Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[C:16]([S:20]([CH3:28])(=[N:22]C(OCC)=O)=[O:21])[CH:17]=[CH:18][CH:19]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:29][CH2:30][CH2:31][OH:32].[O-]CC.[Na+]>C(O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[C:16]([S:20]([CH3:28])(=[NH:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:29][CH2:30][CH2:31][OH:32]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(NCCO)c3cc2Br)c1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=N)(=O)c1cccc(COc2cc3ncnc(NCCO)c3cc2Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
According to GWP 6, (RS)-S-[3-({[6-bromo-4-(2-hydroxyethylamino)quinazolin-7-yl]oxy}methyl)phenyl]-N-(ethoxycarbonyl)-S-methylsulphoximide (67 mg, 0.13 mmol) is reacted with sodium ethoxide (29 mg, 0.46 mmol) in ethanol (3 mL). After cooling to room temperature, the reaction mixture is admixed with brine and stirred for 30 minutes and the resulting precipitate is filtered off with suction to leave the desired product in 81% yield (47 mg).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[N:9]=[CH:10][N:11]2[C:16]=1[C:15](=[O:17])[N:14]1C=N[CH:20]=[C:13]1[C:12]2=[O:21].N[C@@H]1C[CH2:27][N:26]([CH:29]([CH3:49])[CH2:30][C:31]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:25][C@H]1O>CN(C)C=O>[OH:21][C@H:12]1[C@H:13]([NH:14][C:15]([C:16]2[NH:11][CH:10]=[N:9][CH:8]=2)=[O:17])[CH2:20][CH2:27][N:26]([CH:29]([CH3:49])[CH2:30][C:31]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:32]([N:34]([CH3:35])[CH3:36])=[O:33])[CH2:25]1
Reactant: O=c1c2cncn2c(=O)c2cncn12
Reactant: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](N)[C@H](O)C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](NC(=O)c2cnc[nH]2)[C@H](O)C1
Reaction time: 8 h
Yield: 23 %

Procedure:
2.8 Parts of N,N-diethylethanamine were added to a solution of 1 part of 5H, 10H-diimidazo[1,5-a:1',5'-d]pyrazine-5,10-dione in 36 parts of N,N-dimethylformamide. The thus obtained suspension was added dropwise to a stirred and heated (70° C.) solution of 3.95 parts of trans-4-amino-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide in 18 parts of N,N-dimethylformamide. Upon complete addition, stirring was continued overnight at 70° C. After evaporation, the residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further purified by column chromatography (HPLC) over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (90:9:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was pulverised and evaporated again, yielding 1.13 parts (23%) of trans-3-hydroxy-4-[(1H-imidazol-5-yl)carbonylamino] -N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide; mp. 155.0° C. (compound 43).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]([N:19]2[CH2:23][CH2:22][CH2:21][C@@H:20]2[CH3:24])=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:25]([O:27]C)=[O:26])[CH:15]=2)[N:10]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]([N:19]2[CH2:23][CH2:22][CH2:21][C@@H:20]2[CH3:24])=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:25]([OH:27])=[O:26])[CH:15]=2)[N:10]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3F)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
To a solution of (S)-methyl 2-(2,4-difluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (100 mg, 0.39 mmol) in MeOH (20 mL) was added sodium hydroxide (63 mg, 1.57 mmol) and water (2 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (2 mL) and adjusted to pH 6 with hydrochloric acid (1N). The solids were collected by filtration to afford (S)-2-(2,4-difluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a brown solid (82.4 mg, 86%).
Reaction SMILES: [C:1]([NH:4][C:5]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:10][CH2:9][N:8]([CH:11]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)[CH2:12][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:14][NH2:15])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[C:45](OC(=O)C)(=[O:47])[CH3:46].C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C)C1C=CN=CC=1.Cl.ClCCl.O>[C:1]([NH:4][C:5]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:6][CH2:7][N:8]([CH:11]([CH2:24][C:25]2[CH:26]=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:28]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:30]=2)[CH2:12][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:14][NH:15][C:45](=[O:47])[CH3:46])[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1(c2ccccc2)CCN(C(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC(CN)c2ccc(Cl)c(Cl)c2)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCC(CC(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(NC(C)=O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h

Procedure:
To a stirred solution of 4-(4-acetamido-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-N-[3,5-bis(trifluoromethyl)benzyl]butylamine (0.4 g) in tetrahydrofuran (4 mL) was added acetic anhydride (0.085 mL) and diisopropylethylamine (0.32 mL). After 2 hours at room temperature 4-dimethylaminopyridine (7 mg) was added and the mixture was stirred overnight. Additional acetic anhydride (0.06 mL) was added and the reaction mixture was brought to reflux for 3 hours. The mixture was allowed to cool and diluted with aqueous hydrochloric acid (1N, 3 mL), dichloromethane (5 mL), and water (5 mL). The phases were separated and the aqueous layer was extracted with dichloromethane (2×5 mL). The combined organic phases were washed (brine), dried, and evaporated to afford crude product, which was purified by chromatography with dichloromethane:methanol (15:1) as eluent, to afford the title compound as a white solid; mp 115°-117° C.; NMR (d6 -DMSO-trifluoroacetic acid): 8.0-7.5 (m,5), 7.45-7.2 (m,6), 4.80-4.45 (m,2), 3.45 (m,2), 3.1 (m,4), 2.67 (m,1), 2.67 (m,2), 2.55 (s,3), 1.95 (s,3), 2.0 (broad m,5); MS: m/z=702(M+1,100%). Analysis for C34H35Cl2F6N3O2.1.50 H2O: Calculated: C, 55.97; H, 5.25; N, 5.76; Found: C, 55.91; H, 5.11; N, 5.76.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=1[NH2:19]>>[Cl:16][C:17]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Reactant: Nc1ccc(Cl)cc1Cl
Product: CCOC(=O)c1cnc2ccnn2c1Nc1ccc(Cl)cc1Cl
Yield: 79.4 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (7.50 g, 36.2 mmol) and 2,4-dichloroaniline (5.30 g, 32.6 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (9.09 g, 72%) was obtained.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([O:6][CH2:7][C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[CH2:3]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:44]=[C:45]1[NH:54][C:53]2[N:52]=[CH:51][C:50](/[CH:55]=[CH:56]/[C:57](O)=[O:58])=[CH:49][C:48]=2[CH2:47][CH2:46]1>CN(C)C=O>[O:58]=[C:57]([N:2]1[CH2:5][CH:4]([O:6][CH2:7][C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[CH2:3]1)/[CH:56]=[CH:55]/[C:50]1[CH:49]=[C:48]2[C:53](=[N:52][CH:51]=1)[NH:54][C:45](=[O:44])[CH2:46][CH2:47]2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: c1ncc(COC2CNC2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(OCc4cncs4)C3)cnc2N1
Reaction time: 8 h
Yield: 1.8 %

Procedure:
5-((Azetidin-3-yloxy)methyl)thiazole hydrochloride (113 mg, 0.54 mmol), EDCI (121 mg, 0.63 mmol), HOBt (87.7 mg, 0.63 mmol) and diisopropylethylamine (183 μL, 1.05 mmol) were successively added to a solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (107 mg, 0.42 mmol) in dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred overnight then partitioned between ethyl acetate (30 mL) and water (20 mL). The aqueous layer was separated and extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol (10:0 to 98:2) as eluent then on C18 using dichloromethane/methanol (98:2) as eluent. In order to reach the required purity, the residue was finally recrystallized in methanol to afford the title product as a white solid (2.8 mg, 2%).
Reaction SMILES: C([O:8][C:9]1[C:17]([C:18]2[NH:23][C:22](=[O:24])[C:21]([C:25]([O:27][CH3:28])=[O:26])=[C:20]([OH:29])[C:19]=2[CH2:30][CH3:31])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:32])C1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O.[Pd]>[CH2:30]([C:19]1[C:20]([OH:29])=[C:21]([C:25]([O:27][CH3:28])=[O:26])[C:22](=[O:24])[NH:23][C:18]=1[C:17]1[C:9]([OH:8])=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:32])[CH:12]=[CH:11]2)[CH3:31]
Reactant: CCc1c(-c2ccc3c(ccn3C)c2OCc2ccccc2)[nH]c(=O)c(C(=O)OC)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1c(-c2ccc3c(ccn3C)c2O)[nH]c(=O)c(C(=O)OC)c1O

Procedure:
A solution of methyl 6-(4-(benzyloxy)-1-methyl-1H-indol-5-yl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate (Example 373, step 1, 0.086 g, 0.20 mmol) in DCM (5 mL) and EtOAc (2 mL) was hydrogenated under a H2-filled balloon over Pd/C (10% Degussa type, 20 mg) until complete consumption of staring material was observed. The catalyst was filtered off and washed with DCM and EtOAc. The mother liquor was concentrated and the residue was purified by column chromatography (MeOH/DCM, 0-5% gradient). Methyl 5-ethyl-4-hydroxy-6-(4-hydroxy-1-methyl-1H-indol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate was obtained as a yellowish solid (0.0466 g, 68%).
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[Cl:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]([CH3:28])[C:19]([C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=1)=[O:20].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>C1COCC1.C(O)(C(F)(F)F)=O>[Cl:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]([CH3:28])[C:19]([C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=1)([OH:20])[C:2]([F:4])([F:3])[F:1]
Reactant: COc1ccc(C(C)C(=O)c2cnc(C)cn2)c(Cl)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(C(C)C(O)(c2cnc(C)cn2)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
Trifluoromethyltrimethylsilane (2N in THF, 0.6 mL, 1.2 mmol) was added at 0° C. to a solution of 2-(2-chloro-4-methoxy-phenyl)-1-(5-methyl-pyrazin-2-yl)-propan-1-one (290 mg, 1.0 mmol) in THF (7 mL), followed by the addition of tetrabutylammonium fluoride trihydrate (31 mg, 0.1 mmol). After stirring overnight at r.t., the title compound (87 mg, 24%) was isolated from the reaction mixture by reversed-phase, preparative HPLC (Agilent Zorbax XdB-C18 column, solvent gradient 5-95% CH3CN in 0.1% TFA[aq]). 1H NMR (300 MHz, CDCl3) □ 8.75 (1H, s), 8.13 (1H, s), 7.44 (1H, d), 6.64 (1H, d), 6.59 (1H, dd), 5.90 (1H, s), 4.33 (1H, q), 3.67 (3H, s), 2.50 (3H, s), 1.54 (3H, d); MS (m/e, ISP neg. ion)=359.1 [M−H+].
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8](Br)=[CH:7][C:6]=1[CH3:13])[CH:2]=[CH2:3].[Li]CCCC.C[O:20][C:21](=O)[O:22]C>C1COCC1>[CH2:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:21]([OH:22])=[O:20])=[CH:7][C:6]=1[CH3:13])[CH:2]=[CH2:3]
Reactant: COC(=O)OC
Reactant: C=CCOc1c(C)cc(Br)cc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCOc1c(C)cc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-allyloxy-5-bromo-1,3-dimethyl-benzene (23.6 g, 98.0 mmol) in THF (150 mL) is added at −75° C. a solution of n-BuLi (90 mL, 1.5 M in diethyl ether). The temperature remains at −75° C. The mixture is stirred for 30 min and then transferred via double-tip canula into a cooled (0° C.) solution of dimethylcarbonate (21.4 g, 238 mmol) in THF (90 mL). The mixture is stirred for 2 h at 0° C., then warmed to rt during 15 h. The solvent of the mixture is evaporated and re-evaporated with EtOH (200 mL) to remove most of the butylacetate side product. The mixture is taken up in 2 N aq. LiOH (150 mL) and EtOH (200 mL) and stirred at rt for 2 h then at 60° C. for 1 h. The EtOH is evaporated and the remaining mixture is diluted with 0.5 N aq. NaOH and extracted with diethyl ether (200 mL). The org. extract is washed with 1M aq. NaOH (5×50 mL) and the combined aq. washings are re-extracted with ether (100 mL). The aq. phase is acidified with 25% aq. HCl and extracted with DCM (5×50 mL). The combined org. extracts are dried over Na2SO4, filtered, evaporated and dried in vacuo at 60° C. for 15 h to give 4-allyloxy-3,5-dimethyl-benzoic acid (8.0) as a yellow-brown solid. LC-MS: tR=0.90 min.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:11])[C@H:6]([CH2:8][CH2:9][CH3:10])[NH2:7])[CH3:3].[OH-].[Na+].[C:14]([OH:19])(=[O:18])[C:15]([CH3:17])=O>C(O)C.[Pd]>[C:5]([C@@H:6]([NH:7][C@H:15]([C:14]([OH:19])=[O:18])[CH3:17])[CH2:8][CH2:9][CH3:10])([O:4][CH2:2][CH3:3])=[O:11]
Reactant: CCC[C@H](N)C(=O)OCC
Reactant: CC(=O)C(=O)O
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
L-Norvaline ethyl ester hydrochloride (50 gm) was dissolved in ethanol (600 ml). Sodium hydroxide (15.4 gm) dissolved in ethanol (500 ml) was added to the above at 10° C. and stirred for 30 minutes. Pyruvic acid (34.5 gm) solution in ethanol (200 ml) was then added to above reaction mass at 10° C. and stirred for 30 minutes. The reaction mass was then transferred to a hydrogenator along with 10% palladium on carbon (5 gm) and hydrogenated at 7 bar for 8 hours. The contents were filtered over celite and washed with ethanol (200 ml). The filtrate was concentrated completely under vacuum at about 50° C. Acetone (800 ml) was added to the residue and the contents refluxed for 1 hour and then cooled to room temperature and filtered to obtain the product (30 gm) as white crystals.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.[CH2:10]([O:12][C:13]([N:15]=[C:16]=[S:17])=[O:14])[CH3:11]>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:16]([NH:15][C:13]([O:12][CH2:10][CH3:11])=[O:14])=[S:17])[CH:5]=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(N)nc(Br)c1
Reactant: CCOC(=O)N=C=S
Solvent: ClCCl
Product: CCOC(=O)NC(=S)Nc1cc(C)cc(Br)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-bromo-4-methyl-pyridin-2-ylamine (0.5 g, 2.67 mmol) in dichloromethane (20 ml) cooled to 5° C. was added ethoxycarbonyl isothiocyanate (0.32 ml, 2.67 mmol) dropwise over 15 min. The reaction mixture was then allowed to warm to room temperature at which it was stirred for 16 h. Evaporation in vacuo gave a solid that was collected by filtration and thoroughly washed with cyclohexane to give the desired product. Yield 0.59 g, 69%. LCMS MI: 317.92+319.94, RT: 5.05 min, Method: 2
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([C:11]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[C:4]([Cl:20])[CH:3]=1.C(OC([N:28]1[C:32]([CH3:33])=[C:31](B(O)O)[C:30]([CH3:37])=[N:29]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[Cl:8][C:6]1[CH:7]=[C:2]([C:31]2[C:32]([CH3:33])=[N:28][NH:29][C:30]=2[CH3:37])[CH:3]=[C:4]([Cl:20])[C:5]=1[C:9]([C:11]1[C:19]2[C:14](=[CH:15][N:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:10]
Reactant: O=C(c1c(Cl)cc(Br)cc1Cl)c1c[nH]c2cnccc12
Reactant: Cc1nn(C(=O)OC(C)(C)C)c(C)c1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1n[nH]c(C)c1-c1cc(Cl)c(C(=O)c2c[nH]c3cnccc23)c(Cl)c1
Temperature: 100 °C
Yield: 23.1 %

Procedure:
A mixture of (4-bromo-2,6-dichlorophenyl)(1H-pyrrolo[2,3-c]pyridin-3-yl)methanone (50 mg, 0.135 mmol), [1-(tert-butoxycarbonyl)-3,5-dimethyl-1H-pyrazol-4-yl]boronic acid (52 mg, 0.162 mmol), potassium carbonate (55 mg, 0.4 mmol), water (0.5 mL) and 1,1′bis(diphenylphosphino)ferrocene]dichloropalladium (II) (11 mg, 0.0135 mmol) in 1,4 dioxane (2 mL) was heated at 100° C. for 2 hours in a sealed vial. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude mass was purified by preparative thin layer chromatography using methanol in dichloromethane (10%) to afford [2,6-dichloro-4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl](1H-pyrrolo[2,3-c]pyridin-3-yl)methanone (0.012 g, 23%).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:14][C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)=[C:17]([CH3:31])[CH:16]=2)[CH:11]([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[CH:28]([C:25]1[CH:24]=[CH:23][C:22]([C:18]2[C:19]([CH3:21])=[CH:20][C:15]([O:14][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][CH:6]=3)[CH:11]([CH3:13])[CH3:12])=[CH:16][C:17]=2[CH3:31])=[CH:27][CH:26]=1)([CH3:29])[CH3:30]
Reactant: COC(=O)c1ccc(C(Oc2cc(C)c(-c3ccc(C(C)C)cc3)c(C)c2)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OC(c2ccc(C(=O)O)cc2)C(C)C)cc(C)c1-c1ccc(C(C)C)cc1
Reaction time: 4 h
Yield: 91.2 %

Procedure:
To the solution of isomer 1 of 4-[1-(4′-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-benzoic acid methyl ester (510 mg) in methanol (10 mL) is added sodium hydroxide (5 N aqueous, 2 mL) and stirred for 4 h. The reaction mixture is concentrated and acidified by 5 N HCl (2 mL), extracted with ethyl acetate. Combined organic layers are washed with water and brine, dried over sodium sulfate. Concentration gives the title compound (450 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH2:20]([O:22][C:23]([C:25]1[C:26](=[O:45])[C:27]2[CH:32]=[N:31][C:30](S(C)(=O)=O)=[N:29][C:28]=2[N:37]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH:38]=1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23]([C:25]1[C:26](=[O:45])[C:27]2[CH:32]=[N:31][C:30]([NH:18][C:15]3[CH:14]=[CH:13][C:12]([CH:9]4[CH2:8][CH2:7][N:6]([C:4](=[O:5])[CH2:3][N:2]([CH3:19])[CH3:1])[CH2:11][CH2:10]4)=[CH:17][CH:16]=3)=[N:29][C:28]=2[N:37]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH:38]=1)=[O:24])[CH3:21]
Reactant: CN(C)CC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(Nc3ccc(C4CCN(C(=O)CN(C)C)CC4)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenylamine (from Example 70(B)), 73 mg, 0.28 mmol) and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 17(e), 100 mg, 0.26 mmol). The title compound was obtained as a white solid (40 mg, 25%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.21 (s, 1H), 8.99 (s, 1H), 8.41 (s, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.13 (d, J=8.5 Hz, 2H), 4.96 (m, 3H), 4.31 (q, J=7.1 Hz, 2H), 3.00 (m, 4H), 2.77 (m, 1H), 2.30 (s, 6H), 1.93 (m, 6H), 1.64 (m, 5H), 1.42 (m, 2H), 1.34 (t, J=7.1 Hz, 3H), 1.18(m, 1H).
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:33][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:33][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH2:27][C:28]([N:30]([CH3:31])[CH3:32])=[O:29])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CN(C)C(=O)COc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)COc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 25 °C
Yield: 50.5 %

Procedure:
A mixture of 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-N,N-dimethyl-acetamide (276 mg, 0.59 mmol) and 10% palladium on activated carbon (50.0 mg) in methanol (200 mL) was heated at 50° C. under 50 bar of hydrogen in a steel bomb pressure for 6 h. The mixture was then cooled to room temperature. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-N,N-dimethyl-acetamide (140 mg, 50.7%) as a white solid: LC/MS m/e calcd for C25H31N3O4S [M+H]+ 470.61, observed 470.2. solid 1H NMR (400 MHz, CD3OD) δ ppm 7.86-7.93 (m, 4H), 7.59 (d, J=8.1 Hz, 3H), 7.52 (s, 1H), 6.32 (s, 1H), 4.84 (s, 2H), 4.28 (t, J=7.8 Hz, 1H), 3.08 (s, 3H), 3.10 (s, 3H), 2.98 (s, 3H), 2.22-2.30 (m, 1H), 2.03-2.13 (m, 2H), 1.61-1.79 (m, 4H), 1.48 (br. s., 1H), 1.21-1.23 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[N:7]=[CH:6][N:5]=1)[CH3:2].COC1C=CC(/C=[C:31]2/[C:32]([NH:34][C:35]([S:37]/2)=[NH:36])=[O:33])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[NH2:36][C:35]1[S:37]/[C:31](=[CH:14]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][N:5]=[C:4]3[O:3][CH2:1][CH3:2])/[C:32](=[O:33])[N:34]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: CCOc1ncnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOc1ncnc2ccc(/C=C3\SC(N)=NC3=O)cc12
Temperature: 25 °C

Procedure:
The suspension of 4-ethoxy-quinazoline-6-carbaldehyde (example 10b) (1 equiv.), pseudothiohydantoin (1 equiv.), and sodium acetate (4 equiv.) in acetic acid was stirred under reflux for 12 h. After cooling to room temperature, water was added. The solid was collected by filtration, washed with water and dried to 2-amino-5-[1-(4-ethoxy-quinazolin-6-yl)-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 301 (MH+) as a slight yellow solid. LC-MS m/e 256 (MH+).