Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3]([N:5]([CH3:7])[CH3:6])=O.[Cl-:9]>CCOCC>[Cl-:9].[Cl:9][C:3]([N:5]([CH3:7])[CH3:6])=[N+:2]([CH3:8])[CH3:1]
Reactant: CN(C)C(=O)N(C)C
Agent: [Cl-]
Solvent: CCOCC
Product: CN(C)C(Cl)=[N+](C)C
Reaction time: 8 h

Procedure:
1,1,3,3-tetramethylurea (450 mg) was dissolved in anhydrous ether (5 mL) under N2. Oxayl chloride (390 uL) was added over 1 minute and the mixture was left to stir. After 5 minutes a solid had precipitated on the base of the flask, this was broken up and stirring was continued overnight. Volatiles were evaporated to give N-[chloro(dimethylamino)methylene]-N-methylmethanaminium chloride salt as a white solid. Acetonitrile (10 mL) was added and 1 mL of this solution was added to a stirred solution of O-benzyl-2,6-dimethyl-L-tyrosyl-N-[(2S)-2-{[(Z)-{[(benzyloxy)carbonyl]amino}{[(benzyloxy)carbonyl]imino}methyl]amino}-3-phenylpropyl]-D-alaninamide (315 mg, 0.387 mmol) from preparation 23, and triethylamine (65 uL, 0.464 mmol) in acetonitrile (2 mL) under N2 with ice cooling. The reaction mixture was then allowed to stir at room temperature overnight. LCMS showed starting material still remained so more of the N-[chloro(dimethylamino)methylene]-N-methylmethanaminium chloride salt solution (0.1 mL) was added and the reaction was left to stir over a weekend. The reaction mixture was then purified by Trilution HPLC (eluting with acetonitrile/H2O/formic acid gradient) to afford the title compound as a white foam in 24% yield, 90 mg. 1H NMR (400 MHz, MeOH-d4) δ : 0.92 (d, 3H), 2.28 (S, 6H), 2.60-3.20 (m, 17H), 3.48 (m, 1H), 4.04 (m, 2H), 4.44 (m, 1H), 5.04 (s, 4H), 5.22 (s, 2H), 6.69 (s, 2H), 7.18-7.41 (m, 20H), 8.27 (s, 1H). LRMS ES m/z 912 [MH]+
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:10][C:11]2([C:21]#[N:22])[CH2:20][CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH2:12]2)[CH2:9][CH2:8]1.O.[OH-].[Na+]>CCOCC>[CH:7]1([CH2:10][C:11]2([CH2:21][NH2:22])[CH2:20][CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH2:12]2)[CH2:9][CH2:8]1
Reactant: N#CC1(CC2CC2)CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: NCC1(CC2CC2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a stirred suspension of lithium aluminium hydride (1M solution in ether; 94.9 ml; 94.9 mmol) at −78° C. was added a solution of 8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (14 g; 63.264 mmol) in ether (40 ml) over 30 minutes and the mixture stirred cold for 1 hour, then allowed to warm to ambient temperature and stirred for 3 hours. The resultant mixture was cooled in an ice bath and to the mixture was added in turn water (2 ml), 15% NaOH solution (2 ml) and water (2 ml). The resultant white granular solid was collected on a filter and rinsed twice with diethyl ether. The filtrate was evaporated to give the crude product as a colourless oil (12 g). 1H NMR δ (ppm) (CDCl3): 3.93 (4H, s), 2.68 (2H, s), 1.63-1.57 (4H, m), 1.54-1.48 (4H, m), 1.25 (2H, d, J=6.6 Hz), 0.65-0.50 (1H, m), 0.46-0.40 (2H, m), 0.02 (2H, q, J=4.9 Hz). MS (m/e)=226.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[CH:20]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[C:24]=2[CH:23]=[CH:22][N:21]=1>>[CH:20]1[C:29]2[C:24](=[C:25]([C:16]3[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]4[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=4)=[CH:18][CH:17]=3)[CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][N:21]=1
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Reactant: OB(O)c1cccc2cnccc12
Product: O=C(O)c1csc(COc2ccc(-c3cccc4cnccc34)cc2)n1

Procedure:
2-(4-Isoquinolin-5-yl-phenoxymethyl)-thiazole-4-carboxylic acid was prepared using general procedure 2 from 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of Intermediate 2) and 5-isoquinolineboronic acid (available from Frontier Scientific, Inc., Logan, Utah). Mass spectrum MH+=363.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][N:20]2[CH2:19][CH2:18][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:22][CH2:21]2)[CH:7]=[CH:8][CH:9]=1
Reactant: BrCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(Br)c2)CC1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
A solution of 3-bromobenzyl bromide (6 g) and Boc-piperazine (4.06 g) in acetonitrile (30 mL) was treated with triethylamine (3.36 mL). The resulting mixture was heated at reflux for 16 hours. After cooling to room temperature, the reaction mixture was treated with saturated sodium bicarbonate solution (20 mL), and then extracted with ethyl acetate (2×30 mL). The organic phases were combined, dried (MgSO4) and concentrated under vacuum. The residue was purified by chromatography on silica (100 g) eluting with ethyl acetate/cyclohexane to give the title compound (6.95 g). LC/MS: m/z, 355, 357 (M+H), 2.40 min.
Reaction SMILES: [Cl-].[F:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH3+:16].[Cl:17][C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[O:22][C:21]([CH2:23][NH:16][CH2:15][CH2:14][O:13][C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]=2[F:2])=[CH:20][CH:19]=1
Reactant: [NH3+]CCOc1ccc2ccccc2c1F
Reactant: O=Cc1ccc(Cl)o1
Agent: [Cl-]
Product: Fc1c(OCCNCc2ccc(Cl)o2)ccc2ccccc12
Yield: 70 %

Procedure:
Prepared from 2-[(1-fluoronaphthalen-2-yl)oxy]ethanaminium chloride and 5-chlorofuran-2-carbaldehyde in 70% yield as a yellow oil.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([O:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>O>[CH3:34][O:33][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:11]=1[O:10][CH2:9][CH2:8][CH2:7][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)[N:18]=[CH:17][CH:16]=[C:15]2[O:21][C:22]1[C:23]([CH3:32])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: C1COCCN1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 72 h
Yield: 53 %

Procedure:
N,N-Dimethylformamide (1.5 ml) was added to 7-(3-chloro-propoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 375) (52 mg), potassium carbonate (53 mg), and morpholine (33 mg), and the mixture was stirred at 80° C. for 3 days. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (31 mg, yield 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[CH:17]=O)=[CH:5][CH:4]=1.Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[CH:17]=[N:20][OH:21])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(C#Cc2cnccc2C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C#Cc2cnccc2C=NO)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
3-(4-Methoxyphenylethynyl)-4-pyridinecarboxaldehyde (4.965 g) was dissolved in ethanol (70 ml), a solution of hydroxylamine hydrochloride (2.179 g) and sodium acetate (3.429 g) in water (18 ml) was added thereto, and then the mixture was stirred at 70° C. overnight. After cooling as it was, the reaction mixture was evaporated and partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellow solid (4.724 g, yield; 96%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>O.[Pd].CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+]>[C:2]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: O
Product: O=C(O)c1cccc(-c2ccccc2)c1
Yield: 96.9 %

Procedure:
Using 0.1 mol % Pd and microwave irradiation. The general procedure described in Example 3 was used with 3-chlorobenzoic acid (157 mg, 1.00 mmol), phenylboronic acid (145 mg, 1.20 mmol), K2CO3 (345 mg, 2.50 mmol), water (1.5 mL), Pd/L solution (0.200 mL of a Pd(OAc)2 (1.1 mg, 0.005 mmol, 0.5 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (5.0 mg, 0.010 mmol, 1 mol %) solution in 1.0 mL water), 10 min, 150° C. (microwave irradiation with cooling). The product was isolated as a white solid (192 mg, 97%). Mp=164° C. (lit.=165-166° C.) 1H NMR (400 MHz, CDCl3) δ: 11.90 (br-s, 1H), 8.41 (s, 1H), 8.15 (d, 1H, J=7.6 Hz), 7.88 (d, 1H, J=7.6 Hz), 7.68 (d, 2H, J=7.2 Hz), 7.60 (t, 1H, J=6.4 Hz), 7.52 (t, 2H, J=7.6 Hz), 7.43 (t, 1H, J=7.2 Hz). 13C NMR (125 MHz, CDCl3) δ: 172.6, 141.8, 140.1, 132.7, 130.0, 129.3, 129.2, 129.1, 129.0, 128.0, 127.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.[CH2:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([CH2:27][C:26]2[CH:29]=[CH:30][C:23]([CH2:21][CH3:22])=[CH:24][CH:25]=2)[C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCc1cnc(NCCc2ccc(OC)c(Br)c2)nc1
Reactant: CCc1ccc(CBr)cc1
Product: CCc1ccc(CN(CCc2ccc(O)c(Br)c2)c2ncc(CC)cn2)cc1

Procedure:
Similarly prepared from N-[2-(3-bromo-4-methoxyphenyl)ethyl]-5-ethylpyrimidin-2-amine and 4-ethyl benzyl bromide.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1)=[O:6].Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=1>>[CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)=[CH:22][CH:23]=2)=[CH:9][CH:8]=1)=[O:6]
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: CC(C)CNC(=O)c1ccc(B(O)O)cc1
Product: CC(C)CNC(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cc2)cc1
Yield: 23.2 %

Procedure:
The title compound (21 mg, 19%) was prepared from (4-{[(2-methylpropyl)amino]carbonyl}phenyl)boronic acid (44 mg, 0.2 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 71 mg, 0.2 mmol) in a manner similar to Example 21, Step 3 and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.80 (d, 2H, J=8.6 Hz), 7.60 (d, 2H, J=8.6 Hz), 7.54 (d, 2H, J=8.8 Hz), 6.96 (d, 2H, J=8.9 Hz), 6.17 (t, 1H, J=5.8 Hz), 4.97-4.84 (m, 1H), 4.21 (bs, 2H), 3.85 (d, 2H, J=6.4 Hz), 3.34-3.27 (m, 2H), 2.83-2.73 (m, 2H), 2.05-1.95 (m, 1H), 1.95-1.89 (m, 1H), 1.90-1.80 (m, 2H), 1.35-1.26 (m, 2H), 1.24 (d, 6H, J=6.2 Hz), 0.99 (d, 6H, J=6.7 Hz); LRMS (ESI), m/z 453 (M+H).
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].CO[C:12](OC)([CH3:15])[CH:13]=O>>[CH3:13][C:12](=[N:5][NH:6][C:7](=[NH:8])[NH2:9])[CH:15]=[N:5][NH:6][C:7](=[NH:9])[NH2:8]
Reactant: N=C(N)NN
Reactant: COC(C)(C=O)OC
Agent: O=C(O)O
Product: CC(C=NNC(=N)N)=NNC(=N)N

Procedure:
reacting the filtered aminoguanidine bicarbonate with methylglyoxal dimethyl acetal in an aqueous reaction medium to produce 2,2'-(methyl-1,2-ethanediylidene)bis[hydrazine carboximidamide]; and
Reaction SMILES: [NH:1]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1>C(O)C.O.[Li+].[OH-]>[N:1]1([CH2:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: C1CNCCNCCCNCCNC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(CN2CCCNCCNCCCNCC2)cc1
Reaction time: 5 h
Yield: 66.6 %

Procedure:
To solution of Cyclam (0.913 g, 4.5 mmol) dissolved in a mixture of ethanol:water (5:1 by vol.) (18 ml) was added a solution of 4-chloromethylbenzoic acid (0.157 g, 0.92 mmol) in aqueous LiOH (53 mg in 4 ml of water). This mixture was thereafter refluxed vigorously with stirring for 5 hours. Then the solvent was removed at reduced pressure, and the residue was dissolved in 13 ml of water. The aqueous solution obtained was then extracted with chloroform (10 times 3 ml) and the aqueous layer was concentrated at reduced pressure down to 2 ml. The product as a white solid was precipitated by adding the solution of concentrated HCl and ethanol and purified by recrystallizing from ethanol/water/HCl to yield 0.205 g of the title compound. According to the LC-MS, the assay of 4-(1,4,8,11-tetraazacyclotetradec-1-ylmethyl)-benzoic acid hydrochloride was >95%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([OH:25])=O)=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:64][CH2:65][C:66]1[CH:67]=[CH:68][C:69]2[C:73]([CH2:76][CH3:77])([CH2:74][CH3:75])[O:72][B:71]([OH:78])[C:70]=2[CH:79]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:28])([F:27])[F:29])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([NH:64][CH2:65][C:66]5[CH:67]=[CH:68][C:69]6[C:73]([CH2:74][CH3:75])([CH2:76][CH3:77])[O:72][B:71]([OH:78])[C:70]=6[CH:79]=5)=[O:25])=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reactant: CCC1(CC)OB(O)c2cc(CN)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[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: CCC1(CC)OB(O)c2cc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)cc(Cl)c5)(C(F)(F)F)C4)n4cccc34)ccc21
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.24 mmol) and DIPEA (151 mg, 1.17 mmol) in DMF (5.0 mL) can be stirred at rt for 5 min and then HATU (180 mg, 0.47 mmol) was added. The mixture can be stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-diethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (63 mg, 0.25 mmol). And the resulting mixture can be stirred at rt overnight. It can be then concentrated under vacuum, and the residue can be partitioned between 1N HCl and ethyl acetate. The organic layer separated can be concentrated under vacuum, and the residue can be purified by column chromatography and prep-HPLC to provide the final title compound.
Reaction SMILES: [CH:1]1(Br)[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH3:13][CH:14]([CH2:16][CH2:17][CH2:18][C@H:19]([C@@H:21]1[C@:39]2([CH3:40])[C@H:24]([C@H:25]3[C@H:36]([CH2:37][CH2:38]2)[C@:34]2([CH3:35])[C:28]([CH2:29][C@H:30]([CH2:32][CH2:33]2)[OH:31])=[CH:27][CH2:26]3)[CH2:23][CH2:22]1)[CH3:20])[CH3:15]>ClCCl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[C@@H:1]1([CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][C@H:19]([C@@H:21]2[C@:39]3([CH3:40])[C@H:24]([C@H:25]4[C@H:36]([CH2:37][CH2:38]3)[C@:34]3([CH3:35])[C:28]([CH2:29][C@H:30]([CH2:32][CH2:33]3)[OH:31])=[CH:27][CH2:26]4)[CH2:23][CH2:22]2)[CH3:20])[CH3:13])[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: OC[C@H]1OC(Br)[C@H](O)[C@@H](O)[C@H]1O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CC(CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
Compound 4 (see FIG. 12) was prepared from galactose 1 that was treated with pivaloyl chloride in pyridine. Instead of the expected penta-pivaloyl derivative, the partially pivaloylated compound 2 was obtained in good yield and high purity without the need of chromatographic purification. The free hydroxyl group in compound 2 was protected by an acetyl group (→3). This was followed by treatment with hydrogen bromide in acetic acid to provide the galactosyl bromide 4. Bromide 4 was coupled with cholesterol 5 under promotion by silver trifluoromethanesulfonate in dichloromethane to provide the desired β-galactosyl-cholesterol 6 in a stereoselective manner (see FIG. 13). The β-anomeric configuration was demonstrated by 1-H NMR spectroscopy. The O-protecting groups were subsequently removed by treatment with sodium methoxide in a mixture of anhydrous dichloromethane and methanol to provide the cholesteryl β-D-galactopyranoside 7 as an amorphous solid.
Reaction SMILES: [CH3:1][N:2]([CH2:13][C:14]1[C:15]([C:25]2[CH:33]=[C:32]3[C:28]([CH:29]=[N:30][N:31]3[CH3:34])=[CH:27][CH:26]=2)=[N:16][N:17](C2CCCCO2)[CH:18]=1)[CH2:3][CH2:4][NH:5]C(=O)OC(C)(C)C.C(N(CC)CC)C.O.CC#N>O1CCCC1.Cl>[CH3:1][N:2]([CH2:13][C:14]1[C:15]([C:25]2[CH:33]=[C:32]3[C:28]([CH:29]=[N:30][N:31]3[CH3:34])=[CH:27][CH:26]=2)=[N:16][NH:17][CH:18]=1)[CH2:3][CH2:4][NH2:5]
Reactant: CN(CCNC(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1-c1ccc2cnn(C)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CN(CCN)Cc1c[nH]nc1-c1ccc2cnn(C)c2c1
Reaction time: 0.02 h
Yield: 16 %

Procedure:
A solution of tert-butyl N-[2-[methyl([[3-(1-methyl-1H-indazol-6-yl)-1-(oxan-2-yl)-1H-pyrazol-4-yl]methyl])amino]ethyl]carbamate (50 mg, 0.11 mmol, 1.00 equiv) in tetrahydrofuran (3 mL) and 12N hydrochloric acid (2 mL) was stirred at room temperature overnight. The pH of the solution was adjusted to 7 with triethylamine. The resulting mixture was concentrated and the residue purified by Pre-HPLC with the following conditions (1#-Pre-HPLC-005 (Waters)): Column, XBridge Shield RP18 OBD Column, 5 μm, 19×150 mm; mobile phase, water with 10 mmol NH4HCO3 and CH3CN (18% CH3CN up to 58% in 10 min, up to 95% in 1 min, down to 18% in 2 min); Detector, UV 254/220 nm to give 5 mg (16%) of N1-methyl-N1-((3-(1-methyl-1H-indazol-6-yl)-1H-pyrazol-4-yl)methyl)ethane-1,2-diamine as a light yellow oil. 1H-NMR (300 MHz, CDCl3): δ 8.05 (s, 1H), 7.89-7.84 (m, 2H), 7.73 (s, 1H), 7.54-7.50 (m, 1H), 4.12 (s, 3H), 3.67 (s, 2H), 2.84 (d, J=6.3 Hz, 2H), 2.55 (d, J=6.3 Hz, 2H), 2.27 (s, 3H) ppm. LCMS (method A1, ESI): RT=0.90 min, m/z=285.0 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CN1C(=O)CCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:3]([NH2:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: C1CNCCN1
Solvent: CN1CCCC1=O
Product: Nc1cc([N+](=O)[O-])ccc1N1CCNCC1
Yield: 70.3 %

Procedure:
A solution of 2-fluoro-5-nitrobenzenamine (0.50 g, 3.2 mmol) and piperazine (0.83 g, 9.6 mmol) in 15 ml NMP was heated at 100° C. for 16 hours. The reaction was quenched with 100 ml water. Red solids were filtered and dried under high vacuum. 5-Nitro-2-(piperazin-1-yl)benzenamine (0.50 g, 70%) was obtained by crystallization in acetyl acetate and hexanes. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 2.23 (s, 1H), 2.86 (m, 8H), 5.26 (s, 2H), 6.98 (d, J=8.7 Hz, 1H), 7.45 (dd, J=8.7, 2.8 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H).
Reaction SMILES: ClC1C=C(C([N:11]2[CH2:16][CH2:15][O:14][C@@H:13]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:12]2)C)C=CC=1Cl.Br[CH:27]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=1)[CH3:28]>>[C:21]([O:20][C:19](=[O:25])[NH:18][CH2:17][C@@H:13]1[O:14][CH2:15][CH2:16][N:11]([CH:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=2)[CH3:28])[CH2:12]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(c1ccc(Cl)c(Cl)c1)N1CCO[C@@H](CNC(=O)OC(C)(C)C)C1
Reactant: CC(Br)c1ccc(F)c(F)c1
Product: CC(c1ccc(F)c(F)c1)N1CCO[C@@H](CNC(=O)OC(C)(C)C)C1

Procedure:
Prepared in similar fashion to tert-Butyl {(2S)-4-[1-(3,4-dichlorophenyl)ethyl]morpholin-2-yl}methylcarbamate (as described in WO 02/026723) using (+)-4-(1-bromoethyl)-1,2-difluorobenzene.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](Br)[C:27]=1[CH3:33]>ClCCl>[Br:25][C:26]1[C:27]([CH3:33])=[C:28]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:14])[CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1c(Br)cccc1Br
Reactant: CN(C)c1ccc2c(c1)CCNC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1c(Br)cccc1N1CCc2cc(N(C)C)ccc2C1=O
Temperature: 150 °C
Yield: 63.9 %

Procedure:
6-Dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (150 mg, 0.789 mmol), cuprous iodide (30 mg, 0.16 mmol) and potassium carbonate (109 mg, 0.789 mmol) were deposited in a sealed vessel. 3 mL DMSO and 2,6-dibromotoluene (395 mg, 1.58 mmol) were added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150° C. for 24 hours. Cuprous iodide (30 mg, 0.16 mmol) was added and the mixture was heated at 150° C. for an additional 24 hours. This was diluted with dichoromethane and filtered through a pad of celite. The filtrate was partitioned between dichloromethane and 5% aq. ammonium hydroxide. The dichloromethane layer was washed with brine. The combined aqueous layers were washed with dichloromethane. The combined dichloromethane layers were dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 25 to 50% ethyl acetate/hexanes) to yield 2-(3-Bromo-2-methyl-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (181 mg, 0.504 mmol). MS (ESI) 361.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](=O)[CH2:12]Br)[NH:8][N:7]=1)=[O:5])[CH3:2].[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[N:15]=[C:16]([NH2:18])[S:17][CH:12]=2)[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: NC(N)=S
Reactant: CCOC(=O)c1cc(C(=O)CBr)[nH]n1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2csc(N)n2)[nH]n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
A mixture of 5-(2-bromoacetyl)pyrazole-3-carboxylic acid ethyl ester (6.2 g), thiourea (1.8 g), and ethanol (100 ml) was stirred at 60° C. for 30 minutes and concentrated. The residue was dissolved in 100 ml of 1N HCl solution, and washed with ethyl ether (2×100 ml). The aqueous solution was neutralized with NaHCO3. The resulting precipitates were collected through a filtration to afford 4.05 g of 5-(2-aminothiazol-4-yl)pyrazole-3-carboxylic acid ethyl ester as brown solids, mp 205°-207° C. NMR: 1.40 (t, 3H), 4.39 (q, 2H), 5.8 (bs, 2H), 6.85 (s, 1H), 7.03 (s, 1H).