Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[CH:20]1([N:26]2[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH:29]3[CH2:30][CH2:31][N:26]([CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:27][CH2:28]3)[CH3:13])=[CH:8][C:6]=2[N:7]=1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: O=C1CCN(C2CCCCC2)CC1
Product: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)C1CCN(C2CCCCC2)CC1
Yield: 72 %

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)methylamine was reacted with 1-cyclohexyltetrahydro-4(1H)-pyridinone using standard reductive amination conditions. The resulting crude solid was triturated with diethyl ether and methanol to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-cyclohexyl-piperidin-4-yl)-methyl-amine as a solid (72% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethylether and methanol to give 345 as a solid (76% yield). NMR (CDCl3, 400 MHz), 1.06-1.21 (5H, m), 1.51-1.57 (3H, m), 1.74-1.81 (6H, m), 2.12-2.18 (3H, m), 2.24 (3H, s), 2.41-2.47 (1H, m), 2.94-2.96 (2H, m), 3.84 (4H, t, J=4.4), 3.87 (2H, s), 3.99 (4H, t, J=4.4), 5.26 (2H, s), 7.21 (1H, s), 9.25 (2H, s). MS: (ESI+): MH+=523
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:4][C:5]3[CH2:9][N:8]([C@@H:10]([CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[C:11]([NH:13][C:14]4C=C[CH:17]=[CH:16][N:15]=4)=[O:12])[C:7](=[O:27])[C:6]=3[O:28][C:29]=2[CH:30]=[CH:31][CH:32]=1.NC1[S:35]C=CN=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[Cl:1][C:2]1[C:3]2[CH2:4][C:5]3[CH2:9][N:8]([C@@H:10]([CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[C:11]([NH:13][C:14]4[S:35][CH:17]=[CH:16][N:15]=4)=[O:12])[C:7](=[O:27])[C:6]=3[O:28][C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: Nc1nccs1
Reactant: O=C(Nc1ccccn1)[C@H](CC1CCCCC1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Yield: 39.2 %

Procedure:
A solution of (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (200 mg, 2.1 mmol) (from Example 1, Step 3), commercially available 2-aminothiazole (110 mg, 0.63 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (112 mg, 0.59 mmol), and N-hydroxybenzotriazole (HOBt) (79 mg, 0.59 mmol) in methylene chloride (10 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silical gel flash chromatography using hexane-ethyl acetate gradiant elution, afforded (S)-2-(8-Chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-N-thiazol-2-yl-propionamide (113 mg, 46.3%) as a white solid. 1H NMR (DMSO-d6) δ: 12.56 (br. s., 1H), 7.50 (d, J=3.4 Hz, 3H), 7.20-7.36 (m, 10H), 7.05-7.15 (m, 3H), 5.06 (d, J=5.9 Hz, 3H), 4.40 (d, J=18.6 Hz, 3H), 4.09 (d, J=18.6 Hz, 3H), 3.76 (s, 6H), 1.52-1.91 (m, 24H), 1.04-1.32 (m, 17H), 0.90-1.03 (m, 7H), 0.79-0.88 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)(=O)C>C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:19]2[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: OC1CCNCC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(O)CC2)CC1
Reaction time: 24 h
Yield: 18.8 %

Procedure:
1-tert-Butoxycarbonyl-4-piperidone (2.29 g, 0.0114 mol, 1.15 eq) and 4-hydroxypiperidine (1 g, 0.0099 mol, 1 eq) were stirred at room temperature in THF (10 ml) and acetic acid (0.6 ml) for 20 hours. To the solution was added 0.17 g of 5% palladium on carbon type 87L Johnson Matthey catalyst. The reaction was then hydrogenated under a pressure of 3 bar at room temperature for 24 hours. The catalyst was filtered off through CELITE™ and washed with THF (20 ml). The 4-(hydroxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester (18.8% purity by HPLC area %) was not isolated.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15][CH2:16][C:17](=O)[CH3:18])[CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.[Cl:21][C:22]1[CH:23]=[C:24]([NH:28]N)[CH:25]=[CH:26][CH:27]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15][C:16]3[C:25]4[C:24](=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=4)[NH:28][C:17]=3[CH3:18])[CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)C1(c2cccc(SCC(C)=O)c2)CC1
Agent: Cl
Product: CCOC(=O)C1(c2cccc(Sc3c(C)[nH]c4cc(Cl)ccc34)c2)CC1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 1-[3-(2-oxo-propylsulfanyl)-phenyl]-cyclopropanecarboxylic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][C:15]=2[OH:16])[N:12]=[CH:11][N:10]=[C:9]3[NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[C:19]=2[F:26])[CH2:2]1.ClC1C(F)=C(NC2C3C(=[CH:41][C:42](OC)=[C:43]([O:46][C@H]4CCNC4)C=3)N=CN=2)C=C(F)C=1>>[Cl:25][C:20]1[C:19]([F:26])=[C:18]([NH:17][C:9]2[C:8]3[C:13](=[CH:14][C:15]([OH:16])=[C:6]([O:5][CH:3]4[CH2:4][N:1]([C:43](=[O:46])[CH:42]=[CH2:41])[CH2:2]4)[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: Oc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1OC1CNC1
Reactant: COc1cc2ncnc(Nc3cc(F)cc(Cl)c3F)c2cc1O[C@H]1CCNC1
Product: C=CC(=O)N1CC(Oc2cc3c(Nc4ccc(F)c(Cl)c4F)ncnc3cc2O)C1
Yield: 25 %

Procedure:
The procedure of step 7) of Example 1 was repeated except for using the compound obtained in step 2) instead of N-(3-chloro-2,5-difluorophenyl)-7-methoxy-6-((3S)-pyrrolidin-3-yloxy)quinazolin-4-amine to obtain the title compound (20 mg, 25%).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[F:13][C:14]([F:27])([F:26])[C:15]1[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=O)=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.Br.[Cl:39][C:40]1[C:49]([OH:50])=[C:48]([OH:51])[C:47]([Cl:52])=[C:46]2[C:41]=1[CH2:42][CH2:43][NH:44][CH2:45]2>CCOC(C)=O.O>[Cl:39][C:40]1[C:49]([OH:50])=[C:48]([OH:51])[C:47]([Cl:52])=[C:46]2[C:41]=1[CH2:42][CH2:43][N:44]([C:23](=[O:25])/[CH:22]=[CH:21]/[C:18]1[CH:19]=[N:20][C:15]([C:14]([F:13])([F:27])[F:26])=[CH:16][CH:17]=1)[CH2:45]2
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)nc1
Reactant: Oc1c(O)c(Cl)c2c(c1Cl)CCNC2
Agent: Br
Agent: O=C(n1ccnc1)n1ccnc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(/C=C/c1ccc(C(F)(F)F)nc1)N1CCc2c(Cl)c(O)c(O)c(Cl)c2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
To a solution of CDI (83 mg, 0.51 mmol) in EtOAc (2 mL) was added (E)-3-(6-(trifluoromethyl)pyridin-3-yl)acrylic acid (100 mg, 0.46 mmol). The resulting mixture was heated at reflux for 1 h after which HOBt (35 mg, 0.23 mmol) and 5,8-dichloro-1,2,3,4-tetrahydroisoquinoline-6,7-diol hydro bromide (145 mg, 0.46 mmol) were added. Heating at reflux was continued for 3 h before the reaction mixture was allowed to cool to rt. It was then poured into water (15 mL) and the water-phase was extracted with EtOAc (3×15 mL). Combined organics were washed with water (10 mL) and brine (10 mL) and dried (MgSO4). After filtration and evaporation, the crude was purified by column chromatography (SiO2, EtOAc:petroleum ether 50:50) to give a bright yellow solid which was purified further by precipitating the product in EtOAc via addition of petroleum ether. After decantation of the solvent and drying, the title compound (110 mg, 0.25 mmol, 55%) was obtained as a light reddish solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[S-:11][C:12]#[N:13].[NH4+]>O>[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:12]([NH2:13])=[S:11]
Reactant: NCc1ccccc1Cl
Reactant: N#C[S-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: NC(=S)NCc1ccccc1Cl
Yield: 59.8 %

Procedure:
A solution of 2-chlorobenzylamine hydrochloride (41 g, 0.23 mol) and ammonium thiocyanate (19.28 g, 0.253 mol) in water (170 mL) was heated on the steam bath for 18 hours. This mixture was concentrated in vacuo, and the residue was taken up in toluene (1 L) and azeotroped with a Dean-Stark head. The residue was triturated with wet diethyl ether to provide 27.6 g (60%) of 1-(2-chlorophenyl)methyl thiourea. The product was recrystallized from ethanol; mp 120°-122° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.F[C:12]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:13]=1[CH:14]=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1C(=O)CCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:12]3[C:13](=[CH:16][C:17]([I:20])=[CH:18][CH:19]=3)[CH:14]=[N:10]2)=[CH:5][CH:4]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=Cc1cc(I)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1ccc(-n2ncc3cc(I)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4-chlorophenylhydrazine hydrochloride (5.24 g, 29.27 mmol), 2-fluoro-5-iodobenzaldehyde (7.5 g, 30.00 mmol) and cesium carbonate (22.8 g, 69.98 mmol) was suspended in NMP (120 mL) and stirred at ambient temperature for 45 min. The temperature was raised to +160° C. and the reaction mixture was stirred for 1 h, the now black suspension was allowed to reach r.t. Water was added, the slurry was extracted with EtOAc (500 mL. The organic phase was washed with brine (2×). The brine fractions and waterphase was combined and backextracted once with EtOAc. This second EtOAc phase was washed with brine (2×) before combined with the previous EtOAc phase. The organic phases were dried over Na2SO4, filtered and evaporated. The black residue were dissolved in DCM/Heptane (=1/1) and filtered through a silica column, and the column was then further eluted with DCM/Heptane (=1/1) solvent mixture. The fractions containing product was evaporated, residue was dissolved in EtOAc and Heptane was added, evaporation and diluting with Heptane afforded a slurry, the solid material was collected by filtration and washed with Heptane. Yield 2.82 g (27%)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][C:18]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
Trifluoromethanesulfonic anhydride (15.5 mL, 92.0 mmol) was added over approximately 0.1 h, via syringe, to a stirred solution of the product of step B (33.8 g, 84.0 mmol) and N,N-diisopropylethylamine (17.6 mL, 101.0 mmol) in methylene chloride (300 mL) at −78° C. After allowing to warm to ambient temperature overnight, the reaction mixture was quenched with saturated aqueous sodium bicarbonate, poured into water and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient elution; 0–20% ethyl acetate/hexanes as eluent) gave the title compound as an amber colored oil (23.0 g).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH2:13][CH:14]([F:16])[F:15])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:17]([Zn]CC)[CH3:18]>>[F:15][CH:14]([F:16])[CH2:13][O:12][C:3]1[C:2]([CH2:17][CH3:18])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1
Reactant: CC[Zn]CC
Reactant: COC(=O)c1cnc(OCC(F)F)c(Br)c1
Product: CCc1cc(C(=O)OC)cnc1OCC(F)F
Yield: 88 %

Procedure:
The title compound is prepared in 88% yield (660 mg, clear colorless oil) from methyl 5-bromo-6-(2,2-difluoroethoxy)nicotinate (900 mg, 3.0 mmol, Step-2) and diethylzinc instead of dimethylzinc by the similar manner in Step-3 of Amine-27.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>C(#N)C>[CH3:27][N:18]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[NH:10][C:9]([C:7]1[S:8][CH:4]([CH2:3][CH:2]=[O:1])[CH2:5][N:6]=1)=[CH:17]2)[S:19]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:21]
Reactant: CN(c1cccc2cc(C3=NCC(CCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC#N
Solvent: O
Product: CN(c1cccc2cc(C3=NCC(CC=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 70 °C
Yield: 1 %

Procedure:
To a solution of N-{2-[5-(2-hydroxyethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (2.78 g) in acetonitrile (150 mL) was added Dess-Martin reagent (3 g), and the mixture was stirred under heating at 70° C. for 30 min. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (27 mg, yield 22%) as a brown amorphous solid from a fraction eluted with ethyl acetate:hexane=25:75. MS: 420 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[C:15]([O:23][CH3:24])[CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][C:6]=1[CH3:25].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.O>CN(C=O)C>[CH3:25][C:6]1[CH:7]=[C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[C:15]([O:23][CH3:24])[CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[O:4][CH2:3][CH2:2][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COc1cccc2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc12
Reactant: C1CCNC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c(=O)[nH]c(-c3cc(C)c(OCCN4CCCC4)c(C)c3)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-8-methoxy-3H-quinazolin-4-one (537 mg, 1.33 mmol) in DMF (10 mL) was added a pyrrolidine (758 mg, 10.66 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water (100 mL) was added and the solid separated was filtered and dried under vacuum. The solid was triturated with ether and dried to give the title compound as a white solid. Yield: 232 mg (44%). MP 231-232° C. 1H NMR (400 MHz, CDCl3): δ 10.30 (s, 1H), 7.90 (dd, J=8.0 Hz, 1H), 7.806 (br s, 2H), 7.42 (t, J=8.4 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 4.04 (s, 3H), 3.95 (t, J=6.4 Hz, 2H), 2.93 (t, J=6.0 Hz, 2H), 2.65 (m, 4H), 2.40 (s, 6H), 1.84 (m, 4H). MS (ES) m/z: 394.15 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=1.CN(C)[CH:22]=[C:23]([F:26])[CH:24]=O.FC(F)(F)C(O)=O>O1CCOCC1>[F:26][C:23]1[CH:22]=[C:3]2[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:5][N:6]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[F:14])[C:2]2=[N:1][CH:24]=1
Reactant: CN(C)C=C(F)C=O
Reactant: CCOC(=O)c1cc(N)n(Cc2ccccc2F)n1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nn(Cc2ccccc2F)c2ncc(F)cc12
Reaction time: 72 h

Procedure:
13.487 g (51.228 mmol) of ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate (preparation described for example 20A in WO 00/06569) were initially charged in 300 ml of dioxane, and 6 g (51.228 mmol) of 3-(dimethylamino)-2-fluoroacrylaldehyde (preparation described in Justus Liebigs Annalen der Chemie 1970; 99-107) were added at RT. Subsequently, 4.736 ml (61.473 mmol) of trifluoroacetic acid were added and the mixture was heated to reflux while stirring for 3 days. After cooling, the mixture was concentrated under reduced pressure, and water and ethyl acetate were added to the residue. The phases were separated and the organic phase was washed twice with water. The combined aqueous phases were subsequently extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue (22 g) was subsequently purified by chromatography on silica gel (eluent: dichloromethane). This gave 5.67 g (35% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([OH:21])=O)=[CH:11]2)[C:4]=1[CH3:22].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[CH2:48]([CH2:50][NH2:51])[OH:49]>C(Cl)Cl>[OH:49][CH2:48][CH2:50][NH:51][C:19]([C:12]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:18]2[N:10]([CH2:9][C:5]2[C:4]([CH3:22])=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=2)[CH:11]=1)=[O:21]
Reactant: NCCO
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncccc32)c1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncnc(Cn2cc(C(=O)NCCO)c3ncccc32)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45 %

Procedure:
See FIG. 18(a). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (1 g, 3.35 mmol) was taken in DCM (20 mL) to get a suspension. Triethyl amine (1.394 mL, 10.06 mmol) was added followed by the addition of 1-Propanephosphonic acid cyclic anhydride (3.991 mL, 6.70 mmol). The reaction mass was stirred at RT for 5 minutes. Ethanol amine (6.02 mL, 10.06 mmol) was added and stirred at RT for 2 h. After completion of the reaction, diluted with DCM and then washed with water and brine solution. The organic layer was separated, dried, evaporated and the crude compound was purified by silica gel chromatography. Yield-45%. ES+MS m/z: 342 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.24 (s. 3 H ) 3.37-3.64 (m, 4 H ) 3.94 (s, 3 H ) 4.80 (t, J=4.99 Hz, 1 H ) 5.67 (s, 2 H ) 7.24 (dd, J=8.29, 4.52 Hz, 1 H ) 7.92 (d, J=8.10 Hz, 1 H ) 8.23 (s, 1 H ) 8.41 (s, 1 H ) 8.47 (d, J=4.52 Hz, 1 H ) 8.85 (t, J=5.37 Hz, 1 H ).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]([OH:22])([C:18]([F:21])([F:20])[F:19])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][C:10]=1[O:16][CH3:17])([CH3:8])[CH3:7].[CH2:24](C([Sn])=C(CCCC)CCCC)[CH2:25]CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3](=[O:23])[C:4]([OH:22])([C:18]([F:21])([F:20])[F:19])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([CH:24]=[CH2:25])=[CH:11][C:10]=1[O:16][CH3:17])([CH3:8])[CH3:7]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COC(=O)C(O)(CC(C)(C)c1ccc(I)cc1OC)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=Cc1ccc(C(C)(C)CC(O)(C(=O)OC)C(F)(F)F)c(OC)c1
Yield: 43.7 %

Procedure:
1 g of 2-hydroxy-4-(4-iodo-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeric acid methyl ester, 860 mg of tributylvinyl tin, 103 mg of palladium-dibenzylidene acetone complex and 30 mg of triphenylphosphine in 17 ml of THF are refluxed under argon atmosphere for 57 hours. It is filtered through diatomaceous earth and completely concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 0->2%), 339 mg of 2-hydroxy-4-(2-methoxy-4-vinylphenyl)-4-methyl-2-trifluoromethylvaleric acid methyl ester is obtained. The latter is stirred with 56 mg of lithium aluminum hydride in 11 ml of diethyl ether at room temperature for 10 hours. It is added to saturated bicarbonate solution, filtered through diatomaceous earth and extracted with ethyl acetate. The organic phase is washed with bicarbonate solution and brine, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 0->10%), 148 mg of 2-hydroxy-4-(2-methoxy-4-vinylphenyl)-4-methyl-2-trifluoro-methylpentanol is obtained. The latter is hydrogenated in 4.3 ml of ethyl acetate with 14 mg of palladium on activated carbon under normal pressure with hydrogen. The batch is filtered through diatomaceous earth and completely concentrated by evaporation. 127 mg of 4-(4-ethyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanol is obtained. The diol that is obtained is reacted with 0.29 ml of triethylamine and 280 mg of sulfur trioxide-pyridine complex in 1.3 ml of DMSO at room temperature in 10 hours of reaction time. It is added to saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 0->3%), 94 mg of the title compound is obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[C:10]([C:14]([O:16]CC)=[O:15])=[CH:11][NH:12][CH:13]=2)=[CH:4][CH:3]=1>[OH-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:19])[C:10]([C:14]([OH:16])=[O:15])=[CH:11][NH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Temperature: 65 °C

Procedure:
The above ester (1.0 g, 3.8 mmol) was dissolved in 2N NaOH (20 mL) and heated to 65° C. for 2 h. The resulting clear mixture was cooled to ambient temperature and the solids were filtered off. The filtrate was then acidified with 1N HCl to pH=1 and the resulting yellow precipitate was collected as the desired product (0.73 g, 82%). 1H NMR (DMSO-d6) δ 13.52 (br s, 1H), 8.86 (s, 1H), 8.51 (s, 1H), 7.99-7.96 (m, 2H), 7.55-7.51 (m, 2H); MS (ESI+) m/z 234 (M+H)+.
Reaction SMILES: C([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][CH3:13])=[O:11])(OC(C)(C)C)=O.C(N(CC)CC)C.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:34]=1[C:35](Cl)=[O:36]>O1CCCC1>[NH2:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:35](=[O:36])[C:34]1[C:33]([Cl:32])=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:42])[CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)CCCN2)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H](N)Cc1ccc2c(c1)CCCN2C(=O)c1c(Cl)cccc1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 32.8 %

Procedure:
A solution of methyl (S) 2-(N-boc-amino)-3-(1,2,3,4-tetrahydro-quinolin-6-yl)-propionate [500 mg, Reference Example 19(a)] in tetrahydrofuran (20 ml) was treated successively with triethylamine (360 mg) and 2,6-dichlorobenzoyl chloride (380 mg). The mixture was stirred at 40° C. for 2 hours and then partitioned between ethyl acetate (100 ml) and dilute hydrochloric acid (100 ml). The organic phase was washed with sodium bicarbonate solution, then dried and then evaporated. The residue was dissolved in trifluoroacetic acid (2 ml) and the clear solution was left at room temperature for 30 minutes then evaporated. The residue was partitioned between ethyl acetate and dilute hydrochloric acid. The organic phase was washed with sodium bicarbonate solution, then dried and then evaporated to give the title compound (200 mg) as a colourless oil.