Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[NH:6].C[O:12][C:13](=O)[CH2:14][C:15](=O)[CH2:16][CH2:17][CH2:18][CH3:19].[O-]CC.[Na+]>C(O)C>[CH2:16]([C:15]1[N:7]=[C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:6][C:13](=[O:12])[CH:14]=1)[CH2:17][CH2:18][CH3:19]
Reactant: N=C(N)c1cccc(F)c1
Reactant: CCCCC(=O)CC(=O)OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1cc(=O)[nH]c(-c2cccc(F)c2)n1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
To a solution of 3-fluorobenzamidine (1.14 g) and 3-oxoheptanoic acid methyl ester (1.0 g, Fluka, USA) in 15 mL of ethanol was added 3.15 mL of a 3 M solution of sodium ethoxide in ethanol. The mixture was heated to reflux for 48 h, allowed to cool to room temperature, and the volatiles were removed in vacuo. The residue was dissolved in chloroform and washed with water three times. The aqueous extractions were combined, acidified to pH=6, and washed three times with ethyl acetate. All organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo. The product was purified by column chromatography using 60% ethyl acetate in hexanes as the mobile phase to yield 6-butyl-2-(3-fluorophenyl)-3H-pyrimidin-4-one (0.9 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([OH:9])=O.[CH:10]([NH2:13])([CH3:12])[CH3:11].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN(C=O)C>C(Cl)Cl.CO.N>[CH:10]([NH:13][C:7]([C@@H:3]1[CH2:4][CH2:5][CH2:6][C@@H:2]1[NH2:1])=[O:9])([CH3:12])[CH3:11]
Reactant: CC(C)N
Reactant: N[C@H]1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)NC(=O)[C@@H]1CCC[C@@H]1N
Reaction time: 16 h

Procedure:
55 mg (0.43 mmol) cis-(±)-2-amino-cyclopentanecarboxylic acid are suspended in 900 μL (25 eq) isopropylamine and 205 mg (0.064 mmol, 1.5 eq) TBTU and 550 μL DMF are added. The mixture is stirred for 16 h and the reaction mixture is taken up in DCM/MeOH/NH3(aq) 9/1/0.1 and combined with 7 mL silica gel. After all the volatile constituents have been eliminated in vacuo the residue is chromatographed (silica gel DCM/MeOH/NH3 9/1/0.1). 63 mg of the title compound are obtained.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:23][C:7]2[N:8]([CH2:17][C:18]3[CH:22]=[CH:21][S:20][N:19]=3)[C:9]3[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[CH:13][C:14]=3[C:6]=2[CH2:5]1.C(N(CC)CC)C.N12CCN(CC1)CC2.[CH3:39][N:40]([CH3:45])[S:41](Cl)(=[O:43])=[O:42]>C(Cl)(Cl)Cl.C(Cl)Cl>[C:15]([C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:17][C:18]3[CH:22]=[CH:21][S:20][N:19]=3)[C:7]3[CH2:23][C@H:4]([NH:3][S:41]([N:40]([CH3:45])[CH3:39])(=[O:43])=[O:42])[CH2:5][C:6]=3[C:14]=2[CH:13]=1)#[N:16]
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2ccsn2)C[C@H](N)C1
Reactant: CN(C)S(=O)(=O)Cl
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CN(C)S(=O)(=O)N[C@@H]1Cc2c(n(Cc3ccsn3)c3ccc(C#N)cc23)C1
Temperature: 54 °C
Yield: 75.1 %

Procedure:
Mix (R)-2-amino-4-isothiazol-3-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indole-7-carbonitrile dihydrochloride salt (1.0 g, 2.72 mmol), triethylamine (0.76 mL, 5.44 mmol), and 1,4-diazabicyclo[2,2,2]octane (0.52 g, 4.63 mmol) in CHCl3 (80 mL) and heat in an oil bath until the internal temperature reaches to 54° C. Add a solution of dimethylsulfamoyl chloride (0.35 mL, 3.26 mmol) in CHCl3 (10 mL) drop wise to the reaction mixture via addition funnel under a nitrogen atmosphere over 30 min. Stir the resulting mixture for an additional hour at 54° C. and then cool to room temperature. Dilute with CH2Cl2 (150 mL), wash the organic layer with saturated NaHCO3, dry (Na2SO4), filter, and concentrate in vacuo. Purify using silica gel chromatography on with EtOAc/hexane (8/2) to yield 0.82 g (75%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 7.88 (s, 1H), 7.74 (d, J=5.0 Hz, 1H), 7.64 (d, J=5.1 Hz, 1H), 7.38 (d, J=5.0 Hz, 1H), 7.17 (s, 1H), 5.52 (s, 2H), 4.52-4.40 (m, 2H), 3.31-3.18 (m, 2H), 2.62 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[C:4]([NH:6][CH3:7])=O.B.CSC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][NH:6][CH3:7]
Reactant: CNC(=O)c1c(F)cccc1F
Agent: B
Solvent: CSC
Solvent: Cc1ccccc1
Product: CNCc1c(F)cccc1F
Yield: 51 %

Procedure:
Prepared from 2,6-difluoro-N-methyl-benzamide (3.2 g, 18.7 mmol) and borane-methylsulfide (47 mL of a 2 M solution in toluene) according to the procedure used for example 84 (Step B) to give 1.5 g of the title compound which was used directly in the next prep.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([CH3:12])[C:10]#[N:11].[CH2:13](N)[CH2:14][NH2:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([C:10]1[NH:15][CH2:14][CH2:13][N:11]=1)[CH3:12]
Reactant: CC(C#N)c1cc(Cl)ccc1Cl
Reactant: NCCN
Product: CC(C1=NCCN1)c1cc(Cl)ccc1Cl

Procedure:
rac-2-[1-(2,5-Dichloro-phenyl)-ethyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(2,5-dichloro-phenyl)-propionitrile and ethylene diamine in analogy to Example 19 b): white solid; MS (ISP): 243.0 ((M+H)+.).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:11][C:12]([F:19])([F:18])[CH:13]=[CH:14][C:15]([OH:17])=[O:16].C1(O)C=CC(O)=CC=1>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][CH:13]([C:12]([F:19])([F:18])[F:11])[CH2:14][C:15]([OH:17])=[O:16])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccc2ncsc2c1
Reactant: O=C(O)C=CC(F)(F)F
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)CC(Nc1ccc2ncsc2c1)C(F)(F)F
Yield: 58.6 %

Procedure:
Benzothiazol-6-ylamine (1 g, 0.006 mol) was reacted with 4,4,4-trifluoro-but-2-enoic acid (1.39 g, 0.009 mol), benzene-1,4-diol (0.05 g, 0.00046 mol) and toluene (50 mL) to afford the crude product. Purification by column chromatography on silica gel (15% ethyl acetate in hexane) afforded 1.02 g of the product (53.68% yield).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:31])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=4[O:29][CH3:30])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:32][NH2:33]>>[Cl:31][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])[C:15]2[O:14][CH:13]([CH2:12][NH:33][CH3:32])[CH2:17][C:16]=2[CH:18]=1
Reactant: CN
Reactant: COc1ccc(Cl)cc1-c1cc(Cl)cc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Product: CNCC1Cc2cc(Cl)cc(-c3cc(Cl)ccc3OC)c2O1

Procedure:
The title compound was prepared (0.027 g, 21%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.165 g, 0.34 mmol) and methylamine (0.107 g, 3.4 mmol). mp 193-195° C.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:17][C:18]#[N:19])[C:5]=2[CH:4]=[N:3]1.[OH-:20].[K+].O>CC(O)(C)C>[CH3:1][N:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:17][C:18]([NH2:19])=[O:20])[C:5]=2[CH:4]=[N:3]1
Reactant: Cc1ccc2c(c1)c(=O)c1c(cnn1C)n2CC#N
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ccc2c(c1)c(=O)c1c(cnn1C)n2CC(N)=O
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
To a solution warmed at 85° C. of (1,7-dimethyl-9-oxo-1,9-dihydro-4H-pyrazolo[4,3-b]quinolin-4-yl)acetonitrile (EXAMPLE 51, 69 mg, 0.27 mmol) in 2-methyl-2-propanol (5 ml) was added powdered potassium hydroxide (76 mg, 1.4 mmol). The mixture was stirred at 85° C. for 10 min. After cooling to ca. 40° C., the mixture was poured into water (30 ml) and extracted with ethyl acetate (30 ml×3). The combined organic layer was washed with brine (50 ml), dried over magnesium sulfate, and concentrated in vacuo. The residue was washed with diisopropyl ether and ethyl acetate to give 43 mg (59%) of the title compound as a yellow solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=[C:7]([CH3:13])[N:6]=1)([CH3:3])[CH3:2].C1N=CN([C:19](N2C=NC=C2)=[O:20])C=1.[NH2:26][C:27]1[C:32]2[O:33][CH2:34][C:35](=[O:37])[NH:36][C:31]=2[CH:30]=[CH:29][CH:28]=1>C1COCC1.CN(C=O)C>[CH:1]([O:4][C:5]1[C:10]([CH2:11][NH:12][C:19]([NH:26][C:27]2[C:32]3[O:33][CH2:34][C:35](=[O:37])[NH:36][C:31]=3[CH:30]=[CH:29][CH:28]=2)=[O:20])=[CH:9][CH:8]=[C:7]([CH3:13])[N:6]=1)([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccc2c1OCC(=O)N2
Reactant: Cc1ccc(CN)c(OC(C)C)n1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(CNC(=O)Nc2cccc3c2OCC(=O)N3)c(OC(C)C)n1
Temperature: 70 °C
Yield: 21 %

Procedure:
To a solution of 33a (1.14 g, 6.35 mmol) in THF (30 mL) was added CDI (2.1 mol eq, 2.16 g) and the mixture was heated at 70° C. for 6 h. The reaction mixture was evaporated, water was added and the aqueous phase was extracted with EtOAc (3×35 mL). The recombined organic phases were anhydrified over Na2SO4 and evaporated at reduced pressure (yellow oil, 1.61 g, 93% yield). The oil obtained (0.34 g, 1.25 mmol) was dissolved in DMF (20 mL) and the bicyclic amine 1f was added (0.8 mol eq, 0.20 g), then the mixture obtained was heated at 100° C. overnight. The solvent was removed at reduced pressure and the residue was purified by chromatography (1:1 EtOAc:Petroleum ether) to obtain the product as a white solid (0.07 g, 21% Yield). 1HNMR (DMSO, 400 MHz) δ 1.28 (s, 3H), 1.31 (s, 3H), 2.34 (s, 3H), 4.14 (d, 2H, J=6), 4.60 (s, 2H), 5.25 (m, 1H), 6.48 (dd, 1H), 6.77 (m, 2H), 7.11 (t, 1H), 7.44 (d, 1H, J=8), 7.71 (dd, 1H), 8.16 (s, 1H), 10.64 (bs, 1H). [M+1] 370.95 (C19H22N4O4 requires 370.40).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH:9]2[CH:16](OCC)[O:17]CC)=[CH:4][CH:3]=1.Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:16]=[O:17])=[CH:6][CH:7]=1
Reactant: CCOC(OCC)C1CC(C)(C)CCC1(O)c1ccc(Cl)cc1
Agent: Cl
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1

Procedure:
reacting the 1-(4-chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol and aqueous hydrochloric acid to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:26][CH:25]([CH2:27][C:28]([OH:30])=[O:29])[CH2:24]1.CCN(C(C)C)C(C)C>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13]([N:23]3[CH2:26][CH:25]([CH2:27][C:28]([OH:30])=[O:29])[CH2:24]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Reactant: O=C(O)CC1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC(CC(=O)O)C3)c2CC1
Temperature: 75 °C

Procedure:
2.5 g (7.75 mmol) 10-Chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester, 1.1 g (9.1 mmol) azetidin-3-yl-acetic acid and 3 mL (17.4 mmol) DIPEA were suspended in 18 mL ethanol. The reaction mixture was stirred at 75° C. over night. The solvent was evaporated and the residue was taken up in EtOAc and water and was acidified using a KHSO4 solution. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by prep. HPLC to yield the corresponding acid (72% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[C:14]2=[O:32])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(Cl)Cl.Cl>CO>[ClH:1].[Cl:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([CH:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)[C:14]2=[O:32])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](Nc3ncc(C(F)(F)F)cc3Cl)C2=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C1[C@@H](Nc2ncc(C(F)(F)F)cc2Cl)CCCN1C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 176 %

Procedure:
A flask was charged with (S)-tert-butyl 3-(3-chloro-5-(trifluoromethyl)pyridin-2-ylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (0.51 g, 1.1 mmol), DCM (10 mL), methanol (1 mL), and HCl (2.7 mL, 11 mmol) (in dioxane). The reaction mixture was stirred at ambient temperature overnight. The organic solvents were removed under reduced pressure to provide (S)-3-(3-chloro-5-(trifluoromethyl)pyridin-2-ylamino)-[1,4′-bipiperidin]-2-one hydrochloride (0.40 g, 91% yield). Mass spectrum (apci) m/z=377.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[C:26](=[O:34])[CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1>>[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[C:26](=[O:34])[CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[C:14]([C:9]1[N:10]=[C:11]([CH3:13])[S:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:16]
Reactant: O=C(CC1CCCCN1)c1cc2ccccc2o1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2CCCCC2CC(=O)c2cc3ccccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared from 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid and (RS)-1-benzofuran-2-yl-2-piperidin-2-yl-ethanone, D37 according to a procedure similar to that for Description 35.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:18]([O-:20])=[O:19])[CH:8]=2)[N:3]=1.[CH2:21]([NH2:24])[CH:22]=[CH2:23]>O>[ClH:1].[CH2:21]([NH:24][C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:18]([O-:20])=[O:19])[CH:8]=2)[N:3]=1)[CH:22]=[CH2:23]
Reactant: C=CCN
Reactant: O=[N+]([O-])c1ccc2nc(Cl)nc(NC3CCCC3)c2c1
Solvent: O
Product: C=CCNc1nc(NC2CCCC2)c2cc([N+](=O)[O-])ccc2n1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 128 mg (0.44 mmol) of 2-chloro-4-cyclopentylamino-6-nitroquinazoline was added 913 mg (16.00 mmol) of allylamine, followed by stirring at room temperature for 3 hours. To the reaction solution was water added, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 129 mg (yield: 93.6%) of a free base compound of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23]C(=O)OC(C)(C)C)[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[ClH:1].[NH2:23][C@@H:19]1[CH2:20][CH2:21][CH2:22][N:17]([C:3]2[C:2]([Cl:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:14])[CH3:15])[C:4]=23)[CH2:18]1
Reactant: CC(C)C(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](N)C3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 117.3 %

Procedure:
(R)-tert-Butyl 1-(5-chloro-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.100 g, 0.229 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added, and the reaction was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was then purified by reverse phase HPLC (0-50% ACN in water). The resulting product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)-N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide hydrochloride (0.050 g, 53.3% yield). 1H NMR (400 MHz, D2O) δ 8.11 (s, 1H), 7.28 (s, 1H), 3.81-3.78 (m, 1H), 3.52-3.49 (m, 1H), 3.40-3.36 (m, 1H), 3.20-3.15 (m, 2H), 2.66-2.63 (m, 1H), 2.09-2.06 (m, 1H), 1.78-1.77 (m, 1H), 1.65-1.54 (m, 2H), 1.12-0.18 (m, 6H). LCMS (APCI+) m/z 336 (M+H)+.
Reaction SMILES: NC1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4]C=1.CC1C=C[S:28][C:27]=1[C:31](Cl)=[O:32].C([N:36](CC)CC)C>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[C:23]([CH3:24])=[C:27]([C:31]([NH2:36])=[O:32])[S:28][CH:4]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: Cc1ccsc1C(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)N2Cc3ccccc3Cc3ccccc32)csc1C(N)=O
Yield: 64.8 %

Procedure:
As described for Example 9, 0.314 g (1 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.177 g (1.1 mmol) of 3-methyl-2-thiophenecarbonyl chloride in 5 ml of dichloromethane and 0.111 g of triethylamine for 2 hours at room temperature to give crystals. Recrystallization from dichloromethane-hexane gives 0.235 g of crystals, m.p. 201°-204° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[N:7]=[C:6]2O.O=P(Cl)(Cl)[Cl:22]>CN(C)C1C=CC=CC=1>[Cl:22][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[C:8]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:7]=1
Reactant: COc1ccc2nc(-c3cccnc3)nc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
To a mixture of 6-methoxy-2-(pyridin-3-yl) quinazolin-4-ol (600 mg, 2.37 mmol) in POCl3 (5 mL) was added N,N-dimethyl aniline (1 drop). The resulting mixture was stirred at 120° C. for 30 min. After the reaction was completed, POCl3 was removed in vacuo, and the residue was added to ice-water slowly. The pH was adjusted to ˜7 by slowly adding NaHCO3 (sat.) at 0° C. and then a precipitate formed. The solid was collected and was purified by chromatography on silica gel eluted with petroleum ether/ethyl acetate (v/v=4:1 to 1:1) to give 260 mg of 4-chloro-6-methoxy-2-(pyridin-3-yl)quinazoline as a pale yellow solid (40.4%). LCMS m/z=272.1, 274.0 (M+1) (Method B) (retention time=1.90 min).
Reaction SMILES: NCCCCCC(O)=[O:8].[CH:10]1([N:16]=[C:17]=[N:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CN(C)C=O>[CH:19]1([NH:18][C:17](=[O:8])[NH:16][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: NCCCCCC(=O)O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 18 atom homobifunctional linker was then synthesized from 5.0 g disuccinimidyl ester intermediate dissolved in 150 ml dry dimethylformamide, 4.20 g of 6-aminocaproic acid and 6.93 g of dicyclohexylcarbodiimide. The 6-aminocaproic acid was added to the dimethylformamide solution, and the resulting reaction mixture was stirred under a nitrogen blanket for three hours at room temperature of about 22°. The dicyclohexylcarbodiimide was then added, and the reaction mixture was stirred under a nitrogen blanket for about 16 hours at room temperature. Dicyclohexyl urea precipitate which had formed was then separated from the reaction mixture by filtration, and dimethylformamide was evaporated from the filtrate under reduced pressure. Trituration with ether followed by drying under high vacuum yielded 7.94 g 18 atom homobifunctional linker.
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: CC(NC1CC1)C1Cc2ccccc2C1
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
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).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].F[C:8]1[CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12]([CH3:14])[CH:13]=1.[F:18][C:19]([F:25])(C)[C:20]([F:23])([F:22])O>>[N+:15]([C:11]1[CH:10]=[CH:9][C:8]([O:4][CH2:1][C:20]([F:23])([F:22])[CH:19]([F:25])[F:18])=[CH:13][C:12]=1[CH3:14])([O-:17])=[O:16]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(F)(F)C(O)(F)F
Agent: [K+]
Product: Cc1cc(OCC(F)(F)C(F)F)ccc1[N+](=O)[O-]

Procedure:
28 g of potassium carbonate, 70 ml of tetrafluoropropanol and 26.4 g of 5-fluoro-2-nitrotoluene were reacted; 45 g of oily crude product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH:21]([O:29][Si](C(C)(C)C)(C)C)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:6][CH:5]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH:21]([OH:29])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(Cc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(O)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
To a solution of 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (3.37 g, 6.43 mmol) in THF (40 mL) at 0° C. was added tetra-butylammonium fluoride (1M in THF, 9.6 mL, 9.6 mmol). The reaction mixture was stirred at room temperature for 18 h and the volatiles were removed in vacuo. EtOAc was added and the organic solution was washed with saturated aqueous NaHCO3 (2×), water (1×), and brine (1×). The organic solution was dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with EtOAc to yield 2.28 g of 4-{3-[2-(3-hydroxy-4-phenyl-butyl)-5-oxo-pyrrolidin-1-yl]-propyl}-benzoic acid methyl ester. 1H NMR (CDCl3) (selected peaks) δ7.91 (d, 2H), 7.32-7.15 (m, 7H), 3.86 (s, 3H), 3.75 (m, 1H), 3.63 (m, 1H), 3.54 (m, 1H), 2.94 (m, 1H), 2.78 (m, 1H), 2.61 (m, 3H); MS 410.1 (M+1).