Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O.O=[Pt]=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccccn1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCC1CCCCN1
Reaction time: 8 h

Procedure:
The product from step A was mixed with PtO2 (640 mg) in HOAc (30 mL) and hydrogenation was carried out at 58 psi on a Parr apparatus for overnight. Catalyst was removed and solvent was evaporated under reduced pressure to give N-t-butoxycarbonyl 2-(piperidin-2-yl) ethylamine as a black liquid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]2[C:15]3[N:24]=[C:23]([Cl:25])[NH:22][CH2:21][C:16]=3[N:17]=[C:18]([Cl:20])[N:19]=2)[CH:9]=[CH:10][C:11]=1[F:12].C(N(C(C)C)C(C)C)C>C(OCC)(=O)C>[Cl:25][C:23]1[N:22]([C:1](=[O:3])[CH3:2])[CH2:21][C:16]2[N:17]=[C:18]([Cl:20])[N:19]=[C:14]([NH:13][C:8]3[CH:9]=[CH:10][C:11]([F:12])=[C:6]([Cl:5])[CH:7]=3)[C:15]=2[N:24]=1
Reactant: CC(=O)Cl
Reactant: Fc1ccc(Nc2nc(Cl)nc3c2N=C(Cl)NC3)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1Cc2nc(Cl)nc(Nc3ccc(F)c(Cl)c3)c2N=C1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
At 10° C., 56.4 ml (0.789 mol) of acetylchloride are added dropwise to a suspension of 210.6 g (0.608 mol) of (2) and 176 ml of N-ethyldiisopropylamine (0.95 mol) in 2.1 l of ethyl acetate. The mixture is stirred for 90 minutes at ambient temperature and then washed 3 times with 700 ml of water at 60° C. The organic phase is evaporated down and combined with 590 ml of ethanol. The mixture is briefly brought to boiling point, cooled to 0-5° C. and stirred at this temperature for 30 minutes. The product that crystallises out is filtered off and dried at 60° C. in vacuo. Yield: 180.3 g (76.3%), melting point: 177.6° C.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][C:13]1[C:17]([CH2:18][CH:19]2OCCO2)=[C:16]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:15]([CH:31]([CH3:33])[CH3:32])[N:14]=1)C1C=CC=CC=1.[SiH](CC)(CC)CC>C(O)(C(F)(F)F)=O>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:16]2[N:15]([CH:31]([CH3:33])[CH3:32])[N:14]=[C:13]3[C:17]=2[CH2:18][CH2:19][NH:10][CH2:11][CH2:12]3)=[CH:25][CH:26]=1
Reactant: CC(C)n1nc(CCNC(=O)OCc2ccccc2)c(CC2OCCO2)c1-c1ccc(F)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Reaction time: 16 h

Procedure:
A solution of {2-[4-[1,3]dioxolan-2-ylmethyl-5-(4-fluoro-phenyl)-1-isopropyl-1H-pyrazol-3-yl]-ethyl}-carbamic acid benzyl ester (1.0 g, 2.1 mmol) in TFA (10 mL) was treated with Et3SiH (2.5 mL, 21 mmol). After 16 h at 50° C., the solution was concentrated and the residue was purified by FCC to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([NH:31][CH2:32][C:33]2[N:34]=[CH:35][S:36][CH:37]=2)[N:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([NH:31][CH2:32][C:33]2[N:34]=[CH:35][S:36][CH:37]=2)[N:3]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NCc2cscn2)c1F)OC1CCCCO1
Solvent: CC(=O)O
Solvent: O
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NCc2cscn2)c1F
Reaction time: 8 h
Yield: 51.6 %

Procedure:
[(2R)-3-(2-{2-Chloro-5-fluoro-6-[(1,3-thiazol-4-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.1133 g, 0.204 mmol) was dissolved in acetic acid (8 mL) and water (2 mL). This reaction mixture was left to stir overnight. The volatiles were evaporated, and the resulting residue was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(1,3-thiazol-4-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (0.0497 g, 52%). LCMS: (M+H)+=472.1.
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+].[Cl-]>CO>[N:1]1([C:7]([CH:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][CH2:10]2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(c1coc2ccccc12)N1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: O=C(C1COc2ccccc21)N1CCCCC1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
To a solution of 3-(1-piperidylcarbonyl)benzofuran (6.7 g) in methanol (150 ml) kept at 35-50° C. were added small portions (in total 3 g) of Mg turnings during 5 hours. After stirring for another hour at 50° C. the mixture was poured onto an aqueous solution of NH4Cl. The aqueous solution was extracted with dichloromethane (2×200 ml). The combined organic phases were worked-up yielding 6.7 g of the title 2,3-dihydrobenzofuran derivative as an oil.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:9][CH2:8][CH2:7]1)=[O:5])C.[C:10](#[N:12])[CH3:11]>>[CH:6]1([C:4](=[O:5])[CH2:11][C:10]#[N:12])[CH2:7][CH2:8][CH2:9]1
Reactant: CC#N
Reactant: CCOC(=O)C1CCC1
Product: N#CCC(=O)C1CCC1

Procedure:
The title compound was prepared in analogy to example 101 step A from cyclobutanecarboxylic acid ethyl ester and acetonitrile. Light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[N:19]1([CH2:25][CH2:26][O:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][C:32]([CH:37]=O)=[CH:31]3)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13](=[CH:37][C:32]4[NH:33][C:34]5[C:30]([CH:31]=4)=[CH:29][C:28]([O:27][CH2:26][CH2:25][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:36][CH:35]=5)[C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Reactant: COc1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C3=Cc2cc3cc(OCCN4CCOCC4)ccc3[nH]2)cc1

Procedure:
6-(4-Methoxy-phenyl)-1,3-dihydro-indol-2-one was condensed with 5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].C(O[CH2:17][CH3:18])(=O)C>N1C=CC=CC=1.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:2][C:1]2[CH:3]=[CH:4][CH:5]=[CH:6][C:17]=2[CH3:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(C)=O
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccccc1NS(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
O-toluidine (Fluka; 0.118 mL, 1.1 mmol) was added to a clear light yellow solution of 4-cyano-benzenesulfonyl chloride (ABCR GmbH & Co. KG; 202 mg, 1 mmol) in pyridine (5 mL). The resulting clear red-brown solution was then stirred at room temperature for 18 hrs. Subsequently the reaction mixture was diluted with water (50 mL) and ethyl acetate (50 mL). The liquid layers were separated and the aqueous fraction was re-extracted twice with ethyl acetate (25 mL). The combined organic layers were washed with 0.1 M hydrochloric acid and brine (50 mL each), dried with sodium sulfate, filtered and evaporated under reduced pressure. The residue was dried under high vacuum to give 4-cyano-N-o-tolyl-benzenesulfonamide (314 mg, 0.92 mmol, 92% yield) as pale brown oil.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(O[CH:16]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])[C:17]1[N:18]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH:19]=[CH:20][N:21]=1)=O)(C)(C)C.[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([SH:45])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([S:45][CH:16]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[F:37])[C:17]2[N:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH:19]=[CH:20][N:21]=2)=[CH:41][CH:40]=1
Reactant: COc1ccc(-n2ccnc2C(OC(=O)OC(C)(C)C)c2cc(F)ccc2F)cc1
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COc1ccc(-n2ccnc2C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
Trifluoroacetic acid (10 ml) was added to the 2-[(t-butoxycarbonyloxy)-(2,5-difluorophenyl)methyl]-1-(4-methoxyphenyl)-1H-imidazole (667 mg, 1.6 mmol) obtained in Referential Example 16. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. Dioxane was added to the residue, followed by further concentration under reduced pressure. The residue was dissolved in thionyl chloride (2.0 ml) and to the resulting solution was added a drop of dimethylformamide. The resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane, followed by further concentration under reduced pressure. The residue was dissolved in dimethylformamide (5.0 ml). To the resulting solution were added 4-chlorobenzenethiol (347 mg, 2.4 mmol) and potassium carbonate (1.32 g, 9.6 mmol). The resulting mixture was stirred at 50° C. for 2 hours. After the reaction mixture was allowed to stand until it became room temperature, ethyl ether (60 ml) was added thereto. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1 to 5:1), followed by crystallization from ethanol to give the title compound (535 mg, 75%) as colorless needle crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[C:17]([C:18](OCC)=[O:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.C(OC(=O)C)C.O>O1CCCC1>[Cl:7][C:8]1[C:17]([CH2:18][OH:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: CCOC(=O)c1ccc2ncccc2c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1ccc2ncccc2c1Cl
Reaction time: 1 h
Yield: 95.1 %

Procedure:
Lithiumaluminiumhydride (1.66 g) was added portionwise to a solution of intermediate 1 (10.11 g) in tetrahydrofuran (325 ml) at 0° C. under N2 and the mixture was stirred for 1 hour. Ethylacetate (70 ml) and water (3 ml) were added to the mixture which was subsequently filtered. The filtrate was dried over MgSO4, filtered and evaporated, yielding 7.9 g (93%) 5-chloro-6-quinolinemethanol (intermediate 2).
Reaction SMILES: CC(C)(C)[C@H](NC(=O)[C@@H](NC)C)C(N1[C@H](C(N[C@H]2C3C(=CC=CC=3)CCC2)=O)CC2C(=CC(C(N[C@H]3C[C@@H](C(=O)N[C@H]4C5C(=CC=CC=5)CCC4)N(C(=O)[C@@H](NC(=O)[C@@H](NC)C)C(C)(C)C)C3)=O)=CC=2)C1)=O.[C@H:73]1([NH:83][C:84]([C@@H:86]2[CH2:95][C:94]3[C:89](=[CH:90][C:91]([C@H:96]4[CH2:100][C@@H:99]([C:101](=[O:113])[NH:102][C@H:103]5[C:112]6[C:107](=[CH:108][CH:109]=[CH:110][CH:111]=6)[CH2:106][CH2:105][CH2:104]5)[NH:98][CH2:97]4)=[CH:92][CH:93]=3)[CH2:88][N:87]2C(OC(C)(C)C)=O)=[O:85])[C:82]2[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=2)[CH2:76][CH2:75][CH2:74]1>>[C@H:73]1([NH:83][C:84]([C@@H:86]2[CH2:95][C:94]3[C:89](=[CH:90][C:91]([C@H:96]4[CH2:100][C@@H:99]([C:101](=[O:113])[NH:102][C@H:103]5[C:112]6[C:107](=[CH:108][CH:109]=[CH:110][CH:111]=6)[CH2:106][CH2:105][CH2:104]5)[NH:98][CH2:97]4)=[CH:92][CH:93]=3)[CH2:88][NH:87]2)=[O:85])[C:82]2[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=2)[CH2:76][CH2:75][CH2:74]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc([C@@H]3CN[C@H](C(=O)N[C@@H]4CCCc5ccccc54)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Agent: CN[C@@H](C)C(=O)N[C@H](C(=O)N1Cc2cc(C(=O)N[C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Product: O=C(N[C@@H]1CCCc2ccccc21)[C@@H]1Cc2ccc([C@@H]3CN[C@H](C(=O)N[C@@H]4CCCc5ccccc54)C3)cc2CN1
Yield: 99.6 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound G of Example 1, (S)-tert-butyl 3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-7-((3R,5S)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (97 mg, 0.15 mmol) was converted to the title compound (82 mg, 100%). MS (ESI+) m/z 549.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(CCl)ccn1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Product: Cc1cc(Cn2cc(C(=O)N3CCC4(CC3)OCc3ccccc34)c3ccc(Cl)cc32)ccn1
Yield: 56 %

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with 4-chloromethyl-2-methyl-pyridine (described in WO 2006023707) gave the title compound in 56% yield. ES-MS m/e (%): 472.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[C:1]([O:5][C:6](=[O:26])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:33]2[C:28]([F:27])=[N:29][CH:30]=[CH:31][CH:32]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccnc1F
Reactant: Cc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2F)cn1
Temperature: 105 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
A suspension of tert-butyl({5-bromo-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (206 mg), (2-fluoropyridin-3-yl)boronic acid (80 mg), sodium carbonate (119 mg) and tetrakis(triphenylphosphine)palladium (80 mg) in 1,2-dimethoxyethane (5 mL) and water (2.5 mL) was stirred under a nitrogen atmosphere at 105° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=1:1) to give the title compound as a pale-yellow oil (yield 87 mg, 41%).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CC(C)=O.O>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([N:26]=[N+:27]=[N-:28])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(Br)cc1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)C=Cc1ccc(Br)cc1
Reaction time: 1 h
Yield: 95.4 %

Procedure:
4-Bromocinnamic acid (7.45 g, 32.8 mmol) dissolved in acetone (150 mL) and stirred under nitrogen at 0° C. during addition of triethylamine (5.5 ml, 39.4 mmol), followed by ethyl chloroformate (3.76 ml, 39.4 mmol). Stirred reaction mixture at 0° C. for 1 hour, before adding a solution of sodium azide (3.19 g, 49.2 mmol) in water (16 mL) dropwise. Stirred reaction mixture at 0° C. for 1 hour, then room temperature for 1 hour, before pouring into water (1 L). The white precipitate was collected and washed repeatedly with water and dried (high vacuum, P2O5) to give 3-(4-bromophenyl)acryloyl azide (7.91 g, 31.3 mmol). 1H NMR (CDCl3) δ 7.66 (d, 1H), 7.55 (d, 2H), 7.40 (d, 2H), 6.41 (d, 1H). ESI MS (M+1)+: 251, 253 (Br).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Cl:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17]Cl.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Cl:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: ClC/C=C/CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1CCc2ccc(OC/C=C/CCl)cc2N1
Reaction time: 8 h
Yield: 33.8 %

Procedure:
A mixture of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (196 mg, 1.2 mmol), (E)-1,4-dichlorobut-2-ene (450 mg, 3.6 mmol) and anhydrous K2CO3 (166 mg, 1.2 mmol) was dissolved in EtOH and the solution was heated to reflux and stirred overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column to give (E)-7-(4-chlorobut-2-enyloxy)-3,4-dihydroquinolin-2(1H)-one (intermediate 52) (102 mg, 34%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[N:21][CH:22]=3)[N:11]=2)[CH:6]=[CH:7][C:8]=1F)#[N:2].[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]([NH2:35])=[O:34])[CH2:29][CH2:28]1>C(O)CCC>[C:24]([NH:23][C:20]1[N:21]=[CH:22][C:17]([NH:16][C:12]2[N:11]=[C:10]([C:5]3[CH:6]=[CH:7][C:8]([N:27]4[CH2:32][CH2:31][CH:30]([C:33]([NH2:35])=[O:34])[CH2:29][CH2:28]4)=[C:3]([C:1]#[N:2])[CH:4]=3)[CH:15]=[CH:14][N:13]=2)=[CH:18][CH:19]=1)(=[O:26])[CH3:25]
Reactant: NC(=O)C1CCNCC1
Reactant: CC(=O)Nc1ccc(Nc2nccc(-c3ccc(F)c(C#N)c3)n2)cn1
Solvent: CCCCO
Product: CC(=O)Nc1ccc(Nc2nccc(-c3ccc(N4CCC(C(N)=O)CC4)c(C#N)c3)n2)cn1
Yield: 29 %

Procedure:
A stirred solution of N-{5-[4-(3-Cyano-4-fluoro-phenyl)-pyrimidin-2-ylamino]-pyridin-2-yl}-acetamide (100 mg, 0.28 mmol) and piperidine-4-carboxylic acid amide in n-butanol (5 mL) was heated to 115° C. in a sealed tube for 48 h. The solvent was evaporated to obtain the crude compound. The crude compound was purified by preparative-HPLC to obtain the desired product as pale yellow powder (38 mg, 29%); LC-MS, Rt,=2.96 min (Method C), m/z 457 (MH+). In addition to this procedure similar reactions may also be accomplished at 110° for 16-120 h. Purification may be by preparative-HPLC or flash column chromatography.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:2]([NH2:4])=[O:3].[CH3:13][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[NH:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:2]([NH2:4])=[O:3]
Reactant: NC(=O)NCCCCCC(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)CCCCCNC(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-ureidohexanoic acid (0.996 g, 5.72 mmol, 1.0 equiv) in methanol/benzene (2:7, 60 mL) was cooled to 0 degrees C., and a solution of trimethylsilyldiazomethane in hexanes (2.0 M, 3.43 mL, 6.86 mmol, 1.2 equiv) was added. The reaction mixture was warmed to room temperature and stirred for 1 h prior to removing all volatile components in vacuo. The crude methyl ester (1.06 g, 5.61 mmol, 98%) was used without further purification in the Biginelli reaction.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:17]2[CH2:18][C:19]3[C:24]([C:16]2=[N:15][N:14]=1)=[C:23](Br)[CH:22]=[CH:21][CH:20]=3.Br[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:17]2[CH2:18][C:19]3[C:24]([C:16]2=[N:15][N:14]=1)=[C:23]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH:22]=[CH:21][CH:20]=3
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1cccc(Br)c1-2
Reactant: Brc1cccnc1
Product: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1cccc(-c3cccnc3)c1-2
Yield: 3 %

Procedure:
Prepared in a similar manner to Example 7 from 3-(5-methyl-3-phenylisoxazol-4-yl)-9-bromo-5H-[1,2,4]triazolo[3,4-a]isoindole (100 mg) (prepared using 7-bromo-2,3-dihydroisoindol-1-one by analogy with Example 4) and 3-bromopyridine (0.06 ml) to give the title compound (7 mg, 3%). 1H NMR (360 MHz, CDCl3) δ 8.90 (1H, s), 8.71 (1H, s), 8.40 (1H, d, J=5.8 Hz), 7.56–7.40 (8H, m), 7.30 (1H, d, J=7.3 Hz), 4.08 (2H, s), 2.68 (3H, s), miz (ES+) 392 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]1[O:8][C:9]2[C:14]([C:15](=[O:17])[CH:16]=1)=[CH:13][C:12]([C:18](Cl)=[O:19])=[CH:11][CH:10]=2)([CH3:3])[CH3:2].[OH:25]CCN1CCOCC1.N1C=CC=CC=1>C1C=CC=CC=1>[C:18]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:6]1[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2])=[CH:16][C:15]2=[O:17])([OH:25])=[O:19]
Reactant: CC(C)Oc1ccccc1-c1cc(=O)c2cc(C(=O)Cl)ccc2o1
Reactant: OCCN1CCOCC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(C)Oc1ccccc1-c1cc(=O)c2cc(C(=O)O)ccc2o1
Yield: 88.5 %

Procedure:
2'-isopropoxy-flavone-6-carbonyl-chloride (4.3 g) prepared according to Example 18, dissolved in anhydrous benzene (40 ml) was treated with N-hydroxyethyl-morpholine (3.2 g) and pyridine (1 ml) at room temperature for 24 hours. The benzene solution was washed with aqueous citric acid 40% with sodium bicarbonate and water, then evaporated to dryness. The residue, crystallised from acetone, gave morpholinoethyl-ester of 6-carboxy-2'-isopropoxy-flavone (3.6 g; m.p. 133°-135° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[CH:23]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)=O.[BH4-].[Na+]>CO>[N:17]1([S:14]([C:7]2[C:6]3[C:10](=[C:2]([NH:1][CH2:23][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH:3]=[CH:4][CH:5]=3)[NH:9][C:8]=2[C:11]([NH2:13])=[O:12])(=[O:16])=[O:15])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: NC(=O)c1[nH]c2c(N)cccc2c1S(=O)(=O)N1CCOCC1
Reactant: O=Cc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1[nH]c2c(NCc3ccncc3)cccc2c1S(=O)(=O)N1CCOCC1
Reaction time: 8 h

Procedure:
To a solution of 7-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 7 (36 mg, 0.11 mmol) in 1 mL of methanol was added 4-formylpyridine (24 mg, 0.22 mmol). After stirring overnight, sodium borohydride was added (13 mg, 0.33 mmol). After 2 hours, the reaction was quenched with 3N HCl, concentrated in vacuo, taken up in DMF, and purified by preparative reversed phase HPLC. The titled product was obtained as a yellow solid. Proton NMR for the product was consistent with the titled compound. ESI+MS: 416.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.[H-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][CH2:12][CH2:13][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:21][CH:20]=1
Reactant: Cc1sc2cc(OCCOS(C)(=O)=O)ccc2c1-c1ccc(C(F)(F)F)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1sc2cc(OCCn3ccnc3)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 53.1, Methanesulfonic acid 2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl ester (example 49.2) was reacted with imidazole and sodium hydride in N,N-dimethylformamide at room temperature to yield 1-{2-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl}-1H-imidazole as colorless oil, MS: 403 (MH+).