mmol) in THF (0.7 mL) was heated at 70° C. for 4 h. A solution of 4-(4-amino-3-fluoro-phenoxy)-pyridine-2-carboxylic acid methylamide (34.5 mg; 0.13 mmol) in DMF (1.5 mL) was then added and the reaction mixture was heated at 70° C. for another 8 h, then extracted between EtOAc and saturated aqueous NaHCO3. The organic layer was dried and evaporated under reduced pressure to give a crude oil that was purified via HPLC to give the title compound (14 mg, 9%). 1H-NMR (CD3OD) δ 8.73 (s, 1H), 8.48 (d, J=4.0 Hz, 1H), 8.29 (t, J=4.0 Hz, 1H), 7.57 (d, J=4.0 Hz, 1H), 7.58-7.08 (m, 3H), 7.01 (s, 1H), 2.94 (s, 3H), 1.36 (s, 9H). LC-MS m/z 439 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:3]=1.[OH:26][CH2:27][C:28]1[S:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[OH:26][CH2:27][C:28]1[S:32][C:31]([C:2]2[C:11]3[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=3[CH:5]=[C:4]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:3]=2)=[CH:30][CH:29]=1
Reactant: OCc1ccc(B(O)O)s1
Reactant: Cn1cnc2cc(-c3ccc(N4CCOCC4)cc3)nc(Cl)c2c1=O
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: C1COCCO1
Product: Cn1cnc2cc(-c3ccc(N4CCOCC4)cc3)nc(-c3ccc(CO)s3)c2c1=O
Temperature: 140 °C

Procedure:
To a solution of 5-chloro-3-methyl-7-(4-morpholinophenyl)pyrido[4,3-d]pyrimidin-4(3H)-one (6.0 mg, 0.017 mmol) in 1,4-dioxane (0.5 mL) were added crude 5-(hydroxymethyl)thiophen-2-ylboronic acid from Step A, 2M aqueous Na2CO3 solution (0.1 mL, 0.2 mmol), and a catalytic amount of Pd(PPh3)4. The reaction mixture was purged with N2 and heated at 140° C. by a microwave reactor for 15 minutes. The mixture was then cooled, quenched with H2O, extracted with EtOAc, and purified by preparatory LC/MS to provide the title compound; ESI-MS m/z 435.1 (MH+).
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26]>[Pd]>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]4)[CH2:3]2)[CH2:9]3)=[CH:22][C:21]=1[CH3:26]
Reactant: COc1ccccc1C
Reactant: BrC12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1C
Temperature: 150 °C
Reaction time: 24 h
Yield: 82.3 %

Procedure:
To a solution of 1-bromoadamantane (3.25 g, 15.25 mmol) and potassium carbonate (1.05 g, 7.62 mmol) in 1-methoxy-2-methylbenzene (10 mL) was added 10 wt. % Pd/C (2.22 g) and stirred at 150° C. under nitrogen for 24 hours. The reaction mixture was cooled to room temperature and filtered. Solvent was evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give 1-(4-methoxy-3-methylphenyl)adamantane as a white solid (4.9 g, 82.3% yield).
Reaction SMILES: C(OC([N:8]([CH2:21][CH2:22][C:23]#[C:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[NH:32][CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[S:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)(=[O:11])=[O:10])=O)(C)(C)C>[Cu]I.CN(C)C(=O)C>[CH:33]([N:32]1[C:26]2[C:25](=[CH:30][C:29]([Cl:31])=[CH:28][CH:27]=2)[CH:24]=[C:23]1[CH2:22][CH2:21][NH:8][S:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)(=[O:11])=[O:10])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N(CCC#Cc1cc(Cl)ccc1NC(c1ccccc1)c1ccccc1)S(=O)(=O)Cc1ccc(Cl)c(Cl)c1
Agent: [Cu]I
Solvent: CC(=O)N(C)C
Product: O=S(=O)(Cc1ccc(Cl)c(Cl)c1)NCCc1cc2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Temperature: 150 °C
Yield: 98.9 %

Procedure:
A solution of N-t-butoxycarbonyl-N-{4-[2-(benzhydryl-amino)-5-chloro-phenyl]-but-3-ynyl}-C-(3,4-dichlorophenyl)-methanesulfonamide (400 g, 0.585 mol) and N,N-dimethylacetamide (800 mL) was added slowly over 1 h to a hot (150° C.), stirred mixture of copper (I) iodide (12.2 g, 0.064 mol) and N,N-dimethylacetamide (740 mL). The reaction mixture was stirred and maintained at 150° C. for an additional 2 h. The reaction mixture was cooled to 40° C. The mixture was filtered through a celite pad and the pad was washed with IPA (2×100 mL). An additional charge of IPA (1400 mL) was added to the filtrate. The mixture was stirred and warmed to 60° C. Water (2.2 L) was added to the mixture over 30 m, maintaining an internal temperature of 55-60° C. The mixture was held at 60° C. for 30 m, then it was cooled to 5° C. The solid product was collected by filtration and the cake was washed with cold IPA/water (3/2 v/v, 2×200 mL). The solid was vacuum dried at <50° C. to give N-[2-(1-benzhydryl-5-chloro-1 H-indol-2-yl)-ethyl]-C-(3,4-dichloro-phenyl)-methanesulfonamide (338 g, 99%) with 98% purity (as determined by HPLC).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Br:13])=[O:22]
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: O=C=Nc1ccccc1Br
Product: COC(=O)c1ccc(NC(=O)Nc2ccccc2Br)c(O)c1
Yield: 32.9 %

Procedure:
The urea was prepared from 2-hydroxy 4-carbomethoxy aniline(0.167 g, 1 mmol) and 2-bromo phenyl isocyanate(1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.12 g, 33%). EI-MS m/z 363(M-H)-