Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].Br[CH2:20][CH2:21][CH:22]([Br:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[Br:24][CH:22]([CH3:23])[CH2:21][CH2:20][C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: CC(Br)CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(Br)CCC(C#N)(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.8 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 2.2 g of 1,3-dibromobutane were dissolved in 10 ml of dimethyl sulfoxide, 0.83 g of potassium carbonate was added, and the mixture was stirred at room temperature for 4 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.2 g of 2-(3-bromobutyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (62)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)C(N)c1ccccc1F
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccccc1F

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(2-fluorophenyl)acetate hydrochloride (prepared from 2-fluorophenylglycine (Fluka) and ethanol using General Procedure H), the title compound was prepared as a solid (mp=153-170° C.). The reaction was monitored by tlc (Rf=0.3 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.
Reaction SMILES: [ClH:1].[CH:2]1([NH:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:10][C:11]([CH3:18])([CH3:17])[C:12](=O)[CH2:13][C:14]#[N:15]>C(O)C>[ClH:1].[C:11]([C:12]1[CH:13]=[C:14]([NH2:15])[N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[N:9]=1)([CH3:18])([CH3:17])[CH3:10]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNC1CCCCC1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(C2CCCCC2)n1
Temperature: 25 °C
Yield: 38.9 %

Procedure:
A stirred solution of cyclohexylhydrazine hydrochloride (1.5 g, 9.96 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.5 g, 11.98 mmol) in ethanol (5 mL) was refluxed for 15 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure and the obtained crude product was recrystallized from a mixture of diethyl ether and petroleum ether to afford 3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-amine hydrochloride (1.0 g, 39%) as colorless solid. 1H NMR (400 MHz, DMSO-d6) δ13.24 (brs, 1H), 7.02 (brs, 2H), 5.52 (s, 1H), 4.30 (m, 1H), 1.63-1.98 (m, 7H), 1.10-1.40 (m, 12H); LC-MS (ESI) m/z 222 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([F:8])[CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.[OH-].[Na+]>CO>[CH2:9]([N:5]1[CH2:6][C@@H:7]([F:8])[C@@H:3]([CH2:2][NH:1][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:4]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: NC[C@H]1CN(Cc2ccccc2)C[C@H]1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: F[C@@H]1CN(Cc2ccccc2)C[C@@H]1CNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3S,4S)-3-Aminomethyl-1-benzyl-4-fluoropyrrolidine (186 mg) was dissolved in methanol (4 mL). To this solution, molecular sieves 4A (80.0 mg) and benzaldehyde (90.8 μL) were sequentially added and the mixture was stirred at room temperature for 1 hour. Subsequently, a borane-pyridine complex (90.2 μL) was added and the mixture was further stirred at room temperature for 3 hours. This was followed by addition of 6 mol/L hydrochloric acid (1.5 mL) and stirring for 1 hour. Subsequently, a 6 mol/L aqueous solution of sodium hydroxide was added to make the mixture basic and the mixture was extracted with diethyl ether (3×10 mL). The diethyl ether extracts were combined and the combined diethyl ether layer was dried over anhydrous sodium sulfate and was then concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=hexane:ethyl acetate=4:1) to give 179 mg of (3S,4S)-1-benzyl-3-benzylaminomethyl-4-fluoropyrrolidine as a pale brown oil.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=3)[C:20]([O:22]C(C)(C)C)=[O:21])[CH2:13][C@H:12]2[O:30][CH3:31])=[O:9])=[N:5][C:4]=1[C:32]([F:35])([F:34])[F:33])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C:3]1[NH:7][C:6]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=3)[C:20]([OH:22])=[O:21])[CH2:13][C@H:12]2[O:30][CH3:31])=[O:9])=[N:5][C:4]=1[C:32]([F:34])([F:35])[F:33])[CH3:2]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cccc(C(=O)OC(C)(C)C)c3)C[C@H]2OC)nc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cccc(C(=O)O)c3)C[C@H]2OC)nc1C(F)(F)F
Reaction time: 5 h
Yield: 85.3 %

Procedure:
tert-Butyl cis(±)-3-(4-{[(5-ethyl-4-trifluoromethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)benzoate obtained in Example (42e) (78 mg, 0.16 mmol) was dissolved in dichloromethane (3 ml). Trifluoroacetic acid (0.75 ml) was added, followed by stirring for five hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by reverse phase silica gel column chromatography (elution solvent: distilled water, acetonitrile) to obtain 60.1 mg of the title compound as a white solid (87%).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH3:26][O:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:26][O:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33]([C:22]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:25])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:17])([CH3:16])[C:10]=3[CH:18]=2)=[O:23])[CH2:32][CH2:31]1
Reactant: COCCN1CCNCC1
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: COCCN1CCN(C(=O)c2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 1-(2-methoxyethyl)piperazine.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=13)=[O:10])[NH:2]2.[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28](O)=[O:29])[N:25]=1>>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[O:19][CH:18]=[CH:17][C:16]=34)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:29])[N:25]=1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2occc12
Reactant: Nc1nc(-c2ccccc2C(=O)O)cs1
Product: Nc1nc(-c2ccccc2C(=O)N2[C@H](CNC(=O)c3cccc4occc34)C[C@@H]3C[C@@H]32)cs1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-(2-amino-thiazol-4-yl)-benzoic acid. LC-MS (basic): tR=1.28 min; [M+H]+=458.9.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.C(O[CH:17]1[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C.[N+](C1C=CC(OP([O-])(OC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1)([O-])=O>CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:17]3[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]3[O:19][C:20](=[O:22])[CH3:21])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=c1[nH]c2nc(Cl)nc(Cl)c2s1
Agent: O=[N+]([O-])c1ccc(OP(=O)([O-])Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 170 °C

Procedure:
A finely powdered mixture of 24 (3.7 g, 16 mmol), 1,2,3,5-tetra-O-acetyl-D-ribofuranose (5.3 g, 16 mmol) and bis-(p-nitrophenyl)phosphate (20 mg) was heated at 170° C. for 10 min under reduced pressure. After cooling to room temperature the brown solid mass was dissolved in EtOAc (500 mL) and washed with saturated aqueous sodium bicarbonate (3×300 mL). The dried (Na2SO4) organic layer was evaporated to yield a syrup which was purified by silica gel column chromatography (4×40 cm) using toluene-EtOAc (5:1). The resulting syrup was crystallized from ethanol to give a colorless powder: yield 6.4 g, 80%: mp 125°-126° C.: 1H NMR (DMSO-d6) δ 1.99, 2.06, 2.08 (3s, 9H, acetyl), 6.07 (d, J=3.40 Hz, 1H, C1,H), and other sugar protons. Anal. Calcd. for C16H15Cl2N3O8S: C, 40.01: H, 3.15: C1, 14.76: N, 8.75: S, 6.68. Found: C, 40.20: H, 3 31: C1, 14.79: N, 8.61: S, 6 66.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:10])[C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[C:11]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:10][C:21]3[C:22]4[C:27]([CH:18]=[CH:19][C:20]=3[CH:9]=[CH:8]2)=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Oc1cccc2ccccc12
Reactant: C#CC(O)(c1ccccc1)c1ccccc1
Product: C1=CC(c2ccccc2)(c2ccccc2)Oc2c1ccc1ccccc21

Procedure:
The procedure of Step 2 of Example 1 was followed except that 1,1-diphenyl-2-propyn-1-ol was used in place of 1,1-bis(4-methoxyphenyl)-2-propyn-1-ol and 1-hydroxynaphthalene was used in place of methyl-1,4-dihydroxy-2-naphthoate to produce 2,2-diphenyl-[2H]-naphtho[1,2-b]pyran.
Reaction SMILES: CCCCCC.[Li]CCCC.[CH3:12][Si:13]([CH3:28])([CH3:27])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]=[CH:19]1.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C>C1COCC1>[CH3:12][Si:13]([CH3:28])([CH3:27])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]=[C:19]1[B:29]([OH:34])[OH:30]
Reactant: C[Si](C)(C)CCOCn1ccc2cccnc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(B(O)O)cc2cccnc21
Temperature: -45 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
A hexane solution of n-BuLi (60 mL, 150.97 mmol) was added slowly to a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (25.0 g, 100.65 mmol) in dry THF (200 mL) at −70° C. under N2 protection. The mixture was stirred at −45° C. for 2 hour. After (i-PrO)3B (30.29 g, 161.03 mmol) was added, the mixture was stirred overnight warming to RT. Then the reaction mixture was quenched with 1M aqueous HCl and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and the solvent was concentrated in vacuo under reduced pressure. The crude product was purified using column chromatography (petroleum ether:EtOAc=5:1) to provide the product of (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (14.4 g, yield: 49%). 1H-NMR (CDCl3, 400 MHz) δ 8.49 (dd, J=4.8 Hz, 1.6 Hz, 1H), 8.07 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.21 (dd, J=8.0 Hz, 4.8 Hz, 1H), 6.92 (s, 1H), 6.02 (s, 2H), 3.74 (t, J=8.4 Hz, 2H), 1.08 (t, J=8.4 Hz, 2H), 0.04 (s, 9H). MS (M+H)+: 293.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1>>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:21]2[CH2:22][CH2:23][CH:18]([N:4]([CH:1]3[CH2:3][CH2:2]3)[C:5](=[O:17])[C:6]3[CH:7]=[CH:8][C:9]([C:12]4[O:16][CH:15]=[N:14][CH:13]=4)=[CH:10][CH:11]=3)[CH2:19][CH2:20]2)=[N:26][CH:27]=1)#[N:30]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Product: N#Cc1ccc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 6-chloro-nicotinonitrile following a procedure analogous to that described in Example 19. LC (method 9): tR=2.02 min; Mass spectrum (ESI+): m/z=414 [M+H]+.
Reaction SMILES: NCC(O)=O.[F:6][C:7]([F:35])([F:34])[C:8]([N:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([CH2:20][O:21]C(=O)C(F)(F)F)[C:14]=2[O:13][C:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:11]1)=[O:9].O>CO>[F:35][C:7]([F:6])([F:34])[C:8]([N:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([CH2:20][OH:21])[C:14]=2[O:13][C:12]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:11]1)=[O:9]
Reactant: O=C(OCc1cccc2c1OC(c1ccccc1)=CN2C(=O)C(F)(F)F)C(F)(F)F
Agent: NCC(=O)O
Solvent: CO
Solvent: O
Product: O=C(N1C=C(c2ccccc2)Oc2c(CO)cccc21)C(F)(F)F
Reaction time: 0.5 h
Yield: 107.5 %

Procedure:
Glycine buffer (pH 10, 6.33 ml) was added dropwise to a solution of (±)-4-trifluoroacetyl-8-trifluoroacetoxymethyl-2-phenyl-1,4-benzoxazine (953 mg, 2.20 mmol) in methanol (19 ml) at room temperature and the mixture was stirred for 30 min. To the mixture was added water (70 ml) and the mixture was stirred at room temperature for 20 min. and then extracted with ethyl acetate. The extract was washed with water and brine in turn and dried. The solvent was distilled off under reduced pressure to give (±)-4-trifluoroacetyl-2-phenyl-1,4-benzoxazine-8-methanol (793 mg, quantitative yield) as a pale orange oil.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]([C:9]1[S:10][C:11]([Br:14])=[CH:12][CH:13]=1)[OH:8])(=[O:3])[CH3:2].[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1.O>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH:7]([C:9]1[S:10][C:11]([Br:14])=[CH:12][CH:13]=1)[O:8][Si:19]([C:16]([CH3:18])([CH3:17])[CH3:15])([CH3:21])[CH3:20])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC(O)c1ccc(Br)s1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCCC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)s1
Yield: 95.8 %

Procedure:
A solution of 3-(5-bromothiophen-2-yl)-3-hydroxypropyl acetate (1.92 g, 6.9 mmol, 1.0 equiv.), TBDMSCl (1.24 g, 8.3 mmol, 1.2 eq) and 1H-imidazol (1.4 g, 20.7 mmol, 3.0 eq) in CH2Cl2 (50 mL) was stirred for 4 h at 60° C. Water was added and the reaction was extracted with EtOAc (3×200 ml). The combined organic phases were washed (brine), dried (Na2SO4), filtered and concentrated to give a residue, which was purified by silica gel column chromatography (PE/EA=100:1 as eluant) to produce 3-(5-bromothiophen-2-yl)-3-(tert-butyldimethylsilyloxy)propyl acetate (2.6 g, 97.6%) as yellow oil. LC-MS (m/z): 393.1 [M+H]+;
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[C:26]([F:31])[CH:25]=1>C(O)(C)C>[ClH:2].[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:10][CH:11]=3)[N:6]=[CH:5][N:4]=2)=[C:26]([F:31])[CH:25]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: Clc1ncnc2cc(OCCCN3CCOCC3)ccc12
Agent: Cl
Solvent: CC(C)O
Product: Fc1cc(Cl)ccc1Nc1ncnc2cc(OCCCN3CCOCC3)ccc12
Yield: 11.2 %

Procedure:
A mixture of 4-chloro-7-(3-morpholinopropoxy)quinazoline hydrochloride (238 mg, 0.69 mmol) and 4-chloro-2-fluoroaniline (145 mg, 1 mmol) in isopropanol (5 ml) was heated at reflux for 1 hour. The solvent was removed by evaporation and the residue partitioned between water and ethyl acetate and the aqueous layer adjusted to pH8 with sodium hydrogen carbonate. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography eluting with methylene chloride/acetonitrile/methanol (60/30/10 followed by 60/20/20). The resulting semi-purified solid was repurified by chromatography on neutral alumina eluting with methylene chloridelmetlhanol (95/5). The resulting white solid was dissolved in methylene chloride and 4 M ethereal hydrogen chloride (0.5 ml) was added. The volatiles were removed by evaporation, and the residue triturated by the addition of methylene chloride followed by methanol and ether. The precipitated solid was collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-(3-morpholinopropoxy)quinazoline hydrochloride (35 mg, 10%).
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@H:20]([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.[CH2:21]([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36](O)=[O:37])=[CH:30][CH:29]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:11][C@@H:10]2[C@@:2]3([CH3:1])[CH2:3][CH2:4][C@@H:5]4[C@@H:20]5[C:14](=[CH:15][C:16]([CH2:18][CH2:19]5)=[O:17])[CH2:13][CH2:12][C@H:6]4[C@@H:7]3[CH2:8][CH2:9]2)=[O:37])=[CH:30][CH:29]=1
Reactant: CCCCCCOc1ccc(CCC(=O)O)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCCCOc1ccc(CCC(=O)O[C@H]2CC[C@H]3[C@@H]4CCC5=CC(=O)CC[C@@H]5[C@H]4CC[C@]23C)cc1
Reaction time: 4 h
Yield: 92.8 %

Procedure:
To a stirred solution of 5.48 g 19-nortestosterone (20 mmol), 5.5 g 3-(4-hexyloxyphenyl)propionic acid (22 mmol), 0.24 g 4-dimethylaminopyridine (DMAP, 2 mmol) and 0.19 g p-toluenesulfonic acid (pTSA, 1 mmol) in 50 ml CH2Cl2 is slowly added at about 15° C. a solution of 5.2 g N,N'-dicyclohexylcarbodiimide (DCC, 25 mmol) in 30 ml CH2CL2. After 4 h at room temperature (no discolouration of the reaction mixture is seen) 1 ml of acetic acid is added to destroy the excess of DCC. Precipitated urea is then filtered off and the filtrate evaporated in vacuo. To the residue 50 ml ethyl acetate is added and, after stirring for 1 h, undissolved urea is filtered off and the filtrate evaporated in vacuo. The residue is crystallized from methanol/water. There is obtained 9.4 g of Anadur® (93% yield) as white crystals having a m.p. of 53°-55° C. and being pure in TLC.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[CH3:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][N:35]=1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:38]([C:37]3[CH:36]=[N:35][C:34]([CH3:33])=[CH:42][CH:41]=3)=[O:39])[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1ccc(C(=O)N2CCN(c3nc4cc(F)cc(F)c4c(Nc4cncc(N5CCOCC5)c4)c3C)CC2)cn1

Procedure:
Prepared according to Procedure Q using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (40.0 mg, 0.09 mmol) and 6-methylnicotinic acid to give (4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazin-1-yl)(6-methylpyridin-3-yl)methanone. 1H NMR (DMSO-d6) δ ppm 2.09 (br s, 3H), 2.50-2.52 (m, 4H), 3.03-3.05 (m, 4H), 3.33-3.40 (m, 3H), 3.55 (br s, 2H), 3.67-3.69 (m, 4H), 3.82 (br s, 2H), 6.49 (s, 1H), 7.14-7.20 (m, 1H), 7.30-7.26 (m, 1H), 7.35-7.37 (m, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.78 (br s, 2H), 8.37 (s, 1H), 8.54 (d, J=2.4 Hz, 1H). Mass Spectrum (ESI) m/e=560.4 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.[C:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][CH:29]=2)=[C:24]([CH3:37])[CH:23]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([N:15]3[C:16]4[CH:17]=[C:18]5[C:5]6([CH2:8][O:9][C:10]5=[CH:11][C:12]=4[CH2:13][CH2:14]3)[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)=[O:35])=[CH:30][CH:29]=2)=[C:24]([CH3:37])[CH:23]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1ccc(-c2ccc(C(=O)O)cc2)c(C)c1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Product: CC(=O)c1ccc(-c2ccc(C(=O)N3CCc4cc5c(cc43)C3(CCN(C)CC3)CO5)cc2)c(C)c1

Procedure:
The title compound was prepared from 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8) and 4'-acetyl-2'-methylbiphenyl-4-carboxylic acid (D19) using a procedure similar to that of Example 1 (35%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@@H:5]1[CH2:7][C@H:6]1[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)[CH3:3].CC(C)([O-])C.[K+].N#C[Br:25]>C1COCC1>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:7][CH:6]1[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[Br:25])[CH3:1]
Reactant: CN(C)C[C@@H]1C[C@H]1c1ccc2[nH]ccc2c1
Reactant: N#CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CC1CC1c1ccc2[nH]cc(Br)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.4 %

Procedure:
A solution of trans N,N-dimethyl-2-(indol-5-yl)cycloprop-1-yl methylamine (75 mg, 0.35 mmol), and potassium t-butoxide (29 mg, 0.35 mmol) in anhydrous THF at 0° C. was stirred at 0° C. for 30 min before cyanogen bromide (37 mg, 0.35 mmol) was added. The reaction was warmed to room temperature and stirred for 16 h. The reaction was concentrated in vacuo, and the residue was dissolved in water, and extracted with ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give N,N-dimethyl-2-(3-bromoindol-5-yl)cycloprop-1-yl methylamine (100 mg, 98%) as a colorless oil. 1H NMR (MeOH-d4): δ 7.26 (d, J=8.4 Hz, 1H), 7.22 (s, 1H), 7.16 (s, 1H), 6.94 (dd, J=8.7, 1.5 Hz, 1H), 2.58 (dd, J=6.0, 1H), 2.35 (s, 6H), 2.31 (m, 1H), 1.80 (m, 1H), 1.22 (m, 1H), 1.03 (m, 1H), and 0.88 (m, 1H). FIMS: 293.1 (M−H), reverse-phase HPLC purity: 85%.