Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:26][CH2:27][CH2:28][CH2:29]O)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8]C)=[N:6][CH:7]=1.[ClH:31]>>[Cl:31][CH2:29][CH2:28][CH2:27][NH:26][C:24]([C:23]1[CH:22]=[N:21][N:18]2[CH:19]=[CH:20][C:15]([N:11]3[CH2:12][CH2:13][CH2:14][C@@H:10]3[C:4]3[C:5]([OH:8])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:16][C:17]=12)=[O:25]
Reactant: Cl
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCCCO)c2n1
Product: O=C(NCCCCl)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3O)nc12
Temperature: 85 °C
Yield: 106 %

Procedure:
A mixture of (R)-5-(2-(5-fluoro-2-methoxy pyridin-3-yl)pyrrolidin-1-yl)-N-(3-hydroxypropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20 mg, 0.0483 mmol) in HCl (4 N dioxane, 1.2 mL, 4.83 mmol) was heated at 85° C. overnight. The reaction mixture was concentrated, triturated with ether, and filtered, to provide the crude product as a beige solid, which was directly used in the next step without further purification (22 mg, 106% yield). MS (apci) m/z=419.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][C:8]=2[F:16])=[CH:4][C:3]=1[F:19].Cl[C:21]1[CH:31]=[C:25]2[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:21]3[CH:31]=[C:25]4[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]4[C:23](=[O:32])[N:22]=3)=[CH:9][C:8]=2[F:16])=[CH:4][C:3]=1[F:19]
Reactant: OCCc1ccc(Oc2ccc(Cl)c(F)c2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCCc1ccc(Oc3ccc(Cl)c(F)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 2-(4-(4-chloro-3-fluorophenoxy)-3-fluorophenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[C:14](=O)([O:17]C)[O:15][CH3:16].[H-].[Na+]>Cl>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([C:14]([O:15][CH3:16])=[O:17])[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: COC(=O)OC
Reactant: O=C1CCCCc2ccc(Br)cc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1CCCc2ccc(Br)cc2C1=O
Temperature: 85 °C
Reaction time: 3 h
Yield: 107.2 %

Procedure:
To a solution of 3-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one from step A1 (600 mg, 2.51 mmol) in neat dimethyl carbonate (2.81 mL, 33.3 mmol) was slowly added 60% NaH dispersed in mineral oil (251 mg, 6.27 mmol). The mixture was stirred at 85° C. for 3 h, then cooled to rt, treated with 1 N HCl (40 mL), and extracted with EtOAc (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford crude methyl 3-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-carboxylate (800 mg, 2.69 mmol, 107% yield), which was used for the next step without purification. LCMS (M+H)+=297.2. 1H NMR (500 MHz, chloroform-d) δ 12.56 (s, 1H), 7.78 (d, J=2.1 Hz, 1H), 7.47 (dd, J=8.2, 2.1 Hz, 1H), 7.12 (d, J=7.9 Hz, 1H), 3.86 (s, 3H), 2.61 (t, J=6.9 Hz, 2H), 2.18-2.05 (m, 4H).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:14][O:15][C:16](=[O:42])[C@H:17]([O:20][C:21]1[CH:22]=[C:23]([CH:39]=[CH:40][CH:41]=1)[CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=2)[C:27]([CH3:37])=[C:26]1[CH3:38])[CH2:18][CH3:19]>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:34]([C:30]2[CH:29]=[C:28]3[C:33](=[CH:32][CH:31]=2)[N:25]([CH2:24][C:23]2[CH:22]=[C:21]([CH:41]=[CH:40][CH:39]=2)[O:20][C@H:17]([CH2:18][CH3:19])[C:16]([O:15][CH3:14])=[O:42])[C:26]([CH3:38])=[C:27]3[CH3:37])=[O:35])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: CC[C@@H](Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1)C(=O)OC
Agent: Cl
Product: CC[C@@H](Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1)C(=O)OC

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(3-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO[CH2:16][N:17]([CH2:25][Si](C)(C)C)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl.FC(F)(F)C(O)=O>[CH2:12]([O:11][C:1]([C@H:2]1[C@H:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:25][N:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16]1)=[O:10])[CH3:13]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 48 %

Procedure:
To a mixture of ethyl trans-cinnamate (2 g, 11.4 mmol) and N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine (2.37 mL) in dichloromethane (18 mL) was added 3 drops of trifluoroacetic acid and the mixture was stirred at 40° C. for 45 min. Then another 0.56 mL of N-(methoxymethyl)(phenyl)-N-((trimethylsilyl) methyl)methanamine and 1 drop of trifluoroacetic acid were added and the mixture was stirred at 40° C. for another 45 min. Then another 0.26 mL of N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine and 1 drop of trifluoroacetic acid were added and the mixture was stirred at 40° C. for overnight. After cooling down to room temperature, the mixture was concentrated under vacuum and purified by Flash Chromatography with from 8% ethyl acetate/92% hexane to 10% ethyl acetate/90% hexane over 20 min. to give the title compound as a clear colorless sticky oil (1.69 g, 48% yield). 1H NMR (400 MHz, CDCl3) δ 1.20 (3H, t, J=6.4, 9.6 Hz), 2.86 (1H, m), 3.00 (1H, t, J=9.6 Hz), 3.04–3.07 (2H, m), 3.65–3.68 (3H, m), 4.09–4.13 (2H, m), 7.19–7.37 (10H, m). HPLC purity (retention time): 93% (1.30 min, method C). MS: 310.30 (MH+).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:8]([C:17]([N:21]=[C:22]=[O:23])([CH2:19][CH3:20])[CH3:18])=[N:9][C:10]([N:14]=[C:15]=[O:16])([CH2:12][CH3:13])[CH3:11]>CCCCC>[N:8]([C:17]([NH:21][C:22]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:23])([CH2:19][CH3:20])[CH3:18])=[N:9][C:10]([NH:14][C:15]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:16])([CH2:12][CH3:13])[CH3:11]
Reactant: NC1CCCCC1
Reactant: CCC(C)(N=C=O)N=NC(C)(CC)N=C=O
Solvent: CCCCC
Product: CCC(C)(N=NC(C)(CC)NC(=O)NC1CCCCC1)NC(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4.7 grams (0.0474 moles) of cyclohexylamine in 30 ml of pentane in a 50 ml erlenmeyer flask cooled in a water bath was added 5.32 grams (0.0237 moles) of 2,2'-azobis(2-isocyanatobutane) (from Example XXXVI) dropwise over 20 minutes while holding the reaction temperature below 30° C. After the addition was complete, the reaction was stirred for an additional 60 minutes at room temperature and filtered. The filter cake was washed with pentane and dried. The dry white solid weighed 4.7 grams (47% crude yield) and melted at 110°-113° C. The product had a strong carbonyl band at 1665 cm-1 and NH peaks at 3320 cm-1 and 3440 cm-1 in its infrared spectrum.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[Br:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH:21]=[CH:22][C:23](O)=O>>[Br:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[CH:21]=[CH:22]/[C:23]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: COc1ccc(C=CC(=O)O)cc1Br
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(Br)c3)nc2n(CCC)c1=O
Yield: 57.7 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.0 g (13.3 mmol) of 5,6-diamino-1,3-dipropyluracil and 3.75 g (14.6 mmol) of 3-bromo-4-methoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 3.43 g (yield 58%) of Compound 55 as yellow needles.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][CH2:14][OH:15])[CH2:9][C@H:10](O)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].CC1C=CC(S([Cl:28])(=O)=O)=CC=1.Cl>O1CCOCC1.COCCOCCN(CCOCCOC)CCOCCOC>[ClH:28].[CH2:1]([N:8]1[CH2:13][CH2:14][O:15][C@H:10]([CH3:11])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](O)CN(CCO)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@@H]1CN(Cc2ccccc2)CCO1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 33.4 %

Procedure:
To a stirred solution of (R)-1-(benzyl(2-hydroxyethyl)amino)propan-2-ol (110 g, 525.60 mmol) in dioxane (500 mL) under nitrogen, potassium hydroxide powder (88 g, 1576.80 mmol) and tris(2-(2-methoxyethoxy)ethyl)amine (1.681 mL, 5.26 mmol) were successively added. The mixture was cooled to 0° C. and a solution of 4-methylbenzene-1-sulfonyl chloride (105 g, 551.88 mmol) in dioxane (500 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 45 min then at room temperature for an additional 4 h. The mixture was filtered and filtrate evaporated. The residue was dissolved in DCM and purified on silica, eluting with 25% of EtAc in DCM. The solvents were evaporated to afford an oil which was diluted with EtAc (250 mL). A solution of 4N HCl in dioxane (0.066 L, 262.8 mmol) was then added dropwise under stirring. After 30 min, the formed solid was collected by filtration, washed with diethyl ether and dried to afford (R)-4-benzyl-2-methylmorpholine hydrochloride (40 g, 33%) as a white solid. Proton NMR Spectrum: (DMSO-d6): 1.09 (d, 3H), 2.67-2.77 (m, 1H), 2.93-3.04 (m, 1H), 3.14-3.23 (m, 2H), 3.83-4.00 (m, 3H), 4.29-4.34 (m, 2H), 7.43-7.49 (m, 3H), 7.60-7.68 (m, 2H), 11.62 (bs, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl>[Si:17]([O:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCc1ccncc1
Temperature: -78 °C
Yield: 97.9 %

Procedure:
4-(2-Hydroxyethyl)pyridine (8.1 g, 65.8 mmol) and triethylamine (10.1 mL, 66 mmol) were dissolved in CH2Cl2 (100 mL) and cooled to −78° C. To this solution, tert-butyldimethylsilyl chloride (11.0 g, 66 mmol) was added. The mixture was allowed to warm to room temperature overnight. The mixture was placed directly on a bed of SiO2 and eluted with 100:0-10:1 CH2Cl2 methanol to provide 4-[2-(tert-Butyldimethylsilyloxy)ethyl]pyridine (15.3 g, 97%).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:13][N:14]([CH3:18])[C:15]([C:12]1[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12)=[O:16]
Reactant: CC(C)c1cc2ccccn2n1
Reactant: CN(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(C)c1nn2ccccc2c1C(=O)N(C)C

Procedure:
A mixture of 1.6g of 2-isopropylpyrazolo[1,5-a]pyridine and 2.1g of N,N-dimethylcarbamoyl chloride was dissolved in 20 ml of nitrobenzene. Four grams of aluminum chloride (powder) was added at room-temperature to the resulting solution and reaction mixture was refluxed for 8 hr and concentrated under reduced pressure. Water was added to the residue and the mixture was made basic with potassium hydroxide solution, extracted with chloroform. The chloroform solution was dried over sodium sulfate and concentrated. The residue was column chromatographed over alumina to give objective product. Distillation gave colorless oil, bp 175° (2 mmHg). Yield 1.1g (50%).
Reaction SMILES: [CH3:1][N:2]1[CH2:22][CH2:21][CH2:20][N:5]2[C:6]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:7]=3O[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1.[C:23]1(C)C=CC=CC=1.C(O)C>>[CH3:1][N:2]1[CH2:22][CH2:21][CH2:20][N:5]2[C:6]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:7]=3[CH2:23][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1
Reactant: Cc1ccc2c(c1)N1CCCN(C)CC1c1ccccc1O2
Reactant: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc2c(c1)N1CCCN(C)CC1c1ccccc1C2

Procedure:
1,2,3,4,5,15b-hexahydro-2,8-dimethyl-1,4-diazepino[1,2-d]dibenz[b,f](1,4)oxazepine, (oil) Rf in toluene:ethanol (8:2)=0.42 on SiO2 ;
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[C:9]([CH3:14])=[N:10][NH:11][C:12]=1[CH3:13])([CH3:4])([CH3:3])[CH3:2].CC(=O)CC(=O)C.[Cl:23][C:24]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:25]=1[CH2:26]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[C:12]([CH3:13])=[N:11][N:10]([CH2:26][C:25]2[CH:28]=[CH:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][C:24]=2[Cl:23])[C:9]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Reactant: Cc1n[nH]c(C)c1CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)=O
Solvent: CC#N
Product: Cc1nn(Cc2ccc([N+](=O)[O-])cc2Cl)c(C)c1CC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of (3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid tert-butyl ester (2.6 g, 12.4 mmol, preparation according to WO2007/141267 by using 2,4-pentanedione instead of 3,5-heptanedione) and 2-chloro-4-nitrobenzyl bromide (3.11 g, 12.4 mmol) in acetonitrile (30 mL) is added K2CO3 (2.575 g, 18.6 mmol) and the mixture is stirred for 48 hours at room temperature and after that 2 hours at 60° C. The solid is filtered off and the solvent is removed by evaporation. The residue is dissolved in dichloromethane/water. After extraction with dichloromethane the organic layer is dried over MgSO4 and evaporated under reduced pressure to yield 4.4 g of [3,5-dimethyl-1-(2-chloro-4-nitrobenzyl)-1H-pyrazol-4-yl]acetic acid tert-butyl ester (ESI mass spectrum: [M+H]+=380). b) To a solution of [3,5-dimethyl-1-(2-chloro-4-nitrobenzyl)-1H-pyrazol-4-yl]acetic acid tert-butyl ester (4.40 g, 11.6 mmol) in methanol (80 mL) is added Raney nickel (440 mg) and the mixture is hydrogenated at 50 psi and room temperature for 12 hours. The catalyst is filtered off and the filtrate is concentrated under reduced pressure to yield 2.4 g of the title compound (ESI mass spectrum: [M+H]+=350; Retention time HPLC: 0.76 min (method D)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][CH:19]([OH:22])[CH:20]=[CH2:21]>C(Cl)Cl>[OH:22][CH:19]([CH3:18])[CH:20]=[CH:21][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1
Reactant: C=CC(C)O
Reactant: CN1CCC(c2c[nH]c3ccc(Br)cc23)CC1
Solvent: ClCCl
Product: CC(O)C=Cc1ccc2[nH]cc(C3CCN(C)CC3)c2c1

Procedure:
Obtained by a procedure similar to that described in Example 1, using 5-bromo-3-(N-methyl-4-piperidyl)-1H-indole (EP-A-0303507) and but-3-en-2-ol, as a foam. Rf 0.50 (SS 4). Found: C,72.85; H,8.22; N,9.17. C18H24N2O; 0.17 CH2Cl2 requires C,73.08; H,8.22; N,9.38%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH:11]([C:13]1[O:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=1)=O>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]([C:4]1[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[NH:6][CH:5]=1)[C:13]1[O:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=1)=[CH:5][NH:6]2
Reactant: O=Cc1ccc(C(=O)O)o1
Reactant: Clc1cccc2[nH]ccc12
Product: O=C(O)c1ccc(C(c2c[nH]c3cccc(Cl)c23)c2c[nH]c3cccc(Cl)c23)o1

Procedure:
The compound Bis(4-chloroindol-3-yl)-(5-carboxy-2-furyl)methane was prepared following procedure A, starting from 4-chloro indole and 5-formyl 2-furan carboxylic acid. LC: Tr 2.31 min, MS: 425 (M+H)+
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=O.[C:14]1([NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20].C([O-])(=O)C.[Na+]>C(O)C>[N+:11]([C:7]1[CH:6]=[C:5]([C:3]2[CH:2]=[N:21][C:14]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:20]=2)[CH:10]=[CH:9][CH:8]=1)([O-:13])=[O:12]
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: Nc1ccccc1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Yield: 59.2 %

Procedure:
A mixture of 2-bromo-1-(3-nitrophenyl)ethanone (20.5 g, 84 mmol), 1,2-phenylenediamine (8.6 g, 80 mmol) and sodium acetate (12.2 g, 90 mmol) in ethanol (EtOH) (250 mL) was heated at reflux for 5 hrs. The reaction mixture was cooled to room temperature, filtered, washed with EtOH and water, and dried to afford 2-(3-nitrophenyl)quinoxaline (11.9 g, 59% yield). LCMS calculated for C14H9N3O2 (M+H): 252.25. found 252; (M+H+MeCN): 293.10. found 293. 1H-NMR (400 MHz, DMSO-d6) δH: 9.62 (1H, s), 9.12 (1H, m), 8.81 (1H, m), 7.42 (1H, m), 8.30-8.10 (2H, m), 8.00-7.82 (3H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[OH:11][C:12]1[C:7]2[C:2](=[CH:3][CH:4]=[C:5]([OH:8])[CH:6]=2)[N:1]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(O)cc1
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(O)cc2c1O
Temperature: 25 °C
Yield: 5.5 %

Procedure:
A mixture of 4-aminophenol (5.457 g) and diethyl ethoxymethylenemalonate (10.81 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature. Diphenyl ether (50 mL) is added and the mixture is heated to 250° C. for 45 min with removal of ethanol by a Dean-Stark trap. The solution is cooled to 80° C. and the resulting solid is collected and washed with hexanes. The solid is suspended in 250 mL MeOH and brought to a boil. The insoluble material is filtered and the filtrate is adsorbed onto silica and chromatographed, eluting with 5% MeOH/CH2Cl2 then with 10% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo to yield 0.644 g of ethyl 4,6-dihydroxyquinoline-3-carboxylate. A mixture of this ester (0.500 g) and 4-chlorobenzylamine (1.518 g) are heated to 180° C. for 1 h. The solution is cooled to room temperature and diluted with CH2Cl2. The resulting solid is collected and chromatographed on silica, eluting with 3% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo. The residue is sonicated with CH2Cl2 /hexanes. The resulting solid is collected and dried to afford 0.372 g of the desired product as a white solid.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li].[CH3:15][C:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.O>O1CCCC1>[CH:17]1([C:16]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH3:15])[CH:21]=[CH:20][CH:19]=[CH:18]1
Reactant: CC(=C1C=CC=C1)c1ccccc1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccccc1)(C1C=CC=C1)C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A solution of 67.8 mmol of lithium-fluorene in 50 cm3 of tetrahydrofuran was added to a solution of 11.4 g (67.8 mmol) of 6-methyl-6-phenylfulvene in 40 cm3 of tetrahydrofuran at room temperature. After the mixture had been stirred at room temperature for 2 hours, 60 cm3 of water were added. The substance which precipitated out was filtered off with suction, washed with diethyl ether and dried under an oil pump vacuum. 19.2 g (84.2%) of 1-cyclopentadienyl-1-(9-fluorenyl)-ethylbenzene were obtained (correct elemental analyses; 1 H-NMR spectrum). 10.0 g (19.9 mmol) of the compound were dissolved in 60 cm3 of tetrahydrofuran and 26 cm3 (65 mmol) of a 2.5 molar hexane solution of n-butyllithium were added at 0° C. After the mixture had been stirred for 15 minutes, the solvent was stripped off in vacuo. The dark red residue which remained was washed several times with hexane and dried under an oil pump vacuum. 15.6 g of the red dilithium salt were obtained as the tetrahydrofuran adduct which contained about 30% of tetrahydrofuran. A suspension of 4.78 g (14.9 mmol) of HfCl4 in 70 cm3 of CH2CH2 was reacted with 14.9 mmol of the dilithium salt and the reaction product was worked up. Crystallization at -35° C. gave 2.6 g (30%) of the hafnocene dichloride compound as orange crystals. Correct elemental analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Cl:12]NC1C=CC(C(F)(F)F)=CN=1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]([Cl:12])=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccc(NCl)nc1
Reactant: Nc1ccc(C(F)(F)F)cn1
Solvent: Cc1ccccc1
Product: Nc1ncc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
Into the same 300 ml four-necked flask as used in Example 1, 16.2 g (0.1 mol) of 2-amino-5 -trifluoromethylpyridine and 150 g of toluene were added, and 42.2 g of a 30% sodium dichloroisocyanurate aqueous solution (sodium dichloroisocyanurate: 0.0575 mol) was dropwise added thereto over a period of one hour while stirring at 20° C. After the dropwise addition, the reaction mixture was heated to 80° C., and the reaction was conducted for 10 hours with stirring. During the reaction, formation of 2-chloroamino-5-trifluoromethylpyridine was confirmed. After completion of the reaction, the reaction mixture was cooled to room temperature, and an aqueous layer and an oil layer were separated. A 20% hydrochloric acid aqueous solution was added to the oil layer, and the mixture was stirred. An aqueous layer and an oil layer were further separated. The aqueous layer was neutralized with a 25% sodium hydroxide aqueous solution. Precipitated slightly yellow crystals were collected by filtration and dried to obtain 15.7 g 2-amino-3-chloro-5-trifluoromethylpyridine (purity as measured by liquid chromatography: 96%, yield: 77%).
Reaction SMILES: [CH3:1][C:2]12[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]1([CH3:13])[CH2:5][N:4]=[N:3]2.CC[O-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]([CH3:13])=[CH:5][NH:4][N:3]=1
Reactant: CCOC(=O)C1C2(C)CN=NC12C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1C(C)=CNN=C1C
Reaction time: 0.17 h
Yield: 79.7 %

Procedure:
To a solution of ethyl 1,5-dimethyl-2,3-diaza-bicyclo[3.1.0]hex-2-ene-6-carboxylate (1.25 g, 6.9 mmol) in ethanol (20 mL) was added a solution of NaOEt in ethanol (7 mL 0.2N) and the mixture was stirred for 10 min The resulting solution was partitioned between diethyl ether and water. The organic phase was isolated and the aqueous phase was extracted with diethyl ether. The combined organic phases were dried over MgSO4 and the volatiles were removed in vacuo to afford ethyl 3,5-dimethyl-1,4-dihydropyridazine-4-carboxylate (1.0 g, 5.5 mmol, 80%) which was partially (circa 50%) oxidized to the pyridazine analog.