Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH3:23])=[O:10])[CH2:2]1.F[C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28].CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[S:15][C:11]([C:9]([NH:8][CH2:7][CH:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:25]4[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=4[C:27]([O:29][CH3:30])=[O:28])[CH2:2]3)=[O:10])=[C:12]([CH3:23])[N:13]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccccc1F
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccccc1N1CCCC(CNC(=O)c2sc(-c3ccc(Cl)cc3)nc2C)C1
Temperature: 130 °C
Reaction time: 6 h
Yield: 20.3 %

Procedure:
N-(Piperidin-3-yl methyl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (105 mg, 0.300 mmol) and methyl 2-fluorobenzoate (0.0382 mL, 0.300 mmol) were added to dimethylsulfoxide (5 mL). To this mixture, potassium carbonate (82.9 mg, 0.600 mmol) was added and the mixture was stirred for 6 hours at 130° C. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract was washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=10:1->2:1) gave 29.5 mg (20%) of the desired compound as a colorless oil.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:31]([C:34]2[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:3]=1.[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49](B2OC(C)(C)C(C)(C)O2)[C:48]([CH3:61])=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([NH:17][CH:18]5[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:20][CH2:19]5)[CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[N:4]([S:31]([C:34]3[CH:35]=[CH:36][C:37]([CH3:38])=[CH:39][CH:40]=3)(=[O:32])=[O:33])[CH:3]=2)[C:48]([CH3:61])=[N:47]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(NC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4cccc(NC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Yield: 67.4 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-((3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)piperidine-1-carboxylate (intermediate 66E) (200 mg, 0.297 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (141 mg, 0.446 mmol) using Pd(PPh3)2Cl2 (11 mg, 0.014 mmol) and sodium carbonate (79 mg, 0.744 mmol) in Toluene/ethanol/water (5/2/1 ml) to afford 150 mg (67.5% yield) of the titled compound after column purification using 1% methanol in DCM as eluent. MS: m/z=749.3 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[C:4](B(O)O)[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.O.O=[CH:15][C:16]([OH:18])=[O:17].[NH2:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(#N)C>[S:1]1[CH:5]=[C:4]([CH:15]([NH:19][C:20]2[CH:30]=[CH:29][CH:28]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=2)[C:16]([OH:18])=[O:17])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: OB(O)c1csc2ccccc12
Reactant: O=CC(=O)O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cccc(NC(C(=O)O)c2csc3ccccc23)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of benzo[b]thiophen-3-ylboronic acid (500 mg, 2.81 mmol) and 2-oxoacetic acid hydrate (259 mg, 2.81 mmol) in acetonitrile (20 ml), was added ethyl 3-aminobenzoate (419 μl, 2.81 mmol). The reaction was stirred at r.t. for 72 hours, and then the solvent was evaporated under vacuum. The residue was used in the next step without any further purification.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][C:11]#[CH:12])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH3:13][C:14]1([CH3:21])[C:18]([CH3:20])([CH3:19])[O:17][BH:16][O:15]1.[CH2:22](N(CC)CC)[CH3:23]>[H-].[Cl-].C1([Zr+2]C2C=CC=C2)C=CC=C1>[C:1]([Si:5]([CH3:6])([CH3:7])[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:22]=[CH:23][B:16]1[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:21])([CH3:13])[O:15]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C#CCCO[Si](C)(C)C(C)(C)C
Reactant: CC1(C)OBOC1(C)C
Reactant: CCN(CC)CC
Agent: C1=CC([Zr+2]C2C=CC=C2)C=C1
Agent: [Cl-]
Agent: [H-]
Product: CC1(C)OB(C=CCCCCO[Si](C)(C)C(C)(C)C)OC1(C)C
Temperature: 60 °C
Yield: 724.2 %

Procedure:
To a mixture of tert-butyl-but-3-ynyloxy-dimethyl-silane (I) (1.0 g, 7.14 mmol) and 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (II) (958 mg, 7.49 mmol) were added bis(cyclopentadienyl)zirconium chloride hydride (183 mg, 0.714 mmol) and triethylamine (72 mg, 0.714 mmol). The resulting mixture was heated at 60° C. for 6 hours and was diluted with hexanes. The precipitate was removed by filtering over a short pad of silica gel and washed with hexanes. The filtrate was concentrated and dried through vacuum to give 1.76 g (93%) of the title compound as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][S:7][C:6]=2[CH:17]=1.[H-].[Na+].Cl[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][C:26]=1[O:34][CH3:35]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][C:26]=3[O:34][CH3:35])=[CH:8][S:7][C:6]=2[CH:17]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: Clc1ccc2c(Nc3ccncc3)csc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCN(c1ccncc1)c1csc2cc(Cl)ccc12
Temperature: 45 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
6-Chloro-3-(4-pyridinylamino)benzo[b]thiophene (4 g, 15 mmol) was added portionwise as a powder to a suspension of sodium hydride (60% oil dispersion, 0.7 g, 18 mmol, washed with heptane) in 50 mL of dimethylformamide. After the anion formation was completed, 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4 g, 16 mmol) was added. The reaction mixture was stirred two hours at 45° C., and then was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution, and then was dried (anhydrous magnesium sulfate), filtered and concentrated to 8 g of a dark oil. Elution through silica with 10% methanol in ethyl acetate via flash column chromatography afforded 4.1 g of a brown oil. Elution of this oil three times through silica with ethyl acetate via flash column chromatography afforded 3.0 g of a waxy solid. Recrystallization from acetonitrile afforded 2.1 g of white crystals, mp 148°-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=1[O:12][CH3:13].[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1)[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[O:16])[S:10][C:11]=1[O:12][CH3:13]
Reactant: COc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1sc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxylic acid (220 mg, 0.81 mmol) [prepared according to the procedure of Example 188], 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (281 mg, 0.84 mmol) [prepared according to the procedure of Preparation 6, except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (472 mg, 1.0 mmol) in Chloroform (8 mL). DIEA (710 μL, 4.07 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (281 mg, 0.51 mmol, 63%): LC-MS (ES) m/z=553 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH2:7])=O.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.Cl>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]#[N:7]
Reactant: Cc1cc(C(N)=O)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: Cc1cc(C#N)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a stirred, 0° C. solution of 3-methyl-4-nitrobenzamide (30 g, 0.169 mol) in dichloromethane (900 mL) under nitrogen was added pyridine (29.5 g, 0.373 mol), then dropwise trifluoroacetic anhydride (42.7 g, 0.203 mol) in dichloromethane (90 mL). The reaction mixture was stirred at 0° C. for one hour and then 1N HCl was added. The organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure to afford 25.5 g (93%) of the 3-methyl-4-nitrobenzonitrile as a light yellow solid; m.p. 69°-71° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]([OH:17])=O)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:15](=[O:17])[C:14]#[C:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:12][CH:11]=3)=[CH:27][CH:26]=2)=[CH:23][CH:24]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: O=C(O)C#Cc1ccc(CN2CCCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(C#Cc1ccc(CN2CCCC2)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
A solution of 0.3 g (1.30 mmol) of (4-pyrrolidin-1-ylmethylphenyl)propynoic acid, 0.27 g (1.32 mmol) of 4′-chlorobiphenyl-4-ylamine, 0.42 g (1.32 mmol) of TBTU, and 0.18 mL (1.32 mmol) of triethylamine in 30 mL of DMF is stirred for 14 hours at ambient temperature. The reaction mixture is evaporated down and the residue is extracted with water and dichloromethane. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluant: dichloromethane/ethanol (10:1)). Yield: 0.095 g (17.5% of theory); melting point: from 180° C.; C26H23ClN2O (M=414.93); calc.: molecular ion peak (M+H)+: 415/417; found: molecular ion peak (M+H)+: 415/417; Rf value: 0.3 (silica gel, dichloromethane/ethanol (5:1)).
Reaction SMILES: [CH2:1]([N:4]1[C@H:13]2[C@@H:8]([CH2:9][C:10](=O)[CH2:11][CH2:12]2)[CH2:7][CH2:6][C:5]1=O)[CH2:2][CH3:3].[C:16]([NH2:20])(=[O:19])[CH:17]=[CH2:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.COC1C=CC(O)=CC=1>[O:19]=[C:16]1[NH:20][C:10]2[CH2:9][C@H:8]3[C@H:13]([CH2:12][C:11]=2[CH2:18][CH2:17]1)[N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7]3
Reactant: C=CC(N)=O
Reactant: CCCN1C(=O)CC[C@@H]2CC(=O)CC[C@H]21
Agent: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCN1CCC[C@H]2CC3=C(CCC(=O)N3)C[C@@H]21
Yield: 36.6 %

Procedure:
A mixture of (±)-trans-1-propyl-6-oxodecahydroquinolone (30.0 g, 154 mMol), acrylamide (32.8 g, 462 mMol), p-toluenesulfonic acid monohydrate (35.2 g, 185 mMol), and p-methoxyphenol (500 mg) in toluene (1000 mL) was heated to reflux, water being collected in a Dean-Stark trap. After 17 hr of reflux, the reaction was poured into dilute NaOH solution and extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated to give the crude product as a brown foam. Recrystallization (ethyl acetate/hexanes) provided the desired product as a tan solid (14.0 g, 37% yield). Purification of the mother liquors by flash chromatography (2:1 THF: hexanes, 0.5% NH4OH) provided additional product (Rf=0.40, 2.6 g, 7% yield). Recrystallization of this material (ethyl acetate) provided analytically pure material. m.p.=183.0-184.0°.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH:17]([O:19]CCCC)=[CH2:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>Cl[Pd]Cl.CC(O)C>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[N:6]1[C:5]2[CH:15]=[CH:16][C:2]([C:17](=[O:19])[CH3:18])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: C=COCCCC
Reactant: Brc1ccc2c(c1)ncn2C1CCCCO1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(=O)c1ccc2c(c1)ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.1 %

Procedure:
A mixture of 80 (2.81 g, 0.01 mol), butyl vinyl ether (1.5 g, 0.015 mol), PdCl2 (26 mg, 0.14 mmol), (o-tolyl)3P (88 mg, 0.29 mmol), K3PO4 (1.5 g, 0.02 mol), and IPA (20 ml) was heated at reflux under nitrogen overnight. The mixture was cooled to RT and the solvent was removed in vacuo. To the residue was added 6M HCl (60 mL) and the resulting solution stirred for 15 min. The mixture was adjusted to pH 8 with aqueous NH4OH (35%) and was extracted with EtOAc (300 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (5 to 10% MeOH) to afford 1.2 g (86%) of 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)ethanone (82) as yellow oil: MS (ESI) m/z=245.3 (M+1).
Reaction SMILES: [Cu]([C:4]#[N:5])C#N.[Cl:6][C:7]1[C:8](I)=[N:9][CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1>C(#N)C>[Cl:6][C:7]1[C:8]([C:4]#[N:5])=[N:9][CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1
Reactant: O=[N+]([O-])c1cnc(I)c(Cl)c1
Reactant: N#C[Cu]C#N
Solvent: CC#N
Product: N#Cc1ncc([N+](=O)[O-])cc1Cl
Temperature: 80 °C
Reaction time: 5 h
Yield: 94.3 %

Procedure:
A suspension of copper cyanide (7 g) and 3-chloro-2-iodo-5-nitro-pyridine (7 g) in acetonitrile (200 mL) was heated to 80° C. within 1 hour and stirred at 80° C. for 5 hours. The solvent was evaporated and the residue was filtered in ethyl acetate over silicon dioxide gave 3-chloro-2-cyano-5-nitro-pyridine (4.26 g).
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:8][CH2:9][C:10](=O)[CH2:11]Cl.[OH-].[Na+]>>[C:2]([C:1]1[O:6][CH:11]=[C:10]([CH2:9][Cl:8])[N:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(CCl)CCl
Reactant: CC(C)(C)C(N)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1nc(CCl)co1
Temperature: 135 °C
Yield: 51.2 %

Procedure:
25 g of pivalic acid amide and 25 g of 1,3-dichloro-2-propanone were mixed and heated on an oil bath at 135° C. for 2.5 hours. After having been cooled with ice, the mixture was made alkaline with an aqueous solution of sodium hydroxide added thereto. Then, the resulting product was extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was purified through column chromatography (silica gel; ethyl acetate n-hexane=1:8) to obtain 17.5 g of 2-tert-butyl-4-chloromethyloxazole.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([NH:24][NH2:25])[CH2:20][CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S.CC1N(C2CCNCC2)[C:31](=[O:39])[NH:30][C:29]=1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1>[C:40]1([C:29]2[NH:30][C:31](=[O:39])[N:24]([CH:21]3[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:14][CH:12]4[C:13]5[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=5[C:6]5[C:11]4=[CH:10][CH:9]=[CH:8][CH:7]=5)=[O:17])[CH2:19][CH2:20]3)[N:25]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NNC1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reactant: Cc1c(-c2ccccc2)[nH]c(=O)n1C1CCNCC1
Agent: S
Solvent: C1CCOC1
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC(n2nc(-c3ccccc3)[nH]c2=O)CC1

Procedure:
The solutions of 5.56 g (0.0165 mol) of [1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]-hydrazine in 60 ml of tetrahydrofuran and 3.7 g (0.0177 mol) of N-(ethoxycarbonyl)-benzothionamide in 30 ml of tetrahydrofuran were combined and refluxed for 1 hour, whereupon hydrogen sulphide was released. The solvent was distilled off in vacuo, the oily residue remaining was boiled with a little acetonitrile. The mixture was allowed to cool, then additionally cooled from outside with ice water and the resulting precipitate was suction filtered. 4.0 g (52% of theory) of colourless crystals were obtained, melting point 142° C. and Rf=0.38 (eluant 4).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.[Li]CCCC.N#N.CCOCC.[C:22]([O:26][C:27](=[O:34])[NH:28][C@H:29]([CH:32]=[O:33])[CH2:30][CH3:31])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27](=[O:34])[NH:28][C@H:29]([CH:32]([OH:33])[C:2]1[O:1][C:9]2[C:4]([N:3]=1)=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:30][CH3:31])([CH3:23])([CH3:24])[CH3:25]
Reactant: c1cnc2ncoc2c1
Reactant: CC[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1nc2ncccc2o1
Temperature: -45 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
Alternative procedure: To a stirred solution of the oxazolo[4,5-b]pyridine (12 g, 100 mmol) in THF (300 ml) was added n-BuLi (1.6M solution in 62.5 ml of hexane) drop wise under N2 at −78° C. After 1 hour, MgBr.Et2O (25.8 g, 100 mmol) was added and the reaction mixture was allowed to warm to −45° C. for 1 hour before being treated with (S)-(1-formyl-propyl)-carbamic acid tert-butyl ester (11.46 g, 60 mmol) in THF (50 ml). The reaction mixture was stirred for 1 hour, quenched with saturated NH4Cl, and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4 and concentrated. The residue was purified by silica gel column chromatography to yield (S)-[1-(hydroxy-oxazolo[4,5-b]pyridin-2-yl-methyl)-propyl]-carbamic acid tert-butyl ester (14.1 g).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[C:12]([Cl:35])=[C:13]([NH:19][C:20]4[N:25]=[C:24]([NH:26][CH:27]5[CH2:29][CH2:28]5)[C:23]5=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:22]5[N:21]=4)[CH:14]=[C:15]([C:17]#[N:18])[CH:16]=3)[CH2:7][CH2:6]2)[CH2:2]1.C(N([CH2:41][CH3:42])CC)C.ClC(OC)=[O:45]>C(Cl)Cl>[C:41]([N:1]1[CH2:2][CH:3]([N:5]2[CH2:6][CH2:7][CH:8]([C:11]3[C:12]([Cl:35])=[C:13]([NH:19][C:20]4[N:25]=[C:24]([NH:26][CH:27]5[CH2:28][CH2:29]5)[C:23]5=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:22]5[N:21]=4)[CH:14]=[C:15]([C:17]#[N:18])[CH:16]=3)[CH2:9][CH2:10]2)[CH2:4]1)(=[O:45])[CH3:42]
Reactant: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(C2CCN(C3CNC3)CC2)c1
Reactant: CCN(CC)CC
Reactant: COC(=O)Cl
Solvent: ClCCl
Product: CC(=O)N1CC(N2CCC(c3cc(C#N)cc(Nc4nc(NC5CC5)c5ncc(C#N)n5n4)c3Cl)CC2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-((3-(1-(azetidin-3-yl)piperidin-4-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 318) (25 mg, 0.051 mmol) and triethylamine (0.014 mL, 0.102 mmol) in CH2Cl2 (1.5 mL) was added dropwise acetyl chloride (4.41 mg, 0.056 mmol, diluted with DCM, 10V % in DCM, 44 uL) at 0° C. The suspension converted to a clear solution in a few min, and continued stirring at 0° C. for 1 h. Removal of the solvent, and the crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 20-60% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation left the titled product (15.6 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@H:13]3[CH2:18][C@@H:17]([CH3:19])[C@@H:16]([NH2:20])[CH2:15][C@H:14]3[CH3:21])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C2C(C(NC3CCC(N)CC3)=CC=N2)=CC=1.[F:41][C:42]1[CH:43]=[C:44]([CH:48]=[C:49]([F:51])[CH:50]=1)[C:45](O)=[O:46].N1C2C(=CC=C(C(O)=O)C=2)C=C1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@@H:13]3[C@H:14]([CH3:21])[CH2:15][C@H:16]([NH:20][C:45](=[O:46])[C:44]4[CH:43]=[C:42]([F:41])[CH:50]=[C:49]([F:51])[CH:48]=4)[C@H:17]([CH3:19])[CH2:18]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H]1C[C@H](N)[C@H](C)C[C@@H]1Nc1ccnc2cc(Cl)ccc12
Reactant: O=C(O)c1cc(F)cc(F)c1
Agent: NC1CCC(Nc2ccnc3cc(Cl)ccc23)CC1
Agent: O=C(O)c1ccc2cc[nH]c2c1
Product: C[C@@H]1C[C@H](Nc2ccnc3cc(Cl)ccc23)[C@H](C)C[C@@H]1NC(=O)c1cc(F)cc(F)c1

Procedure:
The titled compound was prepared according to the method described in Example 23 substituting (1S,2R,4S,5R)-N-(7-chloroquinolin-4-yl)-2,5-dimethylcyclohexane-1,4-diamine for N-(7-chloroquinolin-4-yl)cyclohexane-1,4-diamine and 3,5-difluorobenzoic acid for indole-6-carboxylic acid. 1H NMR (300 MHz, DMSO) δ ppm 8.87 (d, 1 H), 8.55 (t, 1 H), 8.07 (d, 1 H), 7.93 (d, 1 H), 7.83 (dd, 1 H), 7.42-7.64 (m, 4 H), 7.00 (d, 1 H), 4.00-4.20 (m, 2 H), 1.63-2.34 (m, 6 H), 1.03 (d, 3 H), 1.00 (d, 3 H). MS(ESI(+)Q1MS m/z 444 (M+H)+).
Reaction SMILES: CC(C)([O-])C.[Na+].[CH2:7]([O:9][C:10](=[O:21])[CH:11]([NH:17][C:18](=[O:20])[CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:8].CN(C=O)C.Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[S:36][C:37]3[C:42]([N:43]=2)=[CH:41][CH:40]=[C:39]([C:44]2([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH2:46][CH2:45]2)[N:38]=3)=[C:31]([F:53])[CH:30]=1>C1COCC1.CCOC(C)=O>[C:18]([NH:17][C:11]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[S:36][C:37]3[C:42]([N:43]=2)=[CH:41][CH:40]=[C:39]([C:44]2([C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)[CH2:45][CH2:46]2)[N:38]=3)=[C:31]([F:53])[CH:30]=1)([C:10]([O:9][CH2:7][CH3:8])=[O:21])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:20])[CH3:19]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: Fc1cc(CBr)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)(NC(C)=O)C(=O)OCC
Temperature: 80 °C

Procedure:
In a sealable bottle, sodium tert-butoxide (0.120 g, 1.25 mmol) was added to a mixture of acetamidomalonic acid diethyl ester (0.272 g, 1.25 mmol) in THF (10.00 ml)/DMF (2.00 ml). The reaction was heated to 80° C. for 20 min., cooled to ambient temperature, and a solution of 2-(4-(bromomethyl)-2-fluorophenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (0.500 g, 1.14 mmol) in THF 4 ml was added slowly dropwise. The resulting mixture was heated to reflux (90 deg. C.) for 1.5 h, and the color changed from orange to yellow. The reaction was cooled, poured over ice water, and treated with EtOAc. The organic layer was washed with water, NaCl, dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography, 40 g column, 10-30% EtOAc/hexanes, followed by 30-50% (3% Et3N in EtOAc)/hexanes provided diethyl 2-acetamido-2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)malonate. MS (ESI) m/z: calculated: 575.2; Observed: 576.1 (M++1).