Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([N:20]=[O:21])[C:5]([N:7]([CH2:17][CH:18]=[CH2:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].ClC1C=CC=C(C(OO)=[O:30])C=1.C(Cl)Cl>C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][N:4]([N:20]=[O:21])[C:5]([N:7]([CH2:17][CH:18]1[CH2:19][O:30]1)[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: C=CCN(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: c1ccccc1
Product: O=NN(CCCl)C(=O)N(CC1CO1)C1OC[C@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.2 %

Procedure:
A mixture of 5.3 g of 1-(2-chloroethyl)-1-nitroso-3-(2-propenyl)-3-(L-arabinopyranosyl)urea, 5.9 g of meta-chloroperbenzoic acid, 50 ml of methylene chloride and 50 ml of benzene is stirred at room temperature for 3 hours. After the reaction, the mixture is condensed under reduced pressure. The residue obtained is washed with ether and then purified by silica gel chromatography (Solvent: ethyl acetate). 0.9 g of 1-(2-chloroethyl)-1-nitroso-3-(oxiran-2-yl-methyl)-3-(L-arabinopyranosyl)urea is thereby obtained as yellow caramel.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:17]4[CH2:22][CH2:21][N:20](C(=O)C)[CH2:19][CH2:18]4)[CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+]>C(COC)OC>[C:1]([C:4]1[CH:27]=[CH:26][C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)ncn2-c1cccc(N2CCN(C(C)=O)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CC(=O)c1ccc2c(c1)ncn2-c1cccc(N2CCNCC2)c1
Temperature: 80 °C
Yield: 65.3 %

Procedure:
To a solution of 5-acetyl-1-(3-(1-acetylpiperazin-4-yl)phenyl)benzimidazole (see Example 12) (8.3 g, 23.0 mmol) in dimethoxyethane (140 ml) was added aqueous sodium hydroxide (70 ml, 1M) and the mixture was heated to 80° C. overnight. The organic solvent was removed under reduced pressure and the residue was diluted with water and extracted with dichloromethane. The organic phase was concentrated and purified by column-chromatography on silica gel using a mixture of dichloromethane, methanol and aqueous ammonia (90:10:1 v/v/v) as the eluent. The concentrated eluate was triturated with diethyl ether to yield 5-acetyl-1-(3-(piperazin-1-yl)phenyl)benzimidazole (4.81 g, 65%) as red crystals. This product (2.0 g, 6.25 mmol) was dissolved in refluxing ethanol (20 ml). O-isopropylhydroxylamine, hydrochloride (0.7 g, 6.25 mmol) was added and reflux was continued for 5 hours. The reaction mixture was evaporated to dryness and the residue was partitioned between aqueous sodium hydroxide (1M) and dichloromethane. The organic phase was dried and concentrated and eluted through silica gel with a mixture of dichloromethane, methanol and aqueous ammonia (90:10:1 v/v/v) to yield 5-acetyl-1-(3-(1-piperazinyl)phenyl)-benzimidazole O-i-propyl oxime (1.75 g, 74%). This product was alkylated with methyl bromoacetate in anhydrous DMF on the presence of triethylamine at room temperature to yield 5f, (0.48 g, 77%). M.p. 120-121° C.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]3[C:12](I)=[N:13][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([OH:16])[C:10]=3[O:9][N:8]=2)=[CH:4][CH:3]=1.[C:23]([Cu])#[N:24].[OH-].[NH4+].Cl>CCOC(C)=O.CN1CCCC1=O>[Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]3[C:12]([C:23]#[N:24])=[N:13][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([OH:16])[C:10]=3[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(I)c2c(-c3ccc(Br)o3)noc2c1O
Reactant: N#C[Cu]
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1nc(C#N)c2c(-c3ccc(Br)o3)noc2c1O
Temperature: 110 °C
Yield: 34.3 %

Procedure:
Ethyl 3-(5-bromofuran-2-yl)-7-hydroxy-4-iodoisoxazolo[4,5-c]pyridine-6-carboxylate (155 mg, 0.324 mmol) and CuCN (87 mg, 0.971 mmol) were added to 2.2 mL of N-methyl-2-pyrrolidone. The resulting suspension was heated in an oil bath (T=110° C.) for 1 h. The reaction mixture was cooled slightly and poured into a vigorously stirring mixture of ammonium hydroxide (5 mL, 15% aqueous solution) and EtOAc (50 mL). The mixture was acidified with concentrated hydrochloric acid to pH 3 and extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated, and the residue was purified flash chromatography (0-100% EtOAc/hexanes) to afford 42 mg of the title compound. MS: (+) m/z 378.29, 380.26 (M+1, 79Br/81Br).
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[N:22]1[C:30]([NH2:31])=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[N:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>>[NH2:31][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][N:26]2[CH:2]([C:4]1[O:5][C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: Nc1ncnc2[nH]cnc12
Reactant: Cc1cccc(-c2c(C(C)Br)oc(=O)c3ccccc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cccc(-c2c(C(C)n3cnc4c(N)ncnc43)oc(=O)c3ccccc23)c1
Yield: 54.7 %

Procedure:
The title compound was made in a similar way as that of the compound of example 1, using 3-(1-bromoethyl)-4-m-tolyl-1H-isochromen-1-one (intermediate C5, 80 mg, 0.23 mmol), 9H-purin-6-amine (63 mg, 0.46 mmol) and K2CO3 (64.4 mg, 0.46 mmol) to give the title compound (50 mg, 54%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][OH:10].[CH2:11](Br)[C:12]#[CH:13]>>[CH2:13]([O:10][CH2:9][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:12]#[CH:11]
Reactant: C#CCBr
Reactant: OCCCc1ccccn1
Product: C#CCOCCCc1ccccn1

Procedure:
From 2-pyridinepropanol (13.7 g) and propargyl bromide (80% solution in toluene, 12 ml), with a reaction time of 2 h. FCC eluting with hexane-ether (1:1) gave the title compound as an orange oil (9.0 g), t.l.c. (System B 80:20:1) Rf 0.15.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:50]([O:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=2)=[CH:55][CH:54]=1)[CH3:51]>CN(C=O)C>[CH2:50]([O:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH:65][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:60]=2)=[CH:57][CH:58]=1)[CH3:51]
Reactant: CCOc1ccc(-c2cccc(N)c2)cc1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)cc1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.016 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-ethoxy-biphenyl-3-ylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.021 g of product in 73% yield: LCMS (ESI) m/z 416 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][N:20]=1)[C:14]([O:16][CH3:17])=[O:15].[Sn](Cl)Cl.Cl>CCO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][N:20]=2)[C:14]([O:16][CH3:17])=[O:15])[CH:4]=1
Reactant: COC(=O)c1ccnc(-c2cc([N+](=O)[O-])ccc2Cl)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COC(=O)c1ccnc(-c2cc(N)ccc2Cl)c1

Procedure:
75 mL of (4-methylpyridin-2-yl)zinc(II) bromide was reacted with 4 g of 1-chloro-2-iodo-4-nitrobenzene via Procedure B. To 300 mg of 2-(2-chloro-5-nitrophenyl)-4-methylpyridine in 1.5 mL of Sulfuric Acid was slowly added 362 mg of Chromium (III) Oxide and the reaction was stirred for several hours at room temperature until complete. Icewater was added to dilute the reaction and the aqueous layer was extracted 3 times with Ethyl Acetate. The organic layers were combined, dried over Magnesium Sulfate, filtered and concentrated to give 2-(2-chloro-5-nitrophenyl)isonicotinic acid. 300 mg of 2-(2-chloro-5-nitrophenyl)isonicotinic acid was esterified with 750 μL of 4N HCl in Dioxane in 10 mL of MeOH at 55° C. for 16 hours. The reaction was concentrated and subjected to basic workup, dried over Magnesium Sulfate, filtered and concentrated to give methyl 2-(2-chloro-5-nitrophenyl)isonicotinate. 259 mg of methyl 2-(2-chloro-5-nitrophenyl)isonicotinate was treated with 200 mg of Tin (II) Chloride and 500 μL of HCl in 10 mL of EtOH. Upon completion, EtOH was concentrated and the reaction was extracted with Ethyl Acetate and water with TEA to decrease emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give crude methyl 2-(5-amino-2-chlorophenyl)isonicotinate. 240 mg of methyl 2-(5-amino-2-chlorophenyl)isonicotinate was treated with 204 μL of 2-methyl-6-(trifluoromethyl)nicotinoyl chloride via Procedure D. To 100 mg of methyl 2-(2-chloro-5-(2-methyl-6-(trifluoromethyl)nicotinamido)phenyl)isonicotinate at 0° C. in 5 mL of EtOH was slowly added 135 mg of Sodium Borohydride. The reaction was subsequently refluxed for 1 hour until complete, quenched with water and extracted with Ethyl Acetate. The organic layer was dried over Magnesium Sulfate, filtered, concentrated and purified by reverse phase HPLC to give pure N-(4-chloro-3-(4-(hydroxymethyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide. MS (Q1) 422.1 (M)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][CH:11]2[CH2:13][CH2:12]2)[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([CH3:26])[CH:18]=1>>[CH:11]1([NH:10][C:6]2[C:7]([CH:8]=[O:9])=[C:2]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][C:19]=3[CH3:26])[N:3]=[C:4]([S:14][CH3:15])[N:5]=2)[CH2:13][CH2:12]1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CSc1nc(Cl)c(C=O)c(NC2CC2)n1
Product: CSc1nc(NC2CC2)c(C=O)c(-c2ccc(F)cc2C)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-cyclopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 4-fluoro-2-methylphenylboronic acid to give the title compound 4-cyclopropylamino-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 0.69 (m, 2H), 0.94 (m, 2H), 2.23 (s, 3H), 2.62 (s, 3H), 3.14 (m, 1H), 6.98 (m, 2H), 7.20 (m, 1H), 9.09 (br s, 1H), 9.49 (s, 1H). LC MS (m/e)=318 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:5]=[C:6]([CH3:10])[C:7]([OH:9])=[O:8].[H][H]>CO.[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:5][CH:6]([CH3:10])[C:7]([OH:9])=[O:8]
Reactant: COc1ccc(C=C(C)C(=O)O)cc1F
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: COc1ccc(CC(C)C(=O)O)cc1F

Procedure:
3-fluoro-4-methoxy-α-methylcinnamic acid, 49.5 g (0.236 mol) in 800 ml methanol is hydrogenated at 43 lbs. pressure and room temperature until the theoretical uptake of hydrogen has occurred (24 min. at 20° C., using 1.5 g platinum oxide catalyst). The solution is filtered and is evaporated with warming to 60° to give 3-fluoro-4-methoxy-α-methyl dihydrocinnamic acid, Rf 0.5 on silica-gel G with methylene chloride-methanol (9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][C:11]=2[Cl:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O[CH2:17][C@@H:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[NH2:20][C@@H:18]([CH3:19])[CH2:17][N:13]1[CH:12]=[C:11]([Cl:15])[C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:14]1
Reactant: N#Cc1ccc(-c2[nH]ncc2Cl)cc1Cl
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@H](N)Cn1cc(Cl)c(-c2ccc(C#N)c(Cl)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-1H-pyrazol-5-yl)benzonitrile (0.690 g, 2.9 mmol), (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (0.508 g, 2.9), triphenylphosphine (1.14 g, 4.35 mmol) and di-tert-butyl azodicarboxylate (1 g, 4.35 mmol) using the method of Example 34(c). Yield 0.518 g. 1H NMR (400 MHz; CDCl3): δ 1.16 (d, 3H), 1.32 (bs, 2H), 3.47 (m, 1H), 3.88 (dd, 1H), 4.09 (dd, 1H), 7.56 (s, 1H), 7.69 (d, 1H), 7.99 (dd, 1H), 8.13 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:24][CH:25]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]1>>[C:32]([O:31][C:29]([N:27]1[CH2:28][CH:25]([NH:24][C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][O:10][CH:11]=3)=[CH:23][CH:22]=2)=[O:21])[CH2:26]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Product: CC(C)(C)OC(=O)N1CC(NC(=O)c2ccc(OCc3conc3-c3ccc(Cl)cc3)nc2)C1
Yield: 68 %

Procedure:
As described for example 346b, 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6 mmol) was converted, using 3-amino-1-N-Boc-azetidine instead of ethanolamine, to the title compound (200 mg, 68%) which was obtained as a colourless gum. MS: m/e=483.1 [M−H]−.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C@@H:6]1[C@@H:14]([O:15][CH2:16][CH2:17][CH2:18][NH2:19])[C@@H:13]([O:20][CH2:21][CH2:22][CH2:23][NH2:24])[C@@H:12]([CH2:25][O:26][CH2:27][CH2:28][CH2:29][NH2:30])[O:11][C@@H:7]1[O:8][CH2:9][CH3:10].[C:31]([O-:34])(O)=O.[Na+].COC([C:40]1[C:41](N[C:44](=[O:46])[CH:45]=1)=[O:42])=O.C(Cl)Cl>O.C(#N)C>[C:31]1(=[O:34])[N:1]([CH2:2][CH2:3][CH2:4][O:5][C@@H:6]2[C@@H:14]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[C:41](=[O:42])[CH:40]=[CH:45][C:44]3=[O:46])[C@@H:13]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[C:6](=[O:5])[CH:14]=[CH:13][C:12]3=[O:11])[C@@H:12]([CH2:25][O:26][CH2:27][CH2:28][CH2:29][N:30]3[C:41](=[O:42])[CH:40]=[CH:45][C:44]3=[O:46])[O:11][C@@H:7]2[O:8][CH2:9][CH3:10])[C:16](=[O:15])[CH:17]=[CH:18]1
Reactant: COC(=O)C1=CC(=O)NC1=O
Reactant: CCO[C@H]1O[C@H](COCCCN)[C@H](OCCCN)[C@H](OCCCN)[C@H]1OCCCN
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CCO[C@H]1O[C@H](COCCCN2C(=O)C=CC2=O)[C@H](OCCCN2C(=O)C=CC2=O)[C@H](OCCCN2C(=O)C=CC2=O)[C@H]1OCCCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
A solution of amine 6 (17.8 mg, 0.04 mmol) in 1 M aqueous solution of NaHCO3 (1 mL) was treated with methoxycarbonylmaleimide (37.94 mg, 0.24 mmol) at 0° C. After 5 min, the mixture was diluted with water (1 mL) and acetonitrile (2 mL), and then stirred at room temperature for 4 h. After adding CH2Cl2 (50 mL), the organic layer was separated and washed with brine (3×10 mL). The organic layer was then dried (Na2SO4), filtered, and concentrated. The oily residue was purified by flash chromatography (CH2Cl2/MeOH 95:5) to give maleimide 7 (23.2 mg, 76%); Rf 0.42 (CH2Cl2/MeOH 95:5); 1H-NMR (CDCl3/TMS): δ6.70 (s, 2H, CH═CH), 6.69 (s, 4H, CH═CH), 6.68 (s, 2H, CH═CH), 4.98 (d, 1H, J=3.4 Hz, H-1), 3.95-3.82 (m, 2H, H-4, and OCHHCH2CH2N), 3.80˜3.35 (m, 22H, H-2, H-3, H-5, H-6, H-6′, OCH2CH2CH2N, OCH2CH2CH2N, and OCH2CH3), 1.96-1.78 (m, 8H, OCH2CH2CH2N), 1.25 (t, 3H, J=7.1 Hz, OCH2CH3); ES-MS: 779.28 (M+Na)+, 401.29 (M+2Na)2+.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][NH:4][CH:3]([C:7]([O:9]C)=O)[CH2:2]1.[C:18]1([C@@H:24]2[CH2:26][C@H:25]2[N:27]=[C:28]=[O:29])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[O:9]=[C:7]1[CH:3]2[CH2:2][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][N:4]2[C:28](=[O:29])[N:27]1[C@@H:25]1[CH2:26][C@H:24]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN2C(=O)N([C@@H]3C[C@H]3c3ccccc3)C(=O)C2C1
Temperature: 25 °C
Yield: 60 %

Procedure:
To A3 in toluene (0.4M) was added dropwise trans-2-phenylcyclopropyl isocyanate (1.05 eq.). The mixture was stirred O/N at rt. DIPEA (1.5 eq.) was added and the mixture refluxed for 20 h. The organic phase was washed with phosphate buffer (2×200 mL, 0.75 M NaH2PO4, pH˜4.5) and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 20-100% EtOAc/petroleum ether to give the title compound in 60% yield. MS (ES+) C20H25N3O4 requires 371, found: 394 (M+Na)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)#[CH:14]>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.[Cu]I>[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([C:13]#[C:14][C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=2)=[CH:16][CH:17]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: CS(=O)(=O)Nc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: Cc1ccc(C#Cc2ccc(NS(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-(4-iodo-phenyl)-methanesulfonamide (0.46 g, 1.54 mmol), Pd(PPh3)2Cl2 (54 mg, 0.077 mmol) and CuI (14.7 mg, 0.077 mmol) in TEA/THF (10 mL/3 mL) was treated with 1-ethynyl-4-methyl-benzene (0.29 mL, 2.32 mmol). The reaction mixture was degassed and stirred at room temperature for 30 min. The solvent was removed under the reduced pressure. The residue was diluted with EtOAc and water. After the usual work-up, the obtained crude material was purified by chromatography (35% EtOAc/hexanes) to give the desired product. MS (EI) 286 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[C:22]#[N:23].[I:24]N1C(=O)CCC1=O.C(Cl)(Cl)Cl.[OH-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[C:7]([I:24])=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]([CH3:14])[CH3:15])[CH2:9]2)[C:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:4][C:3]=1[C:22]#[N:23]
Reactant: CN(C)[C@H]1CCN(c2cc(N)c(C#N)cc2-c2ccccc2)C1
Reactant: O=C1CCC(=O)N1I
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CN(C)[C@H]1CCN(c2c(-c3ccccc3)cc(C#N)c(N)c2I)C1
Reaction time: 6 h
Yield: 62 %

Procedure:
4-Amino-6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]biphenyl-3-carbonitrile (I-243) (75 mg, 0.25 mmol) was dissolved in acetic acid (1 ml), and at room temperature, N-iodosuccinimide (66 mg, 0.29 mmol) was added. After stirring under nitrogen atmosphere at the same temperature for 6 hours, the reaction liquid was fractionated with chloroform and aqueous 1 M sodium hydroxide solution. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=9:1) to obtain the entitled compound (67 mg, 63%) as a brown gel.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.CS(C)=O.[OH-].[Na+].Cl[CH2:17][CH2:18][CH2:19][Si:20]([O:25][CH3:26])([O:23][CH3:24])[O:21][CH3:22]>C1(C)C=CC=CC=1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:17][CH2:18][CH2:19][Si:20]([O:25][CH3:26])([O:23][CH3:24])[O:21][CH3:22])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: CO[Si](CCCCl)(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CO[Si](CCCOc1ccc(C=O)cc1)(OC)OC
Yield: 85 %

Procedure:
Using the general procedure described in the preceding Example 1, a reactor was charged with 62.2 g (0.55 mole) p-hydroxybenzaldehyde, 112 cc dimethylsulfoxide, 120 cc toluene and 43.2 g of a 50% aqueous sodium hydroxide solution containing 0.54 mole NaOH. All of the water present was removed by azeotropic distillation at a temperature of about 110° to 115° C. The reaction mixture was heated to the boiling point during the gradual addition of 109 g (0.55 mole) of 3-chloropropyl trimethoxysilane. The product, 3(p-formylphenoxy)propyl trimethoxysilane, was isolated by filtration and removal of the solvents from the recovered liquid phase under reduced pressure, followed by fractional distillation of the residue. The fraction boiling at 208° C. at a pressure of 3 mm of mercury was collected (85% yield, based on silane). The infrared and nuclear magnetic resonance spectra of the distillate confirm the proposed structure ##STR17## The vapor phase chromatogram of the product indicated a purity of greater than 98%.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Sn](CCCC)(CCCC)CCCC)[CH:7]=[N:8][CH:9]=1)(=[O:3])[NH2:2].Br[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH2:33][C@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[CH2:39][CH:40]1[CH2:42][CH2:41]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[C:1]([C:4]1[CH:5]=[C:6]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][CH:28]=[C:27]3[CH2:33][C@H:34]2[CH2:38][CH2:37][CH2:36][N:35]2[CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:7]=[N:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: Brc1ccc2[nH]cc(C[C@H]3CCCN3CC3CC3)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(C(N)=O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: NC(=O)c1cncc(-c2ccc3[nH]cc(C[C@H]4CCCN4CC4CC4)c3c2)c1

Procedure:
5-Carbamoyl-3-pyridyltri-n-butylstannane (see Preparation 43) and 5-bromo-3-(1-cyclopropylmethylpyrrolidin-2(R)-ylmethyl)-1H-indole (see Preparation 56) were reacted together in the presence of palladium (II) acetate, tri-o-tolylphosphine and triethylamine using a procedure similar to that described in Example 1. This yielded the title compound. Found: C,71.56; H,7.13; N,13.72. C23H26N4O.3/16CH2Cl2 requires: C,71.33; H,6.,81; N,14.35%.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[O:19][CH3:20]>>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:16][C:15]1[CH:17]=[CH:18][C:12]([Cl:11])=[C:13]([O:19][CH3:20])[CH:14]=1
Reactant: Clc1nc2ccccc2s1
Reactant: COc1cc(N)ccc1Cl
Product: COc1cc(Nc2nc3ccccc3s2)ccc1Cl

Procedure:
The title compound was synthesised from 2-chloro-benzothiazole (commercially available) and 4-chloro-3-methoxyaniline (commercially available) according to the procedure described for Example 1a) above. MS (m/z): 291.3 (MH+, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)[O:3]1.[H-].[Na+].[CH3:26]I>C1COCC1>[CH3:26][N:15]([C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:23])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under N2, to a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (500 mg, 1.57 mmol) in anhydrous THF (4 mL), was slowly added sodium hydride (94 mg, 2.35 mmol) at 0° C. The mixture was stirred at room temperature for 20 minutes, then cooled to 0° C. CH3I (445 mg, 3.13 mmol) was slowly added. After the completion of the addition, the reaction mixture was stirred at room temperature overnight, quenched with H2O, and extracted with EtOAc. The combined extracts were concentrated, and the residue was purified by flash chromatography to give the title compound. MS (m/z): 278 (M−56)+.