Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([CH2:21][CH2:22][N:23]([CH2:28][CH2:29][NH2:30])[C:24](=[O:27])[CH2:25]Cl)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([CH2:21][CH2:22][N:23]3[CH2:28][CH2:29][NH:30][CH2:25][C:24]3=[O:27])[N:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCCN(CCc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12)C(=O)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(F)cc1)c1nc(CCN2CCNCC2=O)c2cccnc2c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the crude chloroamine from Step 1 (95 mg, 0.21 mmol) and diisopropylethylamine (0.5 mL, 2.87 mmol) in dichloromethane (5 mL) was stirred at room temperature for two hours. The resultant mixture was concentrated under vacuum. The residue was dissolved in DMSO and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound as yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:8]([CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)[CH2:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.C(OC(=O)[NH:29][C:30](=NC(OC(C)(C)C)=O)[N:31]1C=CC=N1)(C)(C)C.C(OC(=O)NC(CCCN(CC1C(C)=CC=CN=1)C1C2N=CC=CC=2CCC1)=NC(OC(C)(C)C)=O)(C)(C)C>C1COCC1>[CH3:1][C:2]1[C:3]([N:8]([CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)[CH2:9][CH2:10][CH2:11][NH:12][C:30]([NH2:31])=[NH:29])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1N(CCCN)C1CCCc2cccnc21
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Agent: Cc1cccnc1CN(CCCC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C1CCCc2cccnc21
Solvent: C1CCOC1
Product: Cc1cccnc1N(CCCNC(=N)N)C1CCCc2cccnc21

Procedure:
N1-(3-methyl-pyridin-2-yl)-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine (63 mg, 0.20 mmol) and (tert-butoxycarbonylimino-pyrazol-1-yl-methyl)carbamic acid tert-butyl ester (110 mg, 0.31 mmol) was stirred in THF (0.3 mL) for 16 hours. The solvent was removed under reduced pressure, CH2Cl2 (10 mL) was added and the organic phase washed with 15% aqueous NaOH solution (5×5 mL). The organic phase was then dried (Na2SO4) and concentrated under reduced pressure to afford, after column chromatography with silica gel (33:1:0.1 CH2Cl2/MeOH:NH4OH), ({3-[(3-methyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-tert-butoxycarbonylimino-methyl)-carbamic acid tert butyl ester as a pale brown sticky solid (50 mg, 49%),
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([OH:11])(=[O:10])[C:8]#[CH:9].[CH3:12][C:13]([CH3:17])=[CH:14][CH2:15]Br>CC(C)=O>[C:7]([O:11][CH2:15][CH:14]=[C:13]([CH3:17])[CH3:12])(=[O:10])[C:8]#[CH:9]
Reactant: CC(C)=CCBr
Reactant: C#CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CC(=O)OCC=C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
41.5 g (0.3 mol) of potassium carbonate were added at 0° to a solution of 18.4 ml (0.3 mol) of propiolic acid in 300 ml of acetone. The mixture was stirred at room temperature for 4 hours, then 34.7 ml (0.3 mol) of 3,3-dimethylallyl bromide were added and the mixture was subsequently boiled at reflux for a further 20 hours. The cooled reaction mixture was concentrated on a rotary evaporator. The residue was poured onto ice/water and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated. Distillation of the residue in a water-jet vacuum yielded 3-methyl-2-butenyl propiolate of boiling point 77°-78°/15 mmHg.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1.[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29](=O)[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(O)(=O)C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC.O.C(O)C>[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1/[C:29](=[N:21]/[O:20][CH2:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:23][CH:22]=1)/[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)CCC(=O)c1ccco1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CON)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCOC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccco1
Temperature: 25 °C
Yield: 24.1 %

Procedure:
After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (500 mg), ethyl 4-(2-furyl)-4-oxobutyrate (347 mg), acetic acid (0.276 ml), sodium acetate (264 mg) and ethanol (20 ml) was heated to reflux for 96 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl E-4-(2-furyl)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate (190 mg, yield 24%) as a colorless oil from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8](O)=[O:9].CO.CCOCC.C(OCC)(=O)C>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][OH:9]
Reactant: O=C(O)CCc1cccs1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCCc1cccs1
Reaction time: 8 h
Yield: 901.6 %

Procedure:
A solution of borane tetrahydrofuran complex (13.03 ml, 13.03 mmol) was added to THF (29.6 ml). 3-(thiophen-2-yl)propanoic acid (0.100 g, 0.640 mmol) was dissolved in THF (5 mL) and added slowly to the reaction. The solution was stirred overnight. Methanol was added and then the solution was rotovapped. More methanol was added and the solution was rotovapped. This was repeated once. The solution was passed through a pad of silica gel eluting with ether and then ethyl acetate and then rotovapped to give 3-(thiophen-2-yl)propan-1-ol (0.820 g, 5.77 mmol, 97% yield) as a light yellow oil: 1H NMR (400 MHz, CDCl3). δ ppm 7.12 (m, 1H), 6.92 (dd, 1H), 6.81 (m, 1H), 3.71 (t, 1H), 2.95 (t, 1H), 2.02-1.87 (m, 1H)
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:14]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][O:16][C:15]=2[C:25]([OH:27])=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:28]([O:32][C:33]([NH:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[C:39]([NH:41][NH2:42])=[O:40])=[O:34])([CH3:31])([CH3:30])[CH3:29].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)(Cl)Cl.O.CN(C=O)C>[C:28]([O:32][C:33]([NH:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[C:39]([NH:41][NH:42][C:25]([C:15]1[O:16][CH:17]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:27])=[O:40])=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: O=C(O)c1occ(-c2ccccc2)c1-c1ccccc1
Reactant: COc1ccc(C(=O)NN)cc1NC(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)cc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
Triethylamine (5.95 ml) was added dropwise to a mixture of 3,4-diphenyl-2-furancarboxylic acid (compound of Reference Example 33, 3.76 g), 3-(tert-butoxycarbonylamino)-4-methoxybenzoic acid hydrazide (compound of Reference Example 65, 4.00 g), BOP reagent (9.43 g) and DMF (40 ml) at 0° C., and the mixture was stirred overnight at 25° C. After adding water thereto, the reaction solution was diluted with chloroform. The organic layer was then successively washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform), thereby giving 6.42 g of the desired compound. Melting point: 137-141° C. (Recrystallized from ethyl acetate/hexane)
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:12][C:10](=O)[NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[C:13](=O)([O-])[O-].[Na+].[Na+].ICC.[OH-].[Na+].Cl>CC(N(C)C)=O>[CH2:10]([NH:9][C:7](=[O:8])[C:5]1[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=1)[OH:12])[CH3:13]
Reactant: O=c1[nH]c(=O)c2ccccc2o1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCI
Solvent: CC(=O)N(C)C
Product: CCNC(=O)c1ccccc1O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Dimethylacetamide (50 ml) and carsalam (10.00 g, 0.0613 mol) were placed into a round bottom flask fitted with nitrogen purge, cold water condenser and a magnetic stir bar. Sodium carbonate (6.50 g, 0.0613 mol) and iodoethane (4.38 ml, 0.0548 mol) were added and heating of the reaction mixture was started. Heating at 80° C. continued for 16 hours at which point heating was discontinued and the reaction mixture was allowed to cool to room temperature. The reaction mixture was then filtered through a sintered glass funnel and the filtrate was collected. Water was added to this filtrate until a white solid precipitated. The solid was isolated by filtration and placed in an Erlenmeyer flask with 2N aqueous sodium hydroxide solution (200 ml). This mixture was heated at reflux for approximately 1 hour and then stirred overnight at room temperature. This mixture was acidified with 2N aqueous hydrochloric acid and a yellow oil was noted to separate out. The reaction mixture was extracted two times with 200 ml portions of ethyl acetate. The combined ethyl acetate layers were washed two times with 200 ml portions of deionized water, dried with sodium sulfate and concentrated under vacuum. N-ethylsalicylamide was recovered as a yellow oil which, after drying overnight under vacuum, was isolated in a yield of 7.93 g.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]1([C@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[N:20]2[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(OCC)C>[C:8]1([C@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[N:20]2[CH2:25][CH2:24][CH:23]([NH:26][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[CH2:22][CH2:21]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Brc1cccnc1
Reactant: NC1CCN([C@@H]2CCCC[C@@H]2c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: c1ccc([C@H]2CCCC[C@H]2N2CCC(Nc3cccnc3)CC2)cc1
Temperature: 70 °C
Yield: 20 %

Procedure:
The title compound, MS (ISP): m/e=440.4 (M+H+), was prepared as for example 209, steps (A) to (C). Step (B) was performed using 3-bromo-pyridine as follows: A suspension of (+/−)-[cis-1-(2-phenyl-cyclohexyl)-piperidin-4-yl]-amine (1.00 g, 3.88 mmol) in toluene (30 ml) was degassed with a flow of argon for 10 minutes. Tris-(dibenzylideneacetone)dipalladium chloroform complex (124 mg, 0.12 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (BINAP, 76.0 mg, 0.12 mmol), sodium tert-butoxide (0.470 g, 4.89 mmol) and 3-bromopyridine (0.483 g, 3.06 mmol) were added under argon. The flask was sealed and warmed to 70° C. for 3 hours. The mixture was diluted with ethyl acetate (30 ml) and diethyl ether (30 ml) and washed three times with saturated sodium chloride solution. The organic phase was dried with sodium sulphate and evaporated, yielding a red oil. Purification was achieved by flash chromatography (dichloromethane/methanol/25% NH3 90:10:1). (+/−)-[cis-1-(2-Phenyl-cyclohexyl)-piperidin-4-yl]-pyridin-3-yl-amine (0.260 g, 20%) was obtained as an orange foam, MS (ISP): m/e=336.3 (M+H+). This was reacted with benzoyl chloride in step (C).
Reaction SMILES: C(OP([CH2:9][C:10](=[O:15])[N:11]([O:13][CH3:14])[CH3:12])(=O)OCC)C.C([N-]C(C)C)(C)C.[Li+].[CH:24]1([O:29][C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=2[O:38][CH3:39])[CH:33]=O)[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.O>[CH3:14][O:13][N:11]([CH3:12])[C:10](=[O:15])[CH:9]=[CH:33][C:32]1[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:30]([O:29][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:31]=1
Reactant: CCOP(=O)(CC(=O)N(C)OC)OCC
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C=CC(=O)N(C)OC)cc1OC1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a stirred solution of diethyl(N-methoxy-N-methyl-carbamoylmethyl)phosphonate (2.60 g, 10.90 mmol) in dry tetrahydrofuran (50 ml) at -78° C. was added lithium diisopropylamide (1.5M solution in cyclohexane, 7.33 ml, 11 mmol) dropwise over 3 minutes. The resulting solution was stirred at -78° C. for 30 minutes, after which time 3-cyclopentyloxy-4-methoxybenzaldehyde (1.5 g, 6.81 mmol) in dry tetrahydrofuran (5 ml) was added in one portion. The reaction was allowed to warm to room temperature and stirring continued overnight. After which time the reaction mixture was diluted with water (25 ml) and the tetrahydrofuran removed in vacuo. The aqueous residue was diluted with brine (25 ml) and extracted with methylene chloride (3×60 ml). The organic extracts were dried (Na2SO4) and evaporated in vacuo to give a yellow liquid. The liquid was purified by flash chromatography (SiO2 ; hexane/ethyl acetate (65:35)) to afford the title compound as a pale yellow liquid (1.986 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]([NH:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][C:12]([Cl:19])=[CH:11][C:10]=1[C:20]#[C:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])=[O:7])[CH3:2].[H-].[Na+]>CS(C)=O>[CH2:1]([O:3][C:4]([C:5]1[C:6](=[O:7])[NH:8][C:9]2[C:10]([C:20]=1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])=[CH:11][C:12]([Cl:19])=[CH:13][C:14]=2[C:15]([F:17])([F:18])[F:16])=[O:29])[CH3:2]
Reactant: CCOC(=O)CC(=O)Nc1c(C#Cc2ccccc2Cl)cc(Cl)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Cc2ccccc2Cl)c2cc(Cl)cc(C(F)(F)F)c2[nH]c1=O

Procedure:
The title compound was prepared in analogy to example 29 step B from N-[4-chloro-2-(2-chloro-phenylethynyl)-6-trifluoromethyl-phenyl]-malonamic acid ethyl ester (1 g, 2.25 mmol) and NaH (140 mg, 3.38 mmol) in DMSO (10 ml). Off white solid (450 mg, 45%). LC-MS (ESI): 444 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=2[O:15][CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C(OC)=C(C=CC=1OC)[CH:21]=[O:22]>>[CH3:16][O:15][C:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([O:13][CH3:14])[CH:11]=[CH:10][C:9]=1[CH:21]=[O:22]
Reactant: COc1ccc(C=O)c(OC)c1Cl
Reactant: COc1cccc(OC)c1-c1ccccc1
Product: COc1ccc(C=O)c(OC)c1-c1ccccc1
Yield: 95 %

Procedure:
Compound 2c was synthesized from 1c in 95% yield using the procedure described for 2a. 1H NMR(acetone-d6): δ 10.28 (s, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.42–7.49 (m, 5H), 7.10 (d, J=8.8 Hz, 1H), 3.89 (s, 3H), 3.48 (s, 3H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8](=[O:10])[CH3:9])=[C:5]([CH3:7])[N:6]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](B(O)O)[CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C(O)C>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:2]2[S:3][C:4]([C:8](=[O:10])[CH3:9])=[C:5]([CH3:7])[N:6]=2)[CH:12]=1
Reactant: CC(=O)c1sc(Br)nc1C
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CC(=O)c1sc(-c2cccnc2)nc1C
Temperature: 25 °C

Procedure:
2-Bromo-4-methyl-5-acetylthiazole (12.0 g, 54.5 mmol) was dissolved in a mixture of dimethoxyethane (180 ml), water (76 ml) and ethanol (52 ml). To this solution was then added 3-pyridineboronic acid (20.1 g, 163.5 mmol), tetrakis(PPh3)palladium(0) (6.3 g, 5.4 mmol), and sodium carbonate (17.3 g, 163.5 mmol), and the reaction mixture was heated to 160° C. in a microwave oven for a period of 1 hour. The reaction was allowed to cool to ambient temperature, the solvents were removed by evaporation, the residue taken up in ethyl acetate, and the mixture filtered through silica gel and celite. The ethyl acetate was washed with water, dried over magnesium sulfate, and the solvent removed by evaporation. The crude product was purified by chromatograph and the product was obtained as a fawn colored solid. 1H NMR (CDCl3): 2.6 ppm (3H, s); 2.8 ppm (3H, s); 7.4 ppm (1H, m); 8.25 ppm (1H, m); 8.7 ppm (1H, m); 9.2 ppm (1H, m).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.[CH2:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:30]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:34]4[CH2:35][CH2:36][N:31]([CH2:29][CH3:30])[CH2:32][CH2:33]4)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: CCN1CCNCC1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Product: CCN1CCN(C(=O)c2ccc(CCc3cnc4c(N)nc5cc(C)ccc5c4c3)c(C)c2)CC1

Procedure:
(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl)(4-ethylpiperazin-1-yl)methanone was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and 1-ethylpiperazine following the procedures described for Example 117. 1H NMR (Methanol-d4): δ 8.59 (s, 1H), 8.37 (s, 1H), 8.06 (d, 1H), 7.32 (s, 1H), 7.00-7.12 (m, 4H), 3.67 (br, 2H), 3.06-3.13 (m, 4H), 2.45 (br, 4H), 2.37 (q, 2H), 2.41 (s, 3H), 2.26 (s, 3H), 2.19 (br, 2H), 1.04 (t, 3H). LRMS [M+H]=468.3
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([NH:15]C(=O)C)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].Cl>[OH-].[Na+]>[CH3:4][C:2]([NH:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)NC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)NS(=O)(=O)c1ccc(N)cc1

Procedure:
N-(1,1-Dimethylethyl)-4-(acetylamino)benzenesulfonamide (Example 11) is deprotected by saponification in 20% NaOH (5 mL), followed by neutralization with 10% HCl. The precipitate that is formed is collected by filtration and recrystallized from methanol/diethyl ether.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12](O)=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].O1CCCC1.B.O.Cl>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][CH2:12][OH:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)CCc1cccc([N+](=O)[O-])c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cccc(CCCO)c1
Reaction time: 2.5 h
Yield: 23.7 %

Procedure:
3-(3-Nitrophenyl)propionic acid (1.00 g) was dissolved in tetrahydrofuran (20 ml), and a tetrahydrofuran-borane.tetrahydrofuran solution (1 mol/l, 7.25 ml) was added dropwise to the mixture under ice-cooling. The mixture was stirred under ice-cooling for 30 min, and further at room temperature for 2.5 hr. Water was added to the reaction mixture, and 1 mol/1 aqueous hydrochloric acid solution was added. The mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the object product (220 mg) as a yellow oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N:15]([CH2:26][CH3:27])[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C.[CH3:28][CH:29]1[CH2:33][CH:32]([CH3:34])[N:31]([CH2:35]CC#N)[CH:30]1[CH2:39][OH:40].Cl>O1CCCC1>[CH3:28][CH:29]1[CH2:33][CH:32]([CH3:34])[N:31]([CH2:35][CH2:27][C:26]2[NH:15][C:16](=[O:25])[C:17]3[C:18]([CH:24]=2)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[CH:30]1[CH2:39][OH:40]
Reactant: CC1CC(C)N(CCC#N)C1CO
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cccc2c(=O)[nH]c(CCN3C(C)CC(C)C3CO)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
Diisopropylamine (3.3 g) was dissolved in tetrahydrofuran (20 mL) and n-butyllithium (1.58M, hexane solution, 19 mL) was is added dropwise under a nitrogen stream at −78° C. After the completion of the dropwise addition, a solution (20 mL) of N,N-diethyl-2,3-dimethylbenzamide (5.2 g) in tetrahydrofuran was added dropwise and the mixture was stirred for 1 hr. A solution (20 mL) of 3-(3,5-dimethyl-2-hydroxymethylpyrrolidin-1-yl)propionitrile (2.3 g) in tetrahydrofuran was added dropwise to the reaction mixture and the temperature of the reaction mixture was raised to room temperature. After the completion of the reaction, the reaction mixture was acidified by adding conc. hydrochloric acid. The reaction mixture was concentrated and washed with hexane. The aqueous layer was basified by adding potassium carbonate and extracted with chloroform. The organic layer was dried over magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel column chromatography The fraction eluted with chloroform:methanol=30:1 was concentrated and the obtained residue was again purified by silica gel column chromatography (NH silica gel, Fuji Silysia Chemical). The fraction eluted with chloroform was concentrated and ether was added to the obtained residue. The precipitated crystals were collected by filtration to give 3-[2-(3,5-dimethyl-2-hydroxymethylpyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (0.5 g).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:8][C@@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)=[C:10]2[CH2:33][CH3:34])[CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:18][C:17]1[C:12]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)=[C:10]([CH2:33][CH3:34])[N:9]([C@@H:7]3[CH2:6][C@H:5]([CH2:3][OH:2])[CH2:8]3)[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: CCc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](C(=O)OC)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CO)C1

Procedure:
In analogy to Example 105, 0.73 g (1.56 mmol) cis-3-[4-amino-5-(3-benzyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylic acid methyl ester of Example 123 are reduced with 69 mg (1.73 mmol) lithium aluminiumhydride in THF. Reaction time: 18 h at 0-5° C. Analytical HPLC: tR=11.15 min (Grad 1); ES-MS: m/eo=429.1; NMR (DMSO-d6): 8.10/s (1H); 7.3-7.5/several m's (6H), 7.04/“d” (1H); 6.93/s (1H); 6.90/“d” (1H); 5.4-6.0/b (NH2); 5.15/s (2H); 4.75/m (1H); 4.63/“t” (OH); 3.60/t (2H); 3.03 q (2H); 2.61/q (2H); 2.14/q (2H); 2.24/m (1H); 1.07/t (3H).