Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([NH2:16])=[O:15])[C:7]2=[O:12].CN(C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([C@H:68]([CH3:72])[C:69](O)=[O:70])=[CH:64][CH:63]=1>>[NH2:16][C:14](=[O:15])[C@H:13]([N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:69](=[O:70])[C@H:68]([C:65]2[CH:66]=[CH:67][C:62]([Cl:61])=[CH:63][CH:64]=2)[CH3:72])[C:7]1=[O:12])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NC(=O)[C@@H](c1ccccc1)n1ccc2c(N)cccc2c1=O
Reactant: C[C@H](C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](C(=O)Nc1cccc2c(=O)n([C@@H](C(N)=O)c3ccccc3)ccc12)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of (R)-2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-2-phenylacetamide (120 mg, 0.00041 mol), N,N-dimethylformamide (1.5 mL, 0.019 mol), N,N-diisopropylethylamine (0.1 mL, 0.0008 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.3 g, 0.0008 mol) and (S)-2-(4-chlorophenyl)propanoic acid (0.091 g, 0.00049 mol) was allowed to stir over night at room temperature. The solvent was removed and the residue purified by flash chromatography (12 g silica gel, 0-10% MeOH/DCM) and again by preparative HPLC (reverse phase) to obtain the product as an off white solid. MS m/z=460.3 (M+H). 1H NMR (400 MHz; DMSO-d6) δ 9.95 (s, 1H), 8.13-8.11 (d, J=7.99 Hz, 1H), 8.02 (s, 1H), 7.74-7.72 (d, J=7.60 Hz, 1H), 7.71-7.69 (d, J=8.03 Hz, 1H), 7.55 (s, 1H), 7.50-7.32 (m, 10H), 6.99-6.97 (dd, J=7.89&1.86 Hz, 1H), 6.74 (s, 1H), 6.39-6.37 (d, J=8.02 Hz, 1H), 4.00-3.94 (q, J=6.97 Hz, 1H), 1.44-1.41 (d, J=7.11 Hz, 3H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([NH2:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]1[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>C(Cl)Cl>[CH2:5]([NH:17][C:28](=[O:29])[CH2:27][CH2:26][CH:25]([OH:30])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCN
Reactant: CCCCCCCC1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(=O)CCC(O)CCCCCCC
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 19.0 g aluminum chloride, dissolved in methylene chloride, was cooled to 0° C. and 46.5 g dodecylamine in methylene chloride was added dropwise (exothermic). At room temperature 19.3 g gamma-undecalactone was added rapidly. The temperature rose to 36° C. The reaction was stirred at room temperature for 4 hours. The mixture was quenched with water and filtered over Celite. The liquid was extracted with ether and washed with water and brine. The solution was dried, filtered and evaporated to dryness. The resulting brown crystals were purified by recrystallization from ether/ethylacetate to give pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[CH:11](NC(C)C)(C)C.[Li].C1CCCCC1.CI.[NH4+].[Cl-]>>[Br:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][C:6]=1[CH3:11]
Reactant: CC(C)NC(C)C
Reactant: Brc1csc2ccccc12
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCCCC1
Product: Cc1sc2ccccc2c1Br
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
1.06 g of 3-Bromo-benzo[b]thiophene (5.0 mmol) is dissolved in 10 ml of dry tetrahedrofuran and cooled to −78° C. and 3.67 ml of lithium diisopropylamine 1.5M in cyclohexane (5.5 mmol) is added slowly and stirred at −78° C. for 15 min. 0.35 ml of Methyl iodide (5.6 mmol) is added and the reaction mixture is stirred at room temperature for 1 h, sat. NH4Cl is added, and the mixture is extracted with CH2Cl2, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt=10:1) to give the title compound. 835 mg (74%). 1H-NMR (CDCl3): 7.76 (t, 2H, J=7.7 Hz), 7.46 (t, 1H, J=7.7 Hz), 7.37 (t, 1H, J=7.7 Hz), 2.60 (s, 3H)
Reaction SMILES: [C:1]1([C:7]2[CH:17]=[CH:16][C:10]([CH2:11][C:12](=[CH2:15])[CH2:13]Cl)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][CH:19]1[CH2:24][CH:23]([CH3:25])[CH2:22][NH:21][CH2:20]1.[OH-].[Na+]>>[C:1]1([C:7]2[CH:17]=[CH:16][C:10]([CH2:11][C:12](=[CH2:15])[CH2:13][N:21]3[CH2:22][CH:23]([CH3:25])[CH2:24][CH:19]([CH3:18])[CH2:20]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(CCl)Cc1ccc(-c2ccccc2)cc1
Reactant: CC1CNCC(C)C1
Agent: [Na+]
Agent: [OH-]
Product: C=C(Cc1ccc(-c2ccccc2)cc1)CN1CC(C)CC(C)C1
Temperature: 120 °C

Procedure:
A mixture of 2-[(4-phenyl)benzyl]-2-propenyl chloride (4 g.), synthesized by method utilized in Example 1, and 3,5-dimethylpiperidine (3.7 g.) was heated at 120° C. for five hours. The mixture was cooled to room temperature and neutralized with 25% aqueous sodium hydroxide (15 ml.). The mixture was extracted with toluene, dried over sodium sulfate and evaporated to give an oil which partially solidified on standing. The product was triturated with petroleum ether, having a boiling point range of 30° C. to 60° C., and the insoluble material was removed by filtration. The filtrate was evaporated under reduced pressure to yield 1-[2-[(4-phenyl)benzyl]-2-propenyl]-3,5-dimethylpiperidine in a yield of 4.9 grams.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].C(N(CC)CC)C.Cl[C:21]([O:23][CH3:24])=[O:22]>CN(C1C=CN=CC=1)C.ClCCl>[C:21](=[O:22])([O:23][CH3:24])[O:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])=[CH:7][C:2]=1[Br:1]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)c1ccc(O)c(Br)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Oc1ccc(C(C)(C)C)cc1Br
Temperature: 25 °C
Yield: 90.4 %

Procedure:
2-Bromo-4-tert-butyl phenol (15.0 g, 65.5 mmol) and DMAP (400 mg, 3.3 mmol) was dissolved in dichloromethane (75 mL) and triethylamine (18.25 mL, 130.9 mmol), cooled to 0° C., then treated with methyl chloroformate (7.6 mL, 98.2 mmol) and allowed to warm to room temperature over 2 h. The reaction was quenched with water and the layers separated. The aqueous layer was extracted with dichloromethane and the combined organic extracts dried over Na2SO4. The solution was filtered and concentrated in vacuo to yield an oil that was purified by silica gel chromatography (20% ethyl acetate/hexane) to yield 2-bromo-4-tert-butylphenyl methyl carbonate (17 g, 90% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.67 (d, J=2.3 Hz, 1H), 7.47 (dd, J=2.3, 8.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 3.86 (s, 3H), 1.29-1.26 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[Br:18]Br>C(O)(=O)C>[Br:18][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: O=C(Cc1ccc(F)cc1F)c1ccccc1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(c1ccccc1)C(Br)c1ccc(F)cc1F
Yield: 47 %

Procedure:
While cooling acetic acid solution prepared by dissolving 25 g (160.1 mmol) of 2,4-difluorophenyl acetophenone in an amount of 50 milliliter down to 10° C. or cooler, 25.5 g (160.1 mmol) of bromine was dripped and the resultant solution reacted for 7 hours. Throwing the resultant solution into 300 milliliter of water, the solution was extracted with the use of methylene chloride. After drying an organic layer with the use of magnesium sulfide, the solvent was removed. Refining the resultant residues by means of silica column (hexane), 23.4 g of α-bromo-2,4-difluorophenyl acetophenone Intermediate 1-2c as brown oil was obtained (yield: 62%). The brown oil was confirmed as the aimed compound from 1H-NMR spectrum. The measurement result is shown as follows:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][CH2:13][CH2:14][CH3:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].[CH2:16]([O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1)[CH3:17]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:13]([NH:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:23]3[CH:24]=[CH:25][C:20]([C:19]([O:18][CH2:16][CH3:17])=[O:27])=[CH:21][CH:22]=3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)[CH2:14][CH3:15]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C2(NCCC)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCNC1(c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
Using General Procedure F; [1-(4-ethynylphenyl)-cyclopropyl]-propylamine (Intermediate 120, 38.0 mg, 0.19 mmol) and ethyl-4-iodo benzoate (Reagent A, 58.0 mg, 0.21 mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (8.0 mg, 0.04 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (27 mg, 0.04 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (5-15% EtOAc-hexanes) afforded 40.0 mg (61%) of the title compound as an orange oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:44][NH2:45]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:45][CH2:44][C:40]3[S:39][CH:43]=[CH:42][CH:41]=3)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: NCc1cccs1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NCc4cccs4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and 2-thiophenylmethylamine.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:34]=[CH:33][CH:32]=[CH:31][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:30])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:21][N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:4]>CO.O>[OH:4][CH2:3][C:5]1[CH:34]=[CH:33][CH:32]=[CH:31][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:30])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:21][N:20]=2)=[O:18])[CH2:10][CH2:9]1
Reactant: O=Cc1ccccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2CO)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 1 h
Yield: 57.5 %

Procedure:
NaBH4 (5 mg, 0.12 mmol) was added to stirred a mixture of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-formyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide (50 mg, 0.1 mmol) in MeOH (2 mL) and stirring was continued for 1 hr. The reaction mixture was diluted with water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford the residue. The residue was purified by recrystallisation from CHCl3 in hexane mixture to afford 25 mg (58% yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-hydroxymethyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 435.2, 93.8%, 1H NMR (300 MHz, DMSO-d6): δ13.8 (m, 1H), 8.0 (m, 1H), 7.8 (m, 2H), 7.5 (m, 2H), 7.4 (m, 2H), 7.2 (m, 1H), 7.1 (m, 1H), 7.0 (m, 1H), 6.9 (m, 1H), 5.0 (m, 1H), 4.7 (m, 1H), 4.5 (m, 2H), 3.7 (m, 3H), 3.5 (m, 2H), 2.0 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]1[CH:13]=[C:14]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19]2)[CH:15]=[N:16][CH:17]=1)[CH3:10]>>[Br:1][C:17]1[N:16]=[CH:15][C:14]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:20][CH2:19]2)=[CH:13][C:12]=1[O:11][CH2:9][CH3:10]
Reactant: CCOc1cncc(N2CCCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: O=C1CCC(=O)N1Br
Product: CCOc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)cnc1Br
Reaction time: 0.03 h

Procedure:
N-Bromosuccinimide (2.7 g, 15.2 mmol) was added to 1-(5-Ethoxy-3-pyridyl)-4-tertbutoxycarbonyl homopiperazine (4.5 g, 14.0 mmol) at roomtemperature. The mixture was stirred for 2 min. The mixture was washed with saturated sodium sulfite (100 ml) was. Chromatography on silica gel with a mixture of petroleum: ethyl acetate (1:1) gave the title compound as an oil. Yield 3.3 g, 58%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](=O)[NH:7][C:6]=2[CH:16]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](=[S:18])[NH:7][C:6]=2[CH:16]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1Nc2cc(F)ccc2Nc2cscc21
Product: Fc1ccc2c(c1)NC(=S)c1cscc1N2

Procedure:
In a similar fashion 7-fluoro-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one is treated with phosphorus pentasulfide to give 7-fluoro-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-thione.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23](O)[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH3:29][CH:10]1[CH:11]=[C:12]2[CH:13]([CH:14]([CH2:19][CH2:20][CH:21]3[CH2:22][CH:23]=[CH:24][C:25](=[O:26])[O:27]3)[CH:15]([CH3:18])[CH:16]=[CH:17]2)[CH:8]([O:7][C:5](=[O:6])[CH:3]([CH3:4])[CH2:2][CH3:1])[CH2:9]1
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC3CC=CC(=O)O3)C21

Procedure:
To a stirred solution of 4.0 g (10 mmol) mevinolin in 20 ml pyridine at room temperature are added 20 ml acetic acid anhydride. After 1 h the reaction mixture is concentrated in-vacuo. The residue is dissolved with 10 ml methyl-t-butyl ether and washed successively with water, 0.1 N HCl and brine. The organic phase is then dried over sodium sulfate and the solvent removed in vacuo. The crude product is purified by silica gel chromatography (methyl-t-butyl ether 1/3) to afford 2-methyl-butyric acid 3,7-dimethyl-8-[2-(6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester) as a white powder.
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1.CN(C)C=O.[CH2:19]([Si:21](Cl)([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:20].N1C=CN=C1>C(OCC)(=O)C>[CH3:12][C:2]([O:13][Si:21]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:19][CH3:20])([CH3:1])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1
Reactant: CC[Si](Cl)(CC)CC
Reactant: CC(C)(O)Cn1ccc([N+](=O)[O-])n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)OC(C)(C)Cn1ccc([N+](=O)[O-])n1
Temperature: 0 °C
Yield: 71.5 %

Procedure:
In a round bottomed flask was placed 2-methyl-1-(3-nitro-pyrazol-1-yl)-propan-2-ol (170 mg, 0.92 mmol) and N,N-dimethylformamide (5 mL) and it was placed in an ice bath and cooled to 0° C. To this stirred solution was added triethylsilyl chloride (169 mL, 1.01 mmol) and imidazole (156 mg, 2.30 mmol) and it was stirred at 0° C. and slowly warmed to 25° C. and stirred for two days. The reaction was then diluted with ethyl acetate (15 mL) and washed with a saturated aqueous brine solution (10 mL). The aqueous layer was then extracted with ethyl acetate (2×15 mL). The organic layers were then combined and dried over sodium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix Intelliflash system (4 g column, 5% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) afforded 1-(2-methyl-2-triethylsilanyloxy-propyl)-3-nitro-1H-pyrazole (197 mg, 72%) as a clear colorless oil: ES-HRMS m/e calcd for C13H25N3O3Si (M+H)+ 300.1738, observed 300.1737; 1H NMR (300 MHz, CDCl3) δ ppm 0.58 (q, J=8.0 Hz, 6H, 3×SiCH2), 0.92 (t, J=8.0 Hz, 9H, 3×CH3), 1.26 (s, 6H, 2×CH3), 4.12 (s, 2H, NCH2), 6.89 (d, J=2.5 Hz, 1H, Ar), 7.56 (d, J=2.5 Hz, 1H, Ar).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CCO>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([S:10]([C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=2)(=[O:12])=[O:11])[CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CN1CCNCC1
Solvent: CCO
Product: CN1CCN(S(=O)(=O)c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-nitrobezenesulfonyl chloride (664 mg, 3.0 mmol) and methylpiperazine (600 mg, 6.0 mmol) in EtOH was stirred for 2 h at RT. The reaction was concentrated and triturated in Et2O to yield a yellowish solid, 3-[(4-methylpiperazinyl)sulfonyl]-1-nitrobenzene, and was used in next step without further purification.
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27].C(Cl)(Cl)Cl>CCCCO>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:13]([CH3:14])[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[N:12]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: NCCCO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCCCO
Product: COc1ccc(N(C)c2nc(NCCCO)nc3ccccc23)cc1
Temperature: 115 °C
Yield: 79.6 %

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride (88 mg, 0.26 mmol) and 3-amino-propan-1-ol (62 μL, 0.82 mmol) in n-BuOH (2 mL) was heated at 115° C. for 29 h then concd in vacuo. Chloroform (5 mL) was added and this washed with satd NaHCO3 (1×2 mL); then dried (MgSO4), filtered through silica with a wash of 100:10:1 CHCl3:MeOH:concd NH4OH, concd then purified by MPLC (amine column (Isco 60-2203-201)/0-100% i-PrOH in CHCl3) yielding the title compound as a pale yellow oil (70 mg; 79%). 1H NMR (CDCl3) δ 7.43 (m, 1H), 7.38 (m, 1H), 7.12 (m, 2H), 6.92 (m, 2H), 6.80 (m, 1H), 6.69 (m, 1H), 3.84 (s, 3H), 3.78-3.66 (m, 4H), 3.52 (s(br), 3H), 1.81 (m, 2H); LC-MS (ESI+; 339 ([M+H]+)).
Reaction SMILES: [OH:1][C:2]1[CH:21]=[C:20]([O:22][CH2:23][CH2:24][OH:25])[CH:19]=[CH:18][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[S:5].[OH:26][C:27]1[CH:28]=[C:29]([CH:39]=[CH:40][C:41]=1[C:42](=[S:55])[C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:45][CH:44]=1)[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](O)=[O:37]>C1(C)C=CC=CC=1>[OH:26][C:27]1[CH:28]=[C:29]([CH:39]=[CH:40][C:41]=1[C:42](=[S:55])[C:43]1[CH:44]=[CH:45][C:46]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[CH:47][CH:48]=1)[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:25][CH2:24][CH2:23][O:22][C:20]1[CH:19]=[CH:18][C:3]([C:4](=[S:5])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)=[C:2]([OH:1])[CH:21]=1)=[O:37]
Reactant: OCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1
Reactant: O=C(O)CCCCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1
Solvent: Cc1ccccc1
Product: O=C(CCCCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1)OCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1

Procedure:
The title compound is prepared by reacting equimolar amounts of the alcohol compound of Example 7 and the acid compound of Example 16 in refluxing toluene in the presence of AMBERLYST® 15 strong acid resin.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]([NH2:13])=[O:12].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O>N1C=CC=CC=1>[C:11]([C:3]1[CH:4]=[C:5]([C:6](=[O:7])[NH2:8])[CH:9]=[CH:10][C:2]=1[NH:1][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21])(=[O:12])[NH2:13]
Reactant: NC(=O)c1ccc(N)c(C(N)=O)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C(N)=O)cc2C(N)=O)cc1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of 4-aminoisophthalamide (1.00 g (5.58 mmol) in pyridine (10.0 ml), p-toluenesulfonyl chloride (1.06 g (5.58 mmol) was added with stirring at room temperature. After 3 hours' stirring at room temperature, water was added to the reaction mixture to separate crystals. The crystals were filtered and washed with water and ethyl acetate to give 0.94 g (51%) of 2′,4′-dicarbamoyl-p-toluenesulfonanilide as white crystals.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=2)=[CH:24][CH:23]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: Cc1ccnc(Oc2ccc(C[C@H](N)C(=O)O)cc2)c1
Solvent: CS(C)=O
Product: Cc1ccnc(Oc2ccc(C[C@H](Nc3nc4ccc(Cl)cc4cc3C(=O)O)C(=O)O)cc2)c1

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(4-methyl-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[C:7]([C:8](Cl)=[O:9])=[C:6]([F:11])[N:5]([CH3:12])[N:4]=1.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[CH:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)[CH3:24].C(N(CC)CC)C>O1CCCC1>[CH:26]1([N:25]([CH:23]([CH:15]2[CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14]2)[CH3:24])[C:8]([C:7]2[C:3]([CH:2]([F:13])[F:1])=[N:4][N:5]([CH3:12])[C:6]=2[F:11])=[O:9])[CH2:28][CH2:27]1
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Reactant: CC(NC1CC1)C1Cc2ccccc2C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C1Cc2ccccc2C1)N(C(=O)c1c(C(F)F)nn(C)c1F)C1CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
At ambient temperature, a solution of 217 mg (1.02 mmol) of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl chloride in 1 ml of tetrahydrofurane is added dropwise to a solution of 202 mg (0.93 mmol) of N-[1-(indan-2-yl)ethyl]cyclopropanamine and 103 mg (1.02 mmol) of triethylamine in 5 ml of tetrahydrofurane. The reaction mixture is stirred for 1 hr at 70° C. The solvent is removed under vacuum and 100 ml of water are then added to the residue. The watery layer is extracted twice with ethyl acetate (2×150 ml) and the combined organic layers are successively washed by a 1 N solution of HCl, a saturated solution of potassium carbonate and filtered over a chemelut™ cardridge to yield after concentration 190 mg of a beige oil. Column chromatography on silica gel (gradient heptane/ethyl acetate) yields 120 mg (30% yield) of N-cyclopropyl-3-(difluoromethyl)-N-[1-(indan-2-yl)ethyl]-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide as a colourless oil (M+H=378).