Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=2[CH3:7])[CH:17]=[CH:18][CH:19]=1
Reactant: COC(=S)c1cc(Br)c(C)s1
Reactant: Nc1cccc(Cl)c1
Product: COC(=S)c1cc(Nc2cccc(Cl)c2)c(C)s1
Yield: 52.8 %

Procedure:
A stirred suspension of 80 mg (0.299 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate and 41 μL (0.389 mol, 1.3 eq) of 3-chloroaniline (Aldrich, Milwaukee, Wis.) was treated in a manner similar to Example 241, step (b) to give 47 mg of the title compound (50%) as a yellow oil. 1H-NMR (CDCl3, 400 MHz) δ7.75 (s, 1H), 7.23-6.89 (m, 4H), 6.10 (s, 1H), 3.89 (s, 3H), 2.42 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C13H2NO12S2Cl, 314.0 (M+H), found 314.1.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:21]1[N:26]=[C:25]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=3)[CH2:32][CH2:31]2)=[O:28])[CH:24]=[CH:23][CH:22]=1.C(Cl)Cl>CN(C=O)C.C(OCC)C>[N:40]1[CH:39]=[CH:38][C:37]([CH2:36][N:33]2[CH2:34][CH2:35][CH:30]([NH:29][C:27](=[O:28])[C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([O:15][CH:12]4[CH2:13][CH2:14][N:9]([C:6]5[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][CH:7]=5)[CH2:10][CH2:11]4)[N:26]=3)[CH2:31][CH2:32]2)=[CH:42][CH:41]=1
Reactant: O=C(NC1CCN(Cc2ccncc2)CC1)c1cccc(Cl)n1
Reactant: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(NC1CCN(Cc2ccncc2)CC1)c1cccc(OC2CCN(c3ccc(C(F)(F)F)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25 %

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-piperidin-4-ol (0.1 g, 0.4 mmol) in anhydrous DMF, NaH (60% in mineral oil, 18 mg, 0.45 mmol) was added. The mixture was allowed to stir at room temperature under N2 atmosphere for 10 min, followed by the addition of 6-chloro-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)picolinamide (0.15 g, 0.4 mmol). The resulting reaction mixture was then stirred with heating at 105° C. overnight. A significant amount of starting material was still present and hence, an additional amount of NaH was added (82 mg, 2.1 mmol). The reaction mixture was allowed to stir at 105° C. for an additional 8 h, and quenched with saturated sodium bicarbonate solution (20 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL), and the combined organic layer was washed with water (2×20 mL) and brine (1×20 mL), dried (MgSO4), filtered and concentrated to give a yellow residue. Column chromatography (100% CH2Cl2 3% MeOH/CH2Cl2) provided a yellow solid, which upon trituration with ethyl ether, yielded N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)picolinamide as a tan solid (54 mg, 25%). 1H NMR (CD3OD) δ 8.53 (d, J=4.1 Hz, 2H), 8.28 (d, J=7.4 Hz, 1H), 7.80 (t, J=7.7 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.51 (d, J=4.1 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 7.05 (d, J=8.3 Hz, 2H), 6.96 (d, J=8.3 Hz, 1H), 5.43 (br s, 1H), 4.10-3.95 (m, 1H), 3.90 (s, 2H), 3.77-3.56 (m, 2H), 3.23-2.98 (m, 3H), 2.71-2.57 (m, 2H), 2.23-1.81 (m, 9H). MS (m/z): 540 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[C:11]([CH3:19])=[CH:12][N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2.[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21].C(=O)([O-])O.[Na+]>ClC(Cl)C>[CH3:8][O:9][C:10]1[C:11]([CH3:19])=[C:12]([C:27]([C:26]2[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=2)=[O:28])[N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1c(C)cn2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1c(C)c(C(=O)c2ccc([N+](=O)[O-])cc2)n2ccccc12
Yield: 89.8 %

Procedure:
1.8 ml (12.92 mmol) of triethylamine are added, at ambient temperature under an inert atmosphere, to 1.7 g (10.77 mmol) of 1-methoxy-2-methylindolizine in 15 ml of dichloroethane, followed, dropwise, by 2.2 g (11.85 mmol) of 4-nitrobenzoic acid chloride. The reaction medium is stirred for 30 minutes at ambient temperature, hydrolysed with a saturated aqueous solution of sodium hydrogen carbonate and then extracted with dichloromethane. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, and then concentrated under reduced pressure. The residue obtained is washed with diethyl ether. 3 g of an orange solid are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[NH2:14][CH2:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][C@@H:22]([N:25]([CH2:29][CH3:30])[CH:26]([CH3:28])[CH3:27])[CH2:21][C@H:20]1[CH2:31][O:32][CH3:33])=[O:17].C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:1][C:2]1[N:11]=[C:10]([NH:14][CH2:15][C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][C@@H:22]([N:25]([CH2:29][CH3:30])[CH:26]([CH3:28])[CH3:27])[CH2:21][C@H:20]2[CH2:31][O:32][CH3:33])=[O:17])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1
Reactant: CCN(C(C)C)[C@@H]1CC[C@H](NC(=O)CN)[C@H](COC)C1
Reactant: Clc1ccc2nc(Cl)nc(Cl)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(C(C)C)[C@@H]1CC[C@H](NC(=O)CNc2nc(Cl)nc3ccc(Cl)cc23)[C@H](COC)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,4,6-trichloroquinazoline (103 mg) and the bis-trifluoroacetic acid salt of 2-amino-N-((1S,2R,4R)-4-(ethyl(isopropyl)amino)-2-(methoxymethyl)cyclohexyl)acetamide (152 mg) in tetrahydrofuran (3 mL) was treated with diisopropylethylamine (0.31 mL) and the mixture was stirred overnight at rt. The mixture was concentrated and purified by reverse phase HPLC and lyophilization to provide the bis-trifluoroacetic acid salt of the title compound, 2-(2,6-dichloroquinazolin-4-ylamino)-N-((1S,2R,4R)-4-(ethyl(isopropyl)amino)-2-(methoxymethyl)cyclohexyl)acetamide, as a white powder (79 mg). MS found: (M+H)+=482.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[CH3:11][Si:12]([CH3:16])([CH3:15])[C:13]#[CH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C.C1CCCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([C:14]#[C:13][Si:12]([CH3:16])([CH3:15])[CH3:11])=[CH:7][N:6]=1)[CH3:10]
Reactant: CCNc1ccc(Br)cn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCNc1ccc(C#C[Si](C)(C)C)cn1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 909 mg (4.5 mmol) 5-bromo-2-ethylamino-pyridine and 0.89 mL (6.3 mmol) 1-trimethylsilyl-ethyne using 26 mg (0.13 mmol) CuI, 118 mg (0.45 mmol) triphenylphosphine, 82 mg (0.12 mmol) PdCl2(PPh3)2 and 6.3 mL (45.0 mmol) triethylamine in 7 mL dry THF. For the work-up the reaction mixture is diluted with ethyl acetate and small amounts of cyclohexane, the organic phase is extracted with water and brine. The product is purified by chromatography on silica gel using a hexane/ethyl acetate gradient.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]([CH2:9][CH:10]([OH:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[N:8][C:4]=2[CH:3]=1.C(Cl)Cl.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:25]>N1C=CC=CC=1.C(OCC)(=O)C>[C:24](=[O:25])([O:26][C:27]1[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=1)[O:16][CH:10]([CH2:9][N:6]1[C:5]2[CH:17]=[C:18]([Cl:19])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=[CH:7]1)[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)CC(O)Cn1cnc2cc(Cl)c(Cl)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)CC(Cn1cnc2cc(Cl)c(Cl)cc21)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 76.9 %

Procedure:
The product from step B (445 mg, 1.48 mmol) was dissolved in pyridine (4 mL) and CH2Cl2 (2 mL) and treated with 4-nitrophenyl chloroformate (328 mg, 1.62 mmol). The reaction vessel was sealed and heated to 80° C. overnight. After cooling to room temperature, the reaction was diluted with ethyl acetate and extracted with water twice, 1 M aqueous HCl 3 times, water once and saturated aqueous NaCl once. The organics were then dried over MgSO4 and the solvent was removed. The residue was treated with ether, heated to reflux and put in the refrigerator overnight at −10° C. The resulting solid was collected, washed with cold ether and dried to afford 531 mg (77%) of the product as a slightly colored solid: 1H NMR (DMSO, 400 MHz) δ 1.01 (s, 9H), 1.66-1.79 (m, 2H), 4.62 (dd, 1H, J1=8.2, J2=14.9), 4.70 (dd, 1H, J1=3.4, J2=14.9), 5.23-5.32 (m, 1H), 7.11-7.17 (m, 2H), 8.03 (s, 1H), 8.21 (s, 1H), 8.28-8.33 (m, 2H), 8.51 (s, 1H); HPLC-MS calcd. for C21H22Cl2N4O2 (M+H+) 466.1, found 466.3.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:26][CH:25]3[CH:20]([N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24]3)[CH2:19]2)[C:5]2[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[C:14](I)[CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1.C(Cl)Cl.C(N(CC)CC)C.[C]=O>CO>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:26][CH:25]3[CH:20]([N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24]3)[CH2:19]2)[C:5]2[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[C:14]([C:27]([O:29][CH3:30])=[O:28])[CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2CN(c3nc(N)nc4c3CCOc3cc(I)ccc3-4)CC21
Agent: [C]=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc2c(c1)OCCc1c-2nc(N)nc1N1CC2CCCN(C(=O)OC(C)(C)C)C2C1

Procedure:
A mixture of the product from Example 102A (55 mg, 0.098 mmol), PdCl2(pddf).CH2Cl2 (4 mg, 0.0049 mmol), triethylamine (0.027 mL, 0.19 mmol) and MeOH (2 mL) was heated at 100° C. in an atmosphere of carbon monoxide at a pressure of 60 psi for 3 hours. The mixture was cooled and filtered to remove the solids. The filtrate was concentrated and purified by chromatography on silica gel using a gradient of 4:1 to 0:1 CH2Cl2:EtOAc to provide the title compound. 1H NMR (CDCl3) δ 1.31-1.43 (m, 1H), 1.49 (s, 9H), 1.54-1.86 (m, 4H), 2.21-2.33 (m, 1H), 2.54-2.68 (m, 1H), 2.75-2.89 (m, 2H), 3.45 (d, J=11.1 Hz, 1H), 3.60-3.78 (m, 2H), 3.85-3.92 (m, 1H), 3.94 (s, 3H), 4.01-4.10 (m, 1H), 4.50-4.68 (m, 2H), 4.79 (s, 2H), 7.80 (d, J=1.6 Hz, 1H), 7.98 (dd, J=7.9, 1.6 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H);
Reaction SMILES: COC1C=CC(C[N:8]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[C:20]([O:28][CH2:29][CH3:30])[N:19]=2)CC2C=CC(OC)=CC=2)=CC=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[NH2:8][C:18]1[N:19]=[C:20]([O:28][CH2:29][CH3:30])[C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=1
Reactant: CCOc1nc(N(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)ccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOc1nc(N)ccc1C(F)(F)F
Temperature: 25 °C

Procedure:
Stir a mixture of N,N-Bis-(4-methoxybenzyl)-(6-ethoxy-5-trifluoromethylpyridine-2-yl)amine (630 mg, 1.41 mmol) and TFA (5 mL) at 60° C. for 18 hours. At this time, TLC (80% Hexanes/EtOAc) reveals no remaining starting material. Cool the reaction mixture to room temperature, and remove excess TFA under vacuum to give a greenish-brown oil. Add EtOAc (20 mL) and sat. aqueous NaHCO3 (20 mL), and stir the mixture until the entire solid dissolves. Separate the layers, and extract the aqueous layer with another 10 mL EtOAc. Dry the combined EtOAc extracts (Na2SO4), filter, and evaporate to give a brown oil. Purification by column chromatography affords the title product as pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.54 (d, 1H, J=8.4 Hz), 6.0 (d, 1H, J=8.4 Hz), 4.56 (bs, 2H), 4.37 (q, 2H, J=6.8 and 7.2 Hz), 1.36 (t, 3H, J=7.2 and 6.8 Hz). Mass spec. (207.13, M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:9]=1[C:17]#[N:18])=[O:6])[CH3:2].C1CCCCC=1>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[C:9]=1[C:17]#[N:18])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)Nc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCOC(=O)C(=O)Nc1cccc(N)c1C#N

Procedure:
The title compound is prepared by reduction of [3-nitro-2-cyanophenylamino]oxoacetic acid ethyl ester with 10% Pd. on charcoal and with cyclohexene in ethanol according to the procedure of I. D. Entwistle and R. A. W. Johnstone, J. Chem. Soc., Perkin I. 1300 (1975). The crude product is chromatographed on silica gel with chloroform and recrystallized from ethanol, m.p. 133°-136° C.
Reaction SMILES: [CH2:1]([C@@:4]1([O:47][CH3:48])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:44][CH3:45])[CH2:25][O:26][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C:5]1=[O:46])[CH:2]=[CH2:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([C@@:4]1([O:47][CH3:48])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:44][CH3:45])[CH2:25][OH:26])[C:5]1=[O:46])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(OC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CC[C@@]1(OC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Reaction time: 8 h

Procedure:
To a solution of (3R,5R,6S)-3-allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxypiperidin-2-one (260 mg, 0.371 mmol; Example 203, Step C) in THF (1 mL) was added 1.0 M tetrabutylammonium fluoride solution in THF (1.484 mL, 1.484 mmol). After stirring overnight, the mixture was partitioned between water and ethyl acetate. Sat. aq. NH4Cl solution was added to break up the emulsion. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (12 g column, eluent: 35 to 100% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: [N:1]1([C:6]2[CH:28]=[CH:27][C:9]3[O:10][CH2:11][CH2:12][N:13](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:14][CH2:15][O:16][C:8]=3[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Na]>CO.N>[N:1]1([C:6]2[CH:28]=[CH:27][C:9]3[O:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][O:16][C:8]=3[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1ccc(S(=O)(=O)N2CCOc3ccc(-n4ccnc4)cc3OCC2)cc1
Agent: N
Agent: [Na]
Solvent: CO
Product: c1cn(-c2ccc3c(c2)OCCNCCO3)cn1

Procedure:
In a manner similar to example 1 react 9-(1H-imidazol-1-yl)-4-[(4-methylphenyl)sulfonyl]-3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonine with sodium in methanol and ammonia to obtain the title compound.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:35])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23](Br)[N:24]=3)[N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].[C:36]([C:40]1[CH:45]=[CH:44][N:43]=[C:42]([Sn](CCCC)(CCCC)CCCC)[CH:41]=1)([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C.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.[Cu]I>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:35])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:42]4[CH:41]=[C:40]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:45]=[CH:44][N:43]=4)[N:24]=3)[N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(C)(C)C)ccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccnc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)cn3COCC[Si](C)(C)C)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
In a round-bottomed flask 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (95 mg, 0.17 mmol) and 4-tert-butyl-2-(tributylstannyl)pyridine (141 mg, 0.20 mmol) were dissolved in DMF (1.6 mL). The reaction mixture was evacuated and backfilled with Argon. Tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) and copper (I) iodide (7 mg, 0.037 mmol) were added. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature, quenched with 5 mL water and extracted with 50 mL diethyl ether (2×). The combined organic layers were washed twice with 5 mL water and once with 5 mL brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 24 g SiO2 with MeOH/CH2Cl2/0.5% NH4OH (gradient: 0-2% MeOH). All fractions containing product were combined and concentrated to provide 68 mg (59%) of 2-(4-tert-butyl-pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide.
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1)=[O:2].C([O-])(=O)C.[Na+].[Br:19]Br>ClCCl>[CH:1]([C:3]1[O:4][C:5]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([Br:19])[C:6]=2[CH:7]=1)=[O:2]
Reactant: BrBr
Reactant: COc1cccc2cc(C=O)oc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(Br)c2cc(C=O)oc12

Procedure:
2-Formyl-7-methoxybenzofuran (1.0 g) was stirred in dichloromethane (10 ml) under nitrogen at 0° C. Sodium acetate (1.4 g) was added followed by the dropwise addition of bromine (0.29 ml). Further dichloromethane (20 ml) was added to the mixture to facilitate stirring and the mixture was stirred overnight. The reaction mixture was diluted with dichloromethane (40 ml) and washed with water (30 ml). Drying over magnesium sulfate followed by removal of the solvent in vacuo gave a pale orange solid. Purification by flash chromatography on silica eluting with 10% ethyl acetate in hexane gave the title compound (0.50 g) as a beige solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([O:13][CH2:14][O:15][CH3:16])=[CH:10][CH:9]=[CH:8]2)[CH3:2].CN(C)[CH:19]=[O:20].O>CCOCC.CCCCCC.C([Li])CCC>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([O:13][CH2:14][O:15][CH3:16])=[C:10]([CH:19]=[O:20])[CH:9]=[CH:8]2)[CH3:2]
Reactant: CCc1cccc2cccc(OCOC)c12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: CCc1cccc2ccc(C=O)c(OCOC)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
300 g of 8-ethyl-1-methoxymethoxynaphthalene was dissolved in 2.2 liters of absolute ether, in which 1.3 liters of a hexane solution of 1.6M n-butyl lithium was gently dropped at -20° C. in a stream of nitrogen. After the dropping, the solution was raised to room temperature and agitated for 2 hours. It was again cooled down to -40° C., to which 215 ml of N,N-dimethylformamide was added. After agitation for 30 minutes, 100 ml of water was added and the resultant organic phase was washed with a saturated saline solution. After drying with anhydrous magnesium sulfate, the solvent was distilled off and the residue was purified by silica gel column chromatography (5% ethyl acetate/hexane) to obtain 253 g of the captioned compound as colorless crystals.
Reaction SMILES: C(O[C@@H](C1C(C)=CC2N=C(C3C=CC4N(C)N=NC=4C=3)SC=2C=1C1C=CC(Cl)=CC=1)C(O)=O)(C)(C)C.[C:37]([O:41][C@@H:42]([C:48]1[C:66]([CH3:67])=[CH:65][C:51]2[N:52]=[C:53]([C:55]3[CH:56]=[CH:57][C:58]4[N:62]=[N:61][N:60]([CH3:63])[C:59]=4[CH:64]=3)[S:54][C:50]=2[C:49]=1[C:68]1[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=1)[C:43]([O:45]CC)=[O:44])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][C@@H:42]([C:48]1[C:66]([CH3:67])=[CH:65][C:51]2[N:52]=[C:53]([C:55]3[CH:56]=[CH:57][C:58]4[N:62]=[N:61][N:60]([CH3:63])[C:59]=4[CH:64]=3)[S:54][C:50]=2[C:49]=1[C:68]1[CH:69]=[CH:70][C:71]([Cl:74])=[CH:72][CH:73]=1)[C:43]([OH:45])=[O:44])([CH3:40])([CH3:38])[CH3:39]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4nnn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Agent: Cc1cc2nc(-c3ccc4c(c3)nnn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(-c3ccc4nnn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
Prepared in a manner similar to (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)benzo[d]thiazol-6-yl)acetic acid, but using (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)benzo[d]thiazol-6-yl)acetate instead of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)benzo[d]thiazol-6-yl)acetate. LCMS-ESI+: calc'd for C27H26ClN4O3S: 521.0 (M+H+); Found: 521.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ 8.44 (s, 1H), 8.12 (dd, J=8.8, 1.4 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.87 (s, 1H), 7.70 (d, J=9.5 Hz, 1H), 7.64-7.57 (m, 3H), 5.27 (s, 1H), 4.39 (s, 3H), 2.62 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12]Cl)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](NCCC)=[CH:18]2.O>CS(C)=O>[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:4][CH2:3][CH2:2][NH:1][CH2:12][CH2:11][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2
Reactant: ClCCOc1cccc2[nH]ccc12
Reactant: CCCNc1cc2cc(F)ccc2[nH]1
Solvent: O
Solvent: CS(C)=O
Product: Fc1ccc2[nH]cc(CCCNCCOc3cccc4[nH]ccc34)c2c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
A solution of 2-(1H-indol-4-yloxy)ethylchloride (0.7 g, 3.6 mmol), 5-fluoro-indolyl-3-propylamine (1.0 g, 5.4 mmol) in dimethylsulfoxide (20 ml) was allowed to stir for 12 hours at 90° C. The reaction mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (5%-10% methanol-methylene chloride) afforded 0.54 g (43%) of product as a white solid: mp 70-73° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[CH3:7][P:8]([CH3:25])([CH2:10][CH2:11][NH:12][CH2:13][C:14]([S:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:16])[CH3:15])=[S:9].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:18]([S:17][C:14]([CH3:16])([CH3:15])[CH2:13][N:12]([CH2:11][CH2:10][P:8]([CH3:25])([CH3:7])=[S:9])[C:4](=[O:5])[CH2:3][O:2][CH3:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COCC(=O)Cl
Reactant: CC(C)(CNCCP(C)(C)=S)SCc1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COCC(=O)N(CCP(C)(C)=S)CC(C)(C)SCc1ccccc1
Reaction time: 1 h
Yield: 65.3 %

Procedure:
Methoxyacetyl chloride (1.03 g) in dry toluene (10 cm3) was added dropwise to a stirred solution of N-(2-dimethylphosphinothioylethyl)-2-benzylthio-2-methylpropylamine (3 g) and pyridine (1.2 cm3) in dry toluene (70 cm3) at 0° C. After stirring for 1 h the mixture was filtered and the volatile components removed under reduced pressure (40° C. at 0.05 mmHg) to give the amide (2.4 g, 65%) as a yellow oil which solidified on standing. An analytically pure sample of the amide (m.p. 91°-92° C.) was obtained by recrystallisation from ethyl acetate.