Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[CH3:11][C:12]([S@@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>O1CCOCC1.[Cl-].[Na+].O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[N:17][S@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])[CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: N#Cc1cccc(C=O)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)[S@](=O)N=Cc1cccc(C#N)c1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
In a flame dried flask under N2, 3-cyanobenzaldehyde (7.050 g, 53.76 mmol) was dissolved in anhydrous dioxane (100 mL). Ti(IV) ethoxide (28.183 mL, 134.40 mmol) was added followed by (S)-(−)-2-methyl-2-propanesulfinamide (7.167 g, 59.14 mmol). The r×n was heated to 110° C. After 2.5 hr the reaction was cooled to RT and brine (150 mL) was added. A precipitate formed and the reaction was rapidly stirred for 1 hr. The suspension was filtered through celite and the filter cake was washed with brine and ethyl acetate. The layers of the filtrate were separated. The aqueous layer was extracted with ethyl acetate (1×). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to afford (S)—N-[(3-cyanophenyl)methylidene]-2-methylpropane-2-sulfinamide as a light orange solid. 1H NMR (CD3OD) (8.61 (s, 1H), 8.26 (s, 1H), 8.22-8.20 (m, 1H), 7.94-7.92 (m, 1H), 7.72 (t, 1H, J=7.81 Hz), 1.28 (s, 9H).
Reaction SMILES: [C:1]([CH2:3][C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7]1)=O)#[N:2].[CH3:21][NH:22][NH2:23]>C(O)C>[NH2:2][C:1]1[N:22]([CH3:21])[N:23]=[C:4]([CH:6]2[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:7]2)[CH:3]=1
Reactant: CNN
Reactant: N#CCC(=O)C1CCN(C(=O)OCc2ccccc2)C1
Solvent: CCO
Product: Cn1nc(C2CCN(C(=O)OCc3ccccc3)C2)cc1N
Yield: 84.7 %

Procedure:
A solution of EXAMPLE 24B (1.9 g, 7 mmol) and methylhydrazine (367 μL, 7 mmol) in ethanol (15 mL) was heated at reflux for 4 hours. After cooling, the mixture was concentrated and the residue purified by flash chromatography on silica gel using 0-15% methanol in dichloromethane to give the title compound (1.78 g, 85%). MS(DCI): m/z 301 (M+1)+.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([F:39])[C:37]=1[F:38])[CH2:33]Br>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:33][C:32]3[CH:31]=[C:30]([F:29])[C:37]([F:38])=[C:36]([F:39])[CH:35]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: Fc1cc(CBr)cc(F)c1F
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2cc(F)c(F)c(F)c2)cc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 27 step D from methyl 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 3,4,5-trifluorobenzyl bromide, and was isolated as beige solid after reverse phase chromatography (81%): 1H NMR (400 MHz, CHLOROFORM-d) ppm 0.99 (s, 9H), 2.43 (s, 3H), 3.65 (s, 3H), 5.46 (s, 1H), 5.75 (s, 2H), 6.08 (d, J=2.7 Hz, 1H), 6.87 (t, J=7.1 Hz, 2H), 7.01 (d, J=2.7 Hz, 1H), 7.28 (d, 2H), 7.31-7.39 (m, 1H), 7.48-7.57 (m, 1H). LCMS (m/z) ES+=513 (M+1).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH2:38])[C:19]3=[O:39])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:40]1([C:46]([NH:59][C:60]2[S:61][CH:62]=[C:63](/[C:65](=[N:69]/[O:70][C:71]([O:74][CH3:75])([CH3:73])[CH3:72])/[C:66](O)=[O:67])[N:64]=2)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH:38][C:66](=[O:67])/[C:65](/[C:63]2[N:64]=[C:60]([NH:59][C:46]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[S:61][CH:62]=2)=[N:69]\[O:70][C:71]([O:74][CH3:75])([CH3:73])[CH3:72])[C:19]3=[O:39])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(=O)n2nc(SCC3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)[C@@H](N)[C@H]4SC3)sc2n1
Reactant: COC(C)(C)O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nn4c(=O)cc(C)nc4s3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
The product obtained in Step 2 (3.25 g) and 2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(1-methoxy-1-methylethyl)oxyimino]acetic acid (5.64 g) were dissolved in dichloromethane (93 ml) and tetrahydrofurnan (93 ml) under a nitrogen stream, and the solution was cooled to 0° C. Dicyclohexylcarbodiimide (2.32 g) was added to this solution by small portions, and the mixture was stirred overnight at room temperature. After filtering off the insoluble matters, the filtrate was concentrated under reduced pressure. The residue was redissolved in ethyl acetate and the insoluble matters were filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, giving 2.5 g of the objective compound as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]1[CH2:23][O:22]1)([CH3:16])([CH3:15])[CH3:14]>CCO.O>[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]([OH:22])[CH2:23][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CO1
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC[C@@H](O)CNc1ccc2c(c1)NC(=O)CS2
Yield: 82.9 %

Procedure:
A solution of 6-amino-4H-benzo[1,4]thiazin-3-one (10.68 g, 59.3 mmol; commercial) and tert-butyl-dimethyl-[(R)-2-oxiranyl-ethoxy]-silane (first eluting compound in step H.i.; 12.0 g, 59.3 mmol) in EtOH/H2O (9:1; 320 mL) was heated at 80° C. for 2 days. The mixture was concentrated under reduced pressure. Residual starting aniline could be removed by addition of Et2O/MeOH followed by filtration. The filtrate containing the product was concentrated under reduced pressure to afford the title intermediate as a brown oil (18.8 g, 83% yield) which was used as such in the next step.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[CH3:14].[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18]([NH2:20])=[O:19].S(=O)(O)[O-].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[Cl:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:16]2[C:17]=1[C:18](=[O:19])[NH:20][C:9]([C:8]1[CH:11]=[C:12]([CH3:13])[C:5]([O:4][CH2:3][CH2:2][OH:1])=[C:6]([CH3:14])[CH:7]=1)=[N:15]2
Reactant: NC(=O)c1c(N)cccc1Cl
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(-c2nc3cccc(Cl)c3c(=O)[nH]2)cc(C)c1OCCO

Procedure:
4-(2-Hydroxyethoxy)-3,5-dimethylbenzaldehyde (0.70 g, 3.58 mmol), 2-amino-6-chlorobenzamide (0.60 g, 3.51 mmol), sodium bisulfite (0.71 g, 3.86 mmol) and p-toluenesulfonic acid monohydrate (0.133 g, 0.699 mmol) in anhydrous N,N-dimethyl acetamide (14 mL) were heated at 120° C. under nitrogen for 23 hours. The solvent was evaporated and the white solid was triturated with water (50 mL), filtered, and washed with water (20 mL). The solid was dried in vacuo and triturated with Et2O (20 mL), filtered, and dried to give 5-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one as a white solid. Yield: 0.77 g, (64%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH2:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([CH2:19][CH2:20][CH2:21][C:22](CC([O-])=O)=[O:23])[CH3:18]>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:22](=[O:23])[CH2:21][C:20]([CH2:19][CH2:17][CH3:18])=[N:16]2)=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCC(=O)CC(=O)[O-]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(NN)cc1
Product: CCCC1=NN(c2ccc(S(=O)(=O)NC(C)(C)C)cc2)C(=O)C1

Procedure:
From the reaction of N-tert.-butyl-4-hydrazinobenzenesulfonamide and ethylbutyrylacetate, N-tert.-Butyl-4-(4,5-dihydro-3-propyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide is obtained. Subsequent reaction with 2-ethoxyaniline yields N-tert-butyl-4-(4-(2-ethoxyanilinomethylen)-4,5-dihydro-3-propyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide, Mp: 254° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:10]1[N:14]([CH3:15])[C:13]2[CH:16]=[C:17]([C:20]([O:22]CC)=[O:21])[CH:18]=[CH:19][C:12]=2[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:25]>C(O)C>[ClH:25].[CH2:3]([C:10]1[N:14]([CH3:15])[C:13]2[CH:16]=[C:17]([C:20]([OH:22])=[O:21])[CH:18]=[CH:19][C:12]=2[N:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1ccc2nc(Cc3ccccc3)n(C)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(Cc2ccccc2)nc2ccc(C(=O)O)cc21

Procedure:
A 5% sodium hydroxide aqueous solution (2.8 g) was added to a solution of 0.340 g of 2-benzyl-6-ethoxycarbonyl-1-methylbenzimidazole in 4 ml of ethanol, and the mixture was heat-refluxed for 1.5 hours. The reaction mixture was acidified with 1-N hydrochloric acid, and was concentrated under reduced pressure. Ethanol was added to the residue to extract the organic substance. Ethanol was distilled off under reduced pressure to give 0.300 g of 2-benzyl-6-carboxy-1-methylbenzimidazole hydrochloride (271).
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[C:9]1[C:14]([F:15])=[CH:13][NH:12][C:11](=[O:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24].CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:8]([CH3:17])[C:9]1[C:14]([F:15])=[CH:13][N:12]([C:23]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)=[O:24])[C:11](=[O:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)c1nc(=O)[nH]cc1F
Reactant: O=C(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1ccccc1)c1nc(=O)n(C(=O)c2cccs2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 6.3 %

Procedure:
To a round-bottomed flask charged with 4-(benzyl(methyl)amino)-5-fluoropyrimidin-2(1H)-one (250 mg, 1.06 mmol) in CH2Cl2 (11 mL) and 2-thiophene carbonyl chloride (172 mg, 1.1 mmol, 1.1 eq) was added Et3N (237 mg, 2.35 mmol) at 0° C. under N2. The reaction mixture was warmed to room temperature after complete addition and stirred at for 12 h. The reaction mixture was diluted with CH2Cl2 (25 mL), washed with satd aq NaCl solution (10 mL), dried over Na2SO4 and evaporated to dryness in vacuo at room temperature. The crude product was purified by reverse phase chromatography to yield the product as a white solid (23 mg, 6%): mp 101.3-102.4° C.; 1H NMR (methanol-d4) δ 8.10 (d, J=6.3 Hz, 1H), 8.00 (d, J=3.8 Hz, 1H), 7.91 (d, J=4.9 Hz, 1H), 7.38-7.20 (m, 6H), 4.88 (s, 2H), 3.22 (d, J=3.2 Hz, 3H); ESIMS m/z 344 ([M+H]+).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([CH3:31])[CH:25]=[CH:24]2.C([O-])(O)=O.[Na+]>ClCCl>[CH3:31][C:26]1[CH:25]=[CH:24][C:23]2[C:28](=[CH:29][CH:30]=[C:21]([NH:20][S:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[CH:22]=2)[N:27]=1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc2cc(N)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1ccc(S(=O)(=O)Nc2ccc3nc(C)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
To a solution- of 0.4n-propylbenzenesulphonyl chloride (145 mg, 0.664 mmol) in dichloromethane (4 mL) was added pyridine (130 μL, 1.58 mmol) and the mixture was stirred- under N2 for 5 min, after which time 6-amino-2-methylquinoline (100 mg, 0.632 mmol) was added. The resulting mixture was stirred for 1 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford an off-white solid (186 mg, 86%), single spot at Rf 0.70 (ethyl acetate). mp 173.7-174.0° C., HPLC purity 99+% (tR 2.32 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.94 (1H, d, J=8.4 Hz), 7.89 (1H, d, J=9.2 Hz), 7.67 (2H, d, J=8.4 Hz), 7.54 (1H, d, J=2.5 Hz), 7.31 (1H, dd, J=8.9, 2.5 Hz), 7.25 (1H, d, J=8.4 Hz), 7.19 (2H, d, J=8.4 Hz), 7.07 (1H, s, N—H), 2.70 (3H, s), 2.56 (2H, t, J=7.5 Hz), 1.58 (2H, sextet, J=7.4 Hz), 0.87 (3H, t, J=7.4 Hz). LCMS: 339.24 (M−). FAB-MS (MH+, C19H20N2O2S): calcd 341.1323, found 341.1324.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][CH:14]=1)[C:5]2=[O:29].C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)CCC>C1(C)C=CC=CC=1>[CH3:12][C:7]1[N:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][CH:14]=2)[C:5](=[O:29])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[CH:3]=2)[N:8]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1nc2ccc(Br)cc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: Cc1nc2ccc(-c3ccccn3)cc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
6-bromo-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone synthesized in Example 34 (100 mg, 0.25 mmol) and 2-(tributylstannyl)pyridine (90 mg, 0.25 mmol) were dissolved in toluene (1 mL), and the atmosphere in the system was replaced by nitrogen. Palladium tetrakis(triphenylphosphine) complex (30 mg, 0.025 mmol) was added, and stirred at 120° C. for 12 hours. Insoluble matter was filtered off through cerite, chloroform was added to the filtrate, the organic phase was washed with distilled water, and dried with anhydrous sodium sulfate. The product was purified by silica gel column chromatography (chloroform/methanol=9/1), and the target substance (20 mg, 20%) was obtained as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH3:31][Si:32]([C:35]#[C:36][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)([CH3:34])[CH3:33]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
21.5 g (0.1 mol) of methyl 4-bromobenzoate, 300 ml of triethylamine and a mixture of 200 mg of palladium acetate and 400 mg of triphenylphosphine are introduced into a three-necked flask. 20 g (0.204 mol) of trimethylsilylacetylene are then added, after which the mixture is heated gradually to 90° C. over 1 hour and left at this temperature for 5 hours. The reaction medium is then cooled, the salt is filtered off and the filtrate is evaporated. The residue is taken up in 200 ml of hydrochloric acid (5%) and 400 ml of ethyl ether. The ether phase is separated out after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with dichloromethane. After evaporation of the solvents, 23 g (100%) of the expected derivative are collected in the form of a colourless oil.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[NH2:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[O:14]>>[N:2]1([CH2:7][C:8]([NH:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)=[O:14])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: N[C@@H](COCc1ccccc1Cl)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Cn1cncn1)N[C@@H](COCc1ccccc1Cl)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 50 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(2-chlorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 181, (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-3-(2-chlorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (100 mg, 50%). 1H-NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 8.20 (s, 1H), 8.00 (s, 1H), 7.50-7.25 (m, 7H), 7.15-6.90 (m, 6H), 5.00 (s, 2H), 4.79-4.60 (m, 3H), 4.00 (m, 1H), 3.70-3.60 (m, 1H). MS (EI) for C26H23ClFN5O4 found 524 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.[C:13]([OH:17])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[C:1]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)(C)O
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of isobutyryl chloride (47 g, 0.44 mol) in CH2Cl2 (75 ml) and tert-butanol (75 ml) at 0° C., pyridine (39.3 ml, 486 mmol) was added slowly by syringe. The mixture was allowed to warm to room temperature, stirred overnight, diluted with CH2Cl2 (400 ml) and washed with H2O, HCl (2N, two times), H2O (two times) and saturated NaHCO3. The organic phase was dried over MgSO4 and filtered. The filtrate was then concentrated under reduced pressure without heat. The resulting oil was simply distilled, collecting the fraction boiling at 128-129° C. to give tert-butyl isobutyrate, 21 (35.9 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH2:23][OH:24]>>[OH:24][CH2:23][CH2:22][NH:21][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:10](/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:11]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Cl)cc1
Reactant: NCCO
Product: COc1ccc(C(=O)NCCO)cc1/C=C/c1ccc(Cl)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-chlorophenyl)vinyl]benzoic acid obtained in step B of Example 2-2-7 and 2-aminoethanol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][CH:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10](B1OC(C)(C)C(C)(C)O1)[CH:11]=2.Cl[C:38]1[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][CH:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([C:38]1[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=1)[CH:11]=2
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(B4OC(C)(C)C(C)(C)O4)ccc3n2Cc2cccc(F)c2)C1
Reactant: Cc1ccc(Cl)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc3c(c2)c2c(n3Cc3cccc(F)c3)CCC(NC(=O)C(C)C)C2)nn1
Temperature: 140 °C
Yield: 24.7 %

Procedure:
Dissolve N-[9-(3-flourobenzyl)-6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]isobutyramide (Preparation 23) (150 mg, 0.31 mmol) and 3-chloro-6-methylpyridazine (39 mg, 0.31 mmol) in dioxane (2.5 mL) and 2M Na2CO3 (388 μL). Sparge the solution with nitrogen for 5 min, add dichlorobis(triphenylphosphine)palladium (II) (11 mg, 0.016 mmol) and seal the reaction vessel. Heat to 140° C. in a microwave reactor for 30 min, then dilute with water (20 mL). Extract into EtOAc (3×25 mL), dry organics (MgSO4), filter, and concentrate in-vacuo to give the crude product (179 mg) as a brown solid. Purify the crude product on silica gel (12 g), eluting with 25-70% (4% (2M NH3/MeOH)/CH2Cl2)/hexanes to afford 35 mg (25%) of the title compound as a white solid. MS (ES): m/z 457 (M+1), 455 (M−1); HPLC (Method B) Rt=3.37 min (100%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][N:9]1[C:17](=[O:18])[C:16]2[N:15](CC=C)[C:14]([Cl:22])=[N:13][C:12]=2[N:11]([CH2:23][CH2:24][CH2:25][CH3:26])[C:10]1=[O:27])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:34]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N1CCOCC1>CN(C=O)C.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>[CH2:23]([N:11]1[C:12]2[N:13]=[C:14]([Cl:22])[NH:15][C:16]=2[C:17](=[O:18])[N:9]([CH2:8][CH2:7][CH2:6][N:44]2[CH2:45][CH2:46][N:41]([CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:42][CH2:43]2)[C:10]1=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCOS(C)(=O)=O)c(=O)n2CCCC
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: [K+]
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCCN2CCN(Cc3ccccc3)CC2)c(=O)c2[nH]c(Cl)nc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 24.1 %

Procedure:
A solution of 3-[3-butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]propyl methanesulfonate (0.08 g, 0.19 mmol) in DMF (5 ml) was treated with potassium carbonate (0.08 g, 0.6 mmol) and 1-benzylpiperazine (0.04 g, 0.23 mmol) and then heated at 70° C. for 2 h. The mixture was cooled, evaporated to dryness and partitioned between 10 ml of DCM and 10 ml of water. The organic phase was evaporated to dryness and the residue dissolved in anhydrous THF (5 ml). The solution was cautiously degassed by the repeated application of vacuum to the reaction mixture and subsequent backfilling with nitrogen gas and then treated with tetrakis(triphenylphosphine)palladium(0) (0.010 g, 0.009 mmol) and morpholine (0.200 ml, 2.3 mmol) and the mixture stirred for 2 h in a nitrogen atmosphere. The mixture was evaporated and the residue taken up in 5 ml of methanol and added to a 2 g aminopropyl SPE cartridge which was then washed with methanol and the product eluted using a 3% solution of acetic acid in methanol. Product-containing fractions were pooled and evaporated to dryness. The product was then purified by flash chromatography using a gradient elution from DCM/2% Acetic acid to DCM/20% MeOH/2% Acetic acid and the final product freeze-dried from 1,4-dioxan to give the title compound as a white solid (0.021 g, 24%).