Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:9]/[CH:10]=[CH:11]/[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)=[O:21])=[CH:16][CH:15]=1.O>CN(C=O)C>[Br:28][C:25]1[CH:24]=[CH:23][C:22]([C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12]/[CH:11]=[CH:10]/[CH2:9][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:15][CH:16]=2)=[O:21])=[CH:27][CH:26]=1
Reactant: c1c[nH]cn1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(OC/C=C/CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(Br)cc1)c1ccc(OC/C=C/Cn2ccnc2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
A solution of 68 mg of imidazole in 4 ml of DMF is added dropwise to a suspension of 44 mg of 55% sodium hydride in 4 ml of DMF. After heating the mixture to 70° C. a solution of 441 mg of (E)-[4-(4-bromo-but-2-enyloxy)-phenyl]-(4-bromo-phenyl)-methanone in 12 ml of DMF is added dropwise. Then, the mixture is stirred at 70° C. for a further 1 h. and, after cooling, poured into 5 ml of water and concentrated. The residue is treated with water and extracted with methylene chloride. The organic phases are washed with saturated sodium chloride solution, dried and evaporated. The residue is purified on silica gel with toluene/acetone/triethylamine (70:29:1). The (E)-(4-bromo-phenyl)-[4-(4-imidazol-1-yl-but-2-enyloxy)-phenyl]-methanone (140 mg) is obtained as the beige solid base which is converted into the hydrochloride, MS: m/e 397 (M, 1Br).
Reaction SMILES: O[C:2]1[CH:16]=[C:15]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:20]>CN(C=O)C>[CH3:20][NH:11][C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][C:8]1[C:15]2[C:5](=[CH:4][CH:3]=[CH:2][CH:16]=2)[NH:6][CH:7]=1
Reactant: N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reaction time: 0.5 h

Procedure:
The protected tryptophan derivative from above (0.573 g, 1.00 mmol) was dissolved in DMF (3 mL) and the solution cooled in ice. Sodium hydride (60% oil dispersion, 0.048 g, 1.2 mmol) was added and the mixture stirred for 30 min. Iodomethane (0.093 mL, 1.5 mmol) was added and stirring continued for an additional hour. The reaction was then quenched with 10% citric acid (2 mL) and water (25 mL), and extracted with Et2O (100 mL). The extract was dried (MgSO4) and concentrated, and the residue purified by flash chromatography (20-30% EtOAc/hexane as eluent) to give the desired N-methyltryptophan derivative (0.284 g).
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[O:8]1)=[O:6])[CH3:3].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[OH:8][CH:7]([CH:9]([O:24][C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1)[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)[C:5]([NH:4][CH:2]([CH3:1])[CH3:3])=[O:6]
Reactant: CC(C)NC(=O)C1OC1c1ccc(Cl)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)NC(=O)C(O)C(Oc1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
This compound was prepared from N-(1-methylethyl)-3-(4-chlorophenyl)-2-oxiranecarboxamide (9.56 g.), p-chlorophenol (5.2 g.), sodium hydride (50% oil dispersion, 2.0 g.) 18-crown-6 (3.0 g.), and acetonitrile (300 ml.) as described in Example 12, and purified by recrystallization from ether. The compound melted at 177°-179°, and weighed 0.76 g.
Reaction SMILES: O.C(OC([NH:12][C@@H:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:22][N:23]3[C:27]([C:28]([F:31])([F:30])[F:29])=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[N:24]3)[CH:19]=2)[CH2:14]1)=O)C1C=CC=CC=1.C(Cl)[Cl:38].Cl>C(O)C.[OH-].[Pd+2].[OH-]>[ClH:38].[NH2:12][C@@H:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:22][N:23]3[C:27]([C:28]([F:29])([F:30])[F:31])=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[N:24]3)[CH:19]=2)[CH2:14]1
Reactant: ClCCl
Reactant: CCOC(=O)c1cnn(Cc2ccc3c(c2)C[C@@H](NC(=O)OCc2ccccc2)C3)c1C(F)(F)F
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnn(Cc2ccc3c(c2)C[C@@H](N)C3)c1C(F)(F)F
Reaction time: 0.75 h
Yield: 100 %

Procedure:
Palladium hydroxide (0.092 mmol, 12.96 mg) was wetted with a small volume of water before addition of (S)-ethyl 1-((2-(benzyloxycarbonylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.092 mmol, 45 mg) in Ethanol (5 mL). A small volume DCM was added to aid solubility. Aq. HCl 5N (0.500 ml) was added before the mixture was left to stand at room temp for around 1.5 h before hydrogenating at 2 bar for 45 min. After this time, the mixture was filtered through a filter tip and concentrated to give the desired product as a colourless oil (36 mg, 0.092 mmol, 100%). 1H NMR (400 MHz, CD3OD) δ 1.33 (t, 3H) 2.98 (m, 2H) 3.40 (m, 2H) 4.10 (m, 1H) 4.31 (q, 2H) 5.50 (s, 2H) 7.05 (d, 1H), 7.10 (s, 1H), 7.27 (d, 1H) 8.04 (s, 1H).
Reaction SMILES: N[C:2]1[N:7]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])[C:6](=[O:17])[NH:5][C:4](=[O:18])[CH:3]=1.[ClH:19].N([O-])=O.[Na+]>O>[Cl:19][C:2]1[N:7]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])[C:6](=[O:17])[NH:5][C:4](=[O:18])[CH:3]=1
Reactant: Cc1cccc(C)c1Nn1c(N)cc(=O)[nH]c1=O
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc(C)c1Nn1c(Cl)cc(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1 mole of 6-amino-1-(2,6-dimethylanilino)-2,4-pyrimidinedione dissolved in 3 moles of dilute aqueous hydrochloric acid cooled to 0°-5° in an ice bath is slowly added 1.1 mole of sodium nitrite (dissolved in water at 5°) with rapid stirring. After addition is complete, add dropwise but rapidly 1.1 mole cuprous chloride dissolved in water. Stir for 30 minutes, then heat to 50° for 1 hour. The mixture is cooled to RT and filtered to obtain 6-chloro-1-(2,6-dimethylanilino)-2,4-pyrimidinedione.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.[I:12]N1C(=O)CCC1=O>FC(F)(F)S(O)(=O)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[I:12]
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1OCc2c1ccc(Br)c2I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) solution of commercially available 5-bromo-2-benzofuran-1(3H)-one (50 g, 0.235 mol) in trifluoromethanesulfonic acid (400 mL) was added N-iodosuccinimide (55.5 g, 0.247 mol). The resulting mixture was stirred at room temperature overnight, then poured slowly into ice water (2 L), filtered and the filtrate extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated to give 5-bromo-4-iodo-2-benzofuran-1(3H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:5]=[N:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=1.C[Si]([C:26]#[N:27])(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:11][CH:12]=2)[C:26]#[N:27])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1Cl
Reactant: C[Si](C)(C)C#N
Product: COc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1Cl

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(3-chloro-4-methoxybenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a slightly yellow powder (yield 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28]C2CCCCO2)=[O:26])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:22])[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10]1.Cl.C(O)C>CCOC(C)=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:22])[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10]1
Reactant: O=C(/C=C/c1cnc(N[C@@H]2CCN(C(=O)CC3CCCCC3)C2)c(Cl)c1)NOC1CCCCO1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(/C=C/c1cnc(N[C@@H]2CCN(C(=O)CC3CCCCC3)C2)c(Cl)c1)NO
Reaction time: 2 h
Yield: 126.1 %

Procedure:
A mixture of (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylacetyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (680 mg) and 2N HCl/Ethanol (13.8 ml) was stirred for 2 hrs. EtOAc (10 ml) and IPE (50 ml) was added and stirred. After 1 hr, precipitate was filtered and dried to give 387 mg (0.63%) of (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylacetyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([F:25])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[I:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[C:17]([F:25])[CH:16]=1)[C:9]([C:31]1[CH:32]=[CH:33][C:28]([I:27])=[CH:29][CH:30]=1)=[O:14])([CH3:3])([CH3:2])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)c(F)c1
Reactant: Ic1ccc(I)cc1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(I)cc1)c1ccc(C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared from rac-[(3-fluoro-4-trifluoromethyl-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 5) and 1,4-di-iodobenzene in analogy to Example 1a): MS (ISN): 522.1 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:12][C:13]1[C:14]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[C:13]([CH3:12])=[CH:18][C:17]([CH3:19])=[CH:16][N:15]=3)[CH2:21][CH2:22]2)=[O:8])=[C:9]([CH3:11])[CH:10]=1
Reactant: Cc1cc(Br)ncc1C(=O)O
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(Br)cc3C)CC2)c(C)c1
Yield: 97.7 %

Procedure:
Using 6-bromo-4-methylnicotinic acid (500 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (443 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (880 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][N:9]2C(OCC2C=CC=CC=2)=O)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCc2ccccc2C1c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(C2NCCc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a round-bottomed flask was added crude benzyl 1-(6-chloropyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (170 mg, 449 μmol), CH2Cl2 (10 mL) and TFA (10 mL). The reaction was allowed to stir at RT. After 3 days, LC-MS shows little progress. The reaction was concentrated in vacuo to remove CH2Cl2 and the resulting solution allowed to stir for another 3 days, then cautiously poured into 10% Na2CO3 and extracted with CH2Cl2 (3×20 mL). The combined organic layers were concentrated in vacuo and purified by reverse-phase preparative HPLC (Shimadzu) on a Phenomenex Gemini® column (5 micron, C18, 110 Å, Axia, 100×50 mm) eluting at 90 mL/min with an linear gradient of 10% to 100% MeCN (0.1% TFA) in water (0.1% TFA) over 20 min to give crude 1-(6-chloropyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline as a white solid. The crude solid was carried into the next step. MS (ESI pos. ion) m/z: 245 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.[C:8]([NH:17][C:18](OC1C=CC=CC=1)=[O:19])(OC1C=CC=CC=1)=[O:9]>O1CCOCC1>[CH3:7][C:4]1[S:3][C:2]2=[N:1][C:8](=[O:9])[NH:17][C:18](=[O:19])[N:6]2[CH:5]=1
Reactant: Cc1cnc(N)s1
Reactant: O=C(NC(=O)Oc1ccccc1)Oc1ccccc1
Solvent: C1COCCO1
Product: Cc1cn2c(=O)[nH]c(=O)nc2s1
Yield: 93.6 %

Procedure:
A mixture of 2-amino-5-methylthiazole (2.0 g), diphenyl imidodicarbonate (CAS 99911-94-1) (4.5 g) and 1,4-dioxane (40 ml) was heated to reflux for 8 hours. After standing to cool, the precipitate was collected by filtration to obtain the title compound (3.00 g).
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.[F-].[K+]>O1CCCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:10][C:5]1[CH:4]=[C:3]([O:11][CH3:12])[C:2]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: OB(O)c1cccs1
Reactant: COc1cc(O)c(C=O)cc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(O)c(C=O)cc1-c1cccs1
Temperature: 60 °C
Yield: 95.9 %

Procedure:
Ex-13C: 5-Bromo-2-hydroxy-4-methoxybenzaldehyde (Ex-13B, 1.5 g, 6.5 mmol) and thiophene-2-boronic acid (0.91 g, 7.1 mmol) were dissolved in tetrahydrofuran (15 mL). Nitrogen was bubbled into the solution for 10 min followed by the sequential addition of potassium fluoride (0.80 g, 14 mmol, spray-dried) and bis(tri-t-butylphosphine)palladium (0) (0.033 g, 0.065 mmol). The solution was immediately heated to 60° C. and aged for 1.5 h. Upon completion, as determined by HPLC, the reaction was diluted with water (25 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over sodium sulfate and concentrated to a brown solid. Silica gel chromatography (ethyl acetate/hexanes, 1:3) gave 1.46 g (97%) of 2-hydroxy-4-methoxy-5-thien-2-ylbenzaldehyde as a yellow solid, mp 118–119° C. 1H-NMR (300 MHz, CDCl3) δ 11.48 (s, 1H), 9.79 (s, 1H), 7.72 (s, 1H), 7.37 (d, 1H, J=3.6 Hz), 7.31 (dd, 1H, J=5.1, 1.5 Hz), 7.08 (dd, 1H, J=5.1, 3.6 Hz), 6.54 (s, 1H), 3.98 (s, 3H). MS (ESI) m/z 235 ([M+H]+, 100%). Anal. Calcd. for C8H7O3S: C, 61.52; H, 4.30; S, 13.69; Found: C, 61.12; H, 4.34; S, 13.56.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(Cl)Cl>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:24]([O:20][C@@H:5]1[C@@H:4]([O:21][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:3]([O:22][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:2]([CH2:1][O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:7][C@@H:6]1[O:8][C@@H:9]1[C@@H:10]([CH2:18][O:19][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:11][CH:12]([O:17][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:13]([O:16][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:14]1[O:15][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OC[C@H]1O[C@H](O[C@H]2[C@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)C(OC(=O)c3ccccc3)O[C@@H]2COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 163.2 %

Procedure:
Maltose (2.0 g, 5.84 mmol) was dissolved in dry pyridine (40 mL) at 0° C. DMAP (cat.) was added. Benzoyl chloride (2.5 equiv., 14.6 mmol, 16.4 g, 13.6 mL) was added dropwise and the solution stirred at room temperature overnight. The solution was poured onto a mixture of ice-water and DCM. The organic layer was washed with NaHCO3(sat.) (×7), brine, H2SO4 (5%) (×2), followed by brine. The solution was dried (Na2SO4) and the solvent evaporated. The product was passed through a short silica plug to remove the remaining benzoyl chloride and the solvent was evaporated to yield 3.5 g (51%) of the white solid product which was reacted on without further purification or characterisation.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1C(OC(C)(C)C)=O)=O.O=P(Cl)(Cl)Cl.[NH2:25][C:26]1[CH:34]=[C:33]([Br:35])[CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=O>>[Br:35][C:33]1[CH:34]=[C:26]2[C:27]([C:28](=[O:30])[N:5]([CH2:6][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]3)[C:3]([CH2:2][Cl:1])=[N:25]2)=[CH:31][CH:32]=1
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCCCC1CNC(=O)CCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1c2ccc(Br)cc2nc(CCl)n1CC1CCCCN1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A solution of tert-butyl 2-((2-chloroacetamido)methyl)piperidine-1-carboxylate (590 mg, 2.02 mmol) and POCl3 (5 mL) was stirred at room temperature for 30 min. Then 2-amino-4-bromobenzoic acid (442 mg, 1.94 mmol) was added to the mixture and stirred for another 20 min. After warming slowly to 100° C., the mixture was maintained at 100° C. for 1.5 h. Then the reaction mixture was poured into ice water, adjusted pH to 8 and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the crude product was directly used for the next reaction. MS (ESI): 370, 372 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([CH2:28][OH:29])[CH:3]=1.C(N(CC)CC)C.[C:37]1([CH3:49])[C:38]([S:43]([N:46]=[C:47]=[O:48])(=[O:45])=[O:44])=[CH:39][CH:40]=[CH:41][CH:42]=1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([CH:3]=1)[CH2:28][O:29][C:47](=[O:48])[NH:46][S:43]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH3:49])(=[O:44])=[O:45]
Reactant: Cc1ccccc1S(=O)(=O)N=C=O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccccc1S(=O)(=O)NC(=O)OCc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 55 °C

Procedure:
To a solution of 2-(4-chloro-2-hydroxymethyl-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.050 g, 0.12 mmol) in dry toluene (2 mL) was added triethylamine (0.05 mL, 0.36 mmol) followed by o-toluenesulfonylisocyanate (0.05 mL, 0.36 mmol) and catalytic 4-dimethylaminopyridine. After 23 hours the reaction was warmed to 55° C. for 2 hours. After cooling the reaction was evaporated to dryness and the title compound purified by silica gel chromatography (0.074 g, LRMS: 618.1).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:26]([N:32]=[C:33]=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O1CCCC1>[CH2:26]([NH:32][C:33](=[O:34])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCN=C=O
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCNC(=O)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (500 mg, 2.09 mM) and triethylamine (0.4 mL) in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, n-hexyl isocyanate (457 mg/ml, 3.14 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere a RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 ml) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chloroform-hexane (1:9) to give 8g as solid. Yield: 0.619 g, 81%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH:12]([CH3:14])[CH3:13])[N:3]=1.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>C(OCC)C>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:17]([CH2:18][CH3:19])[CH2:15][CH3:16])[N:3]=[C:4]([NH:11][CH:12]([CH3:14])[CH3:13])[N:5]=1
Reactant: CCNCC
Reactant: CC(C)Nc1nc(Cl)c(C#N)c(Cl)n1
Solvent: CCOCC
Product: CCN(CC)c1nc(NC(C)C)nc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.2 %

Procedure:
To a stirred solution of 4.3 grams of 4,6-dichloro-2-isopropylamino-5-pyrimidinecarbonitrile in 125 ml of diethyl ether was added dropwise 2.6 grams of diethylamine. Upon complete addition, the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed with water. The diethyl ether layer was separated and dried over magnesium sufate. The mixture was filtered, and the filtrate was evaporated under reduced pressure to a residue. The residue was recrystallized from methylcyclohexane to give 2.5 grams of 4-chloro-6-diethylamino-2-isopropylamino-5-pyrimidinecarbonitrile; mp, 74°-76°.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][NH:26][CH3:27])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:28])[CH2:25][N:26]([C:15]([C:12]1[CH:13]=[C:14]2[C:9]([C:8]([CH2:18][CH3:19])=[N:7][N:6]2[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:10][CH:11]=1)=[O:17])[CH3:27])[CH3:22]
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)O)ccc12
Reactant: CCOC(=O)CNC
Agent: Cl
Product: CCOC(=O)CN(C)C(=O)c1ccc2c(CC)nn(C3CCCC3)c2c1
Yield: 56 %

Procedure:
This compound was prepared according to the method of Example 35, using 284 mg (1.10 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid and 169 mg (1.10 mmol, 1.0 equiv) sarcosine ethyl ester hydrochloride as starting materials, to give 220 mg (56%) of a clear oil: Anal. calcd for C20H27N3O3: C, 67.21; H, 7.61; N, 11.76. Found: C, 66.93; H, 7.73; N, 11.77.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:16][C:17]#[N:18])[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)=O)C.[H][H]>CO.C(O)(=O)C>[O:13]1[C:9]2([CH2:14][CH2:15][C:6]3([CH2:16][CH2:17][NH:18][C:4]3=[O:3])[CH2:7][CH2:8]2)[O:10][CH2:11][CH2:12]1
Reactant: [H][H]
Reactant: CCOC(=O)C1(CC#N)CCC2(CC1)OCCO2
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NCCC12CCC1(CC2)OCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.6 %

Procedure:
8-Cyanomethyl-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (525 mg) was dissolved in methanol (10 mL) and acetic acid (5 mL). Platinium(IV) oxide (235 mg) was added and an atmosphere of hydrogen was introduced. The mixture was then stirred at RT for 18 hours. The reaction was filtered over dicalite speed plus (Acros Organics) and the filtrate was concentrated in vacuo. The residue was poured into ice/water and was basified with 2M aqueous NaOH solution. The aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a colorless solid (169 mg). MS (ESI): 212.2 (MH+.