Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([F:13])([F:12])[F:11])[CH2:6][CH2:5]1)=[C:2]=[O:3].Cl.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[C:26]([C:28]3[CH:37]=[C:36]4[C:31]([CH2:32][CH2:33][NH:34][CH2:35]4)=[CH:30][CH:29]=3)[N:25]=[C:24]([NH2:38])[N:23]=2)[CH2:18][CH2:17]1>>[NH2:38][C:24]1[N:25]=[C:26]([C:28]2[CH:37]=[C:36]3[C:31]([CH2:32][CH2:33][N:34]([C:2]([NH:1][CH:4]4[CH2:5][CH2:6][CH:7]([C:10]([F:11])([F:12])[F:13])[CH2:8][CH2:9]4)=[O:3])[CH2:35]3)=[CH:30][CH:29]=2)[CH:27]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]2)[N:23]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C=NC1CCC(C(F)(F)F)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)NC3CCC(C(F)(F)F)CC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 5 starting from 1-isocyanato-4-(trifluoromethyl)cyclohexane, and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=518.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15](B4OC(C)(C)C(C)(C)O4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH2:37])=[O:36])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:31]4[CH:39]=[CH:38][C:34]([C:35]([NH2:37])=[O:36])=[CH:33][CH:32]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)c1ccc(Br)cc1
Reactant: CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2cc(-c3ccc(C(N)=O)cc3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 90 °C
Yield: 42.8 %

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (1.0 g mg, 2.3 mmol), 4-bromobenzamide (690 mg, 3.45 mmol) and cesium carbonate (2.25 g, 6.9 mmol) in water (6 mL) and N,N-dimethylformamide (20 mL) was degassed with argon and then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (88 mg, 0.12 mmol) was added. The mixture was degassed again and then heated to 90° C. for 2 hours. The mixture was partitioned between water and ethyl acetate (3×) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was partially purified by column chromatography (7:3 hexanes/ethyl acetate to ethyl acetate, then ethyl acetate to 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to give 4-(4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide (423 mg, 43%) as a brown solid: ESI MS m/z 429 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[C:14](=O)[CH2:13][CH:12]1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:34][C:35]([F:49])([F:48])[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:39][NH2:40].C(=O)([O-])[O-].[K+].[K+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl.O>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[C:14](=[N:40][CH2:39][C:38]2[CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=[C:36]([C:35]([F:34])([F:48])[F:49])[CH:37]=2)[CH2:13][CH:12]1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CC(=O)c2cc(C(F)(F)F)ccc2N1C(=O)OCc1ccccc1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CC(=NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(C(F)(F)F)ccc2N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119.6 %

Procedure:
2-Methyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (5.5 g, 15.1 mmol) was combined with triethylamine (15 mL, 106 mmol) and 3,5-bis-trifluoromethyl-benzylamine (5.5 g, 22.7 mmol) in anhydrous dichloromethane (80 mL). This solution was cooled in a room temperature water bath as 7.6 mL of 1M solution of titanium tetrachloride (TiCl4) in dichloromethane (7.6 mmol) was slowly added. The reaction was stirred at room temperature overnight before the mixture was poured into a stirred solution of water (125 mL) and potassium carbonate (15 g). After filtration of the resulting emulsion, the filtrate was extracted with ethyl acetate (1×200 mL, then 2×75 mL), the combined organic phases were washed with water (100 mL), brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title product (10.63 g, >theory). 1H NMR (CDCl3) δ 1.2 (d, 3H), 2.7-2.9 (m, 2H), 4.0-4.1 (m, 1H), 4.65 (d, 1H), 4.75 (d, 1H), 5.1-5.4 (m, 2H), 7.3-7.5 (m, 5H).
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:32][C@H:33]([C:45]([N:47]1[CH2:65][CH2:64][CH2:63][C@H:48]1[C:49]([NH:51][C@H:52]([C:60]([NH2:62])=[O:61])[CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:50])=[O:46])[CH2:34][C:35](=[O:44])[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(OCC)(=O)C.CC(N(C)C)=O>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:32][C@H:33]([C:45]([N:47]1[CH2:65][CH2:64][CH2:63][C@H:48]1[C:49]([NH:51][C@H:52]([C:60]([NH2:62])=[O:61])[CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:50])=[O:46])[CH2:34][C:35](=[O:44])[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:5]
Reactant: NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(N)=O

Procedure:
The mixed anhydride prepared from Boc-Pro (3.44 g, 16 mmoles), N-methyl morpholine (1.76 mL, 16 mmoles) and isobutylchloroformate (2.08 mL, 16 mmoles) in ethyl acetate (160 mL) was treated with the solution of HCl.Asp(OBzl)-Pro-Phe-NH2 and N-methyl morpholine (1.76 mL, 16 mmoles) in dimethylacetamide (30 mL). The reaction conditions and the product work up were described earlier. The product was crystallized from ethyl acetate-hexane.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:33])[C:4]([C:6]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:9]2[N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:17][N:16]=3)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5].[C:34]([NH:41][CH2:42][C:43](O)=[O:44])([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>>[C:37]([O:36][C:34](=[O:35])[NH:41][CH2:42][C:43]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:17]=[N:16][C:15]([NH:14][C:11]3[N:12]=[CH:13][C:8]4[CH:7]=[C:6]([C:4](=[O:5])[N:3]([CH3:33])[CH3:2])[N:27]([CH:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)[C:9]=4[N:10]=3)=[CH:20][CH:19]=2)[CH2:26][CH2:25]1)=[O:44])([CH3:40])([CH3:38])[CH3:39]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)CNC(=O)OC(C)(C)C)CC4)cn3)nc2n1C1CCCC1

Procedure:
By repeating procedures described in Example 88, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide hydrochloride (150 mg, 0.318 mmol), N-BOC-glycine (56 mg, 0.318 mmol) gave a crude product which is purified by SiO2 chromatography, eluting with 0-7% methanol/dichloromethane to give (2-{4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester which is used directly in the next step.
Reaction SMILES: N#N.[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][C:14]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CCCOCc1ccccc1
Reactant: C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCCOCc1ccccc1)N1CCCC1

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-benzyloxybutyric acid (246 mg, 1.27 mmol), pyrrolidine (0.13 mL, 1.52 mmol), EDC.HCl (493 mg, 2.53 mmol), HOBt (262 mg, 1.90 mL) and DIPEA (0.65 mL, 3.80 mmol) in CH2Cl2 (10 mL) was heated at rt until completion of the reaction. Water was added, the layers separated and the aq. layer extracted with CH2Cl2 (2×). The combined org. extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 1:0→0:1) to give 4-(benzyloxy)-1-(pyrrolidin-1-yl)butan-1-one as a colorless oil. LC-MS-conditions 08: tR=0.77 min; [M+H]+=247.95.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Na].[NH2:10][C:11]1[N:12]=[C:13]([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=2[O:27][CH2:28][CH2:29][CH3:30])[NH:14][C:15](=[O:19])[C:16]=1[N:17]=O>O>[NH2:10][C:11]1[N:12]=[C:13]([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=2[O:27][CH2:28][CH2:29][CH3:30])[NH:14][C:15](=[O:19])[C:16]=1[NH2:17]
Reactant: CCCOc1ccc(C)cc1-c1nc(N)c(N=O)c(=O)[nH]1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CCCOc1ccc(C)cc1-c1nc(N)c(N)c(=O)[nH]1
Reaction time: 1.75 h
Yield: 55.4 %

Procedure:
Sodium dithionite (10.8 g.) was added during 5 minutes to a stirred suspension of the crude sodium salt of 4-amino-2-(5-methyl-2-propoxyphenyl)-5-nitrosopyrimid-6-one (9.3 g.) in water (180 ml.). Stirring was continued for a further 105 minutes, and solid obtained was filtered off, washed with water, and recrystallised from aqueous ethanol to give 4,5-diamino-2-(5-methyl-2-propoxyphenyl)pyrimid-6-one (4.9 g.), m.p. 184°-188° C. (with decomposition).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2].CO.[CH3:17]CN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:17])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: CCc1n[nH]c2cc(C(=O)O)ccc12
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCc1n[nH]c2cc(C(=O)OC)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 1.35 g (7.1 mmol) of 3-ethyl-1H-indazol-6-yl-carboxylic acid, [Marfat, A., et al., U.S. Pat. No. 6,262,040], 2.9 mL (71 mmol) of methanol, and 0.95 g (7.8 mmol) of DMAP in 60 mL of CH2Cl2 was added 1.5 g (7.8 mmol) of EDCI-HCl. This mixture was stirred at room temperature overnight, concentrated and the residue dissolved in 50 mL of ethyl acetate. The organic layer was successively washed with 40 mL of 1N HCl, 40 mL of water and 40 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by chromatography over silica gel using a gradient of 35% to 50% ethyl acetate in hexanes over 20 minutes as eluant to yield 860 mg (4.2 mmol) of methyl 3-ethyl-1H-indazol-6-yl-carboxylate. 1H NMR (CDCl3) δ 11.7 (s, 1H), 8.18 (s, 1H), 7.73 (apparent q, 9.0 Hz, 2H), 3.94 (s. 3H), 3.03 (q, 7.5 Hz, 2H), 1.42 (t, 7.5 Hz, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23](OC)=[O:24])=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH:34][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:24])=[N:20][CH:21]=3)=[CH:14][CH:15]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Reactant: NCc1ccccc1
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1

Procedure:
reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide; and
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[NH:12][N:13]=[C:14]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH:15]=2)=[O:9])=[N:6][CH:7]=1.CN1[C@@H](C)CNC[C@H]1C.[CH3:37][C@H:38]1[CH2:43][NH:42][CH2:41][C@@H:40]([CH3:44])[N:39]1[CH2:45][C:46]#[N:47].C(N(C(C)C)C(C)C)C>CS(C)=O.CO>[C:46]([CH2:45][N:39]1[C@@H:38]([CH3:37])[CH2:43][N:42]([C:2]2[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]3[NH:12][N:13]=[C:14]([CH2:16][CH2:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=4)[CH:15]=3)=[O:9])=[N:6][CH:7]=2)[CH2:41][C@H:40]1[CH3:44])#[N:47]
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Reactant: C[C@@H]1CNC[C@H](C)N1CC#N
Agent: C[C@@H]1CNC[C@H](C)N1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CS(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4C[C@@H](C)N(CC#N)[C@@H](C)C4)cn3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (271 mg, 0.70 mmol) was added in one portion to a 3:1 mixture of (2R,6S)-1,2,6-trimethylpiperazine and 2-[(2S,6R)-2,6-dimethylpiperazin-1-yl]acetonitrile (180 mg, 1.40 mmol) in anhydrous dimethylsulfoxide (1.40 ml) at 25° C. The resulting solution was stirred at ambient temperature for 2 h. The reaction was incomplete and N-ethyl-N-propan-2-ylpropan-2-amine (0.24 ml, 1.40 mmol) was added and the solution was stirred at 60° C. for a further 2 h. The reaction mixture was diluted with methanol (20 mL) and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (77 mg, 22%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:32][C:31]([C:33]2[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=2)[C:36]#[N:37])=[CH:30][C:29](=O)[O:28]1>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:10][C:9]=1[NH:24][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:40]=[CH:39][CH:38]=[C:35]([C:36]#[N:37])[CH:34]=1)=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2F)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 76.8 %

Procedure:
Prepared from [2-amino-4-(2,4-difluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G35) (172 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (126 mg, 0.55 mmol) according to the general procedure K. Obtained as an orange oil (198 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]#[N:13])=[CH:9]2)=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]([P:36]([O:41][CH2:42][CH3:43])([O:38][CH2:39][CH3:40])=[O:37])O)=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:29]=[CH:30][C:31]([CH:34]([O:1][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][C:8]([C:12]#[N:13])=[CH:7][CH:6]=4)[CH:11]=3)[P:36]([O:38][CH2:39][CH3:40])([O:41][CH2:42][CH3:43])=[O:37])=[CH:32][CH:33]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:16])([CH3:17])[CH3:15]
Reactant: CCOP(=O)(OCC)C(O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: N#Cc1ccc2ccc(O)cc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(Oc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 47.2 %

Procedure:
A solution of 1.50 g (0.0088 mol) 7-hydroxy-naphthalene-2-carbonitrile, 3.93 g (0.0088 mol) 4-{4-[(diethoxy-phosphoryl)-hydroxy-methyl]-phenoxy}-piperidine-1-carboxylic acid tert.-butyl ester and 3.73 g (0.0142 mol) triphenylphosphine in 150 ml tetrahydrofuran is admixed at 5° C. with 2.23 ml (0.0142 mol) azodicarboxylic acid diethyl ester and stirred for 96 h at room temperature. After concentration the residue is purified by chromatography on a silica gel column (mobile solvent: ethyl acetate/methanol 19:1). After concentrating the appropriate column fractions one obtains 2.47 g (47%) of the title compound as a viscous, yellow oil. 31P-NMR: δ=19.0 ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:6]2([CH2:10][CH2:9][N:8](C(OCC3C=CC=CC=3)=O)[CH2:7]2)[O:5][C:4](=[O:21])[NH:3]1.[H][H]>CO.[Pd]>[CH3:1][C:2]1([CH3:22])[C:6]2([CH2:10][CH2:9][NH:8][CH2:7]2)[O:5][C:4](=[O:21])[NH:3]1
Reactant: [H][H]
Reactant: CC1(C)NC(=O)OC12CCN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: CC1(C)NC(=O)OC12CCNC2

Procedure:
A mixture of benzyl 4,4-dimethyl-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-7-carboxylate (0.50 g, 0.0016 mol) (2nd peak from chiral separation) in 20 mL of MeOH was hydrogenated in the presence of 10% Pd/C, under a balloon pressure of hydrogen, for 2 h. After filtering off the catalyst, the filtrate was concentrated to dryness and the resultant residue was used directly in next step. LCMS (M+H) 171.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([NH2:20])=[CH:17][CH:18]=2)[CH:13]=[N:12]1.Cl>C(O)C>[CH3:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][C:2]3[N:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][N:3]=3)=[CH:17][CH:18]=2)[CH:13]=[N:12]1
Reactant: CSc1ccnc(Cl)n1
Reactant: Cn1ncc2cc(N)ccc21
Agent: Cl
Solvent: CCO
Product: CSc1ccnc(Nc2ccc3c(cnn3C)c2)n1
Temperature: 80 °C

Procedure:
To a solution of 2-chloro-4-(methylthio)pyrimidine (1.0 g, 6.2 mmol) and 1-methyl-1H-indazol-5-amine (1.0 g, 6.8 mmol) in 10 mL of ethanol was added 1 mL of concentrated hydrochloric acid at room temperature. The reaction mixture was heated at 80° C. for 5 hours with monitoring a reaction with LC-MS or thin layer chromatography (TLC). The reaction mixture was cooled to room temperature to form a solid. The resulting solid was collected by filtration and rinsed with cold ethanol to afford 1-methyl-N-(4-(methylthio)pyrimidin-2-yl)-1H-indazol-5-amine, intermediate 11 (0.7 g, 41%). The resulting solid was dissolved in 20 mL of dichloromethane and treated with m-chloroperbenzoic acid (mCPBA, 0.9 g, 5.2 mmol) at room temperature. After being stirred for 12 hours at room temperature, the reaction mixture was extracted with dichloromethane (×3) and washed with brine. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting solid was slurrified with heptane and then collected by filtration to afford the desired intermediate 12 as a white solid (0.6 g, 77%).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][NH:8]2.[CH3:24][N:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[F:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][N:8]2[C:31](=[O:32])[CH2:30][C:26]1[N:25]([CH3:24])[CH:29]=[CH:28][CH:27]=1
Reactant: Cn1cc(-c2ccc3c(c2F)CCN3)c2c(N)ncnc21
Reactant: Cn1cccc1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1cccc1CC(=O)N1CCc2c1ccc(-c1cn(C)c3ncnc(N)c13)c2F
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
A solution of 5-(4-fluoro-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (100 mg, 0.281 mmol), (1-methyl-1H-pyrrol-2-yl)acetic acid (39.1 mg, 0.281 mmol), HATU (107 mg, 0.281 mmol), and DIEA (0.245 mL, 1.404 mmol) was stirred at room temperature for 3 days. The resulting suspension was poured into water (10 mL) and stirred for 30 min, and a precipitate formed. The precipitate was collected by filtration, and the residue was washed with water, then dried at the pump for an hour, then adsorbed onto silica and purified by flash chromatography (0-10% MeOH in EtOAc) to afford 5-{4-fluoro-1-[(1-methyl-1H-pyrrol-2-yl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (70 mg, 61.7% yield) as an off-white solid. LC-MS (ES) m/z=405 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.25 (t, J=8.34 Hz, 2H), 3.54 (s, 3H), 3.69-3.79 (m, 3H), 3.87 (s, 2H), 4.33 (t, J=8.34 Hz, 2H), 5.82-5.95 (m, 2H), 5.95-6.19 (m, 2H), 6.69 (t, J=2.27 Hz, 1H), 7.16-7.24 (m, 1H), 7.26 (s, 1H), 7.93 (d, J=8.08 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: C(OC([N:6]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([Cl:35])[CH:33]=2)[C:8]2([CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[CH2:12][C:11](=[O:21])[NH:10][CH:9]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:7]1=[O:36])=O)C.[OH-].[Na+]>CO>[Cl:35][C:32]1[CH:33]=[C:34]2[NH:6][C:7](=[O:36])[C:8]3([CH:13]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=4)[CH2:12][C:11](=[O:21])[NH:10][CH:9]3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:29]2=[CH:30][CH:31]=1
Reactant: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2ccccc2Cl)N1
Yield: 80.9 %

Procedure:
In a manner similar to the method described in example 4d, racemic (2′R,3R,4′S)-6-chloro-2′-(2-chlorophenyl)-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.3 g, 0.55 mmol) was reacted with NaOH (2N, 5 mL, 10 mmol) in methanol to give racemic (2′R,3R,4′S)-6-chloro-2′-(2-chlorophenyl)-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 0.21 g, 81%).
Reaction SMILES: C[O:2][C:3](=[O:36])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:35])[N:25]([CH3:34])[C:26]([C:30]([F:33])([F:32])[F:31])=[CH:27][C:28]=2[CH3:29])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].[OH-].[Na+]>C(O)C>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:36])=[O:2])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:24](=[O:35])[N:25]([CH3:34])[C:26]([C:30]([F:32])([F:33])[F:31])=[CH:27][C:28]=2[CH3:29])=[CH:21][CH:22]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(C)cc(C(F)(F)F)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(F)(F)F)n(C)c(=O)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1
Temperature: 47.5 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a suspension of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester (243 mg, 0.45 mmol) in ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.8 mL) at room temperature. The mixture was heated to 45-50° C. and was stirred for 2 h. Then, the ethanol was removed under vacuum and the residue was diluted with water (20 mL). The aqueous solution was washed with ethyl acetate (50 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and the product was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine solution (50 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration afforded 186 mg (79% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine as an amorphous white solid. ES-HRMS m/e calcd for C24H19Cl2F3N2O4 (M+Na) 549.0567, found 549.0573.