Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=[O:14])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([Mg]Br)[CH2:18][CH:19]=[CH2:20].[NH4+].[Cl-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH:13]([OH:14])[CH2:20][CH2:19][CH:18]=[CH2:17])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)COC1(C)C
Reactant: C=CCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(O)C1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 8 h

Procedure:
5 g (21.81 mmol) of (S)-4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester are dissolved in 33 ml of THF, placed under argon and cooled to −78° C. 43.62 ml (21.81 mmol) of a 0.5 M 3-butenylmagnesium bromide solution in THF are added dropwise. The mixture is stirred further at room temperature overnight. After TLC check, about 90 ml of a saturated NH4Cl solution are added to the mixture with cooling, the mixture is stirred further overnight and diluted with about 50 ml of water. The phases are separated, and the aqueous phase is extracted a further twice with EA. The combined organic phases are dried over sodium sulfate, filtered and evaporated. The oily residue is subjected to flash chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.[CH3:25][C:26]([CH3:28])=O.[BH3-]C#N.[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][N:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH:26]([CH3:28])[CH3:25]
Reactant: CC(C)=O
Reactant: Fc1cccc(CNCc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)N(Cc1cccc(F)c1)Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26 %

Procedure:
A mixture of [1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethyl]-(3-fluoro-benzyl)-amine, (200 mg, 0.55 mmol), acetone (81 uL, 1.10 mmol) and 3A molecular sieves (300 mg) in MeOH (3 mL) was stirred at ambient temperature under N2. After 5 h, NaBH3CN was added and the mixture stirred for an additional 2 h. Water (2 mL) was added and the reaction mixture concentrated in vacuo. The residue was taken up in 1N NaOH (20 mL) and extracted with CH2Cl2 (3×30 mL). The combined extracts were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by chromatography (silica gel, 100% EtOAc) and the isolated product converted to the di-hydrochloride salt by treatment with excess anhydrous HCl in methanol solution. The volatiles were removed in vacuo to afford the desired product 6a (58 mg, 26%) as an off-white solid: ESI MS m/z 406 [C21H22Cl2FN3+H]+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:20].[C:21]([CH2:24][NH:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)(=[O:23])[CH3:22].C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl>[C:21]([CH2:24][NH:25][CH:26]1[CH2:30][CH2:29][N:28]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:19])[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:20])[CH2:27]1)(=[O:23])[CH3:22]
Reactant: CC(=O)CNC1CCNC1
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(CC)c2nc(N3CCC(NCC(C)=O)C3)c(F)cc2c1=O
Yield: 86.7 %

Procedure:
A mixture containing ethyl 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (2.99 g), 3-(N-acetylmethylamino)pyrrolidine (2.13 g), triethylamine (1.52 g), and chloroform (30 ml) was heated to reflux for 4 hours with stirring. After cooling the mixture, 5% hydrochloric acid (20 ml) was added with stirring. The chloroform layer was separated off and the solvent was evaporated. To the residue was added 20 ml of acetonitrile and the mixture was cooled. The resulting precipitate was collected and recrystallized from acetonitrile to give 3.51 g of ethyl 7-[3-(N-acetylmethylamino)-1-pyrrolidinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. 212°-213° C.
Reaction SMILES: Br[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:22]1([C:28]2[O:32][C:31]([C:33]3[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=3)=[N:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[C:22]1([C:28]2[O:32][C:31]([C:33]3[CH:38]=[CH:37][C:36]([C:2]4[C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[C:9]([C:16]5[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=5)=[C:8]5[C:3]=4[CH:4]=[CH:5][CH:6]=[CH:7]5)=[CH:35][CH:34]=3)=[N:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(-c2nnc(-c3ccccc3)o2)cc1
Reactant: Brc1c2ccccc2c(-c2cccnc2)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(-c2nnc(-c3ccc(-c4c5ccccc5c(-c5cccnc5)c5ccccc45)cc3)o2)cc1
Temperature: 120 °C
Yield: 68.3 %

Procedure:
In a 100 mL three-necked flask were placed 0.66 g (2.0 mmol) of 3-(10-bromo-9-anthryl)pyridine, 0.63 g (2.4 mmol) of 4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenylboronic acid, 0.45 g (4.0 mmol) of sodium carbonate, 25 mL of toluene, 3 mL of water, and 6 mL of ethanol. The mixture was degassed by being stirred under reduced pressure, and the atmosphere in the flask was replaced with nitrogen. To this mixture was added 58 mg (0.050 mmol) of tetrakis(triphenylphosphine)palladium(0), and the resulting mixture was refluxed under a nitrogen stream at 120° C. for 23 hours. After a predetermined time has passed, water was added to this mixture, and the aqueous layer was extracted with ethyl acetate. The obtained extract and the organic layer were combined and washed with saturated brine, and then the organic layer was dried with magnesium sulfate. The obtained mixture was subjected to gravity filtration, and the resulting filtrate was concentrated to give a solid. The obtained solid was purified by silica gel column chromatography (a 5:1 ratio of toluene to ethyl acetate). Recrystallization from a mixed solvent of toluene and hexane gave 0.65 g of a solid in 69% yield, which was the desired substance.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1CN(Cc2ccccc2)CC=C1N1CCCC1

Procedure:
A mixture of 1-benzyl-3-methyl-4-piperidone (91 g), pyrrolidine (35.6 g), p-toluenesulphonic acid (0.5 g) and dry benzene (400 ml) was heated under reflux under a Dean and Stark trap until separation of water was complete.The solvent was removed on a rotary evaporator and the residue distilled togive 95 g of a colourless liquid boiling at 144°-6° C (0.01 mm).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[CH2:12]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>C(Cl)Cl>[Br:35][CH2:12][C:5]1[CH:6]=[C:7]([Cl:11])[C:8]([Cl:10])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:14]
Reactant: COC(=O)c1cc(Cl)c(Cl)cc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c(Cl)cc1CBr
Reaction time: 16 h
Yield: 49.9 %

Procedure:
To a solution of 169 mg (0.72 mmol) of the product of Step B in 3 mL of CH2Cl2 at 0° C. was added 283 mg (1.08 mmol, 1.5 eq) of triphenylphosphine and 360 mg (1.08 mmol, 1.5 eq) of carbon tetrabromide. The mixture was stirred for 16 hours and quenched with methanol. The reaction was concentrated in vacuo and the resultant oil was flash chromatographed with 2:1 hexane/ethyl acetate to afford the titled compound (107 mg, 50%) as a brownish orange oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:11]C(=O)C)[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.[ClH:15]>>[ClH:15].[ClH:15].[NH2:11][C@H:3]([CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][OH:1]
Reactant: CC(=O)N[C@@H](CO)Cc1cccnc1
Agent: Cl
Product: N[C@@H](CO)Cc1cccnc1
Temperature: 100 °C

Procedure:
A suspension of 13.55 g of N-[(1R)-2-hydroxy-1-(3-pyridylmethyl)ethyl]acetamide in 110 cm3 of aqueous 6N hydrochloric acid is heated at a temperature in the region of 100° C. for 3 hours. The water is evaporated off under reduced pressure (3 kPa) at a temperature in the region of 50° C. 16.51 g of (2R)-2-amino-3-(3-pyridyl)-1-propanol dihydrochloride are obtained in the form of an off-white solid. [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 3.13 (d, J=7.5 Hz: 2H); 3.50 (mt: 2H); 3.62 (mt: 1H); 7.94 (dd, J=8 and 5.5 Hz: 1H); 8.27 (unres. mult.: 3H); 8.43 (broad d, J=8 Hz: 1H); 8.79 (broad d, J=5.5 Hz: 1H); 8.86 (broad s: 1H)].
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([OH:16])([CH3:15])([CH3:14])[CH3:13]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:9])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
In this way, 4-nitro-benzaldehyde reacts with tert-butanol in the presence of tert-butyl hypiodite to give tert-butyl 4-nitro-benzoate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C([Li])CCC.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH:23]=1)[CH:21]=[O:22]>O1CCCC1.CCCCCC>[S:1]1[C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[C:5]1[CH:21]([C:20]1[CH:23]=[C:16]([Br:15])[CH:17]=[CH:18][C:19]=1[F:24])[OH:22]
Reactant: c1ccc2sccc2c1
Reactant: O=Cc1cc(Br)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1cc2ccccc2s1)c1cc(Br)ccc1F
Temperature: -17.799999237060547 °C
Reaction time: 0.67 h
Yield: 84.8 %

Procedure:
Into a tetrahydrofuran (100 liters) solution of benzo[b]thiophene (17.4 kg) was dropwise added a n-hexane solution (56.2 kg) of n-butyl lithium (15.08%) in an argon atmosphere at −24.2 to −13.5° C., followed by stirring at −22.1 to −13.5° C. for 40 minutes. Into this solution was dropwise added a tetrahydrofuran (18 liters) solution of 5-bromo-2-fluorobenzaldehyde (25.5 kg) at −22.1 to −11.8° C., followed by stirring at −23.5 to −16.1° C. for 2 hours. To the reaction mixture were added water (100 liters), toluene (130 liters) and 38% hydrochloric acid (12.3 kg), and extraction was conducted. The organic layer was washed with water (130 liters) and then subjected to distillation at normal pressure to distill off the solvent until the residue became 100 liters. Toluene (130 liters) was added to the residue and the mixture was subjected to distillation at normal pressure to distil off the solvent until the residue became 100 liters. The operation of adding toluene to the residue and subjecting the mixture to distillation under reduced pressure to distill off the solvent, was repeated twice: Then, n-heptane (310 liters) was added to the residue, followed by heating to dissolve the residue. To the solution was added, as a seed crystal, about 26 g of the 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol produced in the same manner as that shown in the first step of Reference Example 1, followed by stirring at 1.2 to 5.0° C. for 13 hours. The separated-out crystals were collected by filtration, washed twice with a toluene-n-heptane (1:6) mixed solvent (26 liters), and subjected to vacuum drying to obtain, as white crystals, 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol [35.91 kg, yield: 84.8%, purity: 99% (HPLC)].
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[Cl:32][CH2:33][C:34](Cl)=[O:35].C(O)(=O)C>C(Cl)Cl.O>[Cl:32][CH2:33][C:34]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)=[O:35]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)cc1OC
Temperature: 20 °C

Procedure:
430 g 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B1; synthesis alternative 2) and 215 g potassium carbonate are suspended in 6.5 l of DCM. The mixture is heated to reflux and 162 g chloroacetylchlorid is added drop wise during 1 h. The mixture is stirred at reflux temperature for 5 h, then 30 g of potassium carbonate and further 36 g of chloroacetylchlorid are added. After 1 h additional reaction time at reflux the reaction is complete. 116 g of acetic acid is added to the mixture during 10 min, then the mixture is cooled to 20° C. and during cooling 3 l of water is added. The organic layer is separated from the aqueous layer; the organic layer is washed twice with 1.5 l of water. The combined aqueous layers are extracted twice with 0.5 l of DCM. The organic layers are combined and 6 l is distilled off in vacuum. Then 2.5 l of tert. butylmethylether is added and the solution is concentrated in vacuum until crystallization starts (about 0.8 liter is distilled off). The suspension is cooled down and stirred overnight. The suspension is filtered, the solid dried in vacuum by 50° C.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[C:15](P(C(C)(C)C)C(C)(C)C)(C)([CH3:17])[CH3:16].C#CC>O1CCOCC1.CCOC(C)=O.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[C:16]([C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1)#[C:15][CH3:17]
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Reactant: COC(=O)c1ccc2occ(Br)c2c1
Agent: Cl[Pd]Cl
Agent: C#CC
Solvent: CCOC(C)=O
Solvent: N#Cc1ccccc1
Solvent: C1COCCO1
Product: CC#Cc1coc2ccc(C(=O)OC)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 226 %

Procedure:
Methyl 3-bromobenzofuran-5-carboxylate (750 mg, 2.94 mmol) is combined with bis(benzonitrile)palladium dichloride (169 mg, 0.44 mmol), cuprous iodide (19 mg, 0.10 mmol), tri-t-butylphosphine ((10% in hexane) 1.92 ml, 0.95 mmol), and propyne (2 ml, 35 mmol) in 7 ml dry dioxane in 15 ml screw cap pressure tube under nitrogen. The mixture is treated with DIA (494 μL, 3.6 mmol), is stirred overnight at RT, and is diluted with 50 ml EtOAc. The reaction is washed with 4×25 ml 1:1:0.1 H2O/brine/conc. NH4OH, the organic layer is dried (MgSO4), and the volatiles are removed in vacuo. The crude material is chromatographed over 50 g silica gel (230-400 mesh) eluting with 12% EtOAc/hexane. The appropriate fractions are combined and concentrated to give 460 mg (73%) of methyl 3-prop-1-ynyl-1-benzofuran-5-carboxylate as a pale solid. MS for C13H10O3 (EI) m/z (rel. intensity): 214 (M)+.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](O)=[O:20])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[NH2:41][CH2:42][C:43]([NH:45][C@H:46]([C:68]([NH2:70])=[O:69])[CH2:47][S:48][C:49]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:44].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19]([NH:41][CH2:42][C:43]([NH:45][C@H:46]([C:68]([NH2:70])=[O:69])[CH2:47][S:48][C:49]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[O:44])=[O:20])=[O:14])=[CH:30][CH:31]=1)[CH:2]=[CH2:3]
Reactant: NCC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(N)=O
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
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: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
559 mg (0.99 mmol) of the compound from example 2A was dissolved in 15 ml dichloromethane. 415 mg (0.99 mmol) of the compound from example 18A, 173 μl (0.99 mmol) N,N-diisopropylethylamine and 376 mg (0.99 mmol) HATU were added. The reaction mixture was heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the reaction mixture the solvent was removed under reduced pressure. The raw product was dissolved in dichloromethane and chromatographed over approx. 70 ml silica gel. Solvents used were dichloromethane, dichloromethane/methanol 20/1 to dichloromethane/methanol 5/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 860 mg (0.69 mmol, 70% of theory) of the desired product.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([O:18]C)[N:8]2[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([NH2:20])[N:3]=1.[NH2:21][CH:22]([CH2:24][CH2:25][CH3:26])[CH3:23]>C(O)CO.CCOC(C)=O.C(Cl)Cl>[NH2:20][C:4]1[N:3]=[C:2]([NH:21][CH:22]([CH3:23])[CH2:24][CH2:25][CH3:26])[N:10]=[C:9]2[C:5]=1[NH:6][C:7](=[O:18])[N:8]2[CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COc1nc2c(N)nc(Cl)nc2n1CC1CCOCC1
Reactant: CCCC(C)N
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: OCCO
Product: CCCC(C)Nc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 170 °C

Procedure:
To a solution of 2-chloro-8-methoxy-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (40 mg) in ethylene glycol (1.5 mL) was added 2-aminopentane (0.16 mL) and the mixture was heated in a microwave at 170° C. for 2×30 mins. A further portion of 2-aminopentane (0.08 mL) was added and the reaction was heated in a microwave at 180° C. for 30 mins. The mixture was taken up in EtOAc (15 mL) and was washed with water (3×15 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give a brown residue. This was taken up in DCM and concentrated in a vacuum oven to give the title compound as a brown solid (18 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH3:21])[CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNCCCOc1ccc(OC)c(OC)c1
Product: COc1ccc(OCCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and N-methyl-3-(3,4-dimethoxyphenyloxy)-propylamine analogously to Example 6.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:18]([C:22]1[CH:23]=[C:24]([CH:30]=[C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:32]=1[OH:33])[CH:25]=[CH:26][C:27](O)=[O:28])([CH3:21])([CH3:20])[CH3:19].P(Cl)(Cl)Cl.Cl>N1C=CC=CC=1>[C:34]([C:31]1[CH:30]=[C:24]([CH:23]=[C:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:32]=1[OH:33])[CH:25]=[CH:26][C:27]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=2)[CH2:6][CH2:5]1)=[O:28])([CH3:36])([CH3:37])[CH3:35]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)c1cc(C=CC(=O)O)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: ClP(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(N2CCN(C(=O)C=Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)cc1
Yield: 74 %

Procedure:
To a solution of 18.75 g. (80 mmole) ethyl 4-(piperazin-1-yl)-benzoate and 22.1 g. (80 mmole) 3,5-di-tert.-butyl-4-hydroxycinnamic acid in 160 ml. anhydrous pyridine is added dropwise, with ice cooling, a solution of 5.5 g. (40 mmole) phosphorus trichloride and 25 ml. anhydrous pyridine and the reaction mixture is further stirred for 1 hour with ice cooling, then poured on to ice and acidified with concentrated hydrochloric acid. The aqueous phase is extracted with ethyl acetate and the extracts are washed three times with 0.5N hydrochloric acid, dried and evaporated. The residue is recrystallised twice from a mixture of 240 ml. ethanol and 80 ml. water to give 29.2 g. (74%) of the desired product; m.p. 147°-150° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.Br[CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:3][C:2]([F:17])([F:18])[F:1])[C@H:20]([C:21]([O:23][CH3:24])=[O:22])[CH3:25])=[CH:6][C:7]=1[C:13]([F:16])([F:14])[F:15])#[N:10]
Reactant: COC(=O)C(C)Br
Reactant: N#Cc1ccc(NCC(F)(F)F)cc1C(F)(F)F
Product: COC(=O)[C@H](C)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized according to step B of example 1 using 4-[(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and methyl 2-bromopropanoate: 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.8 Hz, 1H), 7.1 (d, J=2.7 Hz, 1H), 6.95 (dd, J=8.8, 2.7 Hz, 1H), 4.5 (q, J=7.3 Hz, 1H), 4.02-4.13 (m, 2H), 3.74 (s, 3H), 1.64 (d, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[C:18]3[C:13](=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:23]([F:26])([F:25])[F:24])[CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:30].O>C1COCC1>[CH3:30][O:8][CH:7]([C:9]1[C:18]2[C:13](=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([C:23]([F:26])([F:24])[F:25])[CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(c1ccccc1)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(c1ccccc1)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 81.9 %

Procedure:
A solution of α-phenyl-2,8-bis(trifluoromethyl)quinoline-4-methanol (50 mg, 0.13 mmol) in anhydrous THF (4 mL) was treated with NaH (18 mg, 60% dispersion in oil, 0.44 mmol), stirred at room temperature for 2 min, treated with iodomethane (0.8 mL, 1.2 mmol) and stirred for 15 min. The solution was then treated with water (10 mL), extracted with ether (2×10 mL), the extracts washed with water (10 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; heptane-EtOAc (10:1)] to give the title compound (41 mg, 79%) as a pale solid: mp 115-117° C.; IR νmax (liquid film)/cm−1 3070, 2929, 2854, 1589, 1588, 1517, 1491, 1456, 1429, 1378, 1210, 1276, 1211, 1184, 1164, 1129 and 1101; NMR δH (400 MHz, CDCl3) 3.47 (3H, s), 5.90 (1H, s), 7.29-7.35 (5H, m), 7.60-7.64 (1H, t J 8 Hz) and 8.25 (1H, d J 8 Hz).