Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]O.[OH-].[Na+].CS([O:9][CH2:10][C:11]1[CH:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[CH2:18])[N:14]=[C:13]([Cl:22])[N:12]=1)(=O)=O>C1C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:22][C:13]1[N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[CH2:18])[CH:16]=[C:11]([CH2:10][O:9][CH3:1])[N:12]=1
Reactant: C=C(OCC)c1cc(COS(C)(=O)=O)nc(Cl)n1
Reactant: CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: C=C(OCC)c1cc(COC)nc(Cl)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 18.9 %

Procedure:
Methanol (1.06 g, 33.1 mmol) and sodium hydroxide (5 M (aq), 2.0 mL, 9.94 mmol) were added to a solution of (2-chloro-6-(1-ethoxyvinyl)pyrimidin-4-yl)methyl methanesulfonate (1.94 g, 6.63 mmol) in benzene (25 mL). Tetrabutylammonium hydrogen sulfate (0.225 g, 0.66 mmol) was added. The mixture was stirred vigorously at rt for 6 h. The phases were separated and the organic phase was filtered through a short silica plug which was washed with 10% MeOH in EtOAc (75 mL) and the solvent was evaporated. The residue was purified by preparative HPLC to give the title compound 0.287 g (19%).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[C:8]([C:10]2[N:14]3[CH:15]=[CH:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:18][C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH2:25][C:26]([OH:28])=O.[CH3:29][N:30]([CH2:32][C:33]1[N:34]=[C:35]([NH2:42])[S:36][C:37]=1[C:38]1([CH3:41])[CH2:40][CH2:39]1)[CH3:31].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH3:31][N:30]([CH2:32][C:33]1[N:34]=[C:35]([NH:42][C:26](=[O:28])[CH2:25][C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:14]4[CH:15]=[CH:16][C:17]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=5)=[CH:18][C:13]4=[N:12][CH:11]=3)=[CH:9][C:4]=2[F:3])[S:36][C:37]=1[C:38]1([CH3:41])[CH2:40][CH2:39]1)[CH3:29]
Reactant: O=C(O)Cc1ccc(-c2cnc3cc(-c4ccccn4)ccn23)cc1F
Reactant: CN(C)Cc1nc(N)sc1C1(C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)Cc1nc(NC(=O)Cc2ccc(-c3cnc4cc(-c5ccccn5)ccn34)cc2F)sc1C1(C)CC1
Reaction time: 14 h

Procedure:
Combine [2-fluoro-4-(7-pyridin-2-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-acetic acid, dihydrochloride (0.190 g, 0.452 mmol) and 4-Dimethylaminomethyl-5-(1-methyl-cyclopropyl)-thiazol-2-ylamine (0.105 g, 0.497 mmol) in DMF (4 mL). Add N,N-diisopropylethylamine (0.26 mL, 1.49 mmol), then O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.190 g, 0.500 mmol). The reaction mixture is stirred for 14 hours under N2. Purify using an SCX cartridge (10 g VARIAN BondElut®), eluting with 1:1 methanol:dichloromethane, then 1:1 2 M NH3 in methanol:dichloromethane. Purify via reverse phase chromatography using a 25 cm by 50.8 mm (i.d.) column w/10 micron particles (MeCN/0.03% HCl H2O (5:95) to 100% MeCN; 30 min). Partition between ethyl acetate and 1 N NaOH. Wash the organic layer with aqueous saturated sodium chloride, dry over magnesium sulfate, filter, and concentrate to the title compound (0.054 g, 22%). MS (ES), n/z 541 (M+1).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:12]([NH:14][CH3:15])=[O:13].[C:25](Cl)(=O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C(Cl)(Cl)Cl>[CH3:24][N:22]([CH3:23])[CH2:21][CH2:20][N:19]1[C:18]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[CH:10][C:9]=2[N:8]=[C:42]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CNC(=O)c1ccc(NCCN(C)C)c(N)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCc1nc2cc(C(=O)NC)ccc2n1CCN(C)C
Reaction time: 2.5 h

Procedure:
Triethylamine (1.00 ml) was added to a solution containing 3-amino-4-{[2-(dimethylamino)ethyl]amino}-N-methylbenzamide (1.500 g) in chloroform (15 ml), and then stearoyl chloride (2.20 mnl) was added thereto while being cooled with ice. After being stirred for 2.5 hours, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (5.3 ml) was added to a solution containing the residue (3.030 g) in ethanol (30 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (3.737 g) was purified by silica gel column chromatography (silica gel 75 g, chloroform:methanol=50:1-30:1), thereby yielding the entitled compound (2.225 g) as pale yellow solid.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([C:11](O)=[O:12])=[CH:9][N:8]=[C:7]([S:14][CH3:15])[N:6]=1)([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:22]C=2C=1.C(Cl)CCl.[OH-].[NH4+]>C1COCC1.C(#N)C>[CH:1]([NH:4][C:5]1[C:10]([C:11]([NH2:22])=[O:12])=[CH:9][N:8]=[C:7]([S:14][CH3:15])[N:6]=1)([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CSc1ncc(C(=O)O)c(NC(C)C)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CSc1ncc(C(N)=O)c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (180 g, 0.792 mol) and HOBt (123 g, 0.911 mol) in anhydrous THF (6.9 L) was added drop-wise a mixture of EDC (174.6 g, 0.911 mol) in acetonitrile (3.7 L) at ambient temperature. The mixture was stirred for 1 h at ambient temperature and then an aqueous ammonium hydroxide solution (989 mL, 28-30% concentrated, 10 eq) was added drop-wise over 30 min. The resulting mixture was heated to gentle reflux for 3 h and then concentrated under reduced pressure. The remaining residue was diluted with a saturated aqueous sodium bicarbonate solution (5 L) and then extracted twice with ethyl acetate (9 L, and 2 L respectively). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (4 water (4 dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 4-(isopropylamino)-2-(methylthio)-pyrimidine-5-carboxamide (171.2 g, 95.5% yield) as a solid. MS (ESI) m/z 227.4 [MA-1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[NH2:24])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl[CH2:26][CH2:27][N:28]=[C:29]=[O:30].[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[N:24]3[CH2:26][CH2:27][NH:28][C:29]3=[O:30])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: O=C=NCCCl
Reactant: Nc1ccc(F)cc1N1CCN(C/C=C/c2ccc(Cl)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCCN1c1ccc(F)cc1N1CCN(C/C=C/c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.4 %

Procedure:
To a solution of 1-[(E)-3-(4-chloro-phenyl)-allyl]-4-(5-fluoro-2-amino-phenyl)-piperazine (1.0 g, Example 3, Step B) in tetrahydrofuran (10 ml) at 0° C. was added 2-chloroethylisocyanate (327 mg) and the resulting solution was stirred under nitrogen at room temperature for 18 hours. The residue was dissolved in a minimum volume of tetrahydrofuran, then added to a suspension of sodium hydride (146 mg, 50% in oil) in tetrahydrofuran (10 ml). The reaction mixture was stirred at room temperature for 3 hours, concentrated under reduced pressure, then triturated with diethyl ether to afford 1-(2-{4-[(E)-3-(4-chloro-phenyl)-allyl]-piperazin-1-yl}-4-fluoro-phenyl)-imidazolidin-2-one (677 mg) as white crystals. M.p. 170-172° C.; 1H NMR (400 MHz, CDCl3) 2.7 (m, 4H), 3.11 (m, 4H), 3.26 (d, J=6.8 Hz, 2H), 3.63 (t, J=5.7 Hz, 2H), 3.99 (t, J=5.7 Hz, 2H), 5.12 (br s, 1H), 6.32 (dt, J=15.6, 6.8 Hz, 1H), 6.57 (d, J=15.6 Hz, 1H), 6.82 (m, 2H), 7.3-7.4 (m, 4H); MS (ES+) 415/417 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17](=[O:28])[C:18]1[CH:23]=[C:22]([Cl:24])[C:21](O)=[C:20]([Cl:26])[C:19]=1[OH:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:15][O:16][C:17](=[O:28])[C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:20]([Cl:26])[C:19]=1[OH:27]
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1O
Reactant: CC(C)(C)OC(=O)CNCCCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)c(OCCCCNCC(=O)OC(C)(C)C)c(Cl)c1O
Reaction time: 16 h
Yield: 83.4 %

Procedure:
To a solution of 4-tert-butoxycarbonylmethylamino-1-butanol (3 g) and known 3,5-dichloro-2,4-dihydroxybenzoic acid methyl ester (3.85 g) in THF (80 ml) were added triphenylphosphine (4.26 g) and diisopropyl azodicarboxylate (3.2 ml) under ice-cooling, and the mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=4/1 v/v) to give the title compound (5.2 g, yield 83%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[C:13](N1C=CN=C1)([N:15]1C=CN=[CH:16]1)=O.Cl.CNC.C(N(C(C)C)CC)(C)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:15]([CH3:16])[CH3:13])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
A solution of 3-(4-bromophenyl)propionic acid (1.0 g, 4.37 mmol) in dichloromethane (30 ml) was treated in one portion with solid 1,1′-carbonyldiimidazole (707 mg, 4.36 mmol). This mixture was allowed to stir at room temperature for 15 minutes. Dimethylamine hydrochloride (360 mg, 4.42 mmol) was then added followed by diisopropylethylamine (0.76 ml, 4.4 mmol) and the stirring continued for 1 hour at room temperature. The reaction mixture was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give the title compound as a colourless oil (972 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:16])[C:3]=1[N:17]=[C:18]=S.[Cl:20][C:21]1[C:22]([N:30]2[CH2:35][CH2:34][CH:33]([F:36])[CH2:32][CH2:31]2)=[CH:23][C:24]([NH:28][CH3:29])=[C:25]([CH:27]=1)[NH2:26].CC(C)N=C=NC(C)C>>[F:16][C:4]1[C:3]([NH:17][C:18]2[N:28]([CH3:29])[C:24]3[CH:23]=[C:22]([N:30]4[CH2:31][CH2:32][CH:33]([F:36])[CH2:34][CH2:35]4)[C:21]([Cl:20])=[CH:27][C:25]=3[N:26]=2)=[C:2]([Cl:1])[CH:15]=[CH:14][C:5]=1[CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CNc1cc(N2CCC(F)CC2)c(Cl)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1F
Agent: CC(C)N=C=NC(C)C
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2F)nc2cc(Cl)c(N3CCC(F)CC3)cc21
Yield: 49 %

Procedure:
The title compound is prepared from N-(4-chloro-2-fluoro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide and 5-chloro-2-methylamino-4-(4-fluoropiperidin-1-yl)-aniline and DIC in analogy to example 51.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][C:9]([C:17]2[N:18]=[CH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:8]1)(C)(C)C.[OH-].[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[C:17]([C:9]2[O:10][C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:18]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: ON=c1cc(-c2cc3ccccc3cn2)oc2ccccc12
Temperature: 0 °C
Yield: 63.1 %

Procedure:
To an ice cooled solution of 2-isoquinolin-3-yl-chromen-4-one O-tert-butyl-oxime (136 mg, 0.39 mmol) in dichloromethane (10 ml) was cautiously added dropwise a 1M solution of titanium tetrachloride in dichloromethane (1.2 ml, 1.2 mmol). The mixture was stirred at 0° C. 2 hours, then at room temperature 2 more hours and poured onto ice cold water (100 ml). The mixture was basified using a 6N aqueous sodium hydroxide solution until pH 10 and the yellow precipitate was collected by filtration. The solid was washed with water, dried and purified by flash chromatography (cyclohexane/ethyl acetate/dichloromethane:80/10/10; 60/30/10 then 0/50/50) to yield 2-isoquinolin-3-yl-chromen-4-one oxime (71 mg, 62%) as a yellow solid. The product was isolated as a 95/5 mixture of Z/E oxime isomers.
Reaction SMILES: Cl.C(OC([N:12]([CH2:20][CH:21]1[C:30]2[C:25](=[CH:26][C:27]([O:39]CC3C=CC=CC=3)=[C:28]([O:31]CC3C=CC=CC=3)[CH:29]=2)[CH2:24][CH2:23][NH:22]1)[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=O)C1C=CC=CC=1.Cl>C(O)(=O)C>[ClH:19].[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([NH:12][CH2:20][CH:21]2[C:30]3[C:25](=[CH:26][C:27]([OH:39])=[C:28]([OH:31])[CH:29]=3)[CH2:24][CH2:23][NH:22]2)=[CH:18][CH:17]=1
Reactant: O=C(OCc1ccccc1)N(CC1NCCc2cc(OCc3ccccc3)c(OCc3ccccc3)cc21)c1ccc(Cl)cc1
Agent: Cl
Solvent: CC(=O)O
Product: Oc1cc2c(cc1O)C(CNc1ccc(Cl)cc1)NCC2
Temperature: 100 °C

Procedure:
A mixture of 1-(N-benzyloxycarbonyl-p-chloroanilinomethyl)-6,7-dibenzyloxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.1 g), acetic acid (11 ml) and conc. hydrochloric acid (11 ml) was heated for 2 hours at 100° C. The reaction mixture was concentrated to dryness under reduced pressure and the residue was washed with ethyl acetate and ether and pulverized to give crude 1-(p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. The product was converted into its p-toluenesulfonate and then again converted into its hydrochloride to give a pure product, mp 91° to 93° C. The product was identified by means of comparison with an authentic sample prepared by another process by its infrared absorption spectrum and nuclear magnetic resonance spectrum.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](Cl)[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[C:6]2=O.[BH4-].[Na+].Cl>C1COCC1.CO>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5]([CH3:13])=[CH:6]2
Reactant: CC1Cc2c(Br)cc(Cl)cc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1=Cc2cccc(Br)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 116 g (0.52 mol) of 4-bromo-6-chloro-2-methyl-1-indanone in 950 ml of THF-methanol (2:1, vol.), 38.3 g (1.02 mol) of NaBH4 were added in small portions for 2 h at −5° C. (Caution: temperature must be lower 0° C.). The mixture was stirred overnight at ambient temperature. The resulting mixture was poured on 1000 cm3 of ice and acidified with 10% HCl to pH=4. The organic layer was separated and the aqueous layer was extracted with 3×300 ml of methyl-tert-butyl ether. This combined extract was dried over K2CO3 and evaporated to dryness. To the residue 1500 ml of toluene were added and the resulting toluene solution was treated with catalytic amount of pTolSO3H (ca. 2 g) for 2 h at reflux. Then this mixture was cooled to room temperature and passed through a short Silica Gel 60 column (40-63 μm, d 60 mm, 1 40 mm). This column was additionally eluted with 250 ml of toluene. The combined extract was evaporated to dryness. Fractional distillation gave a mixture of the title indenes, b.p. 104-108° C./5 mm Hg. Yield 100 g (93%) of colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:6][CH2:5]2.CC([O-])(C)C.[Na+].[CH3:28][C@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][C@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C@H:34]1[CH2:38][CH2:37][N:36]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH2:8][N:7]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:6][CH2:5]3)[CH2:35]1
Reactant: Cc1ccc(S(=O)(=O)N2CCc3cc(Br)ccc3C2)cc1
Reactant: C[C@H]1CCCN1[C@H]1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCc3cc(N4CC[C@H](N5CCC[C@@H]5C)C4)ccc3C2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
6-Bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline (4.32 g, 11.8 mmol, 1 eq), NaOt-Bu (1.64 g, 17.11 mmol, 1.45 eq), Pd2(dba)3 (110 mg, 0.12 mmol, 0.01 eq) and BINAP (221 mg, 0.354 mmol, 0.03 eq) were combined in a round-bottomed flask and purged with nitrogen. 30 mL of dry toluene was added and the solution became red slurry. To this was added a solution of (2S,3′S)-2-Methyl-[1,3′]bipyrrolidinyl (2 g, 13 mmol, 1.1 eq) in 30 mL of dry toluene. The reaction mixture was heated to 85° C. and stirred overnight. The reaction mixture was cooled to rt and quenched with 50 mL of water. This was transferred to a separatory funnel along with 100 mL of brine. The organics were extracted with ethyl acetate (2×100 mL), where they were combined, dried over Na2SO4, concentrated under vacuum and purified by column chromatography on silica gel (200 g column; 50 mL/min; 5% MeOH in CH2Cl2), which afforded 4.02 g (78%) of the title compound as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[O:15][CH3:16].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:35])=[CH:20][N:19]=1.Cl.O1CCOCC1.C(=O)([O-])[O-]>COCCO>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:1][C:2]2[CH:14]=[CH:13][C:5]3[N:6]([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[O:15][CH3:16])=[N:19][CH:20]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1c(N)ccc2c1CCCC(=O)N2C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: COCCO
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2OC)CCCC(=O)N3C)ncc1Cl
Temperature: 110 °C
Yield: 25.3 %

Procedure:
To a solution of 7-Amino-6-methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (50 mg, 0.227 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (56 mg, 0.189 mmol) in 2.27 mL of 2-methoxyethanol was added 57 μL of 4M HCl in Dioxane (0.227 mmol). The solution was heated to 110° C. for 5 hrs, followed by the addition of MP-Carbonate (135 mg, 0.43 mmol) at RT. The MP-Carbonate was filtered after 30 minutes and the resulting crude material was chromatographed (ISCO) to give 2-[5-Chloro-2-(6-methoxy-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (23 mg, 25%). 1H-NMR (CDCl3) δ 11.12 (s, 1H), 8.66 (d, J=8.6 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.14 (s, 1H), 7.51 (t, J=7.7 Hz, 2H), 7.43 (s, 1H), 7.12 (t, J=7.6 Hz, 1H), 6.90 (t, J=8.8 Hz, 1H), 6.26 (br s, 1H), 3.80 (s, 3H), 3.33 (s, 3H), 3.04 (s, 3H), 2.0-2.4 (m, 6H); LC/MS (ESI-pos) m/z 481.06 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][C@H:19]([C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=2)[CH3:20])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:30][C:31]1[CH:32]=[CH:33][C:34]([S:37]([NH2:40])(=[O:39])=[O:38])=[N:35][CH:36]=1>>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)=[C:4]([CH:3]=1)[C:16]([NH:18][C@H:19]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:40][S:37]([C:34]2[CH:33]=[CH:32][C:31]([CH3:30])=[CH:36][N:35]=2)(=[O:39])=[O:38])=[O:27])=[CH:28][CH:29]=1)[CH3:20])=[O:17]
Reactant: Cc1ccc(S(N)(=O)=O)nc1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)NC(=O)c2ccc([C@H](C)NC(=O)c3cc(Cl)cnc3Oc3ccc(F)cc3)cc2)nc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 103 from 4-[(1S)-1-({[5-chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid (step 5 of Example 44) and 5-methylpyridine-2-sulfonamide: 1H-NMR (DMSO-d6) δ 8.95 (1H, d, J=8.6 Hz), 8.38 (1H, br.s), 8.26 (1H, d, J=2.6 Hz), 8.10 (1H, d, J=2.6 Hz), 7.92–7.70 (4H, m), 7.40 (2H, d, J=7.9 Hz), 7.30–7.23 (4H, m), 5.22–5.08 (1H, m), 2.34 (3H, s), 1.44 (3H, d, J=6.8 Hz); MS (ESI) m/z 569 (M+H)+, 567 (M−H)−.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[N:29]=2)[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)[CH3:11])(C)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[F:59][C:60]1[CH:68]=[C:67]([CH3:69])[C:63](C(O)=O)=[C:62]([CH3:70])[N:61]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O.CN(C=O)C>[C:34]([C:30]1[N:29]=[C:28]([CH2:27][N:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:15]2[CH2:14][CH2:13][N:12]([C@H:10]([CH3:11])[CH2:9][CH2:8][NH:7][C:6](=[O:5])[C:63]3[C:67]([CH3:69])=[CH:68][C:60]([F:59])=[N:61][C:62]=3[CH3:70])[CH2:17][CH2:16]2)[CH:33]=[CH:32][CH:31]=1)#[N:35]
Reactant: COc1ccc(N(Cc2cccc(C#N)n2)C2CCN([C@H](C)CCNC(=O)OC(C)(C)C)CC2)cc1
Reactant: Cc1cc(F)nc(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(N(Cc2cccc(C#N)n2)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(F)nc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
(R)-(3-{4-[(6-Cyano-pyridin-2-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (0.070 g, 0.14 mmol) was dissolved in a 3:1 mixture of CH2Cl2 and TFA and the mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the resulting brown oil dried in vacuo (high vacuum system) for 2 h. The resulting amine, EDCI (0.030 g, 0.0.16 mmol) and HOBT (0.021 g, 0.16 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added 6-fluoro-2,4-dimethyl-nicotinic acid hydrochloride (0.032 g, 0.16 mmol) followed by DIPEA (163 μL, 0.94 mmol) and the resulting mixture was stirred at 25° C. for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by column chromatography on silica gel (Et2O:MeOH:NH4OH, 90:8:2, v/v/v) afforded N-((R)-3-{4-[(6-cyano-pyridin-2-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-6-fluoro-2,4-dimethyl-nicotinamide (0.058 g, 75%) as a white foam. 1H NMR (CDCl3) δ 0.97 (m, 1H), 0.99 (d, 3H, J=6.0 Hz), 1.16 (m, 1H), 1.53 (m, 1H), 1.76 (m, 3H), 2.14 (br t, 1H), 2.37 (s, 3H), 2.47 (s, 3H), 2.53 (br t, 1H), 2.71 (m, 1H), 2.81-2.85 (m, 2H), 3.32-3.36 (m, 2H), 3.72 (s, 3H), 3.81 (m, 1H), 4.02 (s, 2H), 6.64 (m, 3H), 6.74 (d, 2H, J=9.0 Hz), 7.46 (d, 1H, J=6.0 Hz), 7.53 (d, 1H, J=9.0 Hz), 7.69 (t, 1H, J=9.0 Hz), 8.33 (br s, 1H). ES-MS m/z 545 (M+H), 567 (M+Na). Anal. Calcd. for C31H37N6O2F.0.15 CH2Cl2: C, 67.12; H, 6.74; N, 15.08. Found: C, 67.16; H, 6.85; N, 15.06.
Reaction SMILES: Cl.N[CH2:3][C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[CH:7]=[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])[C:5]=1[OH:16].C1N2CN3CN(C2)CN1C3.FC(F)(F)C(O)=[O:30]>>[CH:3]([C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[CH:7]=[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])[C:5]=1[OH:16])=[O:30]
Reactant: CCc1cc(CN)c(O)c(S(C)(=O)=O)c1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: CCc1cc(C=O)c(O)c(S(C)(=O)=O)c1

Procedure:
0.79 g (0.003 mol) of 2-aminomethyl-4-ethyl-6-methylsulfonylphenol hydrochloride is reacted with0.42 g of hexamethylenetetramine in 6 ml of trifluoroacetic acid in analogy to Example 1. Melting point: 114°-116° C.