Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[F:23])([C:14]#[N:15])[CH:12]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:11][NH:10]1.[C:29](Cl)(Cl)=[O:30].C(N(CC)CC)C.[CH3:40][O:41][C:42](=[O:51])[C:43]1[CH:48]=[CH:47][C:46]([CH2:49][NH2:50])=[CH:45][CH:44]=1>C(Cl)Cl>[CH3:40][O:41][C:42](=[O:51])[C:43]1[CH:48]=[CH:47][C:46]([CH2:49][NH:50][C:29]([N:10]2[CH2:11][C@@H:12]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C@@:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[F:23])([C:14]#[N:15])[C@H:9]2[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[O:30])=[CH:45][CH:44]=1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2Cl)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CNC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2Cl)cc1
Yield: 99.8 %

Procedure:
In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2-(2,3-dichloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (88.0 mg, 0.20 mmol) was reacted with phosgene solution (Aldrich, 20% in toluene, 0.23 mL, 0.23 mmol), in the presence of triethylamine (TEA, 272.7 mg, 2.7 mmol) in CH2Cl2 (3 mL) followed by reacting with 4-aminomethyl-benzoic acid methyl ester (AK-Scientific, 60.5 mg, 0.30 mmol) at rt for 2 hrs to give rac-4-({[(2S,3S,4S)-2-(2,3-dichloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-benzoic acid methyl ester (126.0 mg, 43.8%) as a white amorphous solid which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[Br:26]Br>C(Cl)(Cl)Cl>[Br:26][CH:10]([C:11](=[O:16])[C:12]([CH3:14])([CH3:15])[CH3:13])[CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[S:17]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:18]
Reactant: BrBr
Reactant: CC(C)(C)C(=O)CC(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)C(Br)C(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccccc1
Reaction time: 4 h
Yield: 93.1 %

Procedure:
To a solution of 39.9 g of 1-(2,4-dichlorophenyl)-4,4-dimethyl-1-phenylsulfonylpentan-3-one in 500 ml of chloroform, 16.8 g of bromine was added dropwise at 60° C. and the mixture was then kept at 60° C. for 4 hours. The reaction mixture was treated in the same way as that of Example 3 to give 44.5 g of crystals of the captioned compound. m.p. 135°-136° C.
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Si:39]([O:38][C@@H:25]1[C@@H:24]([CH2:23][OH:22])[O:28][C@@H:27]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:26]1)([C:42]([CH3:45])([CH3:43])[CH3:44])([CH3:40])[CH3:41]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 92.3 %

Procedure:
A solution of 5 g (7.6 mmol) 5′-O-(4,4′-dimethoxytrityl)-3′-O-(tert-butyldimethylsilyl)thymidine 17 in 100 ml 80% aq. acetic acid was stirred until the removal of dimethoxytrityl group was completed. Saturated Na2CO3 was then added to adjust the pH of the solution to 6-7. The solution was then extracted with ethyl acetate. The extract was dried and the mixture was chromatographed on a silica gel column (CH2Cl2:MeOH=20:1) to give 2.5 g of 3′-O-(tert-butyldimethylsilyl)thymidine 18 (92.6%).: m.p. 93-95° C. (lit. 83-84° C.); H NMR (200 MHz, CDCl3) δ 9.18 (s, 1H, NH), 7.36 (b, 1H, H-6), 6.12 (t, J=6.8 Hz, 1H, H-1′), 4.44-4.48 (m, 1H, H-3′), 3.69-3.91 (m, 3H, H-4′, H-5′), 2.87 (m, 1H, OH), 2.15-2.35 (m, 2H, H-2′), 1.87 (s, 3H, C═CMe), 0.86 (s, 9H, CMe3), 0.05 (s, 6H, SiMe2); 13C NMR (125 MHz, CDCl3) δ 163.9 (C-4), 150.4 (C-2), 137.1 (C-6), 110.9 (C-5), 87.6 (C-4′), 86.8 (C-1′), 71.5 (C-3′), 61.9 (C-5′), 40.4 (C-2′), 25.7 (SiCMe3), 17.9 (SiCMe), 12.5 (C═CMe), −4.7 (SiMe2), −4.9 (SiMe2).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:14]2[C@H:21]([CH3:22])[CH2:20][CH2:19][C:15]=2[N:16]=[CH:17][N:18]=1.C([O-])(O)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.O>[Cl:12][C:13]1[N:18]=[CH:17][N+:16]([O-:9])=[C:15]2[CH2:19][CH2:20][C@@H:21]([CH3:22])[C:14]=12
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[C@@H]1CCc2c1c(Cl)nc[n+]2[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
Solid 77% maximum m-CPBA (12 g, 53 mmol) was added portionwise to a 0° C. solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (5 g, 30 mmol) in CHCl3 (80 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0° C., and then treated by the addition of NaHCO3 (25 g, 196 mmol) slurry in water (100 mL). This was followed by the dropwise addition of Na2CO3 (14 g, 128 mmol) in water (100 mL). The reaction mixture was stirred for 30 minutes. The aqueous phase was extracted with CHCl3. The organic phase was dried with MgSO4 and concentrated under reduced pressure at low temperature (<25° C.) to afford the crude (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine 1-oxide (5.5 g, 100%), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([NH2:22])=[S:21])[CH2:15][CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:23]=1.Br[CH:25]1[CH2:30][CH2:29][CH2:28][C:27](=[O:31])[C:26]1=O.C1(C)C=CC=CC=1.C([OH:44])(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]4[S:21][C:25]5[CH2:30][CH2:29][CH2:28][C:27](=[O:31])[C:26]=5[N:22]=4)[C:15](=[O:44])[CH2:14]3)(=[O:11])=[O:12])[S:7][C:6]=2[CH:23]=1
Reactant: NC(=S)CN1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1
Reactant: O=C1CCCC(Br)C1=O
Reactant: CC(C)(C)O
Solvent: Cc1ccccc1
Product: O=C1CCCc2sc(CN3CCN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3=O)nc21
Temperature: 90 °C

Procedure:
To a solution of toluene/t-butanol (1:1) is added 2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-piperazin-1-yl]-thioacetamide (180 mg, 0.45 mmol) and 3-bromo-cyclohexane-1,2-dione (135 mg, 0.80 mmol). The reaction is heated at 90° C. for 4 h and is then concentrated and crude product is dissolved in CH2Cl2 and washed with NaHCO3. The solution is concentrated and purified using 1% MeOH/EtOAc to provide 2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-6,7-dihydro-5H-benzothiazol-4-one. 1H NMR (300 MHz, CDCl3) δ7.87-7.82 (m, 3H), 7.47 (dd, 1H), 4.80 (s, 2H), 3.91 (s, 2H), 3.61 (t, 2H), 3.43 (t, 2H), 3.05 (t, 2H), 2.65 (t, 2H), 2.24 (dt, 2H); MS (Ion Spray) 496 (M+H)+.
Reaction SMILES: OC([C:4]([F:7])([F:6])[F:5])=O.[CH3:8][O:9][C:10]([NH:12][C@@H:13]([CH:47]([CH3:49])[CH3:48])[C:14]([N:16]1[CH2:20][C@@H:19]([CH3:21])[CH2:18][C@H:17]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][C:34]=3[O:42]C(F)(F)F)=[CH:29][CH:28]=2)[N:26]=1)=[O:15])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:74][C:75]1[CH:76]=[CH:77][C:78]([N:81]2[CH2:86][CH2:85][N:84]([C:87]([C@H:89]3[CH2:91][C:90]3([CH3:93])[CH3:92])=[O:88])[CH2:83][C@H:82]2[CH3:94])=[N:79][CH:80]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:8][O:9][C:10](=[O:11])[NH:12][C@H:13]([C:14]([N:16]1[CH2:20][C@@H:19]([CH3:21])[CH2:18][C@H:17]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][C:36]([C:39](=[O:40])[NH:74][C:75]4[CH:80]=[N:79][C:78]([N:81]5[CH2:86][CH2:85][N:84]([C:87]([C@H:89]6[CH2:91][C:90]6([CH3:93])[CH3:92])=[O:88])[CH2:83][C@H:82]5[CH3:94])=[CH:77][CH:76]=4)=[CH:35][C:34]=3[O:42][C:4]([F:5])([F:6])[F:7])=[CH:31][CH:32]=2)[N:26]=1)=[O:15])[CH:47]([CH3:48])[CH3:49]
Reactant: C[C@@H]1CN(C(=O)[C@H]2CC2(C)C)CCN1c1ccc(N)cn1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)O)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)Nc4ccc(N5CCN(C(=O)[C@H]6CC6(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
To a mixture of 4′-{2-[(2S,4S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-4-methyl-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-carboxylic acid TFA (11.4 mg, 0.016 mmol) and HATU (6.8 mg, 0.018 mmol) in DMF (0.5 mL) at RT was added [(R)-4-(5-amino-pyridin-2-yl)-3-methyl-piperazin-1-yl]-((S)-2,2-dimethyl-cyclopropyl)-methanone (5.1 mg, 0.018 mmol, Preparation 17) followed by N,N-diisopropylethylamine (14.07 μL, 0.081 mmol). The reaction mixture was stirred at RT overnight, concentrated, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC to provide the di-TFA salt of the title compound (9 mg). (m/z): [M+H]+ calcd for C45H53F3N8O6 859.40. found 859.4.
Reaction SMILES: O.NN.[CH3:4][CH:5]1[N:10]([CH2:11][C:12]2[C:20]3[O:19][CH:18]=[CH:17][C:16]=3[CH:15]=[C:14]([N+:21]([O-])=O)[CH:13]=2)[CH2:9][CH2:8][N:7]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:6]1>[Ni].C(O)C.C1COCC1>[NH2:21][C:14]1[CH:13]=[C:12]([CH2:11][N:10]2[CH2:9][CH2:8][N:7]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:6][CH:5]2[CH3:4])[C:20]2[O:19][CH:18]=[CH:17][C:16]=2[CH:15]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1Cc1cc([N+](=O)[O-])cc2ccoc12
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC1CN(C(=O)OC(C)(C)C)CCN1Cc1cc(N)cc2ccoc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 127 %

Procedure:
Raney nickel (slurry in ethanol) and hydrazine hydrate (97 μL, 2.0 mmol) were added to tert-butyl 3-methyl-4-[(5-nitro-1-benzofuran-7-yl)methyl]piperazine-1-carboxylate (115 mg, 0.31 mmol; obtained in Step 1) in ethanol:THF (4:1; 5 mL). The resulting mixture was stirred at room temperature for 1.5 h, followed by filtration through Celite. The Celite pad was rinsed several times with ethanol. The solvent was evaporated to give the crude product (136 mg) as a light green solid. This material was used in the next step without further purification. HPLC 98%, RT=1.77 min (System A; 5-60% MeCN over 3 min), 100%, RT=1.50 min (System B; 5-60% MeCN over 3 min). MS (ESI+) for C19H27N3O3 m/z 346 (M+H)+.
Reaction SMILES: [ClH:1].N[N:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>>[ClH:1].[CH3:13][C:11]1[CH:10]=[C:9]2[C:8]3[N:3]([C:18]4[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][C:17]=42)[CH2:4][CH2:5][O:6][C:7]=3[CH:12]=1
Reactant: Cc1ccc2c(c1)OCCN2N
Reactant: CN1CCC(=O)CC1
Agent: Cl
Product: Cc1cc2c3c(c1)c1c(n3CCO2)CCN(C)C1

Procedure:
4-Amino-3,4-dihydro-7-methyl-2H-1,4-benzoxazine hydrochloride is reacted with 1-methyl-4-piperidone according to the procedure of Example 110 to yield the title compound, m.p. 248°-249°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][O:6][C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][NH2:30].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][O:6][C:7]1[C:12]([C:13]([NH:30][CH2:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[O:15])=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1
Reactant: NCc1ccccn1
Reactant: COc1ccc(COc2nc(SC)ncc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COc2nc(SC)ncc2C(=O)NCc2ccccn2)cc1Cl
Yield: 47.5 %

Procedure:
4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)pyrimidine-5-carboxylic acid (300 mg, 0.88 mmol) and pyridin-2-ylmethylamine (115 mg, 1.06 mmol) were dissolved in 10 mL of THF, triethylamine (141 mg, 1.4 mmol) was added dropwise, added HATU (405 mg, 1.06 mmol) under ice-water-bath, reacted at room temperature for 4 h, to the reaction solution was added 100 mL of water, then extracted with dichloromethane, dried with anhydrous sodium sulfate, dried by rotation, then the solid was separated with silica gel column (dichloromethane:methanol=20:1) to obtain a white solid 4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)-N-(pyridin-2-ylmethyl)pyrimidine-5-carboxamide 180 mg, yield 48%.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]OS(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C-:35]#[N:36].[Na+].CS(C)=O>O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:35]#[N:36])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [C-]#N
Reactant: CCCCc1ccc(CN(CCCCCCOS(C)(=O)=O)C(=O)Nc2ccc(Cl)cc2C)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1ccc(CN(CCCCCCC#N)C(=O)Nc2ccc(Cl)cc2C)cc1
Yield: 86.8 %

Procedure:
A mixture of 2.0 g of 1-[(4-butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-1-[6-[(methylsulfonyl)oxy]-hexyl]urea, 0.5 g of sodium cyanide, and 3.0 ml of dimethyl sulfoxide was heated at an oil bath temperature of 60°-70° C. for 16 hours. The mixture was poured into water and extracted with dicholormethane. The procedure of Example 518 was continued and gave 1.5 g (88% yield) of the desired product as a brown oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:29][O:30][CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:20]=[N:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([NH2:17])=O)=[CH:11]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>O1CCCC1>[CH3:31][O:30][CH2:29][CH:4]([CH2:3][O:2][CH3:1])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:20]=[N:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15](=[S:41])[NH2:17])=[CH:11]2
Reactant: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=O)[nH]c12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 90.8 %

Procedure:
To a solution of 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide (1.0 g) in tetrahydrofuran (15 mL) was added Lawesson's reagent (1.0 g) and the mixture was stirred at 50° C. for 45 min. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90 to 70/30, volume ratio) to give the title compound (0.94 g, 90%) as a yellow amorphous solid. MS 466 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N+:3]([O-])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.P(Cl)(Cl)([Cl:23])=O.N>C(Cl)(Cl)Cl>[Cl:23][CH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ccc(-c2oc(-c3ccccc3)c(C)[n+]2[O-])cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2nc(CCl)c(-c3ccccc3)o2)cc1
Temperature: 0 °C

Procedure:
6.4 g of 4-methyl-5-phenyl-2-p-tolyloxazole 3-oxide are dissolved in 50 ml of chloroform, 2.4 ml of phosphorus oxychloride are added and the mixture is, under reflux, heated at the boil for 30 minutes. The reaction mixture is cooled to 0° C., the pH is made slightly alkaline using ammonia and the mixture is extracted three times with in each case 100 ml of ethyl acetate. The combined organic phases are washed with water and dried over MgSO4, and the solvent then removed under reduced pressure. This gives 5.4 g of 4-chloromethyl-5-phenyl-2-p-tolyloxazole as a yellow solid. C17H14CINO (283.76), MS (ESI)=284 (M+H+), Rf(n-heptane:ethyl acetate)=7:1)=0.41
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[N:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CN1C(=O)CCC1.C(Cl)Cl>[N:20]1([C:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:4]3[N:3]=[C:2]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:10]=[CH:9][C:5]=3[C:6]([NH2:8])=[O:7])=[CH:13][CH:14]=2)=[O:19])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: C1CNCCN1
Reactant: NC(=O)c1ccc(Cl)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: NC(=O)c1ccc(N2CCNCC2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Yield: 63.3 %

Procedure:
A solution of 6-chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (100 mg, 0.277 mmol) and piperazine (477 mg, 5.54 mmol) in NMP (2 mL) was heated to 120° C. overnight. The reaction mixture was diluted with CH2Cl2, washed with satd NaHCO3, separated, and concentrated. The residue was purified by MPLC chromatography (ISCO, 8% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) to give 72 mg of 2-(4-(morpholine-4-carbonyl)phenylamino)-6-(piperazin-1-yl)nicotinamide as a white solid. LCMS: (M+H)+=411.35. 1H NMR (400 MHz, CDCl3) δ ppm 11.20 (1H, s), 7.70 (2H, d, J=8.56 Hz), 7.54 (1H, d, J=9.06 Hz), 7.38 (2H, d, J=8.56 Hz), 6.04 (1H, d, J=8.81 Hz), 5.58 (2H, s), 3.58-3.78 (12H, m), 2.92-3.01 (4H, m).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13][CH:12]=1.[Cl-].[NH4+]>C(OCC)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Br:1])[OH:5])=[CH:13][CH:12]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=Cc1ccccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC(c1ccc(Cl)cc1)c1ccccc1Br
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2-bromobenzaldehyde (1 ml) was dissolved in diethyl ether (20 ml) and cooled to −78° C. 4-chlorophenylmagnesium bromide (1M diethyl ether solution, 9 ml) was added thereto and the reaction mixture was stirred for one hour at the same temperature. Saturated ammonium chloride aqueous solution was added thereto and the water layer was extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by column chromatography to obtain the title compound (2.50 mg) having the following physical data.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][CH2:9][CH:10]1[CH2:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]=2[NH:11]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH:8]([CH2:9][CH:10]1[CH2:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]=2[NH:11]1)[C:5]([CH3:6])=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: NCC1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCC1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reaction time: 0.33 h

Procedure:
(iv) 7 ml of acetic anhydride were added to a solution of 6.16 g of crude 2-aminomethyl-7 -chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine in 200 ml of methylene chloride. The solution was layered with 200 ml of saturated aqueous sodium bicarbonate and the mixture was stirred for 20 minutes. The organic layer was separated, washed with sodium bicarbonate solution, dried over sodium sulphate and evaporated to leave 6.2 g of resinous 2-acetaminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine. This material was heated with 40 g of polyphosphoric acid at 150° C for 10 minutes. The cooled mixture was dissolved in water, made alkaline with ammonia and ice and extracted with methylene chloride. The extracts were dried and evaporated and the residue (5.7 g) was chromatographed over 120 g of silica gel using 20% methanol in methylene chloride. The clear fractions were combined and evaporated to yield resinous 8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-1-methyl-4H-imidazo-[1,5-a] [1,4]benzodiazepine. A mixture of this material with 500 m1 of toluene and 30 g of manganese dioxide was heated to reflux of 1.5 hours. The manganese dioxide was separated by filtration over Celite. The filtrate was evaporated and the residue crystallised from diethyl ether to yield 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo [1,5-a] [1,4]benzodiazepine of melting point 152°-154° C. An analytical sample was recyrstallised from methylene chloride/hexane.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[N:9]=[C:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[CH3:24])(=[O:16])=[O:15])[S:11][CH:12]=1)(=O)=O.[C:25]([NH:32][CH2:33][CH2:34][NH2:35])(OC(C)(C)C)=[O:26].CCN(C(C)C)C(C)C.[Cl:45][CH2:46]C(Cl)=O>C(O)C.C(Cl)Cl.CN(C1C=CN=CC=1)C>[ClH:23].[NH2:35][CH2:34][CH2:33][N:32]([CH2:6][CH2:7][C:8]1[N:9]=[C:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[CH3:24])(=[O:15])=[O:16])[S:11][CH:12]=1)[C:25](=[O:26])[CH2:46][Cl:45]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(Cl)CCl
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCOS(C)(=O)=O)cs1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCN(CCN)C(=O)CCl)cs1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
A mixture of EXAMPLE 191A (600 mg, 1.46 mmol), N-BOC-ethylenediamine (469 mg, 2.93 mmol) and DIEA (189 mg, 1.46 mmol) was refluxed in ethanol (10 mL) for 3 h. The solvent was evaporated and the residue was flash chromatographed on SiO2 eluting with 10% methanol in DCM affording 265 mg (38%) intermediate tert-butyl 2-{[2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-4-yl)ethyl]amino}ethylcarbamate. This material (255 mg, 0.54 mmol) was dissolved in DCM (4 mL), followed by the addition of DMAP (163 mg, 1.21 mmol). Chloroacetyl chloride (134 mg, 1.18 mmol) dissolved in DCM (2 mL) was added, and the mixture was stirred for 1 h at room temperature followed by a wash with aqueous HCl (2 M). The remaining organic phase was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was taken up in ethyl acetate (25 mL), and at 0° C. HCl gas was bubbled trough under a period of 3 minutes. The mixture was stirred for 10 minutes and the solvent was evaporated giving 284 mg of N-(2-aminoethyl)-2-chloro-N-[2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-4-yl)ethyl]acetamide hydrochloride. This material (280 mg, 0.57 mmol) and sodium bicarbonate (169 mg, 2.01 mmol) were refluxed in ethanol (30 mL) for 2 h. The solvent was evaporated and the residue was flash chromatographed on RP silica gel gradient eluting with (acetonitrile in H2O/1% conc. HCl) giving 113 mg (47%) of 3-chloro-2-methyl-N-{4-[2-(2-oxo-1-piperazinyl)ethyl]-1,3-thiazol-2-yl}benzenesulfonamide hydrochloride.
Reaction SMILES: Br[C:2]1[C:3]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[BH:24]([OH:26])[OH:25]>>[CH2:17]([O:16][C:3]1[CH:2]=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[C:4]=1[B:24]([OH:26])[OH:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: OBO
Reactant: CCCCCCCOc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Product: CCCCCCCOc1ccc2c(c1B(O)O)C(C)(C)CCC2(C)C

Procedure:
In a similar manner to Example 3(a), starting with 10 g (26.2 mmol) of 3-bromo-2-heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene, 6.1 g (67%) of the expected boronic acid are obtained, with a melting point of 102-3° C.