Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:28])[N:8]3[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1C(=O)C2=CC=CC=C2C1=O.O.NN.O>C(O)C>[NH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:8]1[C:9]2[N:5]3[C:4](=[N:3][C:2]([CH3:1])=[C:6]3[C:7]1=[O:28])[CH:12]=[CH:11][CH:10]=2
Reactant: Cc1nc2cccc3n(CCCCN4C(=O)c5ccccc5C4=O)c(=O)c1n23
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1nc2cccc3n(CCCCN)c(=O)c1n23
Yield: 81.1 %

Procedure:
To a suspension of 5.99 g (16.0 mmol) of 1,2-dihydro-3-methyl-1-[4-(phthalimido)butan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 150 ml of ethanol was added 2.40 g (48.0 mmol) of hydrazine monohydrate. The mixture was heated for one hour under reflux. After cooling, and the resulting precipitates were filtered off. The filtrate was concentrated to give the residue, water was water, extracted with chloroform (three times). The extract solution was dried over anhydrous magnesium sulfate. The solvent was distilled off to give 3.17 g of the desired compound (81.1%, pale yellow solid).
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[N:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][S:39][C:40]1[N:41]=[CH:42][N:43]2[CH:47]=[CH:46][S:45][C:44]=12)=[N+:31]=[N-:32].[Cl-].[NH4+]>C1COCC1>[N:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][S:39][C:40]1[N:41]=[CH:42][N:43]2[CH:47]=[C:46]([Sn:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])[S:45][C:44]=12)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=NCCCCCCSc1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCCCCCCN=[N+]=[N-])c2s1
Reaction time: 0.75 h

Procedure:
Tri-n-butylstannyl chloride (0.969 ml) and 5.66 ml of a 1.0 N lithiumbis(trimethylsilyl)amide/THF solution were added to a solution of 636 mg of 7-(6-azidohexyl)thioimidazo[5,1-b]thiazole in 20 ml of THF at −40° C. under an argon atmosphere. The mixture was stirred for 45 min. An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, followed by washing with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to prepare 1.01 g of the title compound.
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[H-].COCCO[Al+]OCCOC.[Na+].[H-].[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH2:36][C@@H:37]([NH:50][C:51]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:38]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[O:48][CH3:49])=O)=[CH:28]1>C1(C)C=CC=CC=1.O1CCCC1>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH2:36][C@@H:37]([NH:50][C:51]([C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:38][NH:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[O:48][CH3:49])=[CH:28]1
Reactant: COc1ccccc1CNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COCCO[Al+]OCCOC
Agent: COCCO[AlH2-]OCCOC
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccccc1CNC[C@@H](Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
RED-AL®, [a 3.4 M, solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene] (535 ml, 1.819 mol), dissolved in anhydrous tetrahydrofuran (400 ml) was slowly added using an addition funnel to a refluxing solution of the acylation product, (R)-3-(1 H-indol-3-yl)-N-(2-methoxybenzyl)-2-(N-triphenylmethylamino)propanamide (228.6 g, 0.404 mols) produced supra, in anhydrous tetrahydrofuiran (1.0 L) under a nitrogen atmosphere. The reaction mixture became a purple solution. The reaction was quenched after at least 20 hours by the slow addition of excess saturated Rochelle's salt solution (potassium sodium tartrate tetrahydrate). The organic layer was isolated, washed with brine (2×), dried over anhydrous sodium sulfate, filtered, and concentrated to an oil on a rotary evaporator. No further purification was done and the product was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH2:13])[S:11][CH:12]=1.[CH2:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)[CH2:15][CH3:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH:13][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[S:11][CH:12]=1
Reactant: Nc1nc(-c2ccccc2Cl)cs1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(-c3ccccc3Cl)cs2)cc1

Procedure:
The title compound was prepared from 4-(2-chlorophenyl)-1,3-thiazol-2-amine and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (30.9 mg) with purity >90%. MS (pos) m/z 393.1.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[C:28]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1)=[O:13])=O)(C)(C)C.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].C1(OC)C=CC=CC=1>ClCCl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[C:16]1([CH2:15][O:14][C:12]([NH:11][CH2:10][CH2:9][NH2:8])=[O:13])[C:28]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCNC(=O)OCc1cccc2c1Cc1ccccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: NCCNC(=O)OCc1cccc2c1Cc1ccccc1-2

Procedure:
N-tert-butyloxycarbonyl-N'-fluorenylmethyloxycarbonylethylene-diamine (20.0 g, 0.052 mol) was treated with trifluoroacetic acid and anisole in dichloromethane (10:10:1) for 1 hour at room temperatute. After evaporation to dryness the crude product was crystallized from solvent mixture of ethyl acetate-n-hexane. Yield 15.0 g (73%). NMR (300 MHz, DMSO-d6, 25° C.) d: 2.85 (m, 2H, CaH2), 3.22 (m, 2H, CbH2), 4.23-4.36 (m, 3H, Fmoc OCH2CH--), 7.37 (m, 1H, NH), 7.34-7.89 (m, 8H, Fmoc), 7.77 (br, 2H, NH2). M.p. 128°-129° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]([CH3:26])([CH3:25])[CH2:18]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[CH:10]=2)=[CH:4][CH:3]=1.[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH:28]=[CH2:29].CCN(CC)CC.CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O.O>[F:16][C:11]1[CH:10]=[C:9]([C:8](=[C:17]2[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20][C:21]([CH3:23])([CH3:24])[CH2:22]2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:29]=[CH:28]/[C:27]([O:31][CH2:32][CH3:33])=[O:30])=[CH:3][CH:4]=2)[CH:14]=[CH:13][C:12]=1[OH:15]
Reactant: C=CC(=O)OCC
Reactant: CC1(C)CC(=C(c2ccc(Br)cc2)c2ccc(O)c(F)c2)CC(C)(C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)c(F)c2)cc1
Temperature: 100 °C
Yield: 68.1 %

Procedure:
To a round-bottomed flask were added 4-[(4-bromophenyl)(3,3,5,5-tetramethyl cyclohexylidene)methyl]-2-fluorophenol (139) (0.33 g, 0.79 mmol), ethyl acrylate (0.87 mL, 7.90 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.056 g, 0.08 mmol), Et3N (0.55 mL, 3.95 mmol) and DMF (10 mL). The stirred reaction mixture was heated overnight at 100° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and transferred to a separatory funnel with the aid of water and EtOAc (100 mL). The layers were separated and the organic phase washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give brown oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 15% EtOAc:hexanes to give 0.235 g (68%) of compound 140 as a light yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 0.92 (s, 6H), 0.94 (s, 6H), 1.29 (s, 2H), 1.32 (t, J=7.1 Hz, 3H), 1.95 (s, 2H), 1.97 (s, 2H), 4.25 (q, J=7.1 Hz, 2H), 4.98 (d, J=4.2 Hz, 1H), 6.39 (d, J=16.0 Hz, 1H), 6.80-6.95 (m, 3H), 7.16 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.65 (d, J=16.1 Hz, 1H). LCMS (ES): m/z, 437 (M+H)+, 435 (M−H)−.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[C:26]4[CH:27]=[CH:28][C:29]([Br:31])=[CH:30][C:25]=4[S:24][N:23]=3)[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:16]=[C:17]([NH:21][C:22]3[C:26]4[CH:27]=[CH:28][C:29]([Br:31])=[CH:30][C:25]=4[S:24][N:23]=3)[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(Nc3nsc4cc(Br)ccc34)c2)COC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(c2cccc(Nc3nsc4cc(Br)ccc34)c2)COCC(N)=N1

Procedure:
To a solution of {5-[3-(6-Bromo-benzo[d]isothiazol-3-ylamino)-phenyl]-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl}-carbamic acid tert-butyl ester (36 mg, 0.07 mmol) in DCM (1 ml) was added at +5° C. 1 ml TFA. After 20 minutes the mixture was quenched with water and EtOH and evaporated. The residue was taken up in EtOAc/THF and washed with soda, dried with K2CO3 and purified by chromatography on silica gel (DCM/5% MeOH, then DCM/5-10% MeOH containing aq NH3) to yield the title compound.
Reaction SMILES: [I-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:17][C:18]1[CH:19]=[C:20]([OH:39])[CH:21]=[CH:22][C:23]=1[CH:24]([CH3:38])[C:25]([OH:37])([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=1)[C:26]([F:29])([F:28])[F:27]>CC(C)=O>[CH2:9]([O:39][C:20]1[CH:21]=[CH:22][C:23]([CH:24]([CH3:38])[C:25]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=2)([OH:37])[C:26]([F:27])([F:28])[F:29])=[C:18]([Cl:17])[CH:19]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)ccn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(C(O)(C(C)c2ccc(OCc3ccccc3)cc2Cl)C(F)(F)F)ccn1
Yield: 22.9 %

Procedure:
Potassium iodide (4 mg, 0.02 mmol), potassium carbonate (45 mg, 0.33 mmol), and benzyl chloride (41 mg, 0.33 mmol) were added to a solution of 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(2-methyl-pyridin-4-yl)-propyl]-phenol (Example 73, 50 mg, 0.14 mmol) in acetone (3 mL), and the mixture was refluxed for 3.5 h. The green suspension was filtered, the solvent evaporated, and the title compound (14 mg) was isolated from the residue by reversed-phase, preparative HPLC (Agilent Zorbax XdB-C18 column, solvent gradient 5-95% CH3CN in 0.1% TFA[aq]). MS (m/e)=436.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1([C:14](=[O:41])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[CH:31][CH:30]=4)[N:23]=3)=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.Cl.O1CCOCC1>C(OCC)(=O)C.CO>[CH3:1][C@@:2]1([C:14]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[CH:31][CH:30]=4)[N:23]=3)=[CH:20][CH:21]=2)=[O:41])[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCCC1(C)C(=O)Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@]1(C(=O)Nc2ccc(-c3ccnc(Nc4ccc(N5CCOCC5)cc4)n3)cc2)CCCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
tert-Butyl 2-methyl-2-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl-carbamoyl)pyrrolidine-1-carboxylate (0.140 g, 0.250 mmoles), was dissolved in an ethyl acetate (5 ml) and methanol (1 ml) mixture. 4 M hydrogen chloride in 1,4-dioxane (0.625 ml, 2.5 mmoles, 10 equivalents, purchased from Sigma-Aldrich) was then added in a drop wise fashion over 5-10 minutes. Upon completion of addition, the reaction mixture was stirred at room temperature, and the progress of the reaction monitored by LC/MS. After 16 hours, additional 4M hydrogen chloride in 1,4-dioxane (0.312 ml, 1.25 mmoles, 5 equivalents) was added. After a total of 48 hours the reaction was complete and the resulting slurry was filtered off. The reaction flask was rinsed with ethyl acetate to ensure complete transfer of product. The resulting solid was washed with ethyl acetate (3×10 ml) and diethyl ether (2×25 ml) and dried under reduced pressure to give of 0.061 mg 2-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}phenyl)prolinamide 367 as its hydrochloride salt (53% yield).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].Cl[C:11]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:16][O:15][C:13]([C:12]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:11]=1[O:8][CH2:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:14]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: OCCN1CCCC1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cc([N+](=O)[O-])ccc1OCCN1CCCC1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
3.43 g (29.8 mmol) of 2-pyrrolidin-1-ylethanol is dissolved in 60 mL of toluene and 575 mg (25.0 mmol) of sodium is added batchwise. The mixture is heated to 100° C. and then stirred for a further 12 hours at 50° C. After cooling, 5.00 g (22.5 mmol) of methyl 2-chloro-5-nitrobenzoate are added batchwise and the mixture is stirred for 1 day at ambient temperature. After this time, the solvent is eliminated, the residue is taken up in methylene chloride and washed with water. The organic phase is dried over sodium sulfate and concentrated by rotary evaporation. Finally the product is purified through a silica gel column with a gradient of methylene chloride/methanol/ammonia (8:2 to 8:2:0.1) as eluant. Yield: 1.65 g (25% of theory); Rf value: 0.45 (silica gel, methylene chloride/methanol/ammonia=9:1:0.1); C14H18N2O5; EII mass spectrum: m/z=295 [M+H]+.
Reaction SMILES: CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH:16](C(OCC1C=CC=CC=1)=O)[C@H:17]([C:30]([NH:32][C@H:33]([C:41]([NH2:43])=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31])[CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN(C=O)C>[NH2:16][C@H:17]([C:30]([NH:32][C@H:33]([C:41]([NH2:43])=[O:42])[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:31])[CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Temperature: -15 °C
Reaction time: 0.03 h

Procedure:
NMM (0.4 g, 4 mmol) and isobutylchloroformate (0.53 g, 4 mmol) are added to the obtained solution, cooled to -15° C. and kept under nitrogen atmosphere and, two minutes later, a DMF solution of Lys(Boc)-PheNH2 (1.6 g, 4 mmol), obtained by cleavage of the benzyloxycarbonyl group from Z-Lys(Boc)-PheNH2 through catalytic hydrogenation over 10% Pd-on-carbon, is added.
Reaction SMILES: [Na].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[NH:10][CH2:11][CH:12]([CH3:17])[C:13](OC)=[O:14]>CO>[Br:9][C:6]1[CH:7]=[CH:8][C:3]2[NH:2][C:13](=[O:14])[CH:12]([CH3:17])[CH2:11][NH:10][C:4]=2[CH:5]=1
Reactant: COC(=O)C(C)CNc1cc(Br)ccc1N
Agent: [Na]
Solvent: CO
Product: CC1CNc2cc(Br)ccc2NC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.8 %

Procedure:
Sodium metal (2.4 g, 104 mmol) was added in portions to methanol (50 mL) and the mixture was stirred at room temperature until sodium metal was dissolved completely. The solution was then added dropwise to a cooled solution of methyl 3-(2-amino-5-bromophenylamino)-2-methylpropanoate (6 g, 20.9 mmol) in methanol (100 mL) at 0° C. After addition, the mixture was stirred at room temperature for 12 hours. The mixture was concentrated in vacuo. To the residue was added water (50 mL). The mixture was extracted with ethyl acetate (100 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to give a crude product, which was purified by column chromatography (silica-gel, petroleum ether/ethyl acetate=3:1) to afford 7-bromo-3-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (1.8 g, 34%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:16]([C:18]3[NH:27][C:26](=[O:28])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[O:17])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:30]1([CH2:39][CH2:40][O:41][CH2:42][CH3:43])[C:35](=[O:36])[NH:34][C:33](=[O:37])[NH:32][C:31]1=[O:38].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:42]([O:41][CH2:40][CH2:39][C:30]1([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:16]([C:18]4[NH:27][C:26](=[O:28])[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[O:17])[CH:9]=3)=[CH:4][CH:3]=2)[C:31](=[O:38])[NH:32][C:33](=[O:37])[NH:34][C:35]1=[O:36])[CH3:43]
Reactant: O=C(NCc1cccc(-c2ccc(O)cc2)c1)c1nc2ccccc2c(=O)[nH]1
Reactant: CCOCCC1(Br)C(=O)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCCC1(Oc2ccc(-c3cccc(CNC(=O)c4nc5ccccc5c(=O)[nH]4)c3)cc2)C(=O)NC(=O)NC1=O
Yield: 51 %

Procedure:
A suspension of N-[(4′-hydroxybiphenyl-3-yl)methyl]-4-oxo-3,4-dihydroquinazoline-2-carboxamide obtained in Reference Example 119 (0.100 g, 0.269 mmol), 5-bromo-5-[2-(ethyloxy)ethyl]pyrimidine-2,4,6(1H,3H,5H)-trione obtained according to the methods described in WO02/34726 and the like (0.075 g, 0.269 mmol) and potassium carbonate (0.186 g, 1.34 mmol) in DMF (5 mL) was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate-IPE to give the title compound as a white powder (0.078 g, 51%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[S:13][C:14]([Br:17])=[CH:15][CH:16]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[H-].[Na+].ClCC1C(C)=CC2OCOC=2C=1.[CH3:32][O:33][CH2:34][CH2:35][O:36][CH2:37]Cl>C1COCC1>[CH3:32][O:33][CH2:34][CH2:35][O:36][CH2:37][N:8]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[C:6]=1[CH3:7])[S:9]([C:12]1[S:13][C:14]([Br:17])=[CH:15][CH:16]=1)(=[O:10])=[O:11]
Reactant: COCCOCCl
Reactant: Cc1noc(NS(=O)(=O)c2ccc(Br)s2)c1C
Agent: Cc1cc2c(cc1CCl)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccc(Br)s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
N-(3,4-dimethyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (680 mg, 2 mmol) in dry THF (2 ml) was added to sodium hydride (1 21 mg of a 60% oil dispersion, 3 mmol) in dry THF (1 ml). The resulting suspension was cooled to 0° C. and methoxyethoxymethyl chloride (334 mg, 2.68 mmol) was added dropwise via syringe. The solution was warmed to room temperature, and stirring continued overnight. Evaporation of solvent left an oil that was extracted into ethyl acetate, washed with brine, dried over magnesium sulfate and evaporated. Flash chromatography of the residue on silica gel using 10-15% ethyl acetate/hexanes yielded 480 mg (56%) of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:15]([NH:18][NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([N:18]([CH:15]([CH3:17])[CH3:16])[NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:8]
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: O=C(O)COc1cc(F)c(F)cc1Br
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1cc(F)c(F)cc1Br
Yield: 52.9 %

Procedure:
A solution of (2-bromo-4,5-difluoro-phenoxy)-acetic acid (985 mg, 3.68 mmol) and benzoic acid N′-isopropyl-hydrazide (787 mg, 4.416 mmol) in DMF (20 mL) was treated with diisopropylethyl amine (1.6 mL, 9.2 mmol) and PyBroP (2.57 g, 5.52 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a white solid (832 mg, 34%).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:21]=[C:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[S:16][C:1]([C:3]2[N:8]=[C:7]([CH2:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: N#Cc1cccc(CC(N)=S)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: NC(=S)Cc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 43.3 %

Procedure:
(6-Cyano-2-pyridyl)thioacetamide (0.47 g, 2.43 mmol) and methyl thiosalicylate (0.45 g, 2.67 mmol) were dissolved in toluene (50 ml), and triethylamine (0.51 ml, 3.64 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.33 g, 41%) as white crystals.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[S:22][C:23](B2OC(C)(C)C(C)(C)O2)=[C:24]([CH3:26])[N:25]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[CH3:20][C:21]1[S:22][C:23]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[C:24]([CH3:26])[N:25]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: Cc1nc(C)c(B2OC(C)(C)C(C)(C)O2)s1
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: O
Solvent: COCCOC
Product: Cc1nc(C)c(-c2cccc3c2OCCN(C(=O)OC(C)(C)C)C3)s1
Temperature: 85 °C
Reaction time: 12 h
Yield: 66.6 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (328 mg, 1.00 mmol), 2,4-dimethyl-1,3-thiazol-5-ylboronic acid pinacol ester (239 mg, 1.00 mmol), saturated aqueous sodium carbonate solution (6 ml) and tetrakis(triphenylphosphine)palladium(0) (32.6 mg, 0.0282 mmol) in dimethoxyethane (10 ml) was stirred at 85° C. for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (240 mg, 66.7%) as an oil.