Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[OH:21][CH2:22][CH2:23][NH2:24]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:24][CH2:23][CH2:22][OH:21])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCCO
Product: O=C(NCCO)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 2-hydroxylethylamine (17.6 mg, 0.12 mmol). The title compound was obtained as a solid (7.8 mg, 17.0% yield). MS m/z: 347.80, 349.80 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[N:3](C(OC(C)(C)C)=O)[C:4]([C:7]([O:9][CH3:10])=[O:8])=[N:5][N:6]=1.[CH3:18][O:19][CH2:20][CH2:21]O.CCOC(/N=N/C(OCC)=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH3:18][O:19][CH2:20][CH2:21][O:1][C:2]1[NH:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[N:5][N:6]=1
Reactant: COC(=O)c1nnc(O)n1C(=O)OC(C)(C)C
Reactant: COCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1nnc(C(=O)OC)[nH]1
Reaction time: 15 h
Yield: 54.9 %

Procedure:
To a solution of 4-tert-butyl 3-methyl 5-hydroxy-4H-1,2,4-triazole-3,4-dicarboxylate (0.170 g, 0.453 mmol) in THF (4 mL) was added 2-methoxyethanol (0.053 mL, 0.672 mmol), DEAD (0.107 mL, 0.682 mmol), PPh3 (0.142 g, 0.542 mmol) and stirred at it for 15 h. Reaction concentrated and ISCO purification (0-5% MeOH in DCM) to get methyl 5-(2-methoxyethoxy)-4H-1,2,4-triazole-3-carboxylate (0.050 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]([CH2:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)(=[O:18])[NH2:17]>>[C:16]([CH2:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:23][CH:22]=1)(=[O:18])[NH2:17]
Reactant: Cc1cccc(Nc2cc(Cl)ncn2)c1
Reactant: NC(=O)COc1ccc(N)cc1
Product: Cc1cccc(Nc2cc(Nc3ccc(OCC(N)=O)cc3)ncn2)c1
Yield: 30 %

Procedure:
Using an analogous procedure to that described in Example 13, 4-chloro-6-(3'-methylanilino)pyrimidine (0.23 g) was reacted with 4-(carbamoylmethoxy)aniline to give 4-[4'-(carbamoylmethoxy)anilino]6-(3'-methylanilino)pyrimidine in 30% yield, m.p. 212°-215° C.;
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][C:15](O)=[S:16])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]1[CH2:28][CH2:27][N:26]2[C:21](=NC[CH2:24][CH2:25]2)[CH2:20][CH2:19]1.ClC(OCC(C)C)=O.C(NC1CCCCC1)C>O1CCCC1>[CH2:25]([N:26]([CH:21]1[CH2:20][CH2:19][CH2:18][CH2:28][CH2:27]1)[C:15](=[S:16])[CH2:14][CH2:13][CH2:12][C:11]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[N:9][N:10]=1)[CH3:24]
Reactant: OC(=S)CCCc1nnnn1-c1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Agent: CC(C)COC(=O)Cl
Agent: CCNC1CCCCC1
Solvent: C1CCOC1
Product: CCN(C(=S)CCCc1nnnn1-c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
4-(1-Phenyl-1,2,3,4-tetrazol-5-yl)thio-butyric acid (45 mmole) is dissolved in tetrahydrofuran (50 ml) and thereto is added DBU (50 mmole). To the mixture is added dropwise with stirring isobutyl chloroformate (50 mmole) under ice-cooling. The mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise N-ethylcyclohexylamine (54 mmole) and the mixture is further stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the residue is extracted with chloroform. The chloroform layer is washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. Chloroform is distilled off and the resulting residue is subjected to column chromatography (Wakogel C-200, eluting solvent, chloroform) to isolate N-ethyl-N-cyclohexyl-4-(1-phenyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (yield: 43%), colorless liquid, nD18 =1.5590.
Reaction SMILES: [Cl:1][C:2]1[C:8]([SH:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[C:11](Cl)(Cl)=[S:12]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:8]([SH:9])=[CH:7][C:5]([N:6]=[C:11]=[S:12])=[C:4]([F:10])[CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1cc(S)c(Cl)cc1F
Solvent: ClC(Cl)Cl
Product: Fc1cc(Cl)c(S)cc1N=C=S
Temperature: 25 °C

Procedure:
2.00 g of 4-chloro-2-fluoro-5-mercaptoaniline was dissolved in chloroform, and 1.12 ml of thiophosgene was dropwise added at 0° C. After the dropwise addition, the temperature was raised to room temperature and then, the mixture was refluxed. After refluxing for six hours, chloroform was distilled off to obtain 2.47 g of the above-identified compound as brown oil.
Reaction SMILES: Cl[C:2]([C:9]1[C:10]([O:25][CH2:26][CH3:27])=[CH:11][C:12]([C:15]2[C:20]([CH2:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:23][CH3:24])=[N:13][CH:14]=1)([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>O>[CH2:23]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH2:21][CH3:22])[C:15]=1[C:12]1[N:13]=[CH:14][C:9]([C:2]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5])=[C:10]([O:25][CH2:26][CH3:27])[CH:11]=1)[CH3:24]
Reactant: CCCC(Cl)(CCC)c1cnc(-c2c(CC)cccc2CC)cc1OCC
Reactant: C1COCCN1
Solvent: O
Product: CCCC(CCC)(c1cnc(-c2c(CC)cccc2CC)cc1OCC)N1CCOCC1
Temperature: 80 °C

Procedure:
A mixture of 5-(1-chloro-1-propyl-butyl)-2-(2,6-diethyl-phenyl)-4-ethoxy-pyridine (prepared using a synthetic method similar to that given in Example 10) (20 mg, 0.052 mmol) and morpholine (0.5 mL) is heated to 80° C. for 2 hours. Water (1 mL) is added and the aqueous solution is extracted with ethyl acetate (2×2 mL). The combined organic layers are dried and concentrated in vacuo. The crude product is purified with PTLC (hexanes/ethyl acetate 4:1) to give 4-{1-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-1-propyl-butyl}-morpholine. 1H NMR: (CDCl3) 8.66 (s, 1H), 7.26 (m, 1H), 7.12 (d, 2H), 6.71 (S, 1H), 4.02 (q, 2H), 3.70 (m, 4H), 2.64 (m, 4H), 2.34 (m, 4H), 1.88 (m, 4H), 1.43 (t, 3H), 1.07 (m, 4H), 1.02 (t, 6H), 0.84 (t, 6H).
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OC1C(OS(C2C=CC(C)=CC=2)(=O)=O)=C(I)C=CC=1.[NH2:34][C:35]([NH2:37])=[S:36]>C(#N)C>[NH2:37][C:35]1[S:36][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:34]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Solvent: CC#N
Product: CCOC(=O)c1sc(N)nc1-c1ccccc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of ethyl 3-phenyl-3-oxopropionate (5.0 g, 26.0 mmol) in 100 mL of acetonitrile was added hydroxy(tosyloxy)iodobenzene (11.2 g, 28.6 mmol). The resulting suspension was stirred at 65° C. for 1 h at which time the reaction was a homogeneous solution. Thiourea (2.2 g, 28.6 mmol) was added and stirring was continued at 65° C. for 2 h. The mixture was cooled and concentrated, and the residue was taken up in ethyl acetate, washed with saturated aq Na2CO3 and brine, dried (MgSO4) and concentrated. The residue was triturated with ethyl ether to afford 4.9 g (70%) of the title compound as a yellow solid. 1H NMR (CDCl3) d 7.65 (m, 2H), 7.39 (m, 3H), 5.98 (broad s, 2H), 4.18 (q, 2H), 1.22 (t, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:15][CH:16]=2)[NH:11][N:10]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][NH2:34].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][NH:34][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Reactant: NCc1ccco1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccco1)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 123 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), C-furan-2-yl-methylamine (19 μL, 0.17 mmol), triethylamine (58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 45 mg (85%) of the title compound as a TFA salt (1.5 H2O, 1.5 TFA, effective MW=633.52). 1H NMR (DMSO-d6): δ 9.82(1H, s), 9.05 (1H, t, J=2.6), 8.73 (1H, d, J=3.7), 8.13 (4H, m), 7.73 (1H, d, J=6.8), 7.57 (2H, m), 7.26 (1H, s), 7.03 (1H, d, J=7.5), 6.40 (1H, m), 6.28 (1H, m), 4.48 (2H, d, J=6.5). ESIMS (M+H+): 436.1.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH:11]([CH2:14][OH:15])[CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:16](I)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CN(C)C=O>[CH2:31]([O:15][CH2:14][CH:11]([O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:12][OH:13])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: CCCCCCCCCCCCCCCCI
Reactant: OCC(CO)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOCC(CO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 26.2 %

Procedure:
To a suspension of about 14.26 g of washed about 50% sodium hydride in about 500 ml of dimethylformamide was added about 49.2 g of 2-(benzyloxy)-1,3-propanediol over about 20 minutes. The mixture was stirred for about 40 minutes, then cooled to about 0° C. and about 95.13 g of hexadecyl iodide were added. After standing about 10 minutes, the mixture was stirred at room temperature for about 3 hours, then filtered through celite and diluted with about 1000 ml of water. This mixture was extracted with petroleum ether. The ether extract was dried and the solvent removed giving an oil. This oil was chromatographed on a column of florisil, eluting first with petroleum ether and then successively with about 5% and about 10% ether in petroleum ether to elute the product, giving about 28.8 g of the desired title compound as a light yellow oil.
Reaction SMILES: C(=O)([O-])O.[Na+].[OH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][NH:13][C@@H:12]([CH3:16])[C:11]1=[O:17].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>CC(C)=O.O>[CH2:22]([O:21][C:19]([N:13]1[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][CH2:7][OH:6])[C:11](=[O:17])[C@@H:12]1[CH3:16])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H]1NCCN(CCCO)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@H]1C(=O)N(CCCO)CCN1C(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 100.6 %

Procedure:
Sodium hydrogencarbonate (976 mg, 11.6 mmol) was added to a solution of (S)-1-(3-hydroxy-propyl)-3-methyl-piperazin-2-one (example 20D; 1.00 g, 5.81 mmol) in acetone (5 mL) and water (5 mL), then a solution of benzyl chloroformate (1.04 g, 5.81 mmol) in acetone (1 mL) was added at 0° C. The reaction mixture was allowed to reach room temperature over 16 h, then partitioned between ethyl acetate and water. The organic layer was dried (MgSO4), filtered, and evaporated to afford the title compound (1.79 g), which was directly used in the next step.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][N:37]=[CH:36]1>C1COCC1>[N:35]1([CH2:34][CH2:33][CH2:32][NH:31][C:14]([C:7]2([CH3:17])[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=3[CH3:18])[O:8]2)=[O:16])[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: NCCCn1ccnc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCn1ccnc1)O2
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 73.3 %

Procedure:
A solution of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (500 mg, 2.00 mmol) in 10 mL THF was treated with 358 mg CDI and stirred for 1.25 h at room temperature. To this clear yellow solution was added a solution of 278 mg 1-(3-aminopropyl)imidazole in 10 mL THF over 1 h. The solution was stirred overnight at room temperature, concentrated to a pale brown oil, dissolved into 70 mL CH2Cl2, washed 1×50 mL saturated NaCl, and dried over Na2SO4. The organic layers were concentrated and flashed chromatographed to yield 524 mg of N-(3-(1H-imidazol-1-yl)propyl)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide as a white crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCI
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Agent: [H-]
Agent: [Na+]
Product: CCCCCCN(C(=O)OC(C)(C)C)n1cccc1

Procedure:
Prepared according to the N-alkylation condition used in Example 17 step a) from starting materials pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 1-iodohexane (3.0 eq.) and sodium hydride (1.3 eq.). 1H NMR (CDCl3, δ in ppm): 6.60 (m, 2H), 6.10 (m, 2H), 3.63 (t, 2H, J=7.2 Hz), 1.42 (s, 9H), 1.9-1.2 (m, 8H), 0.90 (m, 3H).
Reaction SMILES: CC1(C)CC=C(C2C=CC(C)=CC=2)C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC1=2.[CH3:33][C:34]1([CH3:71])[CH2:43][CH:42]=[C:41]([C:44]2C=C[C:47]([O:50][Si](CC(C)C)(C)C)=[CH:46][CH:45]=2)[C:40]2[CH:39]=[C:38]([C:58]#[C:59][C:60]3[CH:70]=[CH:69][C:63]([C:64]([O:66][CH2:67][CH3:68])=[O:65])=[CH:62][CH:61]=3)[CH:37]=[CH:36][C:35]1=2>>[CH3:71][C:34]1([CH3:33])[CH2:43][CH:42]=[C:41]([C:44]2[O:50][CH:47]=[CH:46][CH:45]=2)[C:40]2[CH:39]=[C:38]([C:58]#[C:59][C:60]3[CH:70]=[CH:69][C:63]([C:64]([O:66][CH2:67][CH3:68])=[O:65])=[CH:62][CH:61]=3)[CH:37]=[CH:36][C:35]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O[Si](C)(C)CC(C)C)cc2)=CCC3(C)C)cc1
Agent: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccco2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1), 250.0 mg (0.52 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-2-naphthalenyl)ethynyl]benzoate (Compound G) was converted into the title compound (colorless solid) using 142.4 mg (1.045 mmol) of zinc chloride, 24.1 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium(0) and 2-lithiofuran (prepared by the addition of 53.4 mg (0.52 ml, 0.78 mmol) of n-butyllithium (1.5M solution in hexane) to a cold solution (−78° C.) of 53.4 mg (0.784 mmol) of furan in 1.0 ml of THF). PMR (CDCl3): δ1.32 (6H, s), 1.41 (3H, t, J=7.1 Hz), 2.35 (2H, d, J=5.0 Hz), 4.39 (2H, q, J=7.1 Hz), 6.41 (1H, t, J=5.0 Hz), 6.50 (2H, s), 7.36 (1H, d, J=8.0 Hz), 7.45 (1H, dd, J=1.7, 8.0 Hz), 7.49 (1H, s), 7.57 (2H, d, J=8.2 Hz), 7.63 (1H, d, J=1.7 Hz), 8.02 (2H, d, J=8.2 Hz).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([C@H:7]([OH:10])[CH:8]=[CH2:9])[O:5][C:4](=[O:11])[C@@H:3]1[O:12][CH3:13].C([CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=C>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.C(Cl)Cl>[CH:16]1(/[CH:9]=[CH:8]/[C@H:7]([C@@H:6]2[O:5][C:4](=[O:11])[C@H:3]([O:12][CH3:13])[C@@H:2]2[OH:1])[OH:10])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C=CC1CCCC1
Reactant: C=C[C@@H](O)[C@@H]1OC(=O)[C@H](OC)[C@@H]1O
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: CO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/C2CCCC2)[C@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
2 g of 31 (10.63 mmol), 4.22 g of vinylcyclopentane (43.92 mmol), 80 mL of CH2Cl2 and 226 mg of 2nd generation Grubb's catalyst (C46H65Cl2N2PRu, MW 848.98, 0.266 mmol) are added to a 250 mL round-bottomed flask. The medium is stirred for 2 h at RT and then heated for 4 h at 45° C. The insoluble material is filtered and then the solvent is evaporated and the crude product (3.39 g) is chromatographed on a silica cartridge (150 g), eluting with a heptane/AcOEt (50/50) mixture. 1.39 g of expected product 32 (white solid) are obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[NH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:3])[CH3:2].C([Li])CCC.Cl[P:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[N:21][P:28]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([CH3:2])[CH3:3]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=N)c1ccccc1
Agent: [Li]CCCC
Product: CC(C)c1cccc(C(C)C)c1NC(=NP(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
Procedure as described for NP Amidine I using the following amounts: 4.20 g N1-(2,6-diisopropylphenyl)benzamidine (15.0 mmol), 7.50 mL of 2.0 M butyllithium (15.0 mmol), 2.70 mL of chlorodiphenylphosphine (15.0 mmol). Following removal of lithium chloride via filtration and removal of solvent in vacuo, the sticky residue was dissolved in 20 mL of pentane, reduced in volume to 5 mL (cold), producing a while solid that was filtered and dried (5.33 g, 76%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[NH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[CH:29]=[C:24]([CH:25]=[CH:26][CH:27]=3)[NH2:23])[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: Nc1cccc(B(O)O)c1
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Product: CC(On1ccc2ncc(-c3cccc(N)c3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and (3-aminophenyl)boronic acid according to the procedure described in example 4.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:9][C:10]1[C:11](=[O:20])[C:12]([CH3:19])=[C:13]([CH3:18])[C:14](=[O:17])[C:15]=1[CH3:16].Cl.C(OCC)(=O)C>C1COCC1>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:11]1([OH:20])[C:12]([CH3:19])=[C:13]([CH3:18])[C:14](=[O:17])[C:15]([CH3:16])=[C:10]1[CH3:9])[CH3:8]
Reactant: CCOC(=O)C[Zn]Br
Reactant: CC1=C(C)C(=O)C(C)=C(C)C1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(O)C(C)=C(C)C(=O)C(C)=C1C
Yield: 94 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.45 g (3.33 mmol) of 2,3,5,6-tetramethyl-1,4-benzoquinone in 4 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After cooling, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 0.79 g of the desired product (yield 94%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6](Br)[C:7](=O)[C:8]1[S:9][CH:10]=[CH:11][N:12]=1)[CH3:2].[CH:16]([NH2:18])=[S:17].C(N)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[S:17][CH:16]=[N:18][C:7]=1[C:8]1[S:9][CH:10]=[CH:11][N:12]=1)[CH3:2]
Reactant: CCOC(=O)CC(Br)C(=O)c1nccs1
Reactant: NC=S
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: NC=O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1scnc1-c1nccs1

Procedure:
To a solution of 3-bromo-4-oxo-4-thiazol-2-yl-butyric acid ethyl ester (2.2 g, 7.53 mmol) in 1,4-dioxane (40 mL) is added thioformamide (freshly made from formamide and P2S5 in 1,4-dioxane) (22.59 mmol). The mixture is refluxed overnight. The solvent is removed and NaHCO3 (aq.) (40 mL) and DCM (100 mL) are added to the residue. The organic layer is separated and the aqueous layer is extracted with DCM (2×40 mL). The combined organic layers are dried and solvent removed. The crude is purified by column (1% methanol n DCM) to give [2,4′]bithiazolyl-5′-yl-acetic acid ethyl ester.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:10].Cl[C:25]1[N:30]=[C:29]([CH3:31])[C:28]([F:32])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>C(#N)C>[F:32][C:28]1[C:29]([CH3:31])=[N:30][C:25]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=4[N:19]4[N:20]=[CH:21][CH:22]=[N:23]4)=[O:10])[CH2:3]3)[CH2:6]2)=[N:26][CH:27]=1
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(-n2nccn2)c1
Reactant: Cc1nc(Cl)ncc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)N2CC3CN(c4ncc(F)c(C)n4)CC3C2)c(-n2nccn2)c1

Procedure:
(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Example 288-step B, 33 mg, 0.10 mmol), 2-chloro-5-fluoro-4-methylpyrimidine (Intermediate 55, 15 mg, 0.10 mmol) and DIPEA (54 μL, 0.3 mmol) in ACN (1 mL) were heated in a microwave reactor for 2 h at 200° C. Then the reaction mixture was concentrated and purified via prep HPLC (Agilent, basic) gave the title compound as a clear oil. MS (ESI) mass calcd. C21H22FN7O2, 423.45; m/z found 424.2 [M+H]+. 1H NMR (CDCl3): 8.06 (d, J=1.8 Hz, 1H), 7.74 (s, 2H), 7.50 (d, J=5.8 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 6.95 (dd, J=8.5, 2.5 Hz, 1H), 3.93-3.76 (m, 5H), 3.71-3.59 (m, 2H), 3.53 (dd, J=11.4, 5.2 Hz, 1H), 3.44-3.30 (m, 2H), 3.07-2.87 (m, 3H), 2.37 (t, J=4.9 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:16]=[CH:15][S:14][C:4]=2[S:5](=[O:13])(=[O:12])[CH2:6][C:7]=1[C:8]([O:10]C)=O.[NH2:17][C:18]1[CH:22]=[C:21]([CH3:23])[O:20][N:19]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:3]2[CH:16]=[CH:15][S:14][C:4]=2[S:5](=[O:13])(=[O:12])[CH2:6][C:7]=1[C:8]([NH:17][C:18]1[CH:22]=[C:21]([CH3:23])[O:20][N:19]=1)=[O:10]
Reactant: Cc1cc(N)no1
Reactant: COC(=O)C1=C(O)c2ccsc2S(=O)(=O)C1
Solvent: Cc1ccccc1C
Product: Cc1cc(NC(=O)C2=C(O)c3ccsc3S(=O)(=O)C2)no1
Temperature: 5 °C
Yield: 56.2 %

Procedure:
A mixture of methyl 4-hydroxy-6H-thieno[2,3-b]thiopyran-5-carboxylate 7,7-dioxide (3.1 g, 0.012 mole), 3-amino-5-methylisoxazole (1.5 g, 0.015 mole) and xylene (120 ml) is refluxed for 1.5 hrs. in a Soxhlet apparatus, the thimble of which contains 15 g of Linde type 4A molecular sieve. The mixture is cooled to 5° C. in an ice-bath, and the resulting crystalline precipitate is collected. The filtrate is refluxed for two additional hours and then cooled to give a second crop. The two fractions are combined and recrystallized from CH2Cl2 --CHCl3 mixture to give a off-white crystalline solid (2.2 g, 56%), m.p. 209-210° C.