Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[NH:7][C:6]2=[C:8]([C@@H:11]3[NH:19][C@H:16]([CH2:17][OH:18])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[CH:9]=[N:10][C:5]2=[C:4]([OH:20])[N:3]=1>FC(F)(F)C(O)=O>[OH:20][C:4]1[N:3]=[CH:2][NH:7][C:6]2=[C:8]([C@@H:11]3[NH:19][C@H:16]([CH2:17][OH:18])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[CH:9]=[N:10][C:5]=12
Reactant: OC[C@H]1N[C@@H](c2cnc3c(O)nc(O)[nH]c2-3)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Product: OC[C@H]1N[C@@H](c2cnc3c(O)nc[nH]c2-3)[C@H](O)[C@@H]1O
Reaction time: 8 h
Yield: 40.2 %

Procedure:
A solution of the product from Example 1.6 (66 mg) in trifluoroacetic acid (3 ml) was allowed to stand at room temperature overnight. The solution was concentrated and a solution of the residue in water was washed (×2) with chloroform and then evaporated. The residue was dissolved in methanol and treated with Amberlyst A21 base resin until the solution was pH˜7. The solids and solvent were removed and the residue was dissolved in water, treated with excess aqueous HCl and then lyophilized. Trituration of the residue with ethanol gave (1S)-1,4-dideoxy-1-C-(4-hydroxypyrrolo[3,2-d]pyrimidin-7-yl)-1,4-imino-D-ribitol (7) hydrochloride salt as a white solid (25 mg). Recrystallised from 90% ethanol, the crystalline solid darkened but did not melt below 300° C. NMR (300 MHz, D2O with DCl, δ ppm): 13C (relative to internal acetone at 33.2 ppm) 58.1 (C-1′), 61.4 (C-5′), 68.8 (C-4′), 73.3 (C-3′), 76.7 (C-2′), 107.5 (q), 121.4 (q), 133.5 (C-2), 135.0 (q), 148.0 (C-6) and 155.4 (q); 1H (relative to internal acetone at 2.20 ppm), 3.90 (H-4′), 3.96 (m, H-5′,5″), 4.44 (dd, H-3′, J2′,3′ 5.4 Hz, J3′,4′ 3.2 Hz), 4.71 (dd, J1′,2′ 9.0 Hz, H-2′), 5.00 (d, H-1′), 8.00 (s, H-6) and 9.04 (s, H-2).
Reaction SMILES: C(C1C=CC(C)=NC=1)C.[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:43]=[CH:42][C:24]([C:25]([NH:27][C:28]3[C:37]4[O:36][C:35]([C:38](=O)[NH2:39])=[CH:34][C:33](=[O:41])[C:32]=4[CH:31]=[CH:30][CH:29]=3)=[O:26])=[CH:23][CH:22]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>C1(C)C=CC=CC=1>[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH:27][C:28]3[C:37]4[O:36][C:35]([C:38]#[N:39])=[CH:34][C:33](=[O:41])[C:32]=4[CH:31]=[CH:30][CH:29]=3)=[O:26])=[CH:42][CH:43]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1cc(=O)c2cccc(NC(=O)c3ccc(OCCCCc4ccccc4)cc3)c2o1
Agent: CCc1ccc(C)nc1
Agent: Cl
Solvent: Cc1ccccc1
Product: N#Cc1cc(=O)c2cccc(NC(=O)c3ccc(OCCCCc4ccccc4)cc3)c2o1
Reaction time: 6 h
Yield: 87.5 %

Procedure:
To a mixture containing 50 g of 5-ethyl-2-methylpyridine and 50 g of toluene was added 10 g of 8-[4-(4-phenyl-1-butoxy)benzoyl]amino-2-carbamoyl-4-oxo-4H-benzopyran, and the reaction was allowed to proceed at 60° C. for 6 hours. After completion of the reaction, 400 ml of 4N hydrochloric acid was added, and the mixture was extracted with 400 ml of toluene. The extract was washed with diluted hydrochloric acid, water and aqueous sodium hydrogencarbonate, and the organic layer was concentrated under reduced pressure, which afforded 8.4 g of 8-[4-(4-phenyl-1-butoxy) benzoyl]amino-2-cyano-4-oxo-4H-benzopyran as a pale brown product (yield 88%).
Reaction SMILES: O=[C:2]1[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH:2]2[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])[CH2:3]2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCN(C2CN(C(=O)OCc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A mixture of benzyl 3-oxoazetidine-1-carboxylate (1.026 g, 5 mmol), 1-methylpiperazine (0.833 mL, 7.50 mmol) and acetic acid (0.429 mL, 7.50 mmol) in 1,2-dichloroethane (5 mL) was stirred at room temperature for 3 h. sodium triacetoxyborohydride (2.119 g, 10.00 mmol) was added and the reaction mixture was stirred at room temperature overnight. A small amount of water was added to the reaction mixture and the reaction mixture was directly loaded onto a 120 g ISCO column and eluted with 1-12% 2N ammonia in methanol/dichloromethane). benzyl 3-(4-methylpiperazin-1-yl)azetidine-1-carboxylate (1.45 g) was obtained as a brown oil.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:46]=[CH:45][C:15]([CH2:16][O:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[C:25]4[N:30]=[C:29]([N:31]5[C:35]([C:36]([F:39])([F:38])[F:37])=[C:34]([C:40]([O:42]CC)=[O:41])[CH:33]=[N:32]5)[CH:28]=[CH:27][CH:26]=4)=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[OH-:47].[Li+].Cl.[O:50]1CCOCC1>>[C:35]([OH:50])([C:36]([F:39])([F:38])[F:37])=[O:47].[CH:1]1([C:4]([N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:13]=[CH:14][C:15]([CH2:16][O:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[C:25]4[N:30]=[C:29]([N:31]5[C:35]([C:36]([F:39])([F:38])[F:37])=[C:34]([C:40]([OH:42])=[O:41])[CH:33]=[N:32]5)[CH:28]=[CH:27][CH:26]=4)=[CH:45][CH:46]=3)[CH2:10][CH2:11]2)=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cccc(F)c3OCc3ccc(C4CCN(C(=O)C5CC5)CC4)cc3)n2)c1C(F)(F)F
Reactant: C1COCCO1
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Product: O=C(O)C(F)(F)F
Product: O=C(O)c1cnn(-c2cccc(-c3cccc(F)c3OCc3ccc(C4CCN(C(=O)C5CC5)CC4)cc3)n2)c1C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of the title compound from Example 6 Step A (44 mg, 0.07 mmol) in 1,4-dioxane (2 mL) was added lithium hydroxide (1.0 mL, 2.0 M in water, 2.00 mmol), and the resulting mixture was stirred at 50° C. After 2 h, the reaction mixture was rendered acidic by addition of aqueous hydrochloric acid (1.5 mL), then was diluted with 1,4-dioxane and passed though a 0.45 micron syringe filter. Purification by reverse phase HPLC (40 to 100% acetonitrile in water, each with 0.1% v/v TFA) provided the title compound: LCMS m/z 608.9 [M+H]+; 1H NMR (500 MHz, d6-DMSO) δ 8.33 (s, 1H), 8.15 (t, J=8.0 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.45-7.41 (m, 1H), 7.27 (ddd, J=8.0, 8.0, 4JH-F=5.5 Hz, 1H), 7.08 (dd, J=16.5, 8.0 Hz, 4H), 4.95 (s, 2H), 4.56-4.30 (m, 2H), 3.22-3.04 (m, 1H), 2.78-2.68 (m, 1H), 2.68-2.56 (m, 1H), 2.24-1.94 (m, 1H), 1.82-1.62 (br m, 2H), 1.56-1.30 (br m, 2H), 0.82-0.64 (m, 4H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]([C:15]([O:17]CC)=[O:16])[CH2:7]2.Cl>C1COCC1.CO>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]([C:15]([OH:17])=[O:16])[CH2:7]2
Reactant: CCOC(=O)C1Cc2cc(Cl)ccc2NC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1Cc2cc(Cl)ccc2NC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.6 %

Procedure:
1N Aqueous sodium hydroxide solution (30 ml) was added dropwise to a mixed solution of ethyl 6-chloro-2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxylate (7.278 g) in THF (90 ml) and methanol (60 ml) at 0° C. The reaction mixture was stirred at room temperature for 18 hours. 1N Hydrochloric acid (30 ml) was added dropwise to the reaction mixture at 0° C., which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated. The obtained crude crystals were washed with diethyl ether to obtain the entitled compound (6.06 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][O:6][C:7]1[C:8]([N+:13]([O-:15])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K].O>CN(C)C=O>[N+:13]([C:8]1[C:7]([O:6][CH2:5][C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=2[CH2:2][N:24]2[C:23](=[O:25])[C:22]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]3[C:20]2=[O:30])=[CH:12][CH:11]=[CH:10][N:9]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ncccc1OCc1ccccc1CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1COc1cccnc1[N+](=O)[O-]
Yield: 47.3 %

Procedure:
A solution of 3-(2-chloromethylbenzyloxy)-2-nitropyridine (4.09 g) and potassium phthalimide (2.99 g) in N,N-dimethylformamide (41 ml) was stirred at 50° C. for 9.5 hours. The reaction mixture was poured into water (200 ml) and extracted twice with ethyl acetate (250 ml). The combined extract was washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the resultant residue was recrystallized from ethyl acetate to give 2-nitro-3-(2-phthalimidomethylbenzyloxy)pyridine (2.7 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[Cl:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][O:22][N:23]=[C:24]1[C:28]2([CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)[CH2:27][NH:26][CH2:25]1.C(#N)C>C(N(CC)CC)C>[C:35]([O:34][C:32]([N:30]1[CH2:31][C:28]2([C:24](=[N:23][O:22][CH3:21])[CH2:25][N:26]([C:11]3[C:12]([Cl:14])=[C:13]4[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:16])[CH2:27]2)[CH2:29]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON=C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CC12CN(C(=O)OC(C)(C)C)C2
Reaction time: 4 h
Yield: 31.4 %

Procedure:
1-cyclopropyl-6,7-difluoro-8-chloro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 530 mg of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate and 2 g of AmberliteR IRA-420 were added to 10 ml of acetonitrile and thereto 1 ml of triethylamine was added by dropping. The resulting mixture was refluxed for 72 hours and then the resulting solid was filtered off. The filtrate was concentrated under the reduced pressure and thereto 10 ml of ethylacetate was added and the resulting solution was stirred for 4 hours. The precipitated solid was filtered and dried to give 169 mg of the titled compound (yield: 31.4%).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][O:11][CH:12]([CH3:19])[CH2:13][CH:14]1[O:18][CH2:17][CH2:16][O:15]1.[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22]>C(Cl)Cl>[C:20]([O:8][CH2:9][CH2:10][O:11][CH:12]([CH3:19])[CH2:13][CH:14]1[O:15][CH2:16][CH2:17][O:18]1)(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(CC1OCCO1)OCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCOC(C)CC1OCCO1

Procedure:
Following the above procedure, the monomer was prepared using 22 g triethylamine, 35.2 g 2-[2-(2-hydroxyethoxy)-propyl]-1,3-dioxolane, 23.22 g methacryloyl chloride, and 180 ml methylene chloride. The product was purified by vacuum distillation at 93.2° C. under 0.2 mm Hg pressure.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[C:26](=O)[C:27](OC)=[O:28])#[N:16].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[C:26]1[C:27](=[O:28])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2)#[N:16]
Reactant: COC(=O)C(=O)c1c[nH]c2ccc(C#N)cc12
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5ccc(C#N)cc45)C(=O)NC3=O)c21
Temperature: 50 °C
Yield: 10.1 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (296 mg, 1.57 mmol) and methyl 2-(5-cyano-1H-indol-3-yl)oxoacetate (356 mg, 1.56 mmol) in DMF (6.5 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (4.8 mL, 4.8 mmol) dropwise over 20 min at 4° C. under N2. The resulting dark red solution was heated up to 50° C. for 6 h. The mixture was cooled to 4° C. and quenched with 1.0 N hydrochloric acid (10 mL) and poured into EtOAc (100 mL). The organic layer was separated, washed with saturated NaHCO3 (60 mL), saturated NaCl (60 mL), dried (MgSO4), and concentrated to a red solid. Filtration from a slurry in CH2Cl2 (15 mL) afforded the first batch of the title compound (58 mg, 7.4%) as a red crystalline solid, mp 220° C. dec. Tritration of the concentrated filtrate with Et2O (8.0 mL) afforded a second batch of the title compound (288 mg, 36.9%). 1H NMR (DMSO-d6) δ 8.09 (s, 1H), 7.68 (m, 1H), 7.51 (m, 1H), 7.28–7.19 (m, 2H), 7.09–6.92 (m, 2H), 6.47 (m, 2H), 3.60 (s, 3H). MS (ESI): m/z=367 [C22H14N4O2+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([C:16]3[C:17](=[S:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:24]=1.[C:25](=O)(O)[O-].[Na+].CI>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([C:16]3[C:17]([S:23][CH3:25])=[N:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:24]=1
Reactant: Cc1nc2c(s1)C=Cc1cc(Cl)ccc1C2c1c[nH]c(=O)[nH]c1=S
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CCO
Solvent: O
Product: CSc1nc(=O)[nH]cc1C1c2ccc(Cl)cc2C=Cc2sc(C)nc21
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A suspension of the product from example 38, step (v) (1.8 g) in ethanol (200 ml) and sodium bicarbonate (0.5 g) in water (15 ml) was heated until a complete solution formed. After cooling to room temperature methyl iodide (0.33 ml) was added and the whole stirred for 18 h. Another aliquot of methyl iodide was added (0.2 ml) followed by heating at 50° C. for 4 h. The reaction mixture was concentrated under reduced pressure and then partitioned between dichloromethane and brine. The organic phase was collected, dried (MgSO4) and evaporated under reduced pressure to leave a beige foam. Purification was by chromatography eluting with ethyl acetate/methanol mixtures to give the subtitle product as colourless solid.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:6]([CH2:20][CH2:21][OH:22])[S:7]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH3:18])=[CH:12][C:11]=2[CH3:19])(=[O:9])=[O:8])[CH2:5][CH2:4]1.Cl[C:24]1[N:29]=[CH:28][N:27]=[C:26]([N:30]2[CH2:35][CH2:34][C:33]3([CH2:40][CH2:39][N:38]([C:41]4[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=4)[CH2:37][CH2:36]3)[CH2:32][CH2:31]2)[CH:25]=1.O>O1CCCC1.C(OCC)(=O)C>[CH:3]1([N:6]([CH2:20][CH2:21][O:22][C:24]2[CH:25]=[C:26]([N:30]3[CH2:31][CH2:32][C:33]4([CH2:36][CH2:37][N:38]([C:41]5[CH:42]=[CH:43][N:44]=[CH:45][CH:46]=5)[CH2:39][CH2:40]4)[CH2:34][CH2:35]3)[N:27]=[CH:28][N:29]=2)[S:7]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH3:18])=[CH:12][C:11]=2[CH3:19])(=[O:9])=[O:8])[CH2:4][CH2:5]1
Reactant: COc1cc(C)c(S(=O)(=O)N(CCO)C2CC2)c(C)c1
Reactant: Clc1cc(N2CCC3(CCN(c4ccncc4)CC3)CC2)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C)c(S(=O)(=O)N(CCOc2cc(N3CCC4(CCN(c5ccncc5)CC4)CC3)ncn2)C2CC2)c(C)c1
Reaction time: 8 h
Yield: 7 %

Procedure:
To a suspension of sodium hydride (7.28 mmol, 10 equiv.) in tetrahydrofuran (10 ml) there was added, at 0° C., N-cyclopropyl-N-(2-hydroxyethyl)-4-methoxy-2,6-dimethylphenylsulfonamide (C-10) (0.8 mmol, 1.1 equiv.), followed by 3-(6-chloro-pyrimidin-4-yl)-9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane (0.73 mmol, 1 equiv.). The reaction mixture was stirrred overnight at room temperature; water was then added and the mixture was diluted with ethyl acetate. The organic phase was extracted with water and saturated sodium chloride solution, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (Alox-neutral). Yield: 7%. Rt=3.4 min; m/z=607.5 [MH]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.CC(C)=O.C(=O)=O.[Li]CCCC.[CH3:21][Si:22](Cl)([CH3:35])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C1COCC1.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([Si:22]([CH3:21])([CH3:35])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:3][CH:4]=1
Reactant: CCCCCCCCCCCC[Si](C)(C)Cl
Reactant: Brc1ccc(Br)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCC[Si](C)(C)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
100 mL of THF and 8.5 g (0.036 moles) of 1,4-dibromobenzene were put into a Schlenk flask which had been filled with nitrogen. Then the flask was agitated. The temperature was maintained at −78° C. by using acetone/dry ice. 22.6 mL (0.036 moles) of n-BuLi (1.6 M n-hexane solution) was slowly dropped into the reaction mixture over 10 minutes. After several minutes, a white salt began to be formed. After completion of the dropping of n-BuLi, a further agitation was carried out for about one hour. Then 10 g of dimethyldodecylsilyl chloride dissolved in 20 mL of THF was slowly dropped into the solution. Then the solution became clearer. After about three hours, the solution was put into 300 nL of water, and extracted with ethyl acetate. The extracts were dried by using anhydrous MgSO4 and filtered with a solvent, and then the solvent was evaporated. The obtained oil was either distilled in a vacuum (boiling point of 160-170° C./1.5 mmHg), or purified by a silica gel chromatography (eluent: n-hexane). Thus, 1-bromo-4-(dimethyldodecylsilyl)benzene (I) was obtained with a yield of about 90 % or above. The chemical structure of compound (I) was identified through 1H-NMR as follow: 1H-NMR (CDCl3): δ0.24 (s, 6H, Si(CH3)2), 0.72 (t, 2H, SiCH2), 0.89 (t, 3H,—CH3), 1.27 (m, 20H, (CH2)10, 7.37 and 7.49 (d, 4H, aromatic protons).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@H:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12].[N:29]1([C:33]([C:35]2[S:39][C:38](Br)=[N:37][C:36]=2[CH3:41])=[O:34])[CH2:32][CH2:31][CH2:30]1>C(#N)C>[N:29]1([C:33]([C:35]2[S:39][C:38]([O:7][C:8]3[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)[CH:22]=3)[C:11]([NH:13][C:14]3[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=3)=[O:12])=[N:37][C:36]=2[CH3:41])=[O:34])[CH2:30][CH2:31][CH2:32]1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(O[C@H]3CCOC3)c2)n1
Reactant: Cc1nc(Br)sc1C(=O)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1nc(Oc2cc(O[C@H]3CCOC3)cc(C(=O)Nc3ccn(C)n3)c2)sc1C(=O)N1CCC1
Temperature: 120 °C

Procedure:
Cesium carbonate (489 mg, 1.5 mmol) was added to a solution of 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide (152 mg, 0.5 mmol) and 5-(azetidin-1-ylcarbonyl)-2-bromo-4-methyl-1,3-thiazole (144 mg, 0.55 mmol) in acetonitrile (5 mL) and the stirred mixture heated at 120° C. in a microwave reactor for 2 hours. The mixture was allowed to cool, the acetonitrile evaporated in vacuo, and the residue partitioned between water (25 mL) and ethyl acetate (50 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with ethyl acetate, to give the desired compound as a solid which was further crystallised from an ethyl acetate/isohexane mixture (122 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:11][CH:12]=[N:13][CH:14]=1.[Br:21][C:22]1[C:30]2[N:29]=[C:28](Cl)[NH:27][C:26]=2[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1.C(N(CC)C(C)C)(C)C>>[Br:21][C:22]1[C:30]2[N:29]=[C:28]([N:18]3[CH2:17][CH2:16][N:15]([C:10]4[C:9]([Cl:8])=[CH:14][N:13]=[CH:12][N:11]=4)[CH2:20][CH2:19]3)[NH:27][C:26]=2[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1
Reactant: Clc1cncnc1N1CCNCC1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncncc4Cl)CC3)[nH]c2c1

Procedure:
The reaction of 1-(5-chloropyrimidin-4-yl)piperazine trifluoroacetic acid salt (0.414 g, 0.97 mmol, Example 33d), 4-bromo-2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.29 g, 0.97 mmol, Example 9b) and N,N-diisopropylethylamine (0.5 mL, 2.91 mmol, Aldrich) under the conditions of Example 1d gave the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 461 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@H:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[BH4-].[Na+].C(O)(=O)C>CO>[OH:1][CH:2]1[CH2:6][CH2:5][C@H:4]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:3]1.[OH:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:3]1
Reactant: O=C1CC[C@H](C(=O)OCc2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(OCc1ccccc1)[C@H]1CCC(O)C1
Product: O=C(OCc1ccccc1)[C@H]1CC[C@@H](O)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 158.6 %

Procedure:
To a solution of (S)-benzyl 3-oxocyclopentanecarboxylate (2 g, 9.16 mmol) in methanol (40 ml) was added sodium borohydride (0.35 g, 9.16 mmol) in portion wise manner at 0° C. and the reaction was allowed to stir at 0° C. for 20 min. Upon completion, acetic acid (0.57 ml, 10.08 mmol) was added to the reaction mixture and stirring was continued for 5 min. Methanol was removed under reduced pressure and to the residue was added water (50 ml). The organic mass was extracted using ethyl acetate (2×50 ml). Combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude compound, which was purified by column chromatography over silica gel using ethyl acetate in hexane as eluents to obtain (1S)-benzyl 3-hydroxycyclopentanecarboxylate as a diastereomeric mixture (75:25) of title compound (1.6 g, 79%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[C:13](Cl)[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=[O:21])=[CH:16][CH:15]=1)[C:11]#[N:12].[OH2:24].[NH2:25][NH2:26]>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:21])=[O:24])=[CH:16][CH:15]=2)=[N:26][NH:25][C:11]=1[NH2:12]
Reactant: N#CC(=C(Cl)c1ccc([N+](=O)[O-])cc1)c1nc2ccccc2s1
Reactant: NN
Reactant: O
Solvent: CCO
Product: Nc1[nH]nc(-c2ccc([N+](=O)[O-])cc2)c1-c1nc2ccccc2s1
Yield: 37 %

Procedure:
The 2-benzothiazol-2-yl-3-chloro-3-(4-nitrophenyl)-acrylonitrile (500 mg, 1.46 mmol) prepared above and hydrazine hydrate (150 mg, 3 mmol) were refluxed in ethanol (15 mL) for 6 hrs. The solvent was evaporated and the residue was purified by flash column chromatography eluting with CH2Cl2:MeOH=9:1 to yield 182 mg (37%) of the title compound as a yellow solid. MS (m/z, ES+): 338.04 (M+1, 100%).
Reaction SMILES: C(O[C:4](=[O:19])[C:5]([C:17]#[N:18])=[CH:6][NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][CH2:15][CH3:16])=[CH:12][CH:13]=1)C.CCCCCC>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:15]([O:14][C:11]1[N:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[N:7]=[CH:6][C:5]([C:17]#[N:18])=[C:4]2[OH:19])[CH3:16]
Reactant: CCOC(=O)C(C#N)=CNc1ccc(OCC)nc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOc1ccc2ncc(C#N)c(O)c2n1

Procedure:
A sample of 2-cyano-3-(6-ethoxy-pyridin-3-ylamino)-acrylic acid ethyl ester was heated at 257-259° C. (internal temperature) in Dowtherm for 10-12 hrs under nitrogen. After cooling, the reaction mixture was poured into n-hexane. The black solid was collected, and treated with MeOH and CH2Cl2 mixture (1:5). The title compound (or tautomer) was collected and dried. mass spectrum (electrospray, m/e): 215.9 (M+H); IR cm-1: 3063, 2226; H-NMR δ (DMSO-d6): 1.355 (3H, t, CH3), 4.412 (2H, q, CH2), 7.244 (1H, d, C7-H), 7.983 (1H, d, C8-H), 8.682 (1H, s, C2-H), 10.50 (1H, bs, OH).