Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC(C1C=C(Cl)C=C(Cl)C=1)[C:3]([F:6])([F:5])[F:4].Cl[C:16]1[CH:17]=[C:18]([CH:23]([OH:28])[C:24]([F:27])([F:26])[F:25])[CH:19]=[C:20](Cl)[CH:21]=1.C1C(=O)N(Br)C(=O)C1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(Cl)Cl>[F:25][C:24]([F:27])([F:26])[CH:23]([C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:3]([F:6])([F:5])[F:4])[CH:17]=1)[OH:28]
Reactant: FC(F)(F)C(Br)c1cc(Cl)cc(Cl)c1
Reactant: OC(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: ClCCl
Product: OC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C
Yield: 40 %

Procedure:
1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (AI1). To a stirred solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanol (4.0 g, 16.3 mmol) in CH2Cl2 (50 mL), were added NBS (2.9 g, 16.3 mmol) and triphenyl phosphite (5.06 g, 16.3 mmol), and the resultant reaction mixture was heated at reflux for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to 25° C. and was concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 100% pentane) afforded the title compound as a liquid (2.0 g, 40%): 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 3H), 5.00 (m, 1H); EIMS m/z 306 ([M]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[S:10])[S-:9].C([NH+](CC)CC)C.[CH2:18]=[CH:19][C:20](=[O:23])[CH2:21][CH3:22]>C(#N)C.C(Cl)(Cl)Cl.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[S:9])[S:10][CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH3:22]
Reactant: S=C([S-])Nc1ccccn1
Reactant: C=CC(=O)CC
Agent: CC[NH+](CC)CC
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCC(=O)CCSC(=S)Nc1ccccn1
Reaction time: 3 h
Yield: 31.6 %

Procedure:
The procedure of Example 2 is followed but triethylammonium pyrid-2-yldithiocarbamate (54.0 g) and pent-1-en-3-one (17.0 g) in anhydrous acetonitrile (400 cc) are used as the starting materials at a maximum temperature of 5° C. The reaction is allowed to proceed for 3 hours at between 5° and 20° C. The crude product (45.0 g) is dissolved in a mixture of chloroform (200 cc) and ethyl acetate (50 cc). The solution is chromatographed on a column of diameter 6 cm, containing silica (0.063-0.2 mm; 600 g). Elution is carried out with a mixture of chloroform (400 cc) and ethyl acetate (100 cc), this eluate being discarded, and then with a mixture of chloroform (2,800 cc) and ethyl acetate (700 cc), this eluate being collected and evaporated to dryness under reduced pressure (20 mmHg) at 45° C. The product obtained (30.0 g) is purified by recrystallisation from a mixture of acetonitrile (30 cc) and diisopropyl ether (60 cc). 3-Oxopentyl pyrid-2-yldithiocarbamate (16.0 g) (structure determined by IR spectroscopy in petroleum jelly), which melts at 80° C., is obtained.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:43])[CH3:42])=[C:36]([F:44])[CH:35]=4)=[N:18][CH:19]=[C:20]([CH2:22][N:23]4[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]4)[CH:21]=3)[N:10]=2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.C([O-])(O)=O.[Na+]>>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:43])[CH3:42])=[C:36]([F:44])[CH:35]=3)=[N:18][CH:19]=[C:20]([CH2:22][N:23]3[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:27][CH2:28]3)[CH:21]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(NC(C)=O)c(F)c3)n2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(Nc2ncc(CN3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cc1F
Yield: 81.6 %

Procedure:
A solution of N-(4-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-ylamino)-2-fluorophenyl)acetamide (0.125 g, 0.162 mmol) in trifluoroacetic acid (Aldrich) (1.206 mL, 16.24 mmol) and trifluoromethane sulfonic acid (TCI) (0.431 mL, 4.87 mmol) was stirred at rt in a sealed tube for 1 h. The reaction mixture was first neutralized with sat. NaHCO3 and then extracted with CHCl3 (3×15 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (120 g, 3% MeOH in DCM) to give the product as a yellow solid (0.070 g). m/z (ESI, +ve ion) 530. (M+H)+. 1H NMR (300 MHz, CDCl3) δ 12.03 (s, 1H); 8.73 (s, 1H); 8.31 (s, 1H); 8.19 (t, J=8.70 Hz, 1H); 8.07 (d, J=13.74 Hz, 1H); 7.15 (d, J=9.50 Hz, 1H); 5.44 (br. s., 2H); 3.54 (s, 2H); 3.27 (br. s., 4H); 2.79 (s, 3H); 2.60 (s, 7H); 2.22 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH:9]3[C:17](=O)[NH:16][CH2:15][C:14](=O)[N:10]3[CH2:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].B>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH:9]3[CH2:17][NH:16][CH2:15][CH2:14][N:10]3[CH2:11][C:12]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: O=C1NCC(=O)N2Cc3cc([N+](=O)[O-])ccc3CC12
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)CN1CCNCC1C2
Temperature: 25 °C
Yield: 74.4 %

Procedure:
To 8-nitro-3,6,11,11a-tetrahydro-2H-pyrazino[1,2-b]isoquinoline-1,4-dione (4.5 g, 17.2 mmol) in anhydrous tetrahydrofuran (100 ml) was added 1.0M borane in tetrahydrofuran (255 ml). The reaction mixture was heated at reflux for 6 h. After cooling to room temperature, the excess borane was quenched by the cautious addition of methanol (71 ml) and then 2.5N hydrochloric acid (71 ml). The mixture was then refluxed for 5 h. The reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was dissolved in water, the solution basified with 2.5N sodium hydroxide and the product extracted into dichloromethane. The dark red solid (4.5 g) was purified by chromatography using silica gel and 5% methanol saturated with ammonia in dichloromethane to yield 8-nitro-2,3,4,6,11,11a-hexahydro-1H-pyrazino[1,2-b]isoquinoline (2.984 g), MS 234 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[NH:5][C:4](=[O:12])[C:3]=1[NH:13][C:14]([C:16]12[CH2:23][CH:22]3[CH2:24][CH:18]([CH2:19][CH:20]1[CH2:21]3)[CH2:17]2)=O.[CH2:25](Br)[CH:26]=[CH2:27]>>[CH2:27]([N:5]1[C:4](=[O:12])[C:3]2[NH:13][C:14]([C:16]34[CH2:17][CH:18]5[CH2:24][CH:22]([CH2:21][CH:20]3[CH2:19]5)[CH2:23]4)=[N:1][C:2]=2[N:7]([CH2:8][CH2:9][CH3:10])[C:6]1=[O:11])[CH:26]=[CH2:25]
Reactant: CCCn1c(N)c(NC(=O)C23CC4CC(CC2C4)C3)c(=O)[nH]c1=O
Reactant: C=CCBr
Product: C=CCn1c(=O)c2[nH]c(C34CC5CC(CC3C5)C4)nc2n(CCC)c1=O
Yield: 34.5 %

Procedure:
Substantially the same procedure as in Reference Example 3 was repeated using 300 mg (0.90 mmol) of 6-amino-5-(3-tricyclo[3.3.1.03,7 ]nonylcarbonylamino)-1-propyluracil (Japanese Published Unexamined Patent Application No. 173889/91) and 0.16 ml (1.81 mmol) of allyl bromide. The obtained crude product was subjected to the same cyclization reaction that was used in Example 1, without purification, to give 110 mg (yield 35%) of Compound J as a white powder.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]([O:14]CC)=O)=[N:9][O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C.C(OCC)(=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH:30][C:12]([C:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][O:10][N:9]=1)=[O:14]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CCOC(=O)c1nocc1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1nocc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 28.6 %

Procedure:
A mixture of ethyl 4-phenylisoxazole-3-carboxylate (0.030 g; 0.130 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL) was stirred at room temperature for 2.5 hours. The reaction mixture was then diluted with water and the aqueous layer was extracted with dichloromethane. The aqueous layer was acidified with HCl 6N until pH 2 and extracted with ethyl acetate. The organic layer was dried over magnesium sulphate and concentrated under reduced pressure. The crude residue was added to a mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.030 g; 0.130 mmol), HATU (0.50 g; 0.130 mmol), N,N diisopropylethylamine (0.055 mL; 0.324 mmol), in DMF (2 mL) and was stirred at room temperature for 72 hours. The reaction mixture was diluted with ethyl acetate and was washed with sodium hydrogensulphate, sodium carbonate and brine. The organic layer was dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and then by preparative HPLC method 2 to yield 0.0136 g (30%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:25]>O1CCCC1>[F:21][C:16]1[CH:15]=[C:14]([C:10]2([O:13][CH3:25])[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)c(F)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ccc(F)c(F)c2)CCN(C(=O)OC(C)(C)C)C1
Yield: 76.9 %

Procedure:
Preparation according to Preparation 2. Tert-butyl-3-(3,4-difluorophenyl)-3-hydroxypyrrolidin-1-carboxylate (3.3 g, 11 mmol) in dry tetrahydrofuran (50 mL), sodium hydride (60% dispersion in mineral oil, 0.66 g, 16.5 mmol), iodomethane (1.37 mL, 22 mmol). Purification by flash column chromatography on silica gel (ethyl acetate/isooctane, 1:9 to 1:1) gave the title compound (2.65 g, 77%). MS m/z (rel. intensity, 70 eV) 257 (17), 240 (14), 171 (13), 127 (15), 57 (bp).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]2[O:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[N+]=[N-].[Li].O.[OH-].[Na+]>O1CCCC1>[O:12]1[C:13]2[C:5]([CH2:4][NH2:1])=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:10][CH2:11]1
Reactant: [N-]=[N+]=NCc1cccc2c1OCC2
Agent: [Li]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCc1cccc2c1OCC2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
The product of Example 48C (2.2 g) in tetrahydrofuran (10 mL) was treated with lithium aluminumhydride (0.71 g) in tetrahydrofuran (20 mL) at 0° C. dropwise. The mixture was stirred at 0° C. for 90 minutes then carefully treated in succession with water (0.7 mL), 15% sodium hydroxide (0.7 mL) and water (2.1 mL). After stirring overnight, the mixture was filtered through celite, the filter cake was washed with tetrahydrofuran (70 mL), and the filtrate concentrated under reduced pressure. The crude was dissolved in diethylether, washed with water, and extracted with 1N hydrochloric acid (2×20 mL). The acidic extracts were combined, basified with potassium carbonate, and extracted with methylene chloride (4×). The organic extracts were combined, dried (potassium carbonate), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. MS (DCI/NH3) m/z 150 (M+H)+;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9](Br)[Br:10])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.O>[Br:10][C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Clc1ccc(C=C(Br)Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(C#CBr)cc1
Temperature: 80 °C
Yield: 78.1 %

Procedure:
To a solution of 1-chloro-4-(2,2-dibromovinyl)benzene (9.60 g, 32.7 mmol) in toluene was added potassium tertbutoxide (7.35 g, 65.6 mmol) at RT. The reaction mixture was heated at 80° C. for 3 h. The reaction was monitored by LCMS and TLC. The reaction mixture was diluted with water and extracted with EtOAc. The organic was dried over sodium sulfate and concentrated under reduced pressure to give the desired product (5.5 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([C:16]4[N:17]=[N:18][N:19]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=5)[CH:20]=4)[OH:15])=[CH:6][CH:7]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2cccc(Cl)c2)nn1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cn(Cc5cccc(Cl)c5)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(3-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH2:30]1[C:32]2([CH2:37][CH2:36][NH+:35]([CH2:38][B-](F)(F)F)[CH2:34][CH2:33]2)[CH2:31]1>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:38][N:35]5[CH2:36][CH2:37][C:32]6([CH2:30][CH2:31]6)[CH2:33][CH2:34]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reactant: F[B-](F)(F)C[NH+]1CCC2(CC1)CC2
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCC4(CC3)CC4)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and (6-azonia-spiro[2.5]octan-6-yl)methyltrifluoroborate following a procedure analogous to that described for Intermediate 3. LC (method 1): tR=0.96 min; Mass spectrum (ESI+): m/z=516 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N+:7]([O-])[CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[CH:16][CH:15]=2)[C:4]1=[O:31])[CH3:2].[CH3:32][C:33]([O:35]C(C)=O)=[O:34]>>[C:33]([O:35][CH2:12][C:10]1[CH:9]=[CH:8][N:7]=[C:6]2[N:5]([C:14]3[CH:15]=[CH:16][C:17]([O:20][Si:21]([CH:22]([CH3:23])[CH3:24])([CH:25]([CH3:26])[CH3:27])[CH:28]([CH3:30])[CH3:29])=[CH:18][CH:19]=3)[C:4](=[O:31])[N:3]([CH2:1][CH3:2])[C:11]=12)(=[O:34])[CH3:32]
Reactant: CCn1c(=O)n(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c2c1c(C)cc[n+]2[O-]
Reactant: CC(=O)OC(C)=O
Product: CCn1c(=O)n(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c2nccc(COC(C)=O)c21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 1-ethyl-7-methyl-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 4-oxide (1 g) and Ac2O (20 mL) was stirred at 80° C. for 2 h, and concentrated in vacuo. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (0.49 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21](=[O:35])[N:22]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH:23]=[N:24]3)=[CH:19][C:18]=2[O:36][CH3:37])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21](=[O:35])[N:22]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:31])[CH3:32])[CH:23]=[N:24]3)=[CH:19][C:18]=2[O:36][CH3:37])[CH2:10][CH2:9]1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A solution of 7-(2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (10.5 g, 20 mmol) in methylene chloride (100 ml) containing TFA (25 ml) was stirred for 1 hour at ambient temperature. Water (50 ml) and methylene chloride (100 ml) were added and the pH of the aqueous layer was adjusted to 8 with solid sodium hydrogen carbonate. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was triturated with ether and the solid was filtered and dried under vacuum to give 7-(2-(piperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (8.3 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[C:58]([O:64][CH3:65])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:24]([CH:27](/[CH:44]=[CH:45]/[C:46]1[C:51]([O:52][CH3:53])=[CH:50][C:49]([O:54][CH3:55])=[CH:48][C:47]=1[O:56][CH3:57])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([NH:36][C:37](=[O:43])[CH2:38][O:39]C(=O)C)[CH:29]=1)(=[O:26])=[O:25])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:17](=[O:23])[CH2:18][O:19]C(=O)C)[CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:57][O:56][C:47]1[CH:48]=[C:49]([O:54][CH3:55])[CH:50]=[C:51]([O:52][CH3:53])[C:46]=1/[CH:45]=[CH:44]/[CH:27]([S:24]([CH:7](/[CH:6]=[CH:5]/[C:4]1[C:3]([O:2][CH3:1])=[CH:61][C:60]([O:62][CH3:63])=[CH:59][C:58]=1[O:64][CH3:65])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:17](=[O:23])[CH2:18][OH:19])[CH:9]=1)(=[O:25])=[O:26])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([NH:36][C:37](=[O:43])[CH2:38][OH:39])[CH:29]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)COC(C)=O)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)COC(C)=O)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)CO)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)CO)c2)c(OC)c1
Yield: 87.4 %

Procedure:
A solution of (E)-2,4,6-trimethoxystyryl-3-(acetoxyacetamido)-4-methoxy benzylsulfone (10 mmol) was hydrolyzed in 50% ethanol containing potassium carbonate (70 mmol) to give (E)-2,4,6-trimethoxystyryl-3-(hydroxyacetamido)-4-methoxybenzylsulfone in 87.4% yield. (m.p. 174-176° C.)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[S:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1)[NH2:24]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:25]=[CH:26][C:27]=1[S:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c2cc1OCC

Procedure:
In the manner of Example 141 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with 3-chloro-4-(1-methyl-2-imidazolylthio)aniline (WO-9615118) gave the title compound as a tan solid, mp 285-290° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([NH:18]C(OC(C)(C)C)=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:6]=1.Cl>O1CCOCC1>[CH3:1][O:2][C:3](=[O:26])[CH:4]([NH2:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[CH:6]=1
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)c1cccc(NC2CCCCC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C(N)c1cccc(NC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A solution of (RS)-tert-butoxycarbonylamino-(3-cyclohexylamino-phenyl)-acetic acid methyl ester (200 mg) in dioxane (5 ml) was treated with 4M HCl in dioxane (2.76 ml) and stirred at r.t. overnight, then concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give (RS)-amino-(3-cyclohexylamino-phenyl)-acetic acid methyl ester (126 mg, 87%) as light yellow viscous oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:13][O:14][C:15]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:16]=1[CH2:17][N:18]1[CH2:22][C:21]([CH2:24][OH:25])([CH3:23])[CH2:20][C:19]1=[O:26]>C(Cl)Cl.O>[CH3:1][S:2]([O:25][CH2:24][C:21]1([CH3:23])[CH2:20][C:19](=[O:26])[N:18]([CH2:17][C:16]2[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:15]=2[O:14][CH3:13])[CH2:22]1)(=[O:4])=[O:3]
Reactant: COc1ccc(CN2CC(C)(CO)CC2=O)c(OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CC(C)(COS(C)(=O)=O)CC2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (305 mg, 2.65 mmol) and triethylamine (540 mg, 5.35 mmol) were added to a solution of 1-(2,4-dimethoxybenzyl)-4-(hydroxymethyl)-4-methylpyrrolidin-2-one (500 mg, 1.75 mmol) in DCM (5 mL) at 0° C. The mixture was stirred at room temperature for 16 hours and then diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give [1-(2,4-dimethoxybenzyl)-3-methyl-5-oxopyrrolidin-3-yl]methyl methanesulfonate. MS ESI calc'd. for C16H24NO6S [M+H]+ 358. found 358. 1H NMR (400 MHz, CDCl3): δ 7.15 (d, J=8.4 Hz, 1H), 6.46-6.44 (m, 2H), 4.41 (s, 2H), 4.02-3.96 (m, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.22 (d, J=6.4 Hz, 1H), 2.99-2.95 (m, 4H), 2.41 (d, J=16.8 Hz, 1H), 2.24 (d, J=16.8 Hz, 1H), 1.19 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]3[C:29]4[CH2:30][NH:31][C:32](=[O:33])[C:28]=4[CH:27]=[CH:26]N=3)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.Cl[C:35]1C2CNC(=O)C=2C=CN=1.BrC1C=CC=C2C=1CNC2=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]3[CH:35]=[CH:26][CH:27]=[C:28]4[C:29]=3[CH2:30][NH:31][C:32]4=[O:33])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:7]=1
Reactant: O=C1NCc2c1ccnc2Cl
Reactant: O=C1NCc2c1ccnc2-c1cc(-c2cc(Cl)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1
Agent: O=C1NCc2c(Br)cccc21
Product: O=C1NCc2c1cccc2-c1cc(-c2cc(Cl)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1

Procedure:
The synthesis of the title compound is performed starting from 100 mg (0.24 mmol) of the product from step 3 of the compound from example 10 in a manner analogous to step 4 of the synthesis of the compound from example 10. Instead of the compound from example 22A, 4-bromo-2,3-dihydroisoindole-1-on (61 mg, 0.29 mmol) is used. This produces 28 mg (24% of theoretical yield, 94% purity) of the title compound.
Reaction SMILES: FC1(F)O[C:5]2[CH:7]=[CH:8][C:9]([B:11]3[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]3)=[CH:10][C:4]=2O1.BrC1C=CC([S:28][C:29]([F:32])([F:31])[F:30])=CC=1>>[CH3:17][C:14]1([CH3:16])[C:13]([CH3:18])([CH3:19])[O:12][B:11]([C:9]2[CH:10]=[CH:4][C:5]([S:28][C:29]([F:32])([F:31])[F:30])=[CH:7][CH:8]=2)[O:15]1
Reactant: CC1(C)OB(c2ccc3c(c2)OC(F)(F)O3)OC1(C)C
Reactant: FC(F)(F)Sc1ccc(Br)cc1
Product: CC1(C)OB(c2ccc(SC(F)(F)F)cc2)OC1(C)C

Procedure:
The title compound was prepared using methods analogous to those described for Intermediate 2 substituting 1-bromo-4-trifluoromethylsulfanyl-benzene as a starting material.