Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[S-:11][C:12]#[N:13].[Na+].BrBr.O>C(O)(=O)C>[S:11]1[C:3]2[C:4]3[CH:5]=[N:6][NH:7][C:8]=3[CH:9]=[CH:10][C:2]=2[N:1]=[C:12]1[NH2:13]
Reactant: N#C[S-]
Reactant: Nc1ccc2[nH]ncc2c1
Agent: BrBr
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2ccc3[nH]ncc3c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.6 %

Procedure:
2.0 g (15 mmol) of 5-aminoindazole and 4.9 g (60.5 mmol) of sodium thiocyanate were suspended in 10 ml of acetic acid, and 2.4 g (15 mmol) of bromine was added dropwise to the suspension under ice-cooling. The reaction mixture was allowed to warm to room temperature, and it was stirred overnight. The reaction mixture was poured into water, and the resulting crystals were collected by filtration to give 3.1 g of 6H-pyrazolo[4′,3′:3,4]benzo[1,2-d]thiazol-2-ylamine.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:19])[C:15]([O:17]C)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].B(Br)(Br)Br>ClCCl>[F:20][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:19])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1cc2c(cc1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Cl)cc21
Reaction time: 8 h
Yield: 52 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (48 mg, 0.15 mmol) in dichloromethane (2 mL) was treated with BBr3 (0.30 mL of a 1.0 M solution in CH2Cl2, 0.30 mmol) and stirred overnight at 20 C. The excess BBr3 was quenched with water and the resulting mixture diluted with ether (20 mL), washed with Na2CO3 (10 mL) and brine (10 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 24 mg of a white solid. MS calculated for C13H13ClF3NO2+H: 308, observed: 308.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[CH3:23])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.Br[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[CH3:23])[CH2:9][C:10]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccc(F)cc1C
Reactant: Cc1cc(Br)ccn1
Product: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccc(F)cc2C)ccn1

Procedure:
In analogy to example 74, step 5, from 3-(4-bromophenyl)-3-(4-fluoro-2-methylphenyl)-N-methoxy-N-methylpropanamide and 4-bromo-2-methylpyridine was prepared the title compound as a white solid, MS (ESI+): m/z=414.07 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][C:4]#[CH:5].I[C:8]1[CH:13]=[CH:12][C:11](/[C:14](/[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)=[CH:15]\[CH2:16][O:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:20]([CH3:30])[CH:19]=2)=[CH:10][CH:9]=1>O1CCCC1.C(N(CC)CC)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]([CH2:3][C:4]#[C:5][C:8]1[CH:9]=[CH:10][C:11](/[C:14](/[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=2)=[CH:15]\[CH2:16][O:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:20]([CH3:30])[CH:19]=2)=[CH:12][CH:13]=1)[CH3:6]
Reactant: C#CCN(C)C
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2cccc(C(F)(F)F)c2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN(C)C)cc2)c2cccc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dimethyl(prop-2-ynyl)amine (114 mg, 1.374 mmol) was added to a solution of methyl (E)-[4-[3-(4-iodophenyl)-3-(3-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate (400 mg, 0.687 mmol; prepared as described in example 34) in a mixture of tetrahydrofuran (12 mL) and triethylamine (12 mL). The mixture was degassed and copper(I) iodide (20 mg, 0.109 mmol) and tetrakis(triphenylphosphine)palladium (63 mg, 0.054 mmol) were added. The reaction mixture was stirred at ambient temperature for 24 h. Further portions of dimethyl(prop-2-ynyl)amine (57 mg, 0.687 mmol), copper(I) iodide (10 mg, 0.0545 mmol) and tetrakis(triphenylphosphine)palladium (31.5 mg, 0.027 mmol) were added and the reaction mixture was stirred under argon for additional 20 h. The mixture was evaporated in vacuo; the residue was dissolved in ethyl acetate (30 mL) and was washed with water (2×15 mL) and brine (10 mL). The organic solution was dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 3:5) yielding methyl (E)-[4-[3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]-3-(3-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate as oil.
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)=O.[NH2:18][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH3:17][C:2]1[N:20]2[CH:21]=[CH:22][CH:23]=[N:24][C:19]2=[N:18][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1
Reactant: CC(Br)C(=O)c1ccc2c(c1)NC(=O)C(C)O2
Reactant: Nc1ncccn1
Product: Cc1c(-c2ccc3c(c2)NC(=O)C(C)O3)nc2ncccn12
Yield: 37.1 %

Procedure:
6-(3-Methyl-imidazo[1,2-a]pyrimidin-2-yl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.1 g) was prepared in substantially the same manner as that of Example 16 from 6-(2-bromopropionyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (3.0 g) and 2-aminopyrimidine (2.9 g). mp. 288°-290° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)O)=[CH:5][CH:4]=1.[ClH:35]>CO>[ClH:35].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH2:19][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=C(C(O)c3ccc(OCCN4CCCC4)cc3)c3ccccc3CC2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2ccc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Temperature: -20 °C

Procedure:
To a solution of the product of Example 14 (2.0 g, 4.58 mmol) stirring in methanol (50 mL) at ambient temperature was added methanolic hydrochloric acid (10 mL of a saturated solution). The reaction mixture was then concentrated to 20 mL and cooled to −20° C. for several hours. Filtration gave 0.62 g of the desired product as a white powder: 1H-NMR (CDCl3, 300 MHz) consistent with structure; MS (FD) m/e 437 M+-hydrochloric acid);
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:11][CH3:12])=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9].Cl>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:10]=[C:7]([CH2:8][NH2:9])[CH:6]=[N:5][C:4]=1[O:11][CH3:12]
Reactant: COc1cc(C#N)cnc1OC
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COc1cc(CN)cnc1OC
Reaction time: 2 h

Procedure:
To a solution of 5,6-dimethoxynicotinonitrile (7-3, 0.600 g, 3.65 mmol, 1.0 equiv) in methanol (20 mL) under a nitrogen atmosphere was added Pearlman's catalyst (0.205 g, 0.292 mmol, 0.08 equiv, 20 weight percent) and concentrated HCl (2.44 mL), and the reaction was place under an atmosphere of hydrogen. After 2 h, the reaction was placed under an atmosphere of nitrogen and filtered through celite to remove the catalyst. The reaction mixture was dissolved in EtOAc, dried over MgSO4 and concentrated to an oily solid (7-4) of high purity. ESI+MS [M+H]+ C8H12N2O2 calc'd 169.1, found 169.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:6]=1.[Cl:13][CH:14]([C:20]([CH3:22])=O)[C:15](OCC)=[O:16]>>[Cl:13][C:14]1[C:15](=[O:16])[N:6]2[N:5]=[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:3][C:2]2=[N:1][C:20]=1[CH3:22]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1nnc(-c2ccccc2)s1
Product: Cc1nc2sc(-c3ccccc3)nn2c(=O)c1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 107.8 %

Procedure:
2-amino-5-phenyl-1,3,4-thiadiazole (10 g) was reacted with ethyl 2-chloro-acetoacetate (18.6 g) in polyphosphoric acid (100 g) under stirring at 100° C. for 2 hours. After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate was filtered and washed with water until neutral; crystallization from isopropyl alcohol gave 6-chloro-7-methyl-2-phenyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one (16.9 g), which was reacted with N-bromo-succinimide (10.9 g, added portionwise) in benzene (200 ml) at the reflux temperature for 32 hours. After cooling the reaction mixture was diluted with ethyl acetate and treated with aqueous NaHCO3 and then with water: the separated organic solution was evaporated in vacuo to dryness and the residue was crystallized from methanol to give 7-bromomethyl-6-chloro-2-phenyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one (12.3 g), which was reacted with triphenylphosphine (8.6 g) in acetonitrile (700 ml) at the reflux temperature for 4 hours. After cooling and evaporation in vacuo of the solvent, the residue was purified with ethyl acetate to give (6-chloro-5-oxo-2-phenyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-7-yl)-methyl-triphenylphosphonium bromide (17.6 g), which was treated with aqueous NaHCO3 under stirring at room temperature to give a precipitate of (6-chloro-5-oxo-2-phenyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-7-yl]-methylene-triphenylphosphorane.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:37][CH3:38])=[C:29]([O:32][CH2:33][CH2:34][CH2:35][Cl:36])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:37][CH3:38])=[C:29]([O:32][CH2:33][CH2:34][CH2:35][Cl:36])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCCl
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCCl
Yield: 89 %

Procedure:
The intermediate 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (1.01 g, 3.5 mmol) was reacted with 4-chloro-6-(3-chloropropoxy)-7-methoxyquinazoline (1.0 g, 3.5 mmol) from Example 21 A Step 5 as described in Example 46 to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea (1.69 g, 3.12 mmol, 89%). 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.01 (s, 1H), 8.70 (s, 1H), 7.85 (s, 1H), 7.51 (d, 1H), 7.44 (t, 1H), 7.36 (s, 2H), 7.28 (d, 1H), 6.49 (s, 1H), 4.31 (t, 2H), 4.00 (s, 3H), 3.85 (t, 2H), 2.37-2.25 (m, 2H), 1.29 (s, 9H); LC-MS (ESI) m/z 542 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:14]=[C:13]1[C:12]2[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10](=[O:15])[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: NCCCCCC(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(O)CCCCCN1C(=O)c2ccccc2C1=O
Reaction time: 16 h
Yield: 93.8 %

Procedure:
6-amino hexanoic acid (39a) (13.1 g, 100 mmol) and phthalic anhydride (40) (14.8 g, 100 mmol) were mixed in toluene (150 mL). To the suspension was added triethyl amine (13 mL). The suspension was refluxed using Dean-stark for 16 h. When collection of water ceased, the reaction was cooled and evaporated to dryness. The residue was suspended in water and conc. hydrochloric acid (1.5 mL) was added. The suspension was stirred for 30 mins and filtered. The precipitate was washed with water and dried over sodium sulfate to afford compound 41a (24.5 g, 93%) which was used as such for the next step.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[CH2:26]([O:33][C:34]1[C:41]([O:42][CH3:43])=[CH:40][C:37]([CH:38]=[O:39])=[C:36]([F:44])[CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>O1CCCC1>[CH2:26]([O:33][C:34]1[C:41]([O:42][CH3:43])=[CH:40][C:37]([CH:38]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)[OH:39])=[C:36]([F:44])[CH:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Reactant: COc1cc(C=O)c(F)cc1OCc1ccccc1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)c(F)cc1OCc1ccccc1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (635, 620 mg, 1.5 mmol, prepared as described in Example 45) was dissolved in tetrahydrofuran (15 mL) at −20° C. under an atmosphere of nitrogen. Isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 840 μL) was added to the reaction. The reaction was stirred for 1.5 hours, during which the temperature rose to 5° C. The reaction was cooled to −20° C. 4-Benzyloxy-2-fluoro-5-methoxy-benzaldehyde (654, 250 mg, 0.9606 mmol) in tetrahydrofuran (5.0 mL) was added to the reaction. The reaction was stirred for 2.5 hours during which time the temperature rose to 5° C. The reaction was poured into water. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2-25% ethyl acetate in hexane to provide compound as a white solid (655, 501 mg, 63%). MS (ESI) [M+H+]+=535.4.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:11])[CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:25](OCC)(=[O:27])[CH3:26]>>[C:25]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:11])[CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:27])[CH3:26]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2cc(Br)ccc21
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2cc(Br)ccc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-2-benzoyl-5-bromo-1-(ethoxycarbonyl)indole (step 2). tlc: Rf=0.3 (33% ethyl acetate in hexanes)
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[NH2:15][C:16]1[N:20]([C:21]2[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=2)[N:19]=[C:18]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:17]=1.[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:38][CH2:39][CH2:40]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:28]([C:18]1[CH:17]=[C:16]([NH2:15])[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:40][CH2:39][O:38][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][O:32]3)[CH:22]=2)[N:19]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: OCCOC1CCCCO1
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(O)c2)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1

Procedure:
DIAD (847 μL, 4.32 mmol) was added slowly to a solution of 3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)phenol (for reference procedure see US 2006/35922, which is incorporated herein by reference in its entirety; 500 mg, 2.16 mmol), 2-(tetrahydro-pyran-2-yloxy)-ethanol (439 μL, 3.25 mmol), and triphenylphosphine (1.13 g, 4.32 mmol) in THF (10.0 mL) and stirred for 72 h. The reaction mixture was partitioned between EtOAc (75 mL) and H2O (75 mL), and the aqueous layer extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered and evaporated in vacuo. Purification by FCC, using 5-60% EtOAc in cyclohexane, gave semi-pure title compound (1.26 g). This was used in the next reaction without further purification. LCMS (Method 4): Rt 2.77, m/z 360 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[CH3:13][C:14]([CH3:18])([CH3:17])[CH:15]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[CH3:13][C:14]([CH3:18])([CH3:17])[CH2:15][NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: CC(C)(C)C=O
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(NCC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
4-Methoxy-2-nitroaniline (10 g, 59.5 mmol, 1.0 equiv.) and trimethyl-acetaldehyde (9.73 g, 113 mmol, 1.9 equiv.) were dissolved in anhydrous dichloromethane (100 ml). The resulting solution was then treated with acetic acid (18.72 ml, 327 mmol, 5.5 equiv.), followed by sodium triacetoxyborohydride (30.3 g, 143 mmol, 2.4 equiv.). The mixture was stirred at room temperature. When LCMS showed completion of the reaction, the mixture was treated with saturated aqueous NaHCO3, then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to give the crude N-(2,2-dimethylpropyl)-4-methoxy-2-nitroaniline (1-3), which was used without purification. LRMS m/z (M+H) 239.0 found, 238.1 required.
Reaction SMILES: [OH:1][C@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]3[N:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=3)[CH2:9][C@@H:4]2[CH2:3]1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.[H-].[Na+]>CN(C=O)C.O>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][C@H:2]2[CH2:17][N:5]3[CH2:6][CH2:7][N:8]([C:10]4[N:11]=[CH:12][C:13]([F:16])=[CH:14][N:15]=4)[CH2:9][C@@H:4]3[CH2:3]2)=[CH:21][CH:20]=1
Reactant: O[C@@H]1C[C@H]2CN(c3ncc(F)cn3)CCN2C1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(CO[C@@H]2C[C@H]3CN(c4ncc(F)cn4)CCN3C2)cc1
Temperature: 100 °C
Yield: 8.2 %

Procedure:
A solution of 0.75 g (3.15 mmol) of (7R,8aS)-7-hydroxy-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 6) and 0.79 mL (6.3 mmol) of 4-fluorobenzyl bromide in 30 mL of dry DMF was treated with 0.15 g (3.8 mmol) of sodium hydride (60% oil dispersion), and the mixture was heated at 100° C. for 18 hours. The mixture was cool, diluted with water, and extracted with diethyl ether (5×). The combined organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatograph with 50:50 ethyl acetate:hexane gave 0.090 g (8%) of the title compound. Mp (.HCl) 74-79° C. 13C NMR (base, CDCl3): δ 35.6, 43.9, 48.9, 51.2, 60.4, 60.7, 70.7, 76.7, 115.1, 115.4, 129.35, 129.46, 133.9, 144.9, 145.2, 149.9, 153.2, 158.9, 164.0. HRMS calc'd for C18H20F2N4O (MH+): 347.1683, found: 347.1671.
Reaction SMILES: CCN(CC)CC.[CH2:8]([OH:12])[CH2:9][C:10]#[CH:11].[Cl:13][C:14]1[N:22]=[C:21](I)[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH3:24]>O1CCOCC1.[Cu]I>[Cl:13][C:14]1[N:22]=[C:21]([C:11]#[C:10][CH2:9][CH2:8][OH:12])[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH3:24]
Reactant: Cn1cnc2c(Cl)nc(I)nc21
Reactant: C#CCCO
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1cnc2c(Cl)nc(C#CCCO)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NEt3 (4.9 ml, 34.5 mmol) and but-3-yn-1-ol (1.1 ml, 25.63 mmol) were added to a solution of 6-chloro-2-iodo-9-methyl-9H-purine (6.8 g, 23.3 mmol), CuI (454 mg, 2.23 mmol) and bis-triphenylphosphine palladium dichloride (811 mg, 1.15 mmol) in dioxane (93 ml). The reaction mixture was stirred at RT for 1 h. The solvents were removed under reduced pressure. Water (50 ml) was added to the dark residue obtained. The aqueous phase was extracted with DCM (3×100 ml). The combined organic phases were dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by flash chromatography (DCM/MeOH: 94/6) to give an off-white precipitate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl.[CH:11]12[O:18][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH:5][C@@H:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[OH:18]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: C1CCC2OC2CC1
Agent: Cl
Product: O[C@@H]1CCCCC[C@H]1Nc1ccc(Cl)c(Cl)c1

Procedure:
A solution of 3,4-dichloroaniline (200 g., 1.23 mole), cycloheptene oxide (400 ml.), and concentrated HCl (2 ml.) is heated at reflux temperature for seven (7) days. The unreacted epoxide is evaporated at 60° C. and the residue is treated with excess ethereal HCl, and a syrup results. This is washed with 1000 ml. ether. The residue is crystallized and recrystallized from methanol/ether (1/5,5, v/v ) to give trans-3,4-dichloro-N-(2-hydroxycycloheptyl)aniline, hydrochloride salt.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([CH:10]=1)[OH:9])([CH3:3])[CH3:2].[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[ClH:26]>C(O)(=O)C>[ClH:26].[CH2:12]([N:19]1[CH2:20][CH:21]=[C:22]([C:7]2[C:8]([OH:9])=[CH:10][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=2[OH:11])[CH2:23][CH2:24]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)c1cc(O)cc(O)c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)c1cc(O)c(C2=CCN(Cc3ccccc3)CC2)c(O)c1

Procedure:
5-Isopropyl resorcinol (20.2 g), N-benzyl-4-piperidone (24.6 g) and 45 ml acetic acid was treated with HCl gas as described in Example VI to give 39.15 g product, m.p. 286°-288°.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:12]=[C:13]([N+:27]([O-:29])=[O:28])[CH:14]=[C:15]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)=[O:18])[CH:16]=2)=[O:10])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.[K+].[Br-]>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[CH:12]=[C:13]([N+:27]([O-:29])=[O:28])[CH:14]=[C:15]([C:17](=[O:18])[C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)[CH:16]=2)=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)c2cc(C(=O)c3ccc(OC)cc3)cc([N+](=O)[O-])c2)cc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: O=C(c1ccc(O)cc1)c1cc(C(=O)c2ccc(O)cc2)cc([N+](=O)[O-])c1
Temperature: 120 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
Into a 250 mL three-necked, round-bottomed flask equipped with a magnetic stirrer, a condenser, and nitrogen inlet, 3,5-bis(4-methoxyphenylcarbonyl) nitrobenzene (6.2 g, 15.8 mmol) and freshly prepared pyridine hydrochloride (100 g) were placed. The mixture was heated under reflux until the solution became homogeneous. It took about 4 h. After cooled down 120° C., the mixture was poured into water. The resulting precipitate was collected and dried. The yellow solid was slurred in boiling toluene and collected by suction filtration to give 5.5 g (96% yield), m.p. 230-231.8° C. Anal. Calcd. for C20H13NO6: C, 66.12%; H, 3.61%; N, 3.86%; O, 26.42%. Found: C, 66.07%; H, 3.64%; N, 3.67%; O, 17.01%. FT-IR (KBr, cm−1): 1321, 1538 (A-NO2), 1602, 1648 (carbonyl), 3420 (Ar—OH). Mass spectrum (m/e): 363 (M+, 100% relative abundance). 1H-NMR (DMSO-d6, δ in ppm): 6.93-6.96 (d, 4H, Ar), 7.76-7.79 (d, 4H, Ar), 8.23 (s, 1H, Ar), 8.58 (s, 2H, Ar), 10.66 (s, 2H, OH). 13C-NMR (DMSO-d6, δ in ppm) 115.48, 126.02, 126.65, 132.84, 134.83, 139.44, 147.61, 156.80, 162.70, 191.36.