Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21]([O:23]C)=[O:22])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:26]1[NH:30][C:29]2[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:28]=2[N:27]=1.Cl.[OH-].[Na+]>C(O)CCC.O1CCCC1>[F:36][C:32]1[C:33]([F:35])=[CH:34][C:28]2[NH:27][C:26]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]5[CH2:20][CH2:19][CH2:18][C@H:17]5[C:21]([OH:23])=[O:22])=[O:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)=[N:30][C:29]=2[CH:31]=1
Reactant: Fc1cc2nc(Cl)[nH]c2cc1F
Reactant: COC(=O)C1CCCC1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4cc(F)c(F)cc4[nH]3)cc2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
Methyl 2-[(4′-aminobiphenyl-4-yl)carbonyl]cyclopentanecarboxylate (264 mg, 0.02 mmol) was dissolved in n-butanol (8 mL), 2-chloro-5,6-difluoro-1H-benzimidazole (185 mg, 0.98 mmol) and 4 N HCl (0.2 mL) were then added, and the resulting mixture was heated at 90° C. for 5 h. The mixture was then cooled to rt, and solvent was removed under reduced pressure. The residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), and then treated with 1 N aqueous sodium hydroxide (2.45 mL, 2.45 mmol). The mixture was stirred at rt for 16 h and then concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford trans-2-({4′-[(5,6-difluoro-1H-benzimidazol-2-yl)amino]biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid (9.1 mg, 3%). LC-MS m/z 462.3 (MH+), ret. time 3.23 min; 1H NMR (300 MHz, DMSO-d6) δ 1.69-1.81 (m, 4H), 1.98-2.18 (m, 2H), 3.14-3.22 (m, 1H), 4.04-4.09 (m, 1H), 7.38 (t, 2H), 7.77-7.84 (m, 6H), 8.05 (d, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([Cl:18])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCC(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)CCC(=O)OCc1ccccc1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
4-(benzyloxy)-4-oxobutanoic acid (6.16 g, 1 eq, from Example 1a) was dissolved in toluene (20 mL) and placed in a 300 mL round bottom flask, fitted with a condenser. While the reaction was stirred under inert atmosphere, thionyl chloride (5.30 g, 1.5 eq) was added. A few drops of DMF were also added and tire reaction mixture was heated to 35° C. for 45 minutes and then to 60° C. for 2 hours. The solution was concentrated to 6.71 g of brownish oil.
Reaction SMILES: CN(P(N(C)C)N(C)C)C.Br[C:12](Br)([F:14])[F:13].[CH3:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=O.O>COCCOCCOCCOC>[F:13][C:12]([F:14])=[C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH3:16]
Reactant: FC(F)(Br)Br
Reactant: COc1ccc(C(C)=O)cc1
Agent: CN(C)P(N(C)C)N(C)C
Solvent: COCCOCCOCCOC
Solvent: O
Product: COc1ccc(C(C)=C(F)F)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
At between 0° C. and −10° C., 181 g of tris(dimethylamino)phosphine in 75 ml of triglyme were added dropwise to 84 g of dibromodifluoromethane in 50 ml of triglyme. At 0° C., 30 g of 4-methoxyacetophenone dissolved in 125 ml of triglyme were subsequently added dropwise and the mixture was stirred for ½ h at room temperature and for 24 h at 80° C. The mixture was cooled to room temperature, mixed with 200 ml of water and extracted with petroleum ether. The combined organic phases were dried and concentrated. For purification, the crude product was chromatographed over silica gel (petroleum ether/ethyl acetate 5:1), to give the title product as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C@H:14]([NH:13][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:12])[C:15]([N:54]2[CH2:55][CH2:56][CH:51]([OH:50])[CH2:52][CH2:53]2)=[O:17])=[CH:20][CH:21]=1
Reactant: OC1CCNCC1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
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: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ncc2[nH]1
Reaction time: 0.17 h

Procedure:
Route A: To a solution of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (EXAMPLE 228, 1.4 g, 3.87 mmol) in DMF (35 mL) was added HATU (1.77 g, 4.64 mmol) and the reaction stirred for 10 min. 4-Hydroxypiperidine (0.43 g, 4.26 mmol) was added, followed by DIPEA (0.8 mL, 4.64 mmol) and the reaction stirred at rt for 16 h. Solvent was removed in vacuo and the crude material partitioned between ethyl acetate (50 mL) and water (50 mL). The organics were washed with sodium bicarbonate (2×30 mL) and brine (2×30 mL), dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (SiO2, 96:4 dichloromethane/methanol) gave the title compound. m/z (ES+)=445.15 [M+H]+; RT=3.24 min. Route B: The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-(S)-amino-3-(4-fluorophenyl)-1-(4-hydroxypiperidin-1-yl)propan-1-one hydrochloride (Preparation 20). The product was purified by chromatography on silica gel eluting with methanol/dichloromethane (1:19) to give the title compound as a pale yellow solid. δH (CD3OD): 1.08-1.19 (0.5H, m), 1.29-1.51 (1.5H, m), 1.54-1.62 (0.5H, m), 1.73-1.84 (1.5H, m), 3.06-3.36 (4H, m), 3.67-3.95 (2.5H, m), 4.03-4.10 (0.5H, m), 5.32 (1H, t), 6.97-7.04 (2H, m), 7.14 (1H, s), 7.26-7.33 (2H, m), 7.66 (1H, s), 8.55 (1H, s); m/z (ES+)=445 [M+H]+; RT=3.27 min.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([SH:14])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[CH3:15][O-].[Na+].IC>CO>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14][CH3:15])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(S)cc2C1
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CSc1ccc2c(c1)CN(C(C)=O)CC2
Temperature: 25 °C

Procedure:
A suspension of N-acetyl-7-mercapto-1,2,3,4-tetrahydroisoquinoline (1.0 gm., 0.0048 m.) in 20 ml. of methanol was stirred in a nitrogen atmosphere. Sodium methoxide (0.3 gm., 0.0055 m.) and 5 ml. of iodomethane were added to the suspension. The mixture was stirred at 25° C. for thirty minutes, evaporated and partitioned between chloroform and water. The chloroform layer was washed, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel, eluted with ethyl acetate to give pure N-acetyl-7-methylthio-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17](=[O:22])[CH2:18][CH:19]4[CH2:21][CH2:20]4)[N:15]=3)[N:12]=2)=[CH:4][C:3]=1[NH2:25].[CH3:26][N:27]1[C:31]([C:32](Cl)=[O:33])=[CH:30][C:29]([CH3:35])=[N:28]1>CN(C)C(=O)C>[CH:19]1([CH2:18][C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:23]=[CH:24][C:2]([CH3:1])=[C:3]([NH:25][C:32]([C:31]5[N:27]([CH3:26])[N:28]=[C:29]([CH3:35])[CH:30]=5)=[O:33])[CH:4]=4)=[N:12][N:11]3[CH:13]=2)=[O:22])[CH2:20][CH2:21]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)CC4CC4)cn3n2)cc1N
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CC5CC5)cn4n3)ccc2C)n(C)n1
Yield: 60.5 %

Procedure:
Using N-[6-(4-methyl-3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-cyclopropylacetamide (120 mg, 0.356 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (59 mg, 0.374 mmol) and N,N-dimethylacetamide (4.0 mL), and by a reaction in the same manner as in Example 148, the title compound (99 mg, 61%) was obtained as a pale-yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)=[CH:4][CH:3]=1.[OH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34](O)=[O:35])=[CH:28][CH:27]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=2)[C:34](=[O:35])[CH2:33][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([OH:25])=[CH:27][CH:28]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(NCCc2cccc(OCc3ccccc3)c2)cc1
Reactant: O=C(O)CCc1ccc(O)cc1
Product: O=C(CCc1ccc(O)cc1)N(CCc1cccc(OCc2ccccc2)c1)c1ccc(F)cc1
Yield: 88.9 %

Procedure:
The title compound was prepared as described in Example 44.D using (4-fluorophenyl){2-[3-(phenylmethoxy)phenyl]ethyl}amine (1.4 g, 4.36 mmol) and 3-(4-hydroxyphenyl)propanoic acid (1.01 g, 6.11 mmol) to provide the title compound (1.82 g, 89% yield): ES-MS (m/z) 470 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](=O)[NH:13][C:12]([CH2:19][O:20][CH3:21])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O.CN(C)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:24])=[N:13][C:12]([CH2:19][O:20][CH3:21])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCc1nc2c(c(=O)[nH]1)CCN(Cc1ccccc1)C2
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)c1ccccc1
Product: COCc1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Temperature: 80 °C
Yield: 82.3 %

Procedure:
A mixture of 7-benzyl-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4(3H)-one (2.01 g, 7.04 mmol), phosphorus oxychloride (5.16 mL, 56.35 mmol) and N,N-dimethylaniline (0.89 mL, 7.04 mmol) in 1,2-dichloroethane was heated to 80° C. for two h. The mixture was allowed to cool to r.t. and poured over crushed ice (100 mL). The mixture was made basic (pH=˜8) by the addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (200 mL). The organic layer was dried over magnesium sulfate and concentrated to leave a dark oil which was purified by silica gel chromatography (ethyl acetate/hexane gradient) to yield 1.76 g (82%) of the title compound as a brown oil.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8](O)=[O:9])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:57][C:58]1[S:59][CH:60]=[CH:61][N:62]=1>CN(C)C=O>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:8]([NH:57][C:58]2[S:59][CH:60]=[CH:61][N:62]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Yield: 66.2 %

Procedure:
A solution of 2-biphenyl-4-yl-3-cyclopentylpropionic acid (121.0 mg, 0.41 mmol), benzotriazol-1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate (218.1 mg, 0.49 mmol), triethylamine (172 μL, 1.23 mmol), and 2-aminothiazole (45.3 mg, 0.45 mmol) in dry N,N-dimethylformamide (1 mL) was stirred at 25° C. under nitrogen for 24 h. The reaction mixture was concentrated in vacuo to remove N,N-dimethylformamide. The resulting residue was diluted with ethyl acetate (100 mL). The organic layer was washed with a 10% aqueous hydrochloric acid solution (1×100 mL), water (1×100 mL), and a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 9/1 to 3/1 hexanes/ethyl acetate gradient elution) afforded 2-biphenyl-4-yl-3-cyclopentyl-N-thiazol-2-yl-propionamide (102.2 mg, 66%) as a white solid: mp 194-195° C.; EI-HRMS m/e calcd for C23H24N2OS (M+) 376.1609, found 376.1612.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12].Cl[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[C:24]([C:31]3[NH:39][C:38]4[CH2:37][CH2:36][NH:35][C:34](=[O:40])[C:33]=4[CH:32]=3)[CH:25]=[CH:26][CH:27]=2)[N:22]=1>>[CH2:11]([N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[C:24]([C:31]3[NH:39][C:38]4[CH2:37][CH2:36][NH:35][C:34](=[O:40])[C:33]=4[CH:32]=3)[CH:25]=[CH:26][CH:27]=2)[N:22]=1)[CH3:12]
Reactant: CCNc1ccccc1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CCN(c1ccccc1)c1ccc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
NaHMDS (1.0 M solution in THF; 1.975 ml, 1.975 mmol) was added to N-ethylaniline (0.249 ml, 1.975 mmol) and 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.084 g, 0.282 mmol). The dark red reaction was stirred rapidly at RT. After 2 h, the reaction was quenched with saturated aq. NH4Cl. The reaction was partitioned between saturated aq. NH4Cl and DCM. The aq. layer was extracted with DCM (3×), and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. This material was dissolved in DMSO and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 10-80% ACN/H2O with 0.1% TFA); product-containing fractions were treated with saturated aq. NaHCO3 and DCM. The combined organic layers were then the aq. layer was extracted 3×DCM, the combined organics layers were then dried over Na2SO4, filtered, and concentrated in vacuo to give 2-(2-(ethyl(phenyl)amino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.044 g, 0.115 mmol, 40.8% yield) as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.07-12.29 (1H, m), 7.92-8.19 (2H, m), 7.48-7.63 (3H, m), 7.34-7.47 (3H, m), 7.26 (1H, t, J=7.6 Hz), 6.98-7.07 (1H, m), 6.89-6.98 (1H, m), 6.83 (1H, d, J=9.2 Hz), 4.08 (2H, q, J=7.0 Hz), 3.36-3.44 (2H, m), 2.69 (2H, t, J=6.9 Hz), 1.30 (3H, t, J=7.0 Hz). m/z (ESI, +ve) 383.0 (M+H)+.
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.[CH3:27][C:28]1[CH:29]=[C:30]([CH:32]=[C:33]([CH3:37])[C:34]=1[O:35][CH3:36])[NH2:31].[Cl:38][C:39]1[N:44]=[C:43](Cl)[C:42]([F:46])=[CH:41][N:40]=1>>[Cl:38][C:39]1[N:44]=[C:43]([NH:31][C:30]2[CH:32]=[C:33]([CH3:37])[C:34]([O:35][CH3:36])=[C:28]([CH3:27])[CH:29]=2)[C:42]([F:46])=[CH:41][N:40]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COc1c(C)cc(N)cc1C
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: COc1c(C)cc(Nc2nc(Cl)ncc2F)cc1C

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 3,5-dimethyl-4-methoxyaniline (400 mg, 2.6 mmol) and 2,4-dichloro-5-fluoropyrimidine (200 mg, 1.2 mmol) gave 2-chloro-N4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine. The reaction of 2-chloro-N4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and 3-(methoxycarbonylmethyleneoxy)aniline (650 mg, 3.6 mmol) gave N4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (180 mg, 35%). 1H NMR (CD3OD): δ 2.20 (s, 6H), 3.70 (s, 3H), 3.74 (s, 3H), 4.52 (s, 2H), 6.76 (ddd, J=0.9, 2.4 and 8.4 Hz, 1H), 7.03-7.08 (m, 2H), 7.24 (m, 3H), 7.96 (d, J=5.4 Hz, 1H); 19F NMR (282 MHz, CD3OD): δ −162.92; LCMS: ret. time: 23.13 min.; purity: 100%; MS (m/e): 427.04 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([CH:18]([F:20])[F:19])[N:15]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:27][S:28]([C:31]1[CH:32]=[C:33]([NH2:37])[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29].Cl>>[CH3:27][S:28]([C:31]1[CH:32]=[C:33]([NH:37][C:24]([C:23]2[CH:22]=[N:21][N:15]3[C:16]([CH:18]([F:20])[F:19])=[CH:17][C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:10])([F:11])[F:9])=[C:2]([Cl:1])[CH:3]=4)=[N:13][C:14]=23)=[O:26])[CH:34]=[CH:35][CH:36]=1)(=[O:29])=[O:30]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)c(Cl)c3)nc12
Agent: Cl
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3-chloro-4-trifluoromethyl-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.15) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Light brown solid. MS (ISP) 543.0 [(M+H)+]; mp 228° C.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[C:2]1([C:8]2([C:14]#[N:15])[CH2:9][CH2:10][N:11]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:13]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: N#CC1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC1(c2ccccc2)CCN(Cc2ccccc2)CC1

Procedure:
4-Phenyl-4-cyano-piperidine hydrochloride (10 g, 44.9 mmol), Benzyl bromide (5.4 mL, 45.4 mmol), and potassium carbonate (25.2 g, 182.3 mmol) were combined in THF/water (80 mL/20 mL). After 18 hours the reaction mixture was partitioned between water and dichloromethane. The organic layer was separated and extracted with water, dried over MgSO4, filtered and evaporated in vacuo to give a residue. The residue was recrystallized from hexane to give 4-phenyl -4-cyano-1-benzyl-piperidine as a solid: mp=73°-74° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]([N:20]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:21]2[CH2:26][C@@H:25]([NH:27][C:28](OCC(Cl)(Cl)Cl)=[O:29])[CH2:24][N:23]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:22]2)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[NH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C)C(=O)C.Cl>[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]([N:20]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:21]2[CH2:26][C@@H:25]([NH:27][C:28]([N:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)=[O:29])[CH2:24][N:23]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:22]2)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](NC(=O)OCC(Cl)(Cl)Cl)CN(C(=O)OC(C)(C)C)C1
Reactant: C1COCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](NC(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
tert-Butyl (3S,5R)-3-[({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-{[(2,2,2-trichloroethoxy)carbonyl]amino}piperidine-1-carboxylate (98.0 mg) and N,N-diisopropylethylamine (120 μl) were dissolved in N,N-dimethylacetamide (3 ml), morpholine (20 μl) was added, and the mixture was stirred at 80° C. for 1 day. The reaction mixture was diluted with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object compound (12.7 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][C@H:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=3)[CH2:18][OH:19])[CH:13]=[CH:12][C:11]=2[N+:27]([O-])=O)[CH:5]=1)[CH3:2].[CH2:30](O)C.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[CH2:1]([O:3][C:4]1[NH:8][N:7]=[C:6]([N:9]2[C:10]3=[N:15][C:14]([NH:16][C@H:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=4)[CH2:18][OH:19])=[CH:13][CH:12]=[C:11]3[N:27]=[CH:30]2)[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Reactant: CCO
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1cc(-n2cnc3ccc(N[C@@H](CO)c4ccc(F)cn4)nc32)n[nH]1
Temperature: 25 °C

Procedure:
(2R)-2-({6-[(5-ethoxy-1H-pyrazol-3-yl)amino]-5-nitropyridin-2-yl}amino)-2-(5-fluoropyridin-2-yl)ethanol (Intermediate 27, 0.2 g) was dissolved into ethanol (20 mL) with Pd—C (50 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formylamidine acetate (0.5 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 85° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Ethyl acetate/MeOH) to afford 0.06 g of the title compound MS (electrospray): 384 (M+1) for C18H18FN7O2. 1H NMR (300 MHz, CD3OD) δ ppm 8.20 (d, 1H) 8.15 (s, 1H) 7.50 (d, 1H) 7.30 (dd, 1H) 6.40 (d, 1H) 5.85 (s, 1H) 5.00 (m, 1H) 4.00 (d, 2H) 3.80 (m, 2H) 1.00 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[C:6]([Cl:8])[CH:7]=1.[C:10](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH3:10])[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]nc(Cl)cc1Br
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nc(Cl)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.5 %

Procedure:
4-Bromo-6-chloro-2H-pyridazin-3-one (5.02 g, 23.97 mmol) was dissolved in 40 ml dimethylformamide. Cesium carbonate (9.37 g, 28.76 mmol) was added. After 5 min, iodomethane (5.103 g, 35.95 mmol) was added dropwise over 20 min. The reaction mixture was stirred 3 hours at room temperature. The precipitate was filtered off and concentrated and the resulting residue was treated with 20 ml dichloromethane. The insoluble material was filtered off again and washed with dichloromethane. The filtrate was concentrated in vacuo to yield 4-Bromo-6-chloro-2-methyl-2H-pyridazine-3-one (5.223 g, 23.37 mmol). MS (ESI) 224.9 (M+H)+
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:43])[CH2:5][C@H:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][C@H:16]3[C:24]4[C:19](=[C:20]([CH2:29][N:30]5[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]5)[C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)=[CH:14][C:9]=2[O:8][CH2:7]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.ClCCl>[CH3:2][O:3][C:4](=[O:43])[CH2:5][C@H:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][C@H:16]3[C:24]4[C:19](=[C:20]([CH2:29][N:30]5[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]5)[C:21]([C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)=[CH:14][C:9]=2[O:8][CH2:7]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCNCC3)ccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4 M HCl in 1,4-dioxane (5 mL) is added to a solution of {(S)-6-[(R)-4-(4-tert-butoxycarbonyl-piperazin-1-ylmethyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.42 g) in dichloromethane (5 mL) at room temperature. The solution is stirred at room temperature for 2.5 h. The solution is basified with aqueous K2CO3 solution and extracted with dichloromethane. The combined extract is dried (Na2SO4) and concentrated to give the crude title compound that is used without further purification in subsequent transformations. LC (method 4): tR=0.98 min; Mass spectrum (ESI+): m/z=491 [M+H]+.