Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:28])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[C:19]([F:27])[CH:18]=1.I[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:28])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[C:19]([F:27])[CH:18]=1)[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Reactant: ICC1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 83.2 %

Procedure:
A solution of diisopropylamine (1.5 mL, 10.67 mmol) in dry tetrahydrofuran (24 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (4.3 mL, 10.67 mmol). The resulting reaction mixture was stirred at −78° C. for 45 min and then treated dropwise with a solution of (3-fluoro-4-trifluoromethyl-phenyl)-acetic acid methyl ester (2.40 g, 10.16 mmol) in a small amount of tetrahydrofuran. The reaction mixture was allowed to stir at −78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (2.24 g, 10.67 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (10 mL) and then partitioned between water (75 mL) and ethyl acetate (75 mL). The layers were shaken and separated. The aqueous layer was further extracted with ethyl acetate (1×75 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 5/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionic acid methyl ester (2.69 g, 83%) as a colorless oil: EI-HRMS m/e calcd for C16H18F4O2 (M+) 318.1243, found 318.1250.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:25]([O:27]C)=[O:26])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]=[CH:18][C:17]4[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.CO.O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:25]([OH:27])=[O:26])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]=[CH:18][C:17]4[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC=Cc1ccccc1-3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC=Cc1ccccc1-3
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A mixture of Example 1 (371 mg, 1 mmol) in THF (4 mL), methanol (3 mL), and 1.7M LiOH (3 mL, 5.1 mmol) was stirred at reflux for 1.5 hours. The mixture was cooled to room temperature, diluted with water, and acidified with dilute HCl. The resulting precipitate was collected by filtration, washed with cold water, and dried to provide 324 mg of the desired product (91% yield). ESI-MS m/z 358 (MH+); 1H NMR (300 MHz, DMSO-d6) 1.37-2.05 (m, 10H), 2.78 (m, 1H), 4.06 (s, 1H), 5.17 (s, 1H), 6.39 (m, 1H), 6.89 (d, J=10.61 Hz, 1H), 7.50 (m, 4H), 7.60 (m, 1H), 7.88 (d, J=8.78 Hz, 1H), 8.24 (s, 1H), 12.59, (s, 1H).
Reaction SMILES: COC1C=[CH:14][C:6]([C:7]([C:9]([N:11](C)C)=N)=O)=[C:5]([CH3:16])C=1.CC(C)([O-:20])C.[K+].[CH2:23]1[CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:25][O:26][C:27]1[CH:14]=[C:6]2[C:7](=[CH:24][CH:23]=1)[C:9]([OH:20])=[N:11][CH:16]=[CH:5]2
Reactant: COc1ccc(C(=O)C(=N)N(C)C)c(C)c1
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: COc1ccc2c(O)nccc2c1
Temperature: 30 °C
Yield: 93.6 %

Procedure:
A slurry of 83C (16.33 g) in a small amount of THF (25 mL) was heated to 60° C. in a flask equipped with a stir bar, reflux condenser, and addition funnel. A solution of (1 M potassium tert-butoxide in THF, 105 mL) was titrated in over a period of 30 min. The reaction turned a light yellow, and began to precipitate a solid product after about 10 min and became a thick suspension after 30 min. The reaction was cooled to 30° C. and neutralized to pH 7 with 9.5 mL conc. HCl. Water (about 25 mL) was added to dissolve all the salts, and still an easy phase split remained. The phases were split and the aqueous phase was back extracted with 25 mL ethyl acetate. The organic phases were combined and slowly concentrated at 60° C. to provide a crystalline residue. 12.16 g (93.6%) of 83D was isolated as a light orange solid. An analytical sample was prepared by recrystallization from ethyl acetate. LC retention time=13.533 min. 1H NMR (DMSO-d6) δ 3.86 (s, 3H); 6.46 (d, 1H); 7.02-7.13 (m, 3H), 8.08 (d, 1H); 11.03 (s, 1H).
Reaction SMILES: [C:1](Cl)(=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].ICC[OH:14]>>[C:1]([OH:9])(=[O:14])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5]
Reactant: OCCI
Reactant: CCCC(CCC)C(=O)Cl
Product: CCCC(CCC)C(=O)O
Temperature: 100 °C
Yield: 138.7 %

Procedure:
To the product of Example 87 (4.87 g, 30 mmol), 2-iodoethanol (5.16 g, 30 mmol) was added with stirring and cooling in an ice bath. The neat mixture was then heated to 100° C. in a water bath for 10 minutes, then removed from the heat and stirred for an additional 10 minutes. The reaction mixture was then dissolved in 50 ml of ether, washed with water (1×30 ml), 5% NaOH (2×30 ml), and again with water (2×30 ml). The ether layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. A light yellow liquid product was obtained in 67% yield from valproic acid (6.0 g). Silver nitrate gave a bright yellow precipitate. NMR analysis confirmed the identity of the product.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[C:18]3[C:17](=[O:19])O[C:15](=[O:20])[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:21][N:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[CH2:27][CH2:28][NH2:29]>O1CCOCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:18]=2[C:17](=[O:19])[N:29]([CH2:28][CH2:27][CH:23]2[CH2:24][CH2:25][CH2:26][N:22]2[CH3:21])[C:15]3=[O:20])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc2c1C(=O)OC2=O)c1ccc(Cl)s1
Reactant: CN1CCCC1CCN
Solvent: C1COCCO1
Product: CN1CCCC1CCN1C(=O)c2cccc(NC(=O)c3ccc(Cl)s3)c2C1=O

Procedure:
50 mg (0.16 mmol) of 5-chloro-N-(1,3-dioxo-1,3-dihydro-2-benzofuran-4-yl)-2-thiophenecarboxamide and 20.8 mg of (0.16 mmol) 2-(1-methyl-2-pyrrolidinyl)ethylamine are dissolved in 2 ml of dioxane and heated at reflux for 24 h. Removal of the solvent under reduced pressure gives 65 mg (97% of theory) of the desired product.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=1)=[O:28].[CH2:37]([NH:39][CH2:40][CH2:41][OH:42])[CH3:38]>>[Br:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][C:27](=[O:28])[N:2]([C@H:3]2[CH2:4][CH2:5][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:39]([CH2:37][CH3:38])[CH2:40][CH2:41][OH:42])[CH2:7][CH2:8]2)[CH3:1])=[CH:31][CH:32]=1
Reactant: O=C(Cl)Oc1ccc(Br)cc1
Reactant: CCNCCO
Reactant: CN[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCN(CCO)CCCCC[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Br)cc2)CC1

Procedure:
In analogy to examples 29.10 and 29.11, trans-Methansulfonic acid 5-(4-methyl amino-cyclohexyl)-pentyl ester.Trifluoroacetic acid salt and 4-bromophenyl chloroformate were reacted, followed by treatment with by 2-ethylamino-ethanol to yield trans-(4-{5-[Ethyl-(2-hydroxy-ethyl)-amino]-pentyl}-cyclohexyl)-methyl-carbamic acid 4-bromo-phenyl ester, MS: 469 (MH+, 1Br).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.Cl[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.ClC1C=CC(C2N(CC3C=NC=CC=3)N=C3C=2CCNCC3)=CC=1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: Clc1ccc(-c2c3c(nn2Cc2cccnc2)CCNCC3)cc1
Product: Clc1ccc(-c2nn(Cc3cccnc3)c3c2CCNCC3)cc1

Procedure:
The title compound was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.3 mmol) using 3-chloromethyl-pyridine hydrogen chloride (0.5 mmol) in place of 2-chloromethyl-thiophene. The title compound was obtained as a 2:1 mixture (25 mg) with 3-(4-chloro-phenyl)-2-pyridin-3-ylmethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene. Data for the mixture: MS (ESI): exact mass calculated for C19H19ClN4, 338.13; found, m/z 339.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.47-8.14 (m, 2H), 7.42-7.03 (m, 6H), 5.39-5.07 (two s, 2H), 2.97-2.84 (m, 2H), 2.72-2.43 (m, 2H).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[F:34][C:35]([F:40])([F:39])[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)C(F)(F)F)CC2)cc1

Procedure:
2,2,2-Trifluoro-1-{4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-ethanone was prepared according to General Procedure J by the reaction of 4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 59) with trifluoroacetic acid, followed by reaction of the resulting amine with trifluoroacetic anhydride (available from Alfa Aesar, Ward Hill, Mass., USA). 1H NMR (400 MHz, DMSO-d6) δ 2.10-2.16 (m, 4H), 3.55-3.65 (m, 1H), 4.00-4.04 (m, 1H), 4.41-4.44 (m, 1H), 5.18-5.24 (m, 1H), 7.63-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.41 (s, 1H), 8.58 (s, 1H). Mass spectrum MH+=470.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>CS(C)=O>[CH2:1]([O:8][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
Benzyl alcohol (2.22 g, 20 mmol) was added to a slurry of hexane-washed NaH (60% oil suspension, 820 mg, 20.5 mmol) in DMSO (20 mL), stirred under nitrogen at 20° C., producing strong gas evolution. After 30 minutes, 1-fluoro-4-nitrobenzene (2.826 g, 20 mmol) was added dropwise to the light grey slurry. The reaction mixture became a bright orange red and quite strongly exothermic, and a lot of gas was evolved. After 2 hours, the reaction mixture was poured onto ice-water (200 mL), and the solid was collected by Buchner filtration, rinsed with water (2×50 mL), and air dried to give 1-benzyloxy-4-nitrobenzene (4.188 g, 91.3%) as canary yellow crystals. 1H NMR (DMSO-d6): δ8.16 (2 H, AA'BB', J=9.3 Hz), 7.47 (2 H, d, J=7.1 Hz), 7.41 (2 H, t, J=7.3 Hz), 7.36 (1 H, t, J=7.1 Hz), 7.23 (2 H, AA'BB', J=9.1 Hz), 5.26 (2 H, s).
Reaction SMILES: [NH:1]([C:3]1[NH:8][C:7](NN)([CH3:9])[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:5][N:4]=1)[NH2:2].C(N(CC)CC)C.[C:25]([O:29][C:30](ON=C(C1C=CC=CC=1)C#N)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(OC(C)C)(C)C>O1CCCC1>[C:25]([O:29][C:30]([NH:2][NH:1][C:3]1[N:4]=[N:5][C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([CH3:9])[N:8]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CC1(NN)NC(NN)=NN=C1c1ccccc1
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(NNC(=O)OC(C)(C)C)nnc1-c1ccccc1
Temperature: 63 °C
Reaction time: 61 h
Yield: 104.6 %

Procedure:
A mixture of 3-hydrazino-5-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (6.6 g), triethylamine (5.4 g), 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile (9.76 g) in tetrahydrofuran (60 ml) was heated at 63° C. for 5.5 hours with stirring and then allowed to stand at room temperature for 61 hours. The mixture was treated with diisopropyl ether (40 ml), and the resultant precipitates were collected by filtration, washed successively with diisopropyl ether, methanol and diisopropyl ether, and dried to give 3-(2-t-butoxycarbonylhydrazino)-5-methyl-6-phenyl-1,2,4-triazine (8.92 g).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH:9]1(O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH:9]1([C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[OH:5])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: OC1CCCCC1
Reactant: Oc1cccc(O)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Oc1ccc(C2CCCCC2)c(O)c1
Yield: 156 %

Procedure:
Resorcinol (2.2 g, 0.02 moles) was mixed with cyclohexanol (1 g, 0.01 moles) and zinc (II) chloride (0.48 g, 0.0035 moles) and the reaction mixture heated to 150° with stirring. After heating 2 hours, the reaction mixture was allowed to cool and then dissolved in ethyl acetate. Washed with water and dried over anhydrous magnesium sulphate. The solvent was evaporated to give a brown oil (3.0 g). Excess resorcinol was evaporated by heating in a Kugelrohr oven under reduced pressure (200°, 2 mmHg). Purified using a silica column eluted with ethyl acetate:isohexane 2:8 to give the product as a yellow oil (0.5 g). Trituration with isohexane gave the product as a white solid (0.2 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:5]2.Br[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[CH2:20][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:5]2
Reactant: COC(=O)C(C)(C)Cc1cc2cc(O)ccc2[nH]1
Reactant: BrCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.2 %

Procedure:
A mixture of the phenol from step B (13.62 g, 55.14 mmol) and 2-bromomethylquinoline (12.85 g, 1.05 mol eq.) and anhydrous K2CO3 (15.22 g, 2 mol. eq.) in DMF (40 ml) was stirred at RT for 48 hours. The mixture was then poured onto ice/water and after all the ice had melted, the brown solid was collected and air-dried. The dried material was passed through a plug of silica (using EtOAc/hexane (1:3) as eluent) to remove the color; yield: 19 g, 88%. Recrystallization from EtOH afforded 14.17g of pure title compound, m.p. 131°-132° C.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.CC([Mg]Cl)C.[O:15]=[C:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[NH4+].[Cl-]>C1COCC1>[OH:15][C:16]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=C1CCOCC1
Reactant: N#Cc1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(O)CCOCC2)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-iodobenzonitrile (5.0 g, 21.8 mmol) in dry THF (100 mL) was added 2-propyl magnesium chloride (2M solution in diethyl ether, 11 mL, 21.8 mmol) dropwise at −40° C. After stirring for 1.5 h at this temperature, the reaction mixture was cooled to −78° C. before it was canulated to a solution of 4-oxotetrahydro-2H-pyrane (3.28 g, 32.8 mmol) in dry THF (100 mL) which was likewise cooled to −78° C. After the slow addition of the Grignard reagent was completed, the reaction mixture was stirred at −78° C. for additional 10 minutes, then at 0° C. for 2 h, and finally at rt for 30 minutes. A few mL saturated aqueous NH4Cl were added, and then most of the solvent was evaporated. The residue was partitioned between water and ethyl acetate (200 mL each). After separation, the aqueous layer was extracted using ethyl acetate. The combined organic layers were successively washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the crude material was purified by MPLC (silica, cyclohexane/ethyl acetate 2:1→1:1). The title compound was obtained as a highly viscous oil (1.19 g, 27%): 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, 2H), 7.70 (d, 2H), 5.30 (s, 1H), 3.81-3.70 (m, 4H), 2.02-1.94 (m, 2H), 1.51-1.48 (m, 2H); DCI(NH3)-MS m/z 204 (MH)+, 221 (M+NH4)+; HPLC RT (Method I) 3.35 min.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=[O:15].C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH3:24].CC(=O)OCC>CN(C=O)C>[CH2:23]([N:12]1[C:13]2[CH:1]=[C:2]([CH:14]=[O:15])[CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:24]
Reactant: O=Cc1ccc2c(c1)[nH]c1ccccc12
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2ccc(C=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
A 100-mL round-bottom flask was charged with a solution of 9H-carbazole-2-carbaldehyde (3.7 g, 18.97 mmol, 1.00 equiv) in DMF (50 mL). To this was added K2CO3 (5.23 g, 37.90 mmol, 2.00 equiv) followed by addition of bromoethane (10 g, 91.74 mmol, 4.80 equiv). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by TLC (EA:PE=1:3). Upon completion, the reaction mixture was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL), combined organic layers were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:10) affording 9-ethyl-9H-carbazole-2-carbaldehyde as yellow solid (2.6 g, 61%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](Br)[C:7]([Cl:11])=[N:6][CH:5]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[C:7]([Cl:11])=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of 5-bromo-6-chloro-nicotinic acid methyl ester (10 g, 40 mmol) in toluene (200 mL) was added 4-chlorophenyl-boronic acid (6.4 g, 40 mmol), [1,1′-bis(diphenylphosphino)ferrrocene]dichlorpalladium(II) dichloromethane complex (1.6 g, 2 mmol) and 2 M sodiumcarbonate solution (60 mL). The reaction mixture was stirred for 2 h at 90° C. After cooling, the phases were separated; the aqueous phase was extracted once with ethyl acetate (200 mL), organic phases were washed once with water and brine (150 mL each), combined and dried over MgSO4. After evaporation of the solvent the crude product was purified by flash column chromatography (dichloromethane/heptane 2:1 to 9:1) to give 6-chloro-5-(4-chloro-phenyl)-nicotinic acid methyl ester as a colorless solid, 8.12 g (72% yield). m/z (ES+): 281.1, 283.1 (M+H).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([NH:19][C:20]4[S:21][C:22]5[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=5[N:24]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:5][CH2:4]1.[CH3:33][N:34]([CH2:36][C:37](O)=[O:38])[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:33][N:34]([CH3:35])[CH2:36][C:37]([N:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([NH:19][C:20]4[S:21][C:22]5[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=5[N:24]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:5][CH2:4]1)=[O:38]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCNCC3)ccc21
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCC(NC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(Cl)cc4s2)n3C)CC1
Yield: 57.7 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [1-(2-dimethylamino-acetyl)-piperidin-4-yl]-amide (52 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid piperidin-4-ylamide dihydrochloride (88 mg), dimethylamino-acetic acid (26 mg), HBTU (95 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 525.5. 1H NMR (DMSO-d6, 400 MHz): δ 8.40-8.38 (d, 1H), 8.11 (s, 1H), 7.96 (m, 1H), 7.80-7.78 (d, 1H), 7.55-7.50 (m, 2H), 7.43-7.40 (d, 1H), 4.43-4.25 (m, 2H), 4.09-4.08 (br. m, 1H), 3.68 (s, 3H), 3.67-3.65 (m, 1H), 3.57-3.50 (m, 1H), 3.22-3.17 (m, 1H), 2.93-2.82 (m, 6H), 1.96-1.89 (m, 2H), 1.59-1.46 (m, 2H), 1.30-1.25 (m, 1H) —NH proton signal was not observed.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13]O)=[CH:4][C:3]=1[CH3:15].O1CCCC1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:23][CH2:13][C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:15])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(-c2oncc2CO)ccc1Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(-c2oncc2CCl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To a mixture of 5-(4-chloro-3-methylphenyl)-4-isoxazolylmethanol (5.80 g), tetrahydrofuran (20 ml) and toluene (80 ml) was added dropwise thionyl chloride (4.63 g) at 0° C. and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were filtrated and recrystallized from ethyl acetate-hexane to give 4-chloromethyl-5-(4-chloro-3-methylphenyl) isoxazole (5.47 g, yield 87%) as a colorless prism. melting point: 84–85° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([O:13][C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[Cl:23])[CH3:12]>CCO.O1CCOCC1>[CH2:11]([O:13][C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:18][C:17]=1[Cl:23])[CH3:12]
Reactant: CCOC(=O)Cc1ccc(N)cc1Cl
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 0.600 g of 2-chloro-3-nitro-pyridine (Aldrich) and 0.800 g of (4-amino-2-chloro-phenyl)-acetic acid ethyl ester (see WO 97/21665) in 20 ml of EtOH/dioxane (1:1, v/v) is stirred and refluxed for 72 hours. The mixture obtained is allowed to cool to rt and is concentrated in vacuo. The concentrate obtained is subjected to silica gel column chromatography. A solid is obtained which is triturated with Et2O. [2-Chloro-4-(3-nitro-pyridin-2-ylamino)-phenyl]-acetic acid ethyl ester is obtained in the form of a solid. ES-MS: 336.0 [M+H]+; single peak at tR=5.59 min (System 1); Rf=0.39 (Hexane/EtOAc, 7:3).