Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC([C@H]2CC[C@H](C3C=CC(Cl)=C([N+]([O-])=O)C=3)N2C2C=CC(NC(C)(C)C)=C(F)C=2)=CC=1[N+]([O-])=O.[CH3:38][O:39][C:40](=[O:104])[NH:41][C@@H:42]([CH:101]([CH3:103])[CH3:102])[C:43]([N:45]1[CH2:49][CH2:48][CH2:47][C@H:46]1[C:50]1[NH:54][C:53]2[CH:55]=[C:56]([C@H:59]3[CH2:63][CH2:62][C@H:61]([C:64]4[CH:65]=[CH:66][C:67]5[N:71]=[C:70]([C@@H:72]6[CH2:76][CH2:75][CH2:74][N:73]6[C:77](=[O:87])[C@@H:78]([NH:82][C:83]([O:85][CH3:86])=[O:84])[CH:79]([CH3:81])[CH3:80])[NH:69][C:68]=5[CH:88]=4)[N:60]3[C:89]3[CH:94]=[CH:93][C:92]([NH:95][C:96]([CH3:99])([CH3:98])[CH3:97])=[C:91]([F:100])[CH:90]=3)[CH:57]=[CH:58][C:52]=2[N:51]=1)=[O:44].[C:105](OC(=O)C)(=[O:107])[CH3:106].N1C=CC=CC=1>>[CH3:38][O:39][C:40](=[O:104])[NH:41][C@@H:42]([CH:101]([CH3:103])[CH3:102])[C:43]([N:45]1[CH2:49][CH2:48][CH2:47][C@H:46]1[C:50]1[NH:54][C:53]2[CH:55]=[C:56]([C@H:59]3[CH2:63][CH2:62][C@H:61]([C:64]4[CH:65]=[CH:66][C:67]5[N:71]=[C:70]([C@@H:72]6[CH2:76][CH2:75][CH2:74][N:73]6[C:77](=[O:87])[C@@H:78]([NH:82][C:83]([O:85][CH3:86])=[O:84])[CH:79]([CH3:81])[CH3:80])[NH:69][C:68]=5[CH:88]=4)[N:60]3[C:89]3[CH:94]=[CH:93][C:92]([N:95]([C:105](=[O:107])[CH3:106])[C:96]([CH3:97])([CH3:99])[CH3:98])=[C:91]([F:100])[CH:90]=3)[CH:57]=[CH:58][C:52]=2[N:51]=1)=[O:44]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc([C@H]3CC[C@H](c4ccc5nc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c5c4)N3c3ccc(NC(C)(C)C)c(F)c3)cc2[nH]1)C(C)C
Reactant: CC(=O)OC(C)=O
Agent: CC(C)(C)Nc1ccc(N2[C@@H](c3ccc(Cl)c([N+](=O)[O-])c3)CC[C@@H]2c2ccc(Cl)c([N+](=O)[O-])c2)cc1F
Solvent: c1ccncc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc([C@H]3CC[C@H](c4ccc5nc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c5c4)N3c3ccc(N(C(C)=O)C(C)(C)C)c(F)c3)cc2[nH]1)C(C)C

Procedure:
Starting from 4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-N-tert-butyl-2-fluoroaniline, the initial product of the sequence outlined above was methyl{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[4-(tert-butylamino)-3-fluorophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (ACD Name v12). The N-acetyl group was added by reaction with acetic anhydride/pyridine to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.73-0.90 (m, 12 H), 1.13 (d, J=5.20 Hz, 9 H), 1.37-1.44 (m, 4 H), 1.62-1.72 (m, 2 H), 1.92-2.02 (m, 9 H), 2.10-2.26 (m, 5 H), 2.51-2.58 (m, 2 H), 3.52 (s, 6 H), 3.73-3.85 (m, 4 H), 3.98-4.12 (m, 2 H), 5.09-5.17 (m, 2 H), 5.36-5.48 (m, 3 H), 6.08-6.18 (m, 3 H), 6.74-6.87 (m, 1 H), 7.08 (dd, J=13.72, 8.29 Hz, 3 H), 7.20 (s, 1 H), 7.24-7.31 (m, 4 H), 7.40 (d, J=8.24 Hz, 1 H), 7.48 (d, J=8.13 Hz, 1 H), 12.01 (s, 1 H), 12.17 (s, 1 H); MS (ESI+) m/z 964 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:18])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:6]=2.O[C:20]1[CH:52]=[CH:51][C:23]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]2=[O:50])=[CH:22][CH:21]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH3:18][N:4]1[C:5]2=[N:6][C:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][CH:9]=[C:10]2[N:11]=[C:3]1[CH2:2][O:1][C:20]1[CH:52]=[CH:51][C:23]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]2=[O:50])=[CH:22][CH:21]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CO)nc2ccc(-c3ccccc3)nc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(-c3ccccc3)nc21
Yield: 62.9 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.5 g of 2-hydroxymethyl-3-methyl-5-phenylimidazo[5,4-b]pyridine (prepared as described in Preparation 110), 0.97 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.57 ml of tributylphosphine, 0.53 g of 1,1'-(azodicarbonyl)dipiperidine and 50 ml of benzene were used. After working up the product as described in Preparation 4, the resulting crude product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.9 g of the title compound having Rf=0.26 (on silica gel thin layer chromatography using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5].CS([C:20]1[N:21]=[CH:22][C:23]2[CH:29]=[CH:28][C:27](=[O:30])[N:26]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:34]=[CH:35][CH:36]=3)[C:24]=2[N:25]=1)=O.C(O)(C)(C)C.CCN(C(C)C)C(C)C>>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]2)[CH:7]=[CH:6][C:4]=1[NH:5][C:20]1[N:21]=[CH:22][C:23]2[CH:29]=[CH:28][C:27](=[O:30])[N:26]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])[CH:34]=[CH:35][CH:36]=3)[C:24]=2[N:25]=1
Reactant: CS(=O)c1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Reactant: COc1cc(N2CCN(C)CC2)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Temperature: 80 °C

Procedure:
To a mixture of 2-methoxy-4-(4-methylpiperazin-1-yl)aniline (Combi-Blocks Inc, Cat#: SS-3744; 342 mg, 1.55 mmol) and tert-butyl (3-(2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (52) (521 mg, 1.30 mmol) in tert-butanol (10 mL, 105 mmol) was added DIEA (0.57 mL, 3.25 mmol). The reaction mixture was heated at 80° C. in an oil bath for 21 h. The resulting brown suspension was concentrated under reduced pressure and the crude solid was suspended in Et2O (ca. 20 mL) and filtered affording the crude material of tert-butyl (3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (1a) as a green solid. m/z (ESI, +ve ion) 558.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.57 (1H, s), 8.73 (1H, s), 8.14 (1H, s), 7.89 (1H, d, J=9.4 Hz), 7.57 (1H, d, J=8.4 Hz), 7.42 (3H, t, J=8.0 Hz), 7.28 (1H, d, J=8.8 Hz), 6.87 (1H, d, J=8.6 Hz), 6.53 (1H, d, J=2.3 Hz), 6.43 (1H, d, J=9.4 Hz), 6.05 (1H, br. s.), 3.73-3.82 (3H, m), 3.06 (4H, br. s.), 2.36-2.47 (4H, 2.15-2.26 (3H, s), 1.45 (9H, s).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:11]1([C:14]2[C:19]([C:20]3[CH:21]=[CH:22][C:23]([CH2:26][OH:27])=[CH:24][CH:25]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccc(CO)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OCc1ccc(-c2nccnc2N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.3 %

Procedure:
Dissolve 3′-(4-hydroxymethyl-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (0.560 g, 1.51 mmol) in DCM (10 mL) and add trifluoroacetic acid (2 mL) and allow the mixture to stir at room temperature for six hr. Evaporate the solution then dilute with DCM and wash with saturated sodium bicarbonate. Dry the organics over sodium sulfate then filter and evaporate. Chromatograph the residue over silica gel (eluting with 8:92 methanol (with 2 M ammonia):DCM), to give [4-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl)-phenyl]-methanol as a yellow solid (340 mg, 83%). MS (ES): m/z=271 [M+H]+.
Reaction SMILES: BrC1C([C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)CC2C=C(F)C=C(F)C=2)=NC(SC)=NC=1.[F:37][CH:38]([F:56])[C:39]1[C:47]2[C:46]([F:49])([F:48])[CH2:45][CH2:44][C:43]([F:51])([F:50])[C:42]=2[N:41]([CH2:52][C:53]([OH:55])=O)[N:40]=1.Cl.[N:58]1([CH2:63][CH2:64][NH:65][C:66]2[N:71]=[C:70]([C@@H:72]([NH2:82])[CH2:73][C:74]3[CH:79]=[C:78]([F:80])[CH:77]=[C:76]([F:81])[CH:75]=3)[C:69]([C:83]3[CH:84]=[CH:85][C:86]([F:92])=[C:87]([CH:91]=3)[C:88]([NH2:90])=[O:89])=[CH:68][N:67]=2)[CH:62]=[CH:61][N:60]=[N:59]1>>[N:58]1([CH2:63][CH2:64][NH:65][C:66]2[N:71]=[C:70]([C@@H:72]([NH:82][C:53](=[O:55])[CH2:52][N:41]3[C:42]4[C:43]([F:50])([F:51])[CH2:44][CH2:45][C:46]([F:49])([F:48])[C:47]=4[C:39]([CH:38]([F:37])[F:56])=[N:40]3)[CH2:73][C:74]3[CH:79]=[C:78]([F:80])[CH:77]=[C:76]([F:81])[CH:75]=3)[C:69]([C:83]3[CH:84]=[CH:85][C:86]([F:92])=[C:87]([CH:91]=3)[C:88]([NH2:90])=[O:89])=[CH:68][N:67]=2)[CH:62]=[CH:61][N:60]=[N:59]1
Reactant: NC(=O)c1cc(-c2cnc(NCCn3ccnn3)nc2[C@@H](N)Cc2cc(F)cc(F)c2)ccc1F
Reactant: O=C(O)Cn1nc(C(F)F)c2c1C(F)(F)CCC2(F)F
Agent: CSc1ncc(Br)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Agent: Cl
Product: NC(=O)c1cc(-c2cnc(NCCn3ccnn3)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F

Procedure:
The title compound (23F) was prepared according to the method presented for the synthesis of compound 11G of Example 11 utilizing 2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid and 23E. 1H NMR (400 MHz, CD3OD) δ 8.71 (d, J=7.6 Hz, 1H), 8.06 (s, 1H), 7.99 (s, 1H), 7.74 (s, 1H), 7.43-7.25 (m, 2H), 7.20 (dd, J=10.8, 8.5 Hz, 1H), 6.97-6.58 (m, 2H), 6.42 (d, J=6.2 Hz, 2H), 5.32-5.18 (m, 2H), 5.09 (s, 2H), 4.73 (m, 2H), 4.01 (m, 2H), 3.01 (m, 2H), 2.66-2.34 (m, 4H). MS (m/z) 767.06 [M+H]+.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9](O)=[O:10])[CH2:2][CH2:3][CH3:4].C([N:28](CC)CC)C.CS(Cl)(=O)=O.N>CC(C)=O>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([NH2:28])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCN(CC)CC
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: CC(C)=O
Product: CCCCNc1cc(C(N)=O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 1.5 h

Procedure:
To a solution of 3-butylamino-4-phenoxy-5-sulphamyl-benzoic acid (1 g) in dry acetone (10 ml), triethylamine (0.278 g) was added. Methanesulphonyl chloride (0.315 g) in dry acetone (5 ml) was added to the reaction mixture, while stirring. The agitation was continued for 1.5 hours at 20° C. The resulting solution of the mixed anhydride was added dropwise to aqueous ammonia (30 ml containing 7 g of ammonia), while stirring. Then excess of ammonia and acetone were removed by evaporation under reduced pressure. The pH of the reaction mixture was adjusted to 7.5 by means of 4N hydrochloric acid, and the precipitated 3-butylamino-4-phenoxy-5-sulphamyl-benzamide was isolated by filtration and recrystallized several times from aqueous ethanol. After drying in vacuo at 115° C, the compound was obtained with a melting point of 223°-224° C.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:11][CH2:12][C:13](Cl)=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C.C1COCC1>[CH2:4]([O:11][CH2:12][C:13]([NH:2][NH2:3])=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: NNC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of hydrazine hydrate (10 ml) in ethanol (100 ml) at 0° C. was added a solution of (benzyloxy)acetyl chloride (6.4 ml) in THF (40 ml) by syringe pump over 30 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The ethanol was removed under reduced pressure and the remaining aqueous mixture extracted with dichloromethane (3×100 ml). The combined organic extracts were washed with aqueous K2CO3 (100 ml) then brine (100 ml) and dried (MgSO4). Concentration under reduced pressure gave 2-(benzyloxy)acetohydrazide as a colourless oil that crystallized on standing (5.5 g).
Reaction SMILES: [CH2:1]=O.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[O:13])=[C:6]([F:22])[CH:5]=1.[NH:23]([CH2:25]C(O)=O)[CH3:24].O>C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:12]([CH:11]2[CH:10]([C:7]3[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][C:6]=3[F:22])[CH2:1][N:23]([CH3:25])[CH2:24]2)=[O:13])=[CH:20][CH:19]=1
Reactant: O=C(C=Cc1ccc(Br)cc1F)Nc1ccc(Cl)cc1
Reactant: C=O
Reactant: CNCC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CC(C(=O)Nc2ccc(Cl)cc2)C(c2ccc(Br)cc2F)C1
Reaction time: 4 h
Yield: 40 %

Procedure:
A mixture of paraformaldehyde (15.3 g, 0.51 mol) and 3-(4-bromo-2-fluoro-phenyl)-N-(4-chloro-phenyl)-acrylamide (15 g, 42.5 mmol) was heated under reflux in toluene (150 mL), and sarcosine (15.2 g, 170 mmol, 4.0 equiv) was added in 4 portions over 4 hrs, the H2O formed was removed with the aid of a Dean-Stark trap. After 4 hours, the cooled mixture was filtered. The filtrate was concentrated, and the residue was purified by chromatography on silica gel eluted with dichloromethane-methanol to give 7.0 g of 4-(4-bromo-2-fluoro-phenyl)-1-methyl-pyrrolidine-3-carboxylic acid (4-chloro-phenyl)-amide. Yield was 40%. MS: calc'd 411 (MH+), exp 411 (MH+). 1H NMR (CDCl3, 400 MHz), 9.71 (s, 1H), 7.57 (d, 2H, J=8.8 Hz), 7.51 (t, 1H, J=7.6 Hz), 7.24 (t, 4H, J=8.8 Hz), 4.30 (q, 1H, J=8.8 Hz), 3.76-3.94 (m, 2H), 3.40-3.62 (m, 3H), 2.92 (s, 3H).
Reaction SMILES: [BH4-].[Na+].[CH:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(O)(=O)C.O>C(O)C>[OH:19][CH:13]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:3]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)CCCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(O)c1ccc2c(c1)CCCC2
Temperature: 0 °C
Yield: 99.1 %

Procedure:
A solution of sodium borohydride (2.0 g) in ethanol (100 ml) was added dropwise to an ice-cooled solution of ethyl 5,6,7,8-tetrahydro-2-naphthylglyoxylate (34.5 g) in ethanol (200 ml). After completion of dropwise addition, acetic acid (6 ml) was added and the reaction mixture was poured into water and extracted with chloroform. The chloroform layer was washed with water, dried (MgSO4) and the solvent was distilled off to give ethyl 2-hydroxy-(5,6,7,8-tetrahydro-2-naphthyl)acetate (34.5 g, yield 9%) as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][NH:10][C:9]2=O.O=P(Cl)(Cl)[Cl:24]>C1(C)C=CC=CC=1>[Cl:24][C:9]1[C:8]2[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: COCCOc1cc2nc[nH]c(=O)c2cc1OCCOC
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Temperature: 125 °C
Yield: 91 %

Procedure:
According to the procedure described in Example 6A Step 5, a mixture of 6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one (2.28 g, 7.7 mmol) and POCl3 (10 mL) in toluene (30 mL) was heated at 125° C. for 5 hours, to afford 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline as a solid (2.212 g, 91%). 1H NMR (300 MHz, CDCl3) δ 8.86 (s, 1H), 7.44 (s, 1H), 7.34 (s, 1H), 4.34 (t, 4H), 3.89 (t, 4H), 3.50 (s, 3H), 3.49 (s, 3H); LC-MS (ESI) m/z 313 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]([NH2:10])=O.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[Br:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]#[N:10]
Reactant: Cc1nc(C(N)=O)c(Br)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1nc(C#N)c(Br)s1

Procedure:
5-Bromo-2-methyl-thiazole-4-carboxylic acid amide (11.3 g, 51.1 mmol) was dissolved in 150 ml dichloromethane and triethylamine (14.2 ml, 102.2 mmol) was added. Trifluoroaceticanhydride (14.3 ml, 102.2 mmol) was added dropwise at 0° C. and the mixture stirred without cooling for 2 hrs. The reaction mixture was quenched with saturated NaHCO3-solution and extracted with ethyl acetate. The organic extract was washed with brine, dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10->20:80 gradient). The desired compound was obtained as a light yellow solid (6.4 g, 62%), MS: m/e=204.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=[O:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:19]([O-])(=O)[CH3:20].[Na+]>C(OC(=O)C)(=O)C>[CH3:9][O:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[O:1][C:19]([CH3:20])=[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:10]2=[O:18]
Reactant: CC(=O)[O-]
Reactant: COc1ccc(O)c(C(=O)Cc2ccccc2)c1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2oc(C)c(-c3ccccc3)c(=O)c2c1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
Intermediate 20 (4 g, 16.51 mmoles) was taken in a RB flask and to this acetic anhydride (40 ml) and sodium acetate (9.48 g, 115.57 mmoles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as yellow solid (3 g, 68% yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 7.60 (d, J=3.0 Hz, 1H), 7.45 (t, J=7.1 Hz, 2H), 7.37 (m, 2H), 7.29 (m, 3H), 3.89 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[C:11]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:6][C:7]=1SC.O[O:25][S:26]([O-:28])=O.[K+].CO.[CH2:32]1COCC1.O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[C:11]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:6][C:7]=1[S:26]([CH3:32])(=[O:28])=[O:25]
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Reactant: CSc1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)cc1Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)c(Cl)c2)=C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.2 g of 5-{3-chloro-4-(methylthio)phenyl}-2,2-dimethyl-4-phenyl-3(2H)-furanone (Example 354) was dissolved in 150 ml of 1:1:1 methanol/THF/water, to which was added 2.8 g of OXONE. The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated in vacuo and the resulting residue was extracted with 50 ml water and ethylacetate (100 ml×3). The organic layer was concentrated in vacuo and was purified by column chromatography hexane/ethylacetate=3:1) to give 1.1 g of 5-{3-chloro-4-(methylsulfonyl)phenyl}-2,2-dimethyl-4-phenyl-3(2H)-furanone as a solid. mp: 174-175° C. NMR: δ1.58 (s, 6H), 3.28 (s, 3H), 7.27 (m, 3H), 7.39 (m, 2H), 7.66 (dd, J=8.4, 1.8 Hz, 1H), 7.86 (d, J=1.8 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H). IR (cm−1): 1700, 1587, 1391, 1321, 1241, 1152.
Reaction SMILES: [CH:1]1([N:4]2[C:11](=[O:12])[CH2:10][CH2:9][NH:8][C:7]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:6]=3[CH2:5]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:26][C:27]1[O:31][N:30]=[C:29]([C:32](Cl)=[O:33])[CH:28]=1>ClC(Cl)C>[CH:1]1([N:4]2[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:32]([C:29]3[CH:28]=[C:27]([CH3:26])[O:31][N:30]=3)=[O:33])[C:7]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:6]=3[CH2:5]2)[CH2:2][CH2:3]1
Reactant: COc1ccc2c(c1)CN(C1CC1)C(=O)CCN2
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COc1ccc2c(c1)CN(C1CC1)C(=O)CCN2C(=O)c1cc(C)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To a solution of 5-cyclopropyl-8-methoxy-2,3,5,6-tetrahydrobenzo[b][1,5]diazocin-4(1H)-one (50.0 mg, 0.203 mmol) from Example 1 in dichloroethane (2.0 ml) was added triethylamine (0.057 ml, 0.406 mmol) and 5-methylisoxazole-3-carbonyl chloride (32.5 mg, 0.223 mmol). The reaction mixture was stirred at room temperature overnight and then quenched with saturated aqueous sodium bicarbonate, followed by extraction with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Preparative thin layer chromatography (ethyl acetate/methanol:98/2) of the crude residue gave the desired compound (53 mg, 74%).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[NH:21]1[CH:25]=[C:24](B(O)O)[CH:23]=[N:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[CH3:16][N:12]([CH:13]([CH3:15])[CH3:14])[C:11]1[C:2]([C:24]2[CH:25]=[N:21][NH:22][CH:23]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2
Reactant: OB(O)c1cn[nH]c1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3cn[nH]c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (170 mg, 0.58 mmol) in 1,4-dioxane (6 ml) was added (1H-pyrazol-4-yl)boronic acid (130 mg, 1.16 mmol), Pd(PPh3)4 (34 mg, 0.029 mmol), K3PO4 (367 mg, 1.74 mmol) and water (5 drops) with stirring for 1 h at 90° C. under an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated under vacuum to give the residue, which was purified via silica gel chromatography (1% to 10% ethyl acetate in petroleum ether) to afford methyl 3-[methyl(propan-2-yl)amino]-2-(1H-pyrazol-4-yl)quinoxaline-6-carboxylate as a yellow solid (150 mg, 79%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([OH:20])=[O:19].N(CC)(CC)CC.FC(C(O)=O)(F)F.C(O)(C(F)(F)F)=O>C(O)(C)C.CCN(CC)CC>[CH3:24][C:23]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[NH:14][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: Clc1ncccc1-c1ccncn1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)O)cc1Nc1ncccc1-c1ccncn1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
4-(2-Chloro-pyridin-3-yl)-pyrimidine (10.4 g, 54 mmol), 3-amino-4-methylbenzoic acid (19.4 g, 128 mmol), 17 g Et3N-TFA salt (The liquid Et3N-TFA reagent was generated by adding 2.5 mL TFA dropwise to a 0° C. solution of 3 mL Et3N in isopropanol, then concentrating by rotary evaporator followed by 30 minutes under high vacuum.), and 15 mL DMSO were mixed together in a sealed tube under argon. The mixture was stirred at 95° C. for 65 h. After cooling to RT, the residue was sonicated in 100 mL methanol to break up the solids, then filtered to obtain product as a yellow solid.