Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][CH2:17][NH2:18])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19]OC(C1(CC)CCN(C(OC(C)(C)C)=O)CC1)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][CH2:17][NH2:18])([CH2:14][CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC1(CCCN)CCN(C(=O)OC(C)(C)C)CC1
Product: CCC1(CCCN)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using the method of 4-(3-aminopropyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester, the title compound is synthesized from 4-ethylpiperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester and isolated as a clear oil.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][C:7]=2[C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:20])=O>>[Cl:20][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:7]([C:14]([F:17])([F:16])[F:15])[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(C2CCCC2)c(C(F)(F)F)c1
Product: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Temperature: 17.5 °C
Reaction time: 3.5 h
Yield: 381.7 %

Procedure:
To (4-cyclopentyl-3-(trifluoromethyl)phenyl)methanol (110 g, 113 mmol), thionyl chloride (329 mL, 4.50 mol) was added dropwise at such a rate as to maintain the internal temperature between 10-25° C. (cooled with ice-water). The resulting mixture was stirred at 50° C. for 3.5 h followed by 6 h at 25° C. The mixture was concentrated under reduced pressure and the resulting oily residue poured into ice-water (450 mL) under vigorous stirring. The layers were separated and the aqueous phase extracted with CH2Cl2 (3×400 mL). The combined organic layers were washed with saturated NaHCO3 (400 mL), brine (2×400 mL), dried (Na2SO4), filtered over fresh Na2SO4, and concentrated in vacuo to give the title compound as a pale yellow oil (113.3 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.67-1.57 (m, 2H), 1.81-1.71 (m, 2H), 1.94-1.84 (m, 2H), 2.16-2.07 (m, 2H), 3.39 (quintet, J=8.6 Hz, 1H), 4.61 (s, 2H), 7.49 (d, J=8.4 Hz, 1H), 7.54 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.[CH:19]1([C:22]2[C:23]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[C:23]([N:32]3[CH2:37][CH2:36][N:35]([C:11]([C:10]4[CH:9]=[N:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])=[CH:17][CH:16]=4)=[O:13])[CH2:34][CH2:33]3)=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=2)[CH2:20][CH2:21]1
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Product: O=C(c1ccc(N2CCCS2(=O)=O)nc1)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Yield: 68.2 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (300 mg) described in Preparation Example 25 and 1-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazine (331 mg) described in Preparation Example 90 and by the reaction and treatment in the same manner as in Example 109, the title compound (375 mg) was obtained.
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][C:14]=3[C:6]=2[C:5]([OH:19])=[N:4][CH:3]=1.[C:20]([Cu])#[N:21]>CN1C(=O)CCC1>[OH:19][C:5]1[C:6]2[C:14]3[CH:13]=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=3[NH:8][C:7]=2[C:2]([C:20]#[N:21])=[CH:3][N:4]=1
Reactant: Oc1ncc(Br)c2[nH]c3cc(C(F)(F)F)ccc3c12
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: N#Cc1cnc(O)c2c1[nH]c1cc(C(F)(F)F)ccc12
Temperature: 225 °C

Procedure:
A mixture of 4-bromo-7-(trifluoromethyl)-5H-pyrido[4,3-b]indol-1-ol, CuCN (1.4 equiv) in NMP (0.2 M) was heated in the microwave reactor at 225° C. for 40 min. The reaction mixture was then poured into EtOAc/hexanes (10/1) which was passed through a plug of silica gel and eluted with EtOAc. The EtOAc was evaporated and the resulting mixture was partitioned between EtOAc and brine. The organic phase was separated, dried over Na2SO4 and evaporated. The residue was suspended in EtOAc and hexanes, and was then filtered to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:17]([O:18][C:19](=[O:22])[CH2:20][CH3:21])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[C:4]=2[N:5]=[CH:6][N:7]=1.[N+:30]([O-])([OH:32])=[O:31].OS(O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:10]([N+:30]([O-:32])=[O:31])=[CH:9][N:8]([C@@H:11]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:17]([O:18][C:19](=[O:22])[CH2:20][CH3:21])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2ccc3c(Cl)ncnc32)O[C@@H]1COC(C)=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2cc([N+](=O)[O-])c3c(Cl)ncnc32)O[C@@H]1COC(C)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of the product from Step 2 (700 mg, 1.64 mmol) in DCM was cooled to 0° C. in ice/water bath. Meanwhile fuming HNO3 (1 mL) and H2SO4 (1 mL) were premixed and added dropwise to a vigorously stirred DCM solution containing the protected nucleoside and the mixture. The solution was stirred at 0° C. for 1.5 hours then quenched by pouring into an ice cold saturated Na2CO3 solution (125 mL). The product was extracted with DCM and the organic layers were dried over Na2SO4 and concentrated in vacuo. The crude purified by Isco CombiFlash purification system with a 40 g silica gel column and 0-35% MeOH gradient in DCM over 30 minutes to afford 440 mg (52%).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16](=O)[CH2:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].[NH2:27][NH2:28]>CC(O)=O>[C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:28][N:27]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12
Reactant: NN
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)C)nc23)[nH]n1
Temperature: 85 °C
Yield: 75.9 %

Procedure:
To a 25-mL round-bottomed flask was added EtOH (4 mL) and sodium ethoxyde (1.01 g of 21% in EtOH, 3.11 mmol). The reaction mixture was cooled to −10° C. and added ethyl oxalate (0.21 mL, 1.55 mmol, Sigma-Aldrich) and 1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606a) (0.4 g, 1.55 mmol) slowly. The reaction mixture was warmed to RT and stirred at RT for 18 h. The reaction mixture was diluted with water (10 mL) and partially concentrated under vacuum. The reaction mixture was diluted with HCl (1 N, 5 mL) and extracted with EtOAc (15 mL). The organic extract was washed with brine (10 mL), dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 10% to 30% EtOAc in hexanes to give ethyl 4-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2,4-dioxobutanoate as an orange oil (135 mg, 24% yield). m/z (ESI, +ve) 358.1 (M+H)+. To a 15-mL glass tube was added ethyl 4-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2,4-dioxobutanoate (135 mg, 0.38 mmol), hydrazine (12 μL, 0.38 mmol), and AcOH (2 mL). The tube was sealed and heated at 85° C. for 1 h. The reaction mixture was cooled to RT and the solvent was removed under vacuum. The mixture was diluted with EtOAc (10 mL) and NaOH (1 N, 5 mL). The organic extract was washed with water (5 mL), dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 30% to 40% EtOAc in hexanes to give ethyl 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrazole-3-carboxylate (467a) (102 mg, 76% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.82-7.97 (m, 1H), 7.74 (d, J=7.82 Hz, 1H), 7.51-7.60 (m, 1H), 7.40 (t, J=8.90 Hz, 1H), 6.00-6.07 (m, 1H), 4.31 (q, J=7.11 Hz, 2H), 2.56 (s, 3H), 1.53 (s, 9H), 1.33 (t, J=7.14 Hz, 3H). m/z (ESI, +ve) 354.0 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:26])=[CH:4][CH2:5][C:6]1[C:14]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[C:13]2[C:9]([CH2:10][O:11][C:12]2=[O:22])=[C:8]([CH3:23])[C:7]=1[O:24][CH3:25].CCN(C(C)C)C(C)C.Cl[P:37]1[O:42]C(=O)C2C=CC=CC=2[O:38]1>O1CCOCC1>[CH3:25][O:24][C:7]1[C:8]([CH3:23])=[C:9]2[C:13]([C:12](=[O:22])[O:11][CH2:10]2)=[C:14]([O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[C:6]=1[CH2:5][CH:4]=[C:3]([CH3:26])[CH2:2][O:1][P:37]([OH:42])[OH:38]
Reactant: O=C1OP(Cl)Oc2ccccc21
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CO)C(=O)OC2
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)COP(O)O)C(=O)OC2
Reaction time: 0.17 h

Procedure:
To a solution of 6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (75 mg, 0.20 mmol) and DIEA (49 μL, 0.28 mmol) in dioxane (2 mL) was added 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one (56.7 mg, 0.28 mmol) according the procedure of Shadid, B. et al., Tetrahedron, 1989, 45, 12, 3889. After 10 minutes, another portion of 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one (40 mg, 0.20 mmol) and DIEA (35 μL, 0.20 mmol) were added. The reaction was allowed to proceed at room temperature for an additional hour, after which it was quenched by the addition of H2O. The solution was stirred for another 10 minutes and concentrated in vacuo to a small volume. The product was triturated with diethyl ether and coevaporated from acetonitrile (4×10 mL) to provide the product. 1H NMR (300 MHz, CDCl3) δ 0.03 (s, 9H), 1.08-1.30 (m, 2H), 1.84 (br s, 3H), 2.17 (s, 3H), 3.46 (br s, 2H), 3.76 (s, 3H), 4.21-4.39 (m, 4H), 5.12 (s, 2H), 5.43-5.60 (m, 1H), 7.83 (br s, 1H); 31P (121.4 MHz, CDCl3) δ 7.22; MS (m/z) 441 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[C:7]=1[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:5])[CH3:2].[F:34][C:35]([F:46])([F:45])[C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:39]3[CH:40]=[CH:41][C:36]([C:35]([F:46])([F:45])[F:34])=[CH:37][CH:38]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:20][CH:21]=2)[C:7]=1[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(N2CCOCC2)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(N2CCOCC2)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-morpholin-4-yl-phenyl)indole-3-carboxylic acid ethyl ester (158 mg, 0.35 mmol, see step (b) Example 15) and 4-trifluoromethylphenylboronic acid (100 mg, 0.53 mmol). Yield 120 mg (57%).
Reaction SMILES: [ClH:1].FC1C=CC=C(F)C=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][C:22]([C:24]4C=NC=CC=4)=[CH:23][C:16]=23)=[C:10]([F:30])[CH:9]=1)=[O:6].Cl.FC1C=C([CH:64]([C:68]([NH:70][C:71]2[CH:76]=[CH:75][C:74]([F:77])=[CH:73][CH:72]=2)=[O:69])C(N)=O)C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1.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>CN(C=O)C>[ClH:1].[F:30][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[CH2:64][C:68]([NH:70][C:71]2[CH:76]=[CH:75][C:74]([F:77])=[CH:73][CH:72]=2)=[O:69])[CH:13]=[CH:12][C:11]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[NH:21][C:22]([CH3:24])=[CH:23][C:16]=12
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]c(-c4cccnc4)cc23)c(F)c1)c1c(F)cccc1F
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
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: Cc1cc2c(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)ccnc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
To a mixture of 3-fluoro-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzenamine (20 mg, 0.078 mmol, Compound E of Example 292), 3-(4-fluorophenylamino)-3-oxopropanoic acid (20 mg, 1 mmol, Compound A of Example 25), and HATU (44 mg, 0.12 mmol) in DMF (0.5 mL) was added DIPEA (0.1 mL). The reaction mixture was stirred at rt for 2 h and concentrated in vacuo. The residue was purified by preparative HPLC to give the desired product (HCl salt, 12.5 mg, 34%) as a white solid. 1H NMR (CD3OD) δ 8.05 (d, 1H, J=7.2 Hz), 7.79 (dd, 1H, J=12.7, 2.8 Hz), 7.50–7.53 (m, 2H), 7.27–7.36 (m, 2H), 6.97 (m, 2H), 6.70 (d, 1H, J=6.6 Hz), 6.20 (s, 1H), 3.47 (s, 2H), 2.40 (s, 3H); LC/MS(ESI+) m/z 437 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([C:15]2([CH3:46])[C:23]3[C:18](=[CH:19][C:20]([C:24]4[CH:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][CH2:32][CH2:31][O:30]5)[CH:28]=4)=[CH:21][CH:22]=3)[C:17](=[O:35])[N:16]2[C@@H:36]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[CH3:37])[C:10]=1[F:47].[H][H]>C(OCC)(=O)C.[OH-].[OH-].[Pd+2].ClC1N=CN=C(C2(C)C3C(=CC(C4C=NN(C5CCCCO5)C=4)=CC=3)C(=O)N2[C@@H](C2C=CC(OC)=CC=2)C)C=1F>[F:47][C:10]1[C:11]([C:15]2([CH3:46])[C:23]3[C:18](=[CH:19][C:20]([C:24]4[CH:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][CH2:32][CH2:31][O:30]5)[CH:28]=4)=[CH:21][CH:22]=3)[C:17](=[O:35])[N:16]2[C@@H:36]([C:38]2[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[CH3:37])=[N:12][CH:13]=[N:14][CH:9]=1
Reactant: COc1ccc([C@@H](C)N2C(=O)c3cc(-c4cnn(C5CCCCO5)c4)ccc3C2(C)c2ncnc(Cl)c2F)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H](C)N2C(=O)c3cc(-c4cnn(C5CCCCO5)c4)ccc3C2(C)c2ncncc2F)cc1
Yield: 102.8 %

Procedure:
Add triethylamine (40 mL, 287 mmol) and 20% palladium hydroxide on carbon (14 g) to a solution of 3-(6-chloro-5-fluoro-pyrimidin-4-yl)-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)isoindolin-1-one (80 g, 142 mmol) in ethyl acetate (2.1 L) and hydrogenate with hydrogen gas (30 psi) at 20-25° C. for 16 hours. Repeat reaction conditions with 5 grams 3-(6-chloro-5-fluoro-pyrimidin-4-yl)-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)isoindolin-1-one. Combine both reactions and filter through diatomaceous earth and evaporate to give the title compound as a yellow foam (77 g, 102%). ES/MS m/z: 528 (M+H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8](=[O:10])[CH3:9])[C:5](=[O:7])[CH3:6].[OH:11][CH2:12][C:13]([CH3:17])([CH2:15]O)[CH3:14].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[CH3:1][O:2]/[N:3]=[C:4](/[C:8]1([CH3:9])[O:11][CH2:12][C:13]([CH3:17])([CH3:15])[CH2:14][O:10]1)\[C:5](=[O:7])[CH3:6]
Reactant: CC(C)(CO)CO
Reactant: CON=C(C(C)=O)C(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CO/N=C(\C(C)=O)C1(C)OCC(C)(C)CO1
Reaction time: 2 h
Yield: 79 %

Procedure:
20 g (0.14 mol) of pentane-2,3,4-trione 3-(O-methyloxime), 43.4 g (0.42 mol) of neopentyl glycol and 0.1 g of conc. sulfuric acid in 80 ml of toluene were heated at the boil on a water separator at a pressure of 800 mbar for 2 hours. The mixture was extracted with water and toluene and then worked up as in Example 4b). This gave 30 g of an oil of a purity of 84% (yield 79%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:10]=2)[O:5][C:4]([CH3:18])([CH3:17])[C@H:3]1[OH:19].[CH2:20]([O:22][C:23]1[C:27](OCC)=[N:26][S:25](=[O:32])(=[O:31])[N:24]=1)[CH3:21].[K+].[Br-]>C(#N)C>[CH2:20]([O:22][C:23]1[C:27]([NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]([F:16])([F:14])[F:15])[CH:10]=3)[O:5][C:4]([CH3:17])([CH3:18])[C@H:3]2[OH:19])=[N:26][S:25](=[O:32])(=[O:31])[N:24]=1)[CH3:21]
Reactant: CCOC1=NS(=O)(=O)N=C1OCC
Reactant: CC1(C)Oc2ccc(OC(F)(F)F)cc2[C@@H](N)[C@@H]1O
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Product: CCOC1=NS(=O)(=O)N=C1N[C@@H]1c2cc(OC(F)(F)F)ccc2OC(C)(C)[C@H]1O

Procedure:
(3S, 4R)-4-Amino-2,2-dimethyl-6-(trifluoromethoxy)-chroman-3-ol [prepared by the method of Quagliato et al. Biorg. and Med. Chem. Let. 1991, 1, 39; (1.00 g, 3.61 mmol)] and the thiadiazole derivative (0.78 g, 3.79 mmol) obtained in Step 1 were stirred together in acetonitrile (15 mL) at 90° C. for 18 hours. The mixture was cooled and concentrated, and the residue was purified by column chromatography (1:1:05 hexane/ethyl acetate/dichloromethane) to give after trituration with hexanes 1.10 g (71%) of product as a white solid: mp 192°-194° C.; 1H NMR (DMSO-D6): δ 9.55 (d, 1H), 7.29 (d, 1H), 7.19 (d, 1H), 6.87 (d, 1H), 5.89 (d, 1H), 4.73 (t, 1H), 4.51 (q, 2H), 3.78 (m, 1H), 1.41 (t, 3 H), 1.38 (s, 3H), 1.15 (s, 3H); IR (KBr): 2500-3250, 1620, 1490 cm-1 ; MS (m/z) 438 (MH+, 100%), 261 (20).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[N:6][CH:7]=1.[CH3:17][N:18](C=O)C>CCOCC.[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]([C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[N:6][CH:7]=1)#[N:18]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NCc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCc1cncc(C#N)c1
Temperature: 110 °C
Yield: 86 %

Procedure:
To tert-butyl (5-bromopyridin-3-yl)methylcarbamate (384 mg, 1.34 mmol) in DMF (10 ml), Zn(CN)2 (94 mg, 0.80 mmol) and Pd(PPh3)4 were added and heated at 110° C. for 3 h. Then the reaction mixture was cooled to RT, diluted with ether, washed with ammonium hydroxide solution, water and brine. Crude residue was column chromatographed (40% ethylacetate/60% Hexanes) to yield tert-butyl (5-cyanopyridin-3-yl)methylcarbamate in 86% yield.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[NH2:9][C:10]1[N:15]=[N:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>>[CH2:5]([O:4][C:2](=[O:3])[NH:9][C:10]1[N:15]=[N:14][C:13]([N:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:23])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[CH2:20][CH2:21]2)=[CH:12][CH:11]=1)[CH:6]([CH3:8])[CH3:7]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CC(C)COC(=O)Cl
Product: CC(C)COC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 7, making variations only as required to use 2-methylpropyl chloroformate in place of n-butyl chloroformate to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (47% yield). 1H NMR (500 MHz, CDCl3) δ 8.09, 7.73, 7.65, 7.63, 7.55, 7.36, 7.04, 3.96, 3.95-4.02, 3.88-3.94, 3.61-3.65, 3.52-3.56, 3.32, 1.94-2.04, 0.96. MS (ES+) m/z 452 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6]([OH:18])=[C:7]([C:13]([O:15]CC)=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(OCC)C>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6]([OH:18])=[C:7]([C:13]([NH:25][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=3)=[O:15])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2c(Cl)c(Cl)ccc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: CCOCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(Cl)c(Cl)ccc2c1O
Temperature: 180 °C

Procedure:
2,3-Dichloroaniline (7.83 g) and diethyl ethoxymethylenemalonate (9.76 g) are heated at 130° C. for 1.5 hours. The reaction is cooled to 60° C. and the solution poured into hexanes. The intermediate enamine is collected and dried. The solid is added to 70 mL diphenyl ether and heated to 250° C. for 1.5 hours with removal of ethanol with a Dean-Stark trap. The reaction is cooled to room temperature. The product is collected by filtration, washed thoroughly with hexanes, and dried to yield 11.32 g of ethyl 7,8-dichloro-4-hydroxyquinoline-3-carboxylate. A mixture of this ester (0.48 g) and 4-chlorobenzylamine (1.0 mL) are heated at 180° C. for 1 hour. The reaction is cooled to room temperature and diethyl ether is added. The resulting solid is filtered, washed twice with diethyl ether, and dried. The solid is adsorbed onto silica and purified by Biotage Flash 40S chromatography (eluent 2% MeOH:CH2Cl2). The product-containing fractions are evaporated to give a white solid (0.12 g).
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[C:21]3[O:23][CH2:24][O:25][C:20]3=[CH:19][C:18]=2[N+:26]([O-])=O)[CH2:12]1)=[O:9])=[O:5]>[Pd].[C].CO>[NH2:26][C:18]1[CH:19]=[C:20]2[O:25][CH2:24][O:23][C:21]2=[CH:22][C:17]=1[CH2:16][N:13]1[CH2:14][CH2:15][C@@H:11]([NH:10][C:8](=[O:9])[CH2:7][NH:6][C:4](=[O:5])[C:3]2[CH:29]=[C:30]([C:33]([F:35])([F:34])[F:36])[CH:31]=[CH:32][C:2]=2[NH2:1])[CH2:12]1
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2cc3c(cc2[N+](=O)[O-])OCO3)C1
Agent: [Pd]
Solvent: CO
Product: Nc1cc2c(cc1CN1CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3N)C1)OCO2
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of (R)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]-1-(4,5-methylenedioxy-2-nitrobenzyl)pyrrolidine (30.5 mg) with 10% Pd carbon (6 mg) and methanol (3 mL) was stirred at room temperature under a hydrogen atmosphere for 10 hours. The palladium catalyst was filtered through Celite, and the filtrate was concentrated and purified by solid-phase extraction (Bond Elut™ SI, 20% methanol/ethyl acetate) to thereby afford (R)-1-(2-amino-4,5-methylenedioxybenzyl)-3-[[N2-amino-5-trifluoromethylbenzoyl]glycyl]amino]pyrrolidine (Compd. No. 2127) (21.9 mg, 76%). The purity was determined by RPLC/MS (95%). ESI/MS m/e 480.1 (M++H, C22H24F3N5O4).
Reaction SMILES: [C:1]([S:5]([N:7]=[C:8]([C:28]1[O:29][C:30]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:31]=2[N:32]=1)[C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH3:20])=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:39][Mg]Cl>C1COCC1.[NH4+].[Cl-].CCOC(C)=O>[C:37]([C:34]1[CH:35]=[CH:36][C:30]2[O:29][C:28]([C:8]([C:9]3[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH3:20])=[C:14]4[C:10]=3[CH:11]=[CH:12][N:13]4[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([NH:7][S:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[O:6])[CH3:39])=[N:32][C:31]=2[CH:33]=1)#[N:38]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(=NS(=O)C(C)(C)C)c1nc2cc(C#N)ccc2o1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(NS(=O)C(C)(C)C)c1nc2cc(C#N)ccc2o1

Procedure:
To a solution of tert-butyl 4-((tert-butylsulfinyl)imino)(5-cyanobenzo[d]oxazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 130-A) (0.56 g, 1.047 mmol) in THF (10.47 mL), MeMgCl (3M in THF, 1.047 mL, 3.14 mmol) was added at 0° C. After 10 minutes the mixture was diluted with sat. aq. NH4Cl and EtOAc. The aqueous layer was extracted with EtOAc, and the organic extract was dried over MgSO4, filtered and concentrated. The product was purified by flash chromatography (0-100% EtOAc:Heptanes) to provide the title compound. MS (ESI+) m/z 551.2 (M+H).