Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.[O:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[N:16]1[CH2:25][C:26](Cl)=[N:27][OH:28]>C(Cl)(Cl)Cl>[CH2:3]([C:2]1[O:28][N:27]=[C:26]([CH2:25][N:16]2[C:15](=[O:14])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:24])[CH:1]=1)[CH2:4][CH2:5][CH3:6]
Reactant: C#CCCCC
Reactant: O=C1c2ccccc2C(=O)N1CC(Cl)=NO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCc1cc(CN2C(=O)c3ccccc3C2=O)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
1-Hexyne (5.16 g, 62.9 mmol) and triethylamine (6.36 g, 62.9 mmol) were sequentially added to a suspension of 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-hydroxyethanimidoyl chloride (5.0 g, 21 mmol) in chloroform (80 mL). The solution was stirred overnight at room temperature, washed sequentially with 0.5 M hydrochloric acid and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with 3:1 to 1:1 hexane:ethyl acetate) to provide 2.14 g of 2-[(5-butylisoxazol-3-yl)methyl]-1H-isoindole-1,3(2H)-dione as a white, crystalline solid.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:31])[N:21]([CH3:30])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:30][N:21]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20](=[O:31])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: CN(CCc1ccccc1)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.5 %

Procedure:
N-Methyl-N-((1R)-1-(N-methyl-N-phenethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butylester (1.84 g, 4.12 mmol) was dissolved in dichloromethane (6 ml). The solution was cooled to 0° C. Trifluoroacetic acid (6 ml) was added. The solution was stirred for 10 min at 0° C. The solvent was removed in vacuo at 20° C. The residue was dissolved in dichioromethane (100 ml) and the solvent was removed in vacuo. This latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (70 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 350 mg of (2R)-2-(methylamino)-3-(2-naphthyl)propionic acid N-methyl-N-phenethylamide.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[S:7])[CH2:4][S:3]1.[NH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=N)[NH:10]1>CO>[NH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[S:7])[NH:10]1
Reactant: O=C1NC(=S)CS1
Reactant: N=C1NC(=N)c2ccccc21
Solvent: CO
Product: N=C1NC(=C2SC(=O)NC2=S)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 49.7 parts of 2-oxo-4-thioxothiazolidine in 990 parts of methanol there was added at 40°C and under an atmosphere of nitrogen 54.3 parts of powdered 1,3-diiminoisoindoline. Initially, a thick slurry resulted. The reaction mixture was stirred at room temperature for 2 hours during which time the mixture gradually thinned. The mixture was then heated at reflux for approximately two hours and after cooling to 25°C, was filtered. The collected solid was washed with fresh methanol and dried in vacuo at 50°C to obtain 1-imino-3-(2-oxo-4-thioxo-5-thiazolidinylidene)isoindoline as an orange powder melting at 267°-8°C (dec.).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[F:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][C:35]=1[O:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]2[CH:43]=[CH:44][S:45][C:38]=12)[NH2:32]>C1COCC1>[F:28][C:29]1[CH:30]=[C:31]([NH:32][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:33]=[CH:34][C:35]=1[O:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]2[CH:43]=[CH:44][S:45][C:38]=12
Reactant: O=C(O)CCCc1ccccc1
Reactant: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(CCCc1ccccc1)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4-phenylbutanoic acid (49 mg, 0.3 mmol) in 1 mL THF at −78° C. under nitrogen was added N-methyl morpholine (66 μL, 0.6 mmol) followed by isobutyl chloroformate (34 μL, 0.26 mmol). After 15 minutes, a solution of 3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)aniline (Example 1, Step B) in 1 mL THF was added and the reaction mixture was warmed to reflux. After refluxing overnight, the reaction was cooled to room temperature and partitioned between CH2Cl2 (30 mL) and 10% citric acid (30 mL). The organics were isolated and washed 1×30 mL with 10% citric acid and 2×30 mL with saturated NaHCO3. The organics were dried (MgSO4), filtered, concentrated and loaded onto a Biotage 12S column with 2/3 EtOAc/hexanes and eluted. The fractions containing the product were pooled and concentrated to a white foam (63 mg, 77%). 1H NMR (400 MHz, CDCl3) δ 8.48 (d, 1H), 7.75 (d, 1H), 7.73 (m, 1H), 7.69 (br s, 1H), 7.55 (d, 1H), 7.29 (m, 2H), 7.20 (m, 5H), 6.50 (d, 1H), 2.72 (m, 2H), 2.38 (m, 2H), 2.09 (m, 2H). LRMS (ESI pos) m/e 407.0 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:5])[CH3:4].[N+:15]([C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([N+]([O-])=O)[C:19]=1[C:20]#[N:21])([O-:17])=[O:16]>>[C:20]([C:19]1[C:18]([N+:15]([O-:17])=[O:16])=[CH:25][CH:24]=[CH:23][C:22]=1[O:1][CH2:2][C:3]([NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:5])[CH3:4])#[N:21]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)(CO)NC(=O)c1ccccc1
Product: CC(C)(COc1cccc([N+](=O)[O-])c1C#N)NC(=O)c1ccccc1
Yield: 91 %

Procedure:
Prepared as in Example 215c from N-(1-hydroxy-2-methylpropan-2-yl)benzamide (Boyd, R. N.; Hansen, R. H. J. Am. Chem. Soc. 1953, 75, 5896) and 2,6-dinitrobenzonitrile in 91% yield as a pale yellow solid. MS 340 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([O:9][CH:10]2[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccnc(Cl)n2)C1
Temperature: 80 °C
Yield: 95 %

Procedure:
A flask was charged with a solution of 2,4-dichloropyrimidine (300 mg, 2.0 mmol) in N,N′-dimethylformamide (10 mL). tert-Butyl 3-hydroxyazetidine-1-carboxylate (349 mg, 2.0 mmol) and cesium carbonate (1.11 g, 3.42 mmol) were added and the resulting mixture was heated to 80° C. for 2 h. Upon completion, the mixture was diluted with ethyl acetate (20 mL) and washed with 1:1 water:brine (3×40 mL). The organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by Chromatography on silica gel (0-80% ethyl acetate in hexanes) afforded tert-butyl 3-[(2-chloropyrimidin-4-yl)oxy]azetidine-1-carboxylate (550 mg, 1.9 mmol, 96%). MS EST: [M+H]+ m/z 286.1.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8](COCC[Si](C)(C)C)[N:9]=2)[CH:5]=[C:4]([CH2:19][CH:20]([C:41]2[CH:42]=[C:43]([CH:47]=[CH:48][N:49]=2)[C:44]([OH:46])=O)[O:21][C:22]([N:24]2[CH2:29][CH2:28][CH:27]([N:30]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[NH:32][C:31]3=[O:40])[CH2:26][CH2:25]2)=[O:23])[CH:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH:61]1[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1>C(Cl)Cl>[O:40]=[C:31]1[N:30]([CH:27]2[CH2:26][CH2:25][N:24]([C:22]([O:21][CH:20]([C:41]3[CH:42]=[C:43]([C:44]([N:61]4[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]4)=[O:46])[CH:47]=[CH:48][N:49]=3)[CH2:19][C:4]3[CH:5]=[C:6]4[C:10](=[C:2]([CH3:1])[CH:3]=3)[NH:9][N:8]=[CH:7]4)=[O:23])[CH2:29][CH2:28]2)[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32]1
Reactant: Cc1cc(CC(OC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cc(C(=O)O)ccn2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: C1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(CC(OC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cc(C(=O)N3CCCCC3)ccn2)cc2cn[nH]c12
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a solution of (±)-2-(2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carbonyloxy)ethyl)isonicotinic acid (39.2 mg, 0.057 mmol, 1.0 equiv.) in methylene chloride (0.7 mL) was added a drop of dimethylformamide (catalytic) followed by dropwise addition of oxalyl chloride (2 M in methylene chloride, 0.15 mL, 0.3 mmol, 5 equiv) at room temperature under nitrogen. After 2 h, excess piperidine was added dropwise and the mixture was further stirred for 1 h. The mixture was concentrated to a gel and was suspended in methylene chloride (2 mL). Trifluoroacetic acid (1 mL) was added and the resulting clear tan solution was stirred at room temperature for 6 h. The solvents were removed in vacuo and the residue was partitioned between 1 N sodium hydroxide and ethyl acetate. The layers were separated. The organic layer was washed with brine, dried and concentrated. Purification by flash column chromatography (6% methanol/methylene chloride) afforded the desired product (30.4 mg, 85.4%) as an off-white powder. MS (ESI) [M+H]+=622. 1H-NMR (400 MHz, CDCl3) δ 8.69 (d, J=4.4 Hz, 1H), 7.95 (br., 1H), 7.70 (br., 1H), 7.50-6.80 (m, 6H), 6.68 (br., 1H), 6.05-5.94 (m, 1H), 4.65-3.80 (m, 4H), 3.64 (br., 2H), 3.50-3.18 (m, 2H), 3.18-2.60 (m, 4H), 2.48 (s, 3H), 1.85-1.44 (m, 9H), 1.44-1.10 (m, 4H). HPLC tR=1.79 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].C(=O)(O)[O-:20].[Na+]>S(=O)(=O)(O)O>[C:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1)(=[O:20])[NH2:2]
Reactant: COC(=O)c1ccc(-c2ccnc(C#N)c2)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1ccc(-c2ccnc(C(N)=O)c2)cc1

Procedure:
A solution of methyl 4-(2-cyano-pyridin-4-yl)-benzoate (400 mg, 1.68 mmol) (reference example 57) in 80% sulphuric acid (3 mL) is stirred at room temperature for 12 hours. The resulting solution is poured onto ice and the mixture brought to pH 8 with sat. sodium bicarbonate solution then extracted with ethyl acetate, washed with brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 40% ethyl acetate in chloroform) to give 340 mg of the title compound. 1H NMR (CDCl3) δ 3.94 (s, 3H), 5.72 (bs, 1H), 7.67 (dd, J=5, 1 Hz, 1H), 7.75 (d, J=8 Hz, 2H), 7.9 (bs, 1H), 8.15 (d, J=8 Hz, 2H), 8.46 (bs, 1H), 8.63 (d, J=5 Hz, 1H). MS (EI) m/z 256.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[OH:11].C(N(C(C)C)C(C)C)C.OC1C=CC=C[N+]=1[O-].[NH2:29][C:30]1[C:35]([C:36](O)=[O:37])=[CH:34][C:33]([C:39]2[CH:40]=[N:41][N:42]([CH:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)[CH:43]=2)=[CH:32][N:31]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[NH2:29][C:30]1[C:35]([C:36]([NH:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=2[OH:11])=[O:37])=[CH:34][C:33]([C:39]2[CH:40]=[N:41][N:42]([CH:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)[CH:43]=2)=[CH:32][N:31]=1
Reactant: CN1CCC(n2cc(-c3cnc(N)c(C(=O)O)c3)cn2)CC1
Reactant: COc1ccc(N)c(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)c2cc(-c3cnn(C4CCN(C)CC4)c3)cnc2N)c(O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.2 %

Procedure:
2-amino-5-methoxy-phenol hydrochloride (210 mg), N-ethyl-N-isopropyl-propan-2-amine (0.208 ml) and 2-hydroxypyridine-1-oxide (221 mg) were added to a stirred solution of 2-amino-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridine-3-carboxylic acid (300 mg) dissolved in DMF (5 ml) under nitrogen. 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (382 mg) was added portionwise to this mixture and the resulting solution was stirred at 25° C. for 48 hours. The reaction mixture was purified by preparative HPLC using a Waters X-Terra reverse-phase column and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 2-amino-N-(2-hydroxy-4-methoxy-phenyl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridine-3-carboxamide (190 mg). NMR Spectrum: (DMSOd6) 1.88-2.10 (m, 6H), 2.20 (s, 3H), 2.82-2.90 (m, 2H), 3.71 (s, 3H), 4.06-4.15 (m, 1H), 6.42 (dd, 1H), 6.49 (d, 1H), 6.99 (bs, 2H), 7.26 (d, 1H), 7.85 (s, 1H), 8.16 (s, 1H), 8.30 (d, 1H), 8.39 (d, 1H), 9.51 (bs, 1H), 9.58 (bs, 1H) Mass spectrum: M+H+ 423
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10](Cl)(=[O:13])[CH2:11][CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:3]1([CH2:2][CH2:1][NH:9][C:10](=[O:13])[CH2:11][CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NCCc1ccccc1

Procedure:
The title compound was prepared in a reaction between phenethylamine (12.1 g, 100 mmol), propionyl chloride (9.25 g, 100 mmol) and triethylamine (20 ml) in methylene chloride (200 ml). The product (10.1 g) was used without purification; MS [M+H]+ 178.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][CH2:6][S:5](=[O:9])(=[O:8])[NH:4]1)[CH3:2].[CH3:10][C:11]1[C:12]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=3)=[O:25])[CH2:20][CH2:19]2)=[N:13][CH:14]=[C:15]([CH3:17])[CH:16]=1>>[CH3:10][C:11]1[C:12]([N:18]2[CH2:19][CH2:20][N:21]([C:24]([C:26]3[CH:31]=[CH:30][C:29]([N:4]4[C@H:3]([CH2:1][CH3:2])[CH2:7][CH2:6][S:5]4(=[O:9])=[O:8])=[CH:28][CH:27]=3)=[O:25])[CH2:22][CH2:23]2)=[N:13][CH:14]=[C:15]([CH3:17])[CH:16]=1
Reactant: CC[C@@H]1CCS(=O)(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: CC[C@@H]1CCS(=O)(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1
Yield: 12.9 %

Procedure:
Using (R)-3-ethylisothiazolidine 1,1-dioxide (150 mg) described in Preparation Example 3 and [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (421 mg) described in Preparation Example 113 and by the reaction and treatment in the same manner as in Example 1, the title compound (57 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7]C.[C:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)#[N:24]>>[C:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[N:4][N:5]([C:9]3[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=3)[C:6]=2[OH:7])=[CH:28][CH:27]=1)#[N:24]
Reactant: N#CCc1ccc(B(O)O)cc1
Reactant: COCCCNC(=O)c1ccc(-n2ncc(Br)c2OC)nc1
Product: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(CC#N)cc3)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 212 using 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-(3-methoxypropyl)nicotinamide and (4-(cyanomethyl)phenyl)boronic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.71 (quin, J=6.7 Hz, 2 H) 3.18 (s, 3 H) 3.21-3.30 (m, 2 H) 3.33 (t, J=6.2 Hz, 2 H) 3.94 (s, 2 H) 7.25 (d, J=8.3 Hz, 2 H) 7.86 (d, J=8.1 Hz, 2 H) 8.25-8.34 (m, 2 H) 8.36 (br. s., 1 H) 8.62 (t, J=5.6 Hz, 1 H) 8.79-8.86 (m, 1 H) 12.97 (br. s., 1 H). MS m/z 392 [M+H]+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C[Si]([CH2:13][C:14]([O:16][CH3:17])=[O:15])(C)C.[Si:18]([O:25][C:26]1[C:27]([F:38])=[C:28]([C:32](=O)[CH2:33][CH:34]2[CH2:36][CH2:35]2)[CH:29]=[CH:30][CH:31]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C1COCC1>[Si:18]([O:25][C:26]1[C:27]([F:38])=[C:28]([C:32]([CH2:33][CH:34]2[CH2:36][CH2:35]2)=[CH:13][C:14]([O:16][CH3:17])=[O:15])[CH:29]=[CH:30][CH:31]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: COC(=O)C[Si](C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)CC2CC2)c1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C=C(CC1CC1)c1cccc(O[Si](C)(C)C(C)(C)C)c1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.5 %

Procedure:
A 25 mL round bottom flask was cooled to −78° C. under N2 and charged with THF (2 mL) and lithium diisopropylamide (2.0 M in heptane/THF/ethylbenzene) (2.1 mL, 4.1 mmol) (available from Aldrich). To the cold, brown solution was added methyl (trimethylsilyl)acetate (0.61 mL, 3.7 mmol) (available from Aldrich) dropwise. The orange mixture was stirred for 15 minutes, and to it was added a solution of 84.C (0.46 g, 1.5 mmol) in THF (2 mL) dropwise. The mixture was stirred for 30 minutes at −78° C., the cooling bath was removed, and the mixture was stirred for 30 minutes at ambient temperature. The reaction was quenched with saturated aqueous NH4Cl and diluted with EtOAc. The organic phase was washed with water, 1 N HCl and brine. The organic phase was then dried (MgSO4) and concentrated. The residue was purified by silica gel flash chromatography (0-2% EtOAc/hexane) to afford 84.D (mixture of geometric isomers) (0.44 g, 81% yield) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:24])[N:7]([C:13]3[C:22]4[CH2:21][CH2:20][CH2:19][C:18](=O)[C:17]=4[CH:16]=[N:15][CH:14]=3)[C:8]2([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[BH3-]C#[N:27].[Na+].CC([O-])=O.[NH4+]>C(O)(C)C>[NH2:27][CH:18]1[C:17]2[CH:16]=[N:15][CH:14]=[C:13]([N:7]3[C:8]([CH3:12])([CH3:11])[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=4)[C:6]3=[O:24])[C:22]=2[CH2:21][CH2:20][CH2:19]1
Reactant: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc2c1CCCC2=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(C)O
Product: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc2c1CCCC2N
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A mixture of 4-(6-chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H-isoquinolin-8-one (408 mg, 1.2 mmol), NaBH3CN (75 mg, 1.2 mmol) and CH3COONH4 (1.0 g, 12 mmol) in isopropanol (10 mL) was heated to reflux for 3 hours. After cooling to room temperature, it was concentrated to afford a yellowish oil which was extracted between water with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to afford the crude title compound (327 mg, 80%) as a brown solid. MS: 342.1 & 325.1 (M+H+).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][OH:6]
Reactant: OCCOCCO
Reactant: C1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: OCCOCCOC1CCCCO1
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To 800 mL of CH2Cl2 were added diethylene glycol (57 mL, 0.6 mol) and p-toluenesulfonic acid monohydrate (5.7 g, 30 mmol) successively. Then tetrahydropyran (27.4 mL, 0.3 mol) was added dropwise at 0° C. The reaction mixture was stirred overnight and quenched with H2O, extracted with CH2Cl2, washed with H2O and brine successively, concentrated through rotary evaporation, and subjected to silica gel chromatography using CH2Cl2/MeOH as the eluent to afford compound 28 (32.5 g, 0.17 mol, 57% yield) as a clear oil: 1H NMR (500 MHz, CDCl3) δ 4.59 (t, J=4.0 Hz, 1H), 3.85-3.80 (m, 2H), 3.68-3.64 (m, 4H), 3.59-3.55 (m, 3H), 3.48-3.44 (m, 1H), 2.98 (br, 1H), 1.81-1.76 (m, 1H), 1.71-1.65 (m, 1H), 1.59-1.46 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:23][CH2:22][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH3:19])[C:12]2(O)[CH3:20])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.C(OC(=O)C)(=O)C>[CH2:1]([N:8]1[CH2:23][CH2:22][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH3:19])[C:12]2=[CH2:20])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCN1C(=O)OC2(CCN(Cc3ccccc3)CC2)C1(C)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C=C1N(CCC)C(=O)OC12CCN(Cc1ccccc1)CC2
Yield: 86.4 %

Procedure:
After refluxing a solution containing 9.6 g of 8-benzyl-4-hydroxy-4-methyl-2-oxo-3-propyl-1-oxa-3,8-diazaspiro[4,5]decane in a mixture of 96 ml of acetic acid and 5.7 ml of acetic anhydride under argon for 5 hours the solvent is evaporated under reduced pressure. After adding 5% by weight aqueous sodium hydroxide solution to the residue up to a pH value of 10, the mixture is extracted with benzene and the organic phase is washed to neutral with water. After drying the organic phase over anhydrous sodium sulfate benzene is evaporated under reduced pressure. After recrystallizing the residue from diisopropyl ether the title compound is obtained in 86.4% yield, m.p.: 70°-71° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]=[CH2:10])=[CH:7][N:6]=[C:5]2[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][C:4]=12.I[C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH3:1][O:2][C:3]1[C:8](/[CH:9]=[CH:10]/[C:23]2[CH:24]=[C:25]([CH:31]=[CH:32][C:33]=2[CH3:34])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:7][N:6]=[C:5]2[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][C:4]=12
Reactant: CCOC(=O)c1ccc(C)c(I)c1
Reactant: C=Cc1cnc2c(ccn2COCC[Si](C)(C)C)c1OC
Product: CCOC(=O)c1ccc(C)c(/C=C/c2cnc3c(ccn3COCC[Si](C)(C)C)c2OC)c1
Yield: 57.8 %

Procedure:
(E)-ethyl 3-(2-(4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)vinyl)-4-methylbenzoate (302 mg, 58% yield) was prepared as described for Example 5-C starting from 4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-5-vinyl-1H-pyrrolo[2,3-b]pyridine (340 mg, 1.12 mmol) and ethyl 3-iodo-4-methylbenzoate (360 mg, 1.24 mmol). 1H NMR (600 MHz, CDCl3) δ 8.52 (s, 1H), 8.35 (d, J=1.2 Hz, 1H), 7.87 (dd, J=1.8, 7.8 Hz, 1H), 7.45 (d, J=16.2 Hz, 1H), 7.34 (d, J=16.2 Hz, 1H), 7.31-7.27 (m, 2H), 6.81 (d, J=3.6 Hz, 1H), 5.71 (s, 2H), 4.45 (q, J=7.2 Hz, 2H), 4.43 (s, 3H), 3.62 (t, J=8.4 Hz, 2H), 2.51 (s, 3H), 1.46 (t, J=7.2 Hz, 3H), 0.97 (t, J=8.4 Hz, 2H), 0 (s, 9H). MS m/z: 467 [M+1].
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](=[O:21])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[CH2:22]([O:24][C:25]([CH:27]1[CH2:32][NH:31][C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[O:28]1)=[O:26])[CH3:23]>ClCCl>[CH2:14]([O:13][C:11]([CH2:10][C:9]([N:31]1[C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[O:28][CH:27]([C:25]([O:24][CH2:22][CH3:23])=[O:26])[CH2:32]1)=[O:21])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1CNc2ccccc2O1
Reactant: O=C(Cl)CC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(C(=O)CC(=O)OCc2ccccc2)c2ccccc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
54.6 mmol (7.6 ml) of triethylamine and 35.9 mmol (7.64 g) of benzyl 3-chloro-3-oxopropanoate are added to 17.1 mmol (3.53 g) of 2-ethoxycarbonyl-3,4-dihydro-2H-1,4-benzoxazine (described in J. Heterocyclic Chem., 1985, 22, 177) in 35 ml of dichloromethane. The reaction mixture is stirred at room temperature for 1 hour. After hydrolysis and extraction with dichloromethane, the organic phase is concentrated and purified by chromatography on silica gel using an ethyl acetate/petroleum ether mixture (2/8) as eluant to yield the expected compound.