Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12](B(O)O)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl.Cl.Br[C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][N:31]=[C:30]2[C:36]1[N:41]=[C:40]([N:42]2[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]2)[CH:39]=[N:38][CH:37]=1>>[CH3:1][O:2][C:3]1[C:12]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][N:31]=[C:30]3[C:36]2[N:41]=[C:40]([N:42]3[CH2:43][CH2:44][CH:45]([NH2:48])[CH2:46][CH2:47]3)[CH:39]=[N:38][CH:37]=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: NC1CCN(c2cncc(-c3n[nH]c4ccc(Br)cc34)n2)CC1
Reactant: COc1nc2ccccc2cc1B(O)O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1nc2ccccc2cc1-c1ccc2[nH]nc(-c3cncc(N4CCC(N)CC4)n3)c2c1
Temperature: 150 °C

Procedure:
To a 5 mL conical vial was added 2-methoxyquinolin-3-ylboronic acid (Frontier Scientific, 89 mg, 0.437 mmol), potassium phosphate (Aldrich, 285 mg, 1.345 mmol), PdCl2(AmPhos) (23.80 mg, 0.034 mmol), and 1-(6-(5-bromo-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-amine dihydrochloride salt (Example 1) (150 mg, 0.336 mmol) which was sealed, evacuated and back-filled with N2 3×. Dioxane (2.8 mL) and water (0.6 mL) were added, and the reaction mixture was heated at 150° C. for 30 min with microwave irradiation. After the reaction mixtures were filtered, the crude reaction mixture was concentrated and purified on silica gel (eluent: 0 to 4% MeOH (with 2M NH3) in DCM) to afford the title compound. MS (ESI, pos. ion) m/z: 438 (M+1).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Cl:10][C:11]1[CH:12]=[C:13]([C:18](OCC)=[O:19])[CH:14]=[N:15][C:16]=1[I:17].C(=O)=O.C(C(C(C([O-])=O)O)O)([O-])=O>C1COCC1.CCOC(C)=O>[Cl:10][C:11]1[CH:12]=[C:13]([CH2:18][OH:19])[CH:14]=[N:15][C:16]=1[I:17]
Reactant: CCOC(=O)c1cnc(I)c(Cl)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: O=C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1cnc(I)c(Cl)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
DIBAL-H (3.37 ml, 3.37 mmol) was slowly added to a solution of ethyl 5-chloro-6-iodo-3-pyridinecarboxylate (500 mg, 1.605 mmol) in THF (10 ml) at −78° C. The solution turned yellow and was stirred at that temperature for 3 h and then still in the dry-ice bath allowed to slowly attain room temperature overnight. Next morning, TLC showed starting material remaining. The solution was cooled to −78° C. and DIBAL-H (3.37 ml, 3.37 mmol) was added. 3 h later it was allowed to warm to room temperature and after 2 h starting material was still observed. More DIBAL-H (6.74 ml) was added and the solution stirred at room temperature overnight. Full conversion was observed. Saturated, aqueous NaK-tartrate solution and EtOAc were added. Extraction, drying (MgSO4), filtration, and concentration afforded (5-chloro-6-iodo-3-pyridinyl)methanol (393 mg, 91%) as a brown solid pure enough to be used in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)CCC>>[CH2:1]([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(Br)cc2)CC1
Product: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(-c3cccs3)cc2)CC1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared starting from 1-(4-Bromo-benzyl)-4-(4-methoxy-benzensulfonyl)-piperidine-4-carboxylic acid ethyl ester (3 g, 6.05 mmol) and 2-(tributylstannyl)-thiophene (6.8 g, 18.14 mmol) in the presence of tetrakis palladium (0) in boiling tolune. Yield 1.58 g (52%); brown solid; mp 130° C.; MS: 500 (M+H)+
Reaction SMILES: C([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[I:16])[NH2:8])(C)(C)C.C(=N)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[I:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][C@@H:7]([C:6]([OH:17])=[O:5])[NH2:8]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1I
Agent: Cl
Agent: N=C(c1ccccc1)c1ccccc1
Agent: O=C(c1ccccc1)c1ccccc1
Product: N[C@@H](Cc1ccccc1I)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 109.7 %

Procedure:
A 500 mL round bottomed flask equipped with a reflux condenser and a magnetic stirrer was charged with 15.72 g of 2-iodo-L-phenylalanine tert-butyl ester-benzophenone imine (86% ee) and 165 mL of 6N aqueous HCl. The mixture was heated at reflux with stirring for 4 h and cooled to RT to afford a mixture of white crystalline solid and an immicible organic phase (benzophenone). The mixture was partitioned between water (100 mL) and ethyl ether (70 mL). The aqueous phase was separated, washed with four additional 70 mL portions of ether and concentrated in vacuo to dryness to give 9.5 g (94%) of 2-iodo-L-phenylalanine.HCl as a fluffy white solid, m.p. 240° C. (dec).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][C:10](=[O:12])[NH:9][C:8](=[O:13])[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.C[O-].[Na+].[CH2:17]([C:19]1[CH:34]=[C:33](C)[CH:32]=[CH:31][C:20]=1S(OC1C=CC=CC=1)(=O)=O)[CH3:18].[BH4-].[Na+]>CC(N(C)C)=O.C(O)C.[Cl-].[Mn+2].[Cl-]>[CH:1]1([C:4]([N:6]2[CH2:11][C:10](=[O:12])[N:9]([CH2:18][CH2:17][C:19]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:20]=3)[CH:8]([OH:13])[CH2:7]2)=[O:5])[CH2:2][CH2:3]1
Reactant: O=C1CN(C(=O)C2CC2)CC(=O)N1
Reactant: CCc1cc(C)ccc1S(=O)(=O)Oc1ccccc1
Agent: [Mn+2]
Agent: C[O-]
Agent: [BH4-]
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: O=C(C1CC1)N1CC(=O)N(CCc2ccccc2)C(O)C1
Reaction time: 1 h

Procedure:
0.067 mol of 4-(cyclopropylcarbonyl)-2,6-dioxopiperazine are dissolved in 200 ml of dimethylacetamide. 0.073 mol of sodium methylate are added and the mixture is left for 1 hour at ambient temperature. To the reaction medium is added, dropwise and in an inert atmosphere, a solution of 0.081 mol of (2-ethyl tosyloxy)-benzene in 50 mol of dimethylacetamide and the mixture is brought to 90° C. for 4 hours. It is evaporated to dryness under reduced pressure, the residue is taken up in a mixture of water and methylene chloride and the decanted organic phase is dried over dry sodium sulphate. The solvent is evaporated and the residue, formed by crude 4-(cyclopropylcarbonyl)-2,6-dioxo-1-phenethyl piperazine, is dissolved in 600 ml of ethanol. The solution as thus obtained has added thereto, at 0° C. and in an inert atmosphere, 0.059 mol of manganese chloride and is left for 1 hour at 0° C. 0.23 mol of sodium borohydride is added in portions to the reaction medium, kept at 0° C., and the reaction medium is left for 45 minutes at 0° C. The excess of reducing agent is destroyed by adding acetone. The insoluble salts are filtered, the filtrate is evaporated to dryness and the residue is treated with a mixture of water and methylene chloride. The decanted organic phase is dried over dry sodium sulphate and evaporated to dryness. The residue is purified by filtration on a silica bed and the product as thus obtained, formed by the 4-(cyclopropylcarbonyl)-2-hydroxy-6-oxo-1-phenethyl piperazine, is added in portions to 150 ml of hydrochloric acid previously cooled to 0° C. After one night at ambient temperature, the reaction medium is poured into iced water and extracted with dichloromethane. The organic phase is dried on an anhydrous sodium sulphate and it is evaporated. In this way, there is obtained the 2-(cyclopropylcarbonyl)-1,3,4,6,7,11b-hexahydro-2H-pyrazino(2,1-a)-4-isoquinoleinone; m.p.=148°-149° C., yield: 57%.
Reaction SMILES: [F:1][CH:2]([F:21])[CH2:3][NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1[O:19][CH3:20].[F:22][C:23]([F:38])([F:37])[C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[N:32]=1)[C:27](O)=[O:28]>>[F:21][CH:2]([F:1])[CH2:3][N:4]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1[O:19][CH3:20])[C:27](=[O:28])[C:26]1[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[N:32]=[C:24]([C:23]([F:38])([F:22])[F:37])[CH:25]=1
Reactant: COc1cc(F)c(F)cc1-c1ccncc1NCC(F)F
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: COc1cc(F)c(F)cc1-c1ccncc1N(CC(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from (2,2-difluoro-ethyl)-[4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-yl]-amine and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 66 hours. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light brown solid (66%). MS (ESI): m/z=542.09 [M+H]+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:15][CH:14]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(Cc1ccc(Cl)cc1)C(=O)OCC
Yield: 41.8 %

Procedure:
In the same manner as in Example 6 (1), a crude product was obtained using diethyl malonate (13.6 g) and 4-chlorobenzyl bromide (17.5 g). This was purified by silica gel column chromatography to give the title compound (10.1 g) as an oil.
Reaction SMILES: C(OC[C@@H]1OC(=O)N(C2C=CC(Cl)=CC=2)[C@H]1C1C=CC=C(C(F)(F)F)C=1)C1C=CC=CC=1.[N:33]([CH2:36][C@@H:37]1[O:41][C:40](=[O:42])[N:39]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[C@H:38]1[C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=1)=[N+:34]=[N-:35].[N-]=[N+]=[N-].[F:63][C:64]1[CH:65]=[C:66]([C:70]#[CH:71])[CH:67]=[CH:68][CH:69]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>C(O)(C)(C)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:49][C:46]1[CH:45]=[CH:44][C:43]([N:39]2[C@@H:38]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=3)[C@H:37]([CH2:36][N:33]3[CH:71]=[C:70]([C:66]4[CH:67]=[CH:68][CH:69]=[C:64]([F:63])[CH:65]=4)[N:35]=[N:34]3)[O:41][C:40]2=[O:42])=[CH:48][CH:47]=1
Reactant: [N-]=[N+]=NC[C@@H]1OC(=O)N(c2ccc(Cl)cc2)[C@H]1c1cccc(C(F)(F)F)c1
Reactant: C#Cc1cccc(F)c1
Agent: [Cu+2]
Agent: O=C1O[C@@H](COCc2ccccc2)[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Cl)cc1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: O
Solvent: CC(C)(C)O
Product: O=C1O[C@@H](Cn2cc(-c3cccc(F)c3)nn2)[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
(4S,5R)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one (from Example 72) was converted into (4S,5S)-5-(azidomethyl)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)oxazolidin-2-one as described in Example 34. The azide (0.076 mmol) was then dissolved in t-butanol:water (2:1, 0.5 mL) and treated with 3-fluorophenylacetylene (0.076 mmol), followed by copper (II) sulfate pentahydrate (0.4 mg) and sodium ascorbate (0.75 mg). After stirring for 2 h, the reaction mixture was quenched with water and extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. Purification on silica gel (30% ethyl acetate/hexanes) gave the title compound as a colorless oil. 1H NMR (acetone-d6) δ (ppm) 8.57 (s, 1H), 7.88 (s, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.72-7.70 (m, 2H), 7.67-7.63 (m, 2H), 7.50-7.44 (m, 3H), 7.30-7.28 (m, 2H), 7.11 (td, J=8.5, 2.3 Hz, 1H), 5.81 (d, J=5.2 Hz, 1H), 5.22-5.16 (m, 2H), 5.07 (ddd, J=5.5, 5.5, 4.4 Hz, 1H), 4.73-4.64 (m, 3H), 4.01 (d, J=3.6 Hz, 2H); HPLC-MS calculated C25H17ClF4N4O2 (M+H+): 517.1, found: 517.1.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@@H:6]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.C(N(CC)CC)C.[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40])([O-:32])=[O:31].O>C1COCC1>[N:10]1([C:8]([C@@H:6]2[CH2:7][C@H:2]([NH:1][S:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[N+:30]([O-:32])=[O:31])(=[O:40])=[O:41])[CH2:3][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5]2)=[O:9])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@@H](C(=O)N2CCOCC2)C1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](NS(=O)(=O)c2ccccc2[N+](=O)[O-])C[C@@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94 %

Procedure:
tert-Butyl (3S,5R)-3-amino-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (3.13 g) and triethylamine (2.1 ml) were dissolved in THF (30 ml), 2-nitrobenzenesulfonyl chloride (2.44 g) was added at room temperature, and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object product (4.68 g).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:16]2[C:15]3[CH:14]=[C:13]([OH:17])[CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH3:18].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(O)C>CN(C=O)C>[CH3:3][N:4]1[C:16]2[C:15]3[CH:14]=[C:13]([O:17][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH3:18]
Reactant: Cc1nc2cnc3ccc(O)cc3c2n1C
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)COc1ccc2ncc3nc(C)n(C)c3c2c1
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
Sodium hydride (0.61 g, 15 mmol, available as a 60% dispersion in mineral oil) was added to a solution of 1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-ol (2.5 g, 12 mmol) in DMF. The reaction mixture was stirred for 30 minutes, and ethyl bromoacetate (1.96 g, 11.7 mmol) was added. The stirring was continued for five hours, and a small volume of ethanol was added. The volatiles were removed under reduced pressure, and the residue was dissolved in dichloromethane. The resulting solution was washed three times with deionized water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting yellow solid was recrystallized from ethyl acetate to provide 1.65 g of ethyl 2-[(1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]acetate as a white solid.
Reaction SMILES: Br([O-])(=O)=O.[Na+].[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1.CC[O:17]CC>C(#N)C.O>[F:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]([OH:17])=[O:12])=[CH:9][CH:8]=1
Reactant: OCc1ccc(F)cc1
Reactant: CCOCC
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 40 h
Yield: 86 %

Procedure:
A mixture of the Ceiv catalyst from EXAMPLE 47 (0.08 g), sodium bromate (0.3 g) and 4-fluorobenzyl alcohol (0.256 g, 2 mmol) in acetonitrile:water (1:1, 10 ml) was stirred at 80° C. for 40 h under an atmosphere of nitrogen. On cooling ether (70 ml) was added and the catalyst was filtered off. The organic layer was separated and the aqueous phase was extracted with ether (2×50 ml). The combined organic extracts were washed with water (25 ml), dried with anhydrous magnesium sulphate and concentrated to give 4-fluorobenzoic acid as a white solid (0.24 g, 86%). M.p. 182° C., lit. 185° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH2:10][CH3:11])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:13][C:14]([C@H:17]1[CH2:21][CH2:20][NH:19][C@H:18]1[CH3:22])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:1][C:2]1[C:9]([CH2:10][CH3:11])=[C:8]([N:19]2[CH2:20][CH2:21][C@H:17]([C:14]([OH:13])([CH3:16])[CH3:15])[C@@H:18]2[CH3:22])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: CCc1c(F)ccc(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CCc1c(N2CC[C@H](C(C)(C)O)[C@@H]2C)ccc(C#N)c1Cl

Procedure:
Using 2-chloro-4-fluoro-3-ethylbenzonitrile (1.10 g), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (1.24 g) and lithium carbonate (930 mg), the title compound was obtained as a colorless solid (yield: 255 mg) by an operation similar to that in Example 3.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.Cl.N1C=CC=CC=1>O>[CH3:12][C:10]1[CH:11]=[C:3]([OH:2])[CH:4]=[C:5]2[C:9]=1[NH:8][CH:7]=[C:6]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1
Reactant: COc1cc(C)c2[nH]cc(C3CCN(C)CC3)c2c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(O)cc2c(C3CCN(C)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82 %

Procedure:
In a round bottom flask was placed 5-methoxy-7-methyl-3-(1-methylpiperidin-4-yl)-1H-indole (3.9 mmole, 1.01 g) and pyridine hydrochloride (25 g). The flask was then placed in a preheated oil bath set at 190° C. for 45 minutes. This solution was cooled to room temperature. The resulting solidified material was dissolved in water (200 mL). The pH was adjusted to approximately 10.3, which resulted in a precipitate. The insoluble material was collected by filtration, rinsed with water to afford 0.781 g (82%) of the title compound: mass spectrum (ion spray): m/z=245 (M+1); 1H NMR (DMSOd6): 10.40 (s, 1H), 8.45 (s, 1H), 6.93 (s, 1H), 6.68 (s, 1H), 6.40 (s, 1H), 2.90 (m, 2H), 2.60 (m, 1H), 2.36 (s, 3H), 2.26 (s, 3H), 2.08 (m, 2H), 1.90 (m, 2H), 1.70 (m, 2H); Calculated for C15H20N2O: C, 73.74; H, 8.25; N, 11.47. Found: C, 73.76; H, 8.15; N, 11.71.
Reaction SMILES: [OH:1][C@@H:2]([CH3:7])[CH2:3][C:4]([O-:6])=O.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.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][N:51]=[C:50]([NH:54][C:55]3[CH:60]=[CH:59][C:58]([N:61]4[CH2:66][CH2:65][O:64][CH2:63][CH2:62]4)=[CH:57][CH:56]=3)[N:49]=2)=[CH:44][CH:43]=1>CN(C=O)C>[OH:1][C@@H:2]([CH3:7])[CH2:3][C:4]([NH:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][N:51]=[C:50]([NH:54][C:55]3[CH:56]=[CH:57][C:58]([N:61]4[CH2:62][CH2:63][O:64][CH2:65][CH2:66]4)=[CH:59][CH:60]=3)[N:49]=2)=[CH:44][CH:43]=1)=[O:6]
Reactant: Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Reactant: C[C@H](O)CC(=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)CC(=O)Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
To a solution of (S)-3-hydroxybutyrate (0.180 g, 1.73 mmol), HATU (0.602 g, 1.58 mmol), DIEA (1.0 mL, 5.4 mmol) in DMF (3.0 mL) was added a solution of 4-(4-aminophenyl)-N-(4-morpholinophenyl)pyrimidin-2-amine (0.500 g, 1.44 mmol) in DMF (1.0 mL). The reaction mixture was stirred at rt for 2 hours, at which time it was quenched with saturated NaHCO3 (10 mL, aq.), extracted into DCM (3×), and washed with brine (1×). The organic layers were dried with sodium sulfate and concentrated. The product was purified by reverse phase HPLC to afford (S)-3-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)butanamide (0.136 g, 22% yield) as a light brown solid. (363) 1H-NMR (400 MHz, DMSO-d6): 10.14 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.77 (d, 2H), 7.68 (d, 2H), 7.27 (d, 1H), 6.94 (d, 2H), 4.79 (d, 1H), 4.11 (m, 1H), 3.74 (m, 4H), 3.05 (m, 4H), 2.47 (dd, 1H), 2.35 (dd, 1H)), 1.15 (d, 3H); MS (EI) m/z for C24H28N5O3: 434.3 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:9][N:10]=2)[N:7]=1.[CH2:20]([Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:23]#[CH:24])[CH3:21].C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.[Cu](I)I.C(#N)C>[C:15]([O:14][C:13](=[O:19])[NH:12][CH2:11][C:8]1[N:6]2[N:7]=[C:2]([C:21]#[C:20][Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: C#C[Si](CC)(CC)CC
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(Cl)nn12
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: [Fe+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: CC[Si](C#Cc1ccc2nnc(CNC(=O)OC(C)(C)C)n2n1)(CC)CC
Temperature: 25 °C

Procedure:
A 1 L-round-bottomed flask flushed with argon was charged with tert-butyl (6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (12.00 g, 42.3 mmol), Pd(dppf)Cl2—CH2Cl2 adduct (3.45 g, 4.23 mmol), copper iodide (2.01 g, 10.6 mmol) at room temperature. Acetonitrile (400 mL) was added followed by triethyl(ethynyl)silane (37.9 ml, 211 mmol). Upon stirring the reaction mixture turned dark red. Triethylamine (177 ml, 1269 mmol) was added via cannula over five minutes. The first drops resulted in a change of color to light yellow/orange. At the end of the addition, the reaction mixture was dark red again. After stirring at 50° C. for one hour, the mixture was cooled to room temperature and concentrated in vacuo. Purification by MPLC (ISCO, EtOAc/MeOH: 100/0 to 90/10) afforded the desired product. The material was taken forward without further purification. MS m/z=388.3 [M+1]+. Calc'd for C19H29N5O2Si: 387.2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[C:7]([C:11]([O:13]CC)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.O.O.O.[OH-].[Li+]>O1CCCC1.O>[C:18]([CH2:17][CH2:16][C:6]1[C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[NH:8][C:7]=1[C:11]([OH:13])=[O:12])([OH:20])=[O:19]
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(Br)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1c(C(=O)O)[nH]c2cc(Br)ccc12
Temperature: 25 °C
Yield: 95 %

Procedure:
Ethyl 6-bromo-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (3.68 g, 10 mmol) was dissolved in 25 ml tetrahydrofurane (THF) with stirring at rt. Then a solution of 1.26 g of lithium hydroxide trihydrate (3 equiv.) in 25 ml water was added and the resulting mixture was let to stir at rt for 24 h. After completion of the reaction THF was removed under reduced pressure and the pH was adjusted to 4-5, and the product was extracted with diethyl ether (3×30 ml). The organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness to yield a light-beige-colored solid in 95-100% yield. mp. 234-235° C. 1H-NMR (DMSO-d6) δ 2.50 (m, 2H, 2′-H); 3.23 (m, 2H, 1′-H); 7.16 (dd, 1H, J=1.8 Hz, 5-H); 7.54 (dd, 1H, J=1.8 Hz, 7-H); 7.64 (dd, 1H, J=8.5 Hz, 4-H); 11.57 (s, 1H, NH); 12.54 (b, 1H, 2CO2H). 13C-NMR (DMSO-d6) δ 19.9 (C-2′); 35.2 (C-1′); 114.9 (C-7); 117.6 (C-4); 121.6 (C-3); 122.5 (C-6, C-5); 125.0 (C-2); 126.2 (C-3a); 136.8 (C-7a); 163.0 (2′-CO2H); 174.0 (2-CO2H). LC-MS (m/z): 329 [M-NH4+]+, 312 [M]+, 312 [M]−. Purity (LC-MS): 99%.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][N:9]=[C:10]=[O:11])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1.[CH:34]1([NH2:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>C(Cl)Cl>[CH:34]1([NH:40][C:10]([NH:9][CH2:8][CH2:7][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[O:11])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: NC1CCCCC1
Reactant: C=C(C)C(=O)OCCN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: ClCCl
Product: C=C(C)C(=O)OCCNC(=O)NC1CCCCC1

Procedure:
A 3-neck, 250-mL round bottom flask equipped with a reflux condenser was charged with isocyanatoethyl methacrylate (7.79 g), 1,1'-bi-2-naphthol (1.3 mg) and 50 mL of methylene chloride. While stirring, cyclohexylamine (5.24 g) and dibutyltin dilaurate (52.3 mg) in 50 mL of methylene chloride were added over a 15 minute period. The reaction mixture was kept stirred for an additional 30 minutes. The solution was filtered and evaporated to dryness to recover the product. The product was characterized by H-NMR, 0.72-2.10 ppm (m, 1H), 1.90 ppm (s, 3H), 3.45 ppm (t, 2H), 3.50 ppm (hidden, 1H), 4.18 ppm (t, 2H), 5.12 ppm (s, 1H), 5.26 ppm (s, 1H), 5.52 ppm (s, 1H), 6.10 ppm (s, 1H).