Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:9]2=[N:10][C:11]([Sn](C)(C)C)=[CH:12][N:13]=[C:8]2[NH:7][CH2:6][C:5]1=[O:18])([CH3:3])[CH3:2].Br[C:20]1[C:25]([CH3:26])=[CH:24][C:23]([C:27]2[N:31]=[CH:30][N:29]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:28]=2)=[C:22]([F:38])[CH:21]=1>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:38][C:22]1[C:23]([C:27]2[N:31]=[CH:30][N:29]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:28]=2)=[CH:24][C:25]([CH3:26])=[C:20]([C:11]2[N:10]=[C:9]3[N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:18])[CH2:6][NH:7][C:8]3=[N:13][CH:12]=2)[CH:21]=1
Reactant: CC(C)N1C(=O)CNc2ncc([Sn](C)(C)C)nc21
Reactant: Cc1cc(-c2ncn(C3CCCCO3)n2)c(F)cc1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2ncn(C3CCCCO3)n2)c(F)cc1-c1cnc2c(n1)N(C(C)C)C(=O)CN2
Temperature: 140 °C
Yield: 52.7 %

Procedure:
1-Isopropyl-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (300 mg, 0.84 mmol), 3-(4-bromo-2-fluoro-5-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (428 mg, 1.26 mmol) and bis(triphenylphosphine)palladium(II)dichloride (56 mg, 0.08 mmol) were combined in N,N-dimethylformamide (5 mL). The mixture was degassed and heated at 140° C. under nitrogen for 3 h. After being cooled to room temperature, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (15 mL) and water (15 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by preparative TLC (15% methanol in dichloromethane) to give the title compound (200 mg, yield 52%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29]C(=O)OC(C)(C)C)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:19]4[C@H:26]([CH3:27])[CH2:25][CH2:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C@@H:14]([CH3:28])[CH2:13]2)=[O:11])=[CH:4][C:3]=1[F:37].[ClH:38]>C(Cl)Cl>[ClH:1].[ClH:38].[NH2:29][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:37])[CH:4]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:19]3[C@H:26]([CH3:27])[CH2:25][CH2:24][C:20]=3[N:21]=[CH:22][N:23]=2)[C@@H:14]([CH3:28])[CH2:13]1)=[O:11]
Reactant: C[C@@H]1CCc2ncnc(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)c(F)c4)NC(=O)OC(C)(C)C)C[C@@H]3C)c21
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)[C@H](N)Cc4ccc(Cl)c(F)c4)C[C@@H]3C)c21
Yield: 99 %

Procedure:
tert-Butyl (R)-3-(4-chloro-3-fluorophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate was treated with HCl (4M in dioxane, 2 mL) in DCM (5 mL) for 6 hours to provide (R)-2-amino-3-(4-chloro-3-fluorophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (54 mg, 99%). MS (APCI+) [M+H] +432.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:10]1[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=1)[O:13][CH2:14][C:15]1[O:16][CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]1[CH:34]=[N+:35]([O-:53])[CH:36]=[C:37]([Cl:52])[C:38]=1[CH2:39][C@@H:40]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[C:44]([O:50][CH3:51])[CH:43]=1)O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:52][C:37]1[CH:36]=[N+:35]([O-:53])[CH:34]=[C:33]([Cl:32])[C:38]=1[CH2:39][C@H:40]([O:21][C:20]([C:18]1[N:19]=[C:15]([CH2:14][O:13][C:12]2[CH:23]=[CH:24][CH:25]=[C:10]([C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:11]=2)[O:16][CH:17]=1)=[O:22])[C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[C:44]([O:50][CH3:51])[CH:43]=1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccccc1)c1cccc(OCc2nc(C(=O)O)co2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2coc(COc3cccc([C@@H](NC(=O)OC(C)(C)C)c4ccccc4)c3)n2)cc1OC
Temperature: 25 °C
Reaction time: 23 h
Yield: 36.4 %

Procedure:
To a stirred suspension of 2-[[3-[(S)-(tert-butoxycarbonylamino)-phenyl-methyl]phenoxy]methyl]oxazole-4-carboxylic acid (350 mg, 0.825 mmol) in DMF (12.3 mL) was added (1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethanol (284 mg, 0.825 mmol), DMAP (50.4 mg, 0.412 mmol) and EDC hydrochloride (316.2 mg, 1.65 mmol). The reaction was stirred at room temperature for 23 h. The majority of the DMF was removed in vacuo and the residue was partitioned between ethyl acetate (30 mL) and saturated aqueous NaHCO3 solution (30 mL). The aqueous phase was extracted twice with ethyl acetate (20 mL) and the combined organic phases were washed with brine, dried on MgSO4, filtered then concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-50% EtOAc in dichloromethane, to give the title compound (225.6 mg, 36%) as a colourless solid.
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[F:16][CH2:17][C:18]1[N:23]=[C:22]([O:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:21]=[CH:20][CH:19]=1>>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:30]1[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][O:24][C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:17][F:16])[N:23]=2)[CH2:28][CH2:29]1)#[N:2]
Reactant: FCc1cccc(OCCN2CCNCC2)n1
Reactant: CC(C)C(C#N)(CCCI)c1cccs1
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2cccc(CF)n2)CC1)c1cccs1

Procedure:
The title compound was synthesized in accordance with Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and 1-[2-(6-fluoromethyl-2-pyridyloxy)ethyl]piperazine. The physico-chemical data of the compound was as below.
Reaction SMILES: C(N1C2C(=CC(Cl)=C(F)C=2)C(C)=N1)(C)(C)C.CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N(Br)C(=O)C1.[C:37]([N:41]1[C:49]2[C:44](=[CH:45][C:46]([Cl:51])=[C:47]([F:50])[CH:48]=2)[C:43]([CH:52](Br)[Br:53])=[N:42]1)([CH3:40])([CH3:39])[CH3:38]>ClC(Cl)C>[Br:53][CH2:52][C:43]1[C:44]2[C:49](=[CH:48][C:47]([F:50])=[C:46]([Cl:51])[CH:45]=2)[N:41]([C:37]([CH3:40])([CH3:39])[CH3:38])[N:42]=1
Reactant: CC(C)(C)n1nc(C(Br)Br)c2cc(Cl)c(F)cc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cc1nn(C(C)(C)C)c2cc(F)c(Cl)cc12
Agent: O=C1CCC(=O)N1Br
Solvent: CC(Cl)Cl
Product: CC(C)(C)n1nc(CBr)c2cc(Cl)c(F)cc21
Temperature: 25 °C

Procedure:
To 1-tert-butyl-5-chloro-6-fluoro-3-methyl-1H-indazole (153 mg, 0.636 mmol) in dichloroethane (3.0 mL) were added AIBN (20.88 mg, 0.127 mmol) and NBS (124 mg, 0.699 mmol) and the reaction mixture was refluxed under a sunlamp for 3 hours. The reaction was cooled to room temperature and after filtering through a pad of celite, the solution was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (2×15 mL) and water (10 mL), washed with saturated sodium bicarbonate (15 mL), brine (10 mL) and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure to give a mixture of the title compound and 1-tert-butyl-5-chloro-3-(dibromomethyl)-6-fluoro-1H-indazole (168 mg).
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]([CH3:13])([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH3:12])[CH2:7]1)[CH3:5].[OH-].[Li+].Cl>CO>[CH3:13][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH3:12])[CH2:7]1)([CH3:5])[C:3]([OH:14])=[O:2]
Reactant: COC(=O)C(C)(C)C1CCCN(C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CN1CCCC(C(C)(C)C(=O)O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.200 g of 2-methyl-2-(1-methyl-piperidin-3(R,S)-yl)-propionic acid methyl ester are dissolved in 4 ml of methanol. 4 ml of a 1M aqueous lithium hydroxide solution are added and the mixture is stirred for 16 hours at room temperature. The reaction mixture is neutralised with 1M HCl and extracted with ethyl acetate (3×50 ml). The organic phases are combined and concentrated by evaporation. The residue is purified by means of flash chromatography (SiO2 60 F) to provide the title compound as a colourless oil. Rf 0.15 (150:54:10:1 dichloromethane-methanol-acetic acid-water).
Reaction SMILES: [OH:1][C:2]([CH:15]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8].Cl.C([O-])([O-])=O.[K+].[K+].C(=O)=O>CC#N>[CH3:8][O:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)[OH:1]
Reactant: COCCCCC(O)(c1ccccc1)C1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: CC#N
Product: COCCCCC(O)(c1ccccc1)C1CCNC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 66.4 %

Procedure:
To a stirred solution of tert-butyl 3-(1-hydroxy-5-methoxy-1-phenylpentyl)pyrrolidine-1-carboxylate (290 mg, 0.80 mmol) in MeCN (20 mL) was added 5% aq HCl (20 mL). The mixture was stirred at rt for 17 h and solid K2CO3 was added until CO2 evolution ceased. MeCN was removed under reduced pressure and the aqueous residue was extracted with CH2Cl2 (2×90 mL). The combined organic extracts were dried over Na2SO4 and concentrated to afford 5-methoxy-1-phenyl-1-(pyrrolidin-3-yl)pentan-1-ol (140 mg, 66%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[O:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH:17]([NH2:18])[C:11]3=[CH:10][C:9]=2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:4]([Cl:28])[CH:3]=1.[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[O:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH:17]([NH:18][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:11]3=[CH:10][C:9]=2[C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[C:4]([Cl:28])[CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1(C)CC(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Br)cc3Cl)nc2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Br)cc3Cl)nc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the 7-(4-bromo-2-chlorophenyl)-6-(4-chlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine (536.2 mg, 1.12 mmol) in 10 mL of CH2Cl2 at 0° C. was added pivaloyl chloride (166 μL, 1.34 mmol) and NEt3 (313 μL, 2.24 mmol). After stirring at rt for 1 h, the reaction mixture was concentrated. Chromatography on a Biotage 40+M cartridge using 1:3 v/v EtOAc/hexanes as the eluant afforded the product: 1H NMR δ 1.26 (s, 9H), 1.47 (s, 3H), 1.55 (s, 3H), 1.82 (t, J=12.3, 1H), 2.26 (dd, J=6.2, 13.3, 1H), 5.48 (m, 1H), 5.81 (br. s, 1H), 6.97 (d, J=8.5, 2H), 7.16-7.20 (m, 3H), 7.33-7.42 (m, 2H), 7.55 (s, 1H).
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7]/[CH:8]=[CH:9]/[CH3:10].[Li]CCCC.C([O:19][B:20](OC(C)C)[O:21]C(C)C)(C)C.C([K])/C=C/C.Cl.[Na+].[Cl-].[C:37]([C@@H:43]([C@H:45]([C:47]([O:49][CH:50]([CH3:52])[CH3:51])=[O:48])[OH:46])[OH:44])([O:39][CH:40]([CH3:42])[CH3:41])=[O:38]>CCOCC.C1COCC1>[CH2:7]([B:20]([OH:21])[OH:19])/[CH:8]=[CH:9]/[CH3:10].[C:47]([C@@H:45]([C@H:43]([C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[OH:44])[OH:46])([O:49][CH:50]([CH3:51])[CH3:52])=[O:48]
Reactant: C/C=C/C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: C/C=C/C[K]
Agent: CC(C)(C)[O-]
Agent: CC(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: C/C=C/CB(O)O
Temperature: -78 °C

Procedure:
An oven-dried 1 L three-neck round bottom flask equipped with a magnetic stir bar and a −100° C. thermometer was charged with 206 mL of anhydrous THF and KOtBu (28.2 g, 250 mmol). This mixture was flushed with Ar and cooled to −78° C., then trans-2-butene (23 mL, 250 mmol), condensed from a gas lecture bottle into a rubber-stoppered round bottom flask immersed in a −78° C. dry ice-acetone bath, was poured into the reaction mixture. n-BuLi (100 mL, 2.5 M in hexane) was then added dropwise via cannula over 1.5 h. After completion of the addition, the cooling bath was removed and the reaction mixture was allowed to warm to an internal temperature of −50° C. for 15 min then immediately recooled to −78° C. Triisopropylborate (57.8 mL, 250 mmol) was added drop-wise via cannula to the (E)-crotylpotassium solution over 2 h. After addition, the reaction mixture was maintained at −78° C. for 30 min and then rapidly poured into a 2 L separatory funnel containing 470 mL of 1 N HCl saturated with NaCl. The aqueous layer was adjusted to pH 1 by using 1 N HCl (100–150 mL), and then a solution of (R,R)-diisopropyl tartrate (52.8 g, 250 mmol) in 88 mL of Et2O was added. The phases were separated, and the aqueous layer was extracted with additional Et2O (4×120 mL). The combined extracts were dried over MgSO4 for 1 h then vacuum filtered through a fritted glass funnel under Ar blanket into an oven-dried round-bottom flask. The filtrate was concentrated in vacuo, and pumped to constant weight at under vacuum. Anhydrous toluene (170 mL) was added to the flask make a 1M solution.
Reaction SMILES: O[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[O:9])=[C:6]([S:18][CH3:19])[N:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:35])=O>>[Cl:35][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[O:9])=[C:6]([S:18][CH3:19])[N:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1
Reactant: CSc1ccc(-c2nc(O)c(C(=O)Nc3ccc(C)cc3)c(SC)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CSc1ccc(-c2nc(Cl)c(C(=O)Nc3ccc(C)cc3)c(SC)n2)cc1
Temperature: 25 °C
Yield: 57 %

Procedure:
4-Hydroxy-N-(4-methylphenyl)-6-(methylthio)-2-[4-(methylthio)phenyl] pyrimidine-5-carboxamide (0.5 g, 1.25 mmol) was refluxed in phosphorus oxychloride (10 ml) for 3 hours and subsequently cooled to room temperature. The reaction mixture was poured onto ice-water mixture, neutralised with saturated sodium bicarbonate solution and the solid thus separated was extracted with ethylacetate. The organic layer was washed with water; dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound, 0.3 g, yield 57%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][OH:14])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].N1C=CN=C1.[C:20]([Si:24](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:23])([CH3:22])[CH3:21].CCCCCC>ClCCl.CN(C)C=O.C(OCC)(=O)C>[Si:24]([O:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][OH:14])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])([C:20]([CH3:23])([CH3:22])[CH3:21])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N(CCO)CCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCO)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 53.9 %

Procedure:
In a dichloromethane/N,N-dimethylformamide (70 ml/70 ml) mixture were dissolved t-butyl N,N-bis(2-hydroxyethyl)carbamate (9.00 g, 43.8 mmol) and imidazole (2.60 g, 38.2 mmol), followed by the dropwise addition of t-butylchlorodiphenylsilane (8.1 ml, 31 mmol) at room temperature. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 14 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was added with diethyl ether. The resulting mixture was washed with water and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure, whereby the title compound (7.41 g, 16.7 mmol, 54%) was obtained as a colorless oil.
Reaction SMILES: [C:1]([N:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].[NH2:15][C@H:16]([C:18]([N:20]1[C:26](=[O:27])[CH:25]([CH3:28])[C:24]2[CH:29]=[CH:30][CH:31]=[CH:32][C:23]=2[C:22]2[C:33]([NH2:37])=[CH:34][CH:35]=[CH:36][C:21]1=2)=[O:19])[CH3:17]>>[C:1]([N:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][C:6]([NH:15][C@H:16]([C:18]([N:20]1[C:26](=[O:27])[CH:25]([CH3:28])[C:24]2[CH:29]=[CH:30][CH:31]=[CH:32][C:23]=2[C:22]2[C:33]([NH2:37])=[CH:34][CH:35]=[CH:36][C:21]1=2)=[O:19])[CH3:17])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)N(CC(=O)O)c1ccccc1
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Product: CC(=O)N(CC(=O)N[C@@H](C)C(=O)N1C(=O)C(C)c2ccccc2-c2c(N)cccc21)c1ccccc1

Procedure:
Following one or more of the general procedures outlined above, using acetyl-N-phenylglycine and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 485 (M+H).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:14]1([C:2]2[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Product: O=Cc1ccc(C(F)(F)F)cc1N1CCCC1

Procedure:
The title compound was synthesized from 2-fluoro-4-(trifluoromethyl)benzaldehyde and pyrrolidine as described in Example 67, Step 1 (1.6 g, 63%): LCMS (ESI, m/z): 244 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:14](OC)=[O:15])=[N:11][S:12][N:13]=2)=[CH:5][CH:4]=1)#[N:2].[Li+].[BH4-]>O1CCCC1>[OH:15][CH2:14][C:10]1[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[N:13][S:12][N:11]=1
Reactant: COC(=O)c1nsnc1-c1ccc(C#N)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2nsnc2CO)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
To a solution of methyl 4-(4-cyanophenyl)-1,2,5-thiadiazole-3-carboxylate (260 mg, 1.06 mmol, 1.00 equiv) in anhydrous tetrahydrofuran (20 mL) maintained under nitrogen at −5° C. was added LiBH4 (117 mg, 5.32 mmol, 5.02 equiv) portion-wise. The reaction was stirred at room temperature for 1.5 h and then quenched with 5 mL of saturated NH4Cl solution. The mixture was extracted with 3×20 mL of ethyl acetate. The combined organic layers were washed with 3×100 mL of brine, dried over anhydrous sodium sulfate and concentrated to afford 230 mg (100%) of 4-(4-(hydroxymethyl)-1,2,5-thiadiazol-3-yl)benzonitrile as a light yellow solid. 1H-NMR (400 MHz, DMSO-d6): δ 8.12 (d, J=8.4 Hz, 2H), 8.03 (d, J=8.4 Hz, 2H), 4.81 (s, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[O:14])=[C:11]([Cl:24])[CH:10]=1.[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>C(O)(=O)C>[Cl:24][C:11]1[CH:10]=[C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:23]=[CH:22][C:12]=1[C:13](=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2N)cc1Cl
Reactant: O=C1CCC(=O)O1
Solvent: CC(=O)O
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)CCC(=O)O)cc1Cl
Reaction time: 0.33 h

Procedure:
A stirred solution of 4-(2-aminophenylamino)-2-chloro-2′-methylbenzophenone (3.0 mmol) in glacial acetic acid (5.0 ml) was heated to 70° C., then succinic anhydride (4.0 mmol) was added. The temperature was held at 100° C. for 20 min after which the reaction mixture was concentrated in vacuo to afford a light brown syrupy, which crystallised on standing. Trituration with a mixture of Et2O/CH2Cl2 3:1 followed by filtration and washing yielded the product as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[S:18](O)=O.CS(O)(=O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[S:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[S:18]2
Reactant: O=C(O)c1ccc(Sc2ccccc2Br)c(S(=O)O)c1
Agent: CS(=O)(=O)O
Product: O=C(O)c1ccc2c(c1)Sc1cccc(Br)c1S2
Temperature: 60 °C

Procedure:
4-(2-bromo-phenylsulfanyl)-3-sulfino-benzoic acid (14 g, 38 mmol) was added slowly to a stirred solution of methanesulphonic acid (160 ml). The purple solution was heated to 60° C. for 3 hours. The reaction was cooled down to room temperature and was poured into ice (300 ml) where an off-white precipitate appeared. The solid was filtered and washed with water (100 ml) and then dried in a vacuum dessicator over activated silica (9.48 g, 73%). 1HNMR (300 MHz, CDCl3): δH=7.29 (1H, t), 7.59 (1H, dd), 7.70 (1H,dd) 7.74 (1H, d), 7.87 (1H, dd), 8.03 (1H, d).m/z (LC-MS, ESP), RT=4.99 min, (M−−1)=339
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:11]2=[O:23])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12][C:11]2=[O:23])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)C(=O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)C(=O)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 95.2 %

Procedure:
To a solution of 332b (1.1 g, 3.4 mmol) in methanol (20 mL) was added Pd/C (10%) (250 mg). After three cycles of vacuum/H2 flash, the mixture was stirred under H2 at room temperature for 10 h. The mixture was filtered and the filtrate was evaporated in vacuo to afford 332c (946 mg, 95%), which was used for the next step without further purification. MS: [M+H]+ 293.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1ON=C(NC(NC2C=CC=C(O[C:41]3[C:50]4[C:45](=[CH:46][C:47]([O:53][CH2:54][CH3:55])=[C:48]([O:51][CH3:52])[CH:49]=4)[N:44]=[CH:43][N:42]=3)C=2)=O)C=1)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:41]3[C:50]4[C:45](=[CH:46][C:47]([O:53][CH2:54][CH3:55])=[C:48]([O:51][CH3:52])[CH:49]=4)[N:44]=[CH:43][N:42]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: CCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Temperature: 70 °C
Yield: 48 %

Procedure:
A mixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (0.146 g 0.5 mmol), 4-chloro-7-ethoxy-6-methoxyquinazoline from Example 6B Step 1 (0.12 g, 0.5 mmol), and Cs2CO3 (0.161 mg, 0.5 mmol) in isopropanol (10 mL) was heated at 70° C. for 7 hours. It was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. It was purified by silica gel chromatography with EtOAc/hexane as eluant to afford 1-(5-tert-butylisoxazol-3-yl)-3-[3-(7-ethoxy-6-methoxyquinazolin-4-ylthio)phenyl]urea as solid (0.118 g, 48%). 1H NMR (300 MHz, CDCl3) δ 9.3 (br, 1H), 8.74 (s, 1H), 8.05 (s, 1H), 7.86 (s, 1H), 7.62 (d, 1H), 7.37 (m, 3H), 7.25 (1H), 5.91 (s, 1H), 4.29 (q, 2H), 4.06 (s, 3H), 1.58 (t, 3H), 1.32 (s, 9H); LC-MS (ESI) m/z 494 (M+H)+.