Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([CH:33]=2)[C:30](O)=[O:31])[N:21]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:30](=[O:31])[C:29]3[CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=[N:27][CH:28]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1csc(-c2ccc(Cl)cc2)n1
Product: CC(C)(CNC(=O)c1cncc(-c2noc(C(F)(F)F)n2)c1)c1csc(-c2ccc(Cl)cc2)n1
Yield: 51 %

Procedure:
This compound was synthesized from 2-(2-(4-chlorophenyl)thiazol-4-yl)-2-methylpropan-1-amine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (50 mg, yield 51%). 1H NMR (400 MHz, CDCl3) δ 9.46 (d, J=1.5 Hz, 1H), 9.24 (d, J=1.8 Hz, 1H), 8.79 (m, 1H), 8.22 (t, J=4.5 Hz, 1H), 7.85-7.83 (d, J=8.5 Hz, 2H), 7.38-7.36 (d, J=8.5 Hz, 2H), 7.09 (s, 1H), 3.72 (d, J=5.5 Hz, 2H), 1.50 (s, 6H). MS (ESI) m/z: Calculated for C22H17ClF3N5O2S: 507.07. found: 508.0 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.O>S(=O)(=O)(O)O>[N+:1]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:5])[CH:15]=[CH:14]2)([O-:4])=[O:2]
Reactant: Oc1ccc2ccccc2n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1ccc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
Nitric acid (70%), 2.3 mL, was added dropwise to a stirred mixture of 2-hydroxyquinoline (available commercially or by one of the methods described in Beilstein 21, 77), 3.5 g (0.024 mole), in 20 mL of concentrated sulfuric acid at 0° C. The reaction mixture was stirred for 2 hours at room temperature and then poured into ice and water. The resulting solid was collected by filtration, washed with cold water and then digested twice with hot methanol to yield 3 g (67%) of 6-nitrocarbostyril as crystals; m.p. 280°-282° C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH:9]1(B2OC(C)(C)C(C)(C)O2)[CH2:11][CH2:10]1.CC([O-])(C)C.[K+].O1CCOCC1>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.O>[CH:9]1([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH2:11][CH2:10]1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: Nc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cnc(C2CC2)cn1
Temperature: 150 °C

Procedure:
To a microwave vial was charged with 5-bromopyrazin-2-amine (400 mg. 2.3 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.16 g, 6.9 mmol), KOt-Bu (1M in t-BuOH, 9.2 mL), 1,4-dioxane (10 mL), and water (0.10 mL), and the mixture was purged with Argon, followed by addition of Palladium tetrakis (266 mg, 0.23 mmol) and final Argon purge, then the mixture was sealed and heated at 150° C. via microwave reactor for 20 min. To the reaction mixture was added 2nd portion of PalladiumTetrakis (266 mg) and the reaction was heated at 160° C. via microwave reactor for 20 min. The reaction mixture was filtered through a thin layer of Celite, and the filtrate was concentrated. The residue was triturated with EtOAc (6 mL), and the precipitates were removed via centrifugation and filtration. The EtOAc supernatant was back extracted with aqueous TFA solution (3×3 mL, TFA/water—1 mL/10 mL). The TFA solutions were combined, diluted with acetonitrile (10 mL), frozen and lyophilized to afford 5-cyclopropylpyrazin-2-amine in a yellow powder. The product after lyophilization was transferred to a vial, basified to pH>12 with sat. Na2CO3 (3 mL), extracted with EtOAc(4×6 mL), and the EtOAc extracts were combined, and concentrated and further dried under high vacuum, and final 5-cyclopropylpyrazin-2-amine free base was obtained (79 mg, 25.4% yield). LCMS (m/z): 136.1 (MH+), 0.30 min. 1H NMR (CD3OD) δ ppm 8.29 (d, J=1.2 Hz, 1H), 7.70 (d, J=1.6 Hz, 1H), 2.00-2.08 (m, 1H), 0.94-1.00 (m, 2H), 0.87-0.93 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:13])[C:8](=[CH:11][CH:12]=1)[CH:9]=O)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:27])([C:23]([F:26])([F:25])[F:24])[CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:2][C:1]([C:5]1[CH:12]=[CH:11][C:8]2[CH:9]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]([C:15]([F:14])([F:27])[C:23]([F:25])([F:24])[F:26])[O:13][C:7]=2[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CCOC(=O)C=CC(F)(F)C(F)(F)F
Reactant: CC(C)(C)c1ccc(C=O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2ccc(C(C)(C)C)cc2OC1C(F)(F)C(F)(F)F
Yield: 70 %

Procedure:
A mixture of 4-tert-butylsalicylaldehyde Example 8, step 1 (1.15 g, 6.4 mmol) and the ethyl ester from Step 2 (1.59 g, 7.3 mmol) was dissolved in anhydrous DMF (4 mL). With stirring, K2CO3 (1.10 g, 9.0 mmol) was added causing the reaction to become deep red. The reaction was stirred at room temperature for 100 hours, acidified with 3 N HCl, diluted with ethyl acetate and washed with saturated NaHCO3 solution, brine, dried over MgSO4, filtered and concentrated in vacuo yielding a brown oil. This oil was purified by flash chromatography over silica gel, eluting with 10% ethyl acetate/hexanes to afford a yellow oil (1.72 g, 70%): 1H NMR (CDCl3/300 MHz) 7.76 (s, 1H), 7.14 (d, 1H, J=8.1 Hz), 7.04 (dd, 1H, J=8.1 Hz 1.8 Hz), 6.94 (s, 1H), 5.92 (dd, 1H, J=22.4 Hz 3.0 Hz), 4.32 (m, 2H), 1.35 (t, 3H, J=7.2 Hz), 1.30 (s, 9H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]4[CH3:25])=[N:17][C:16]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]4[CH3:32])=[N:15][C:14]=3[N:33]=2)=[CH:6][C:5]=1OC.CC(N(C)C)=O.[CH2:43]([NH2:46])[CH2:44][NH2:45].CC(N(C)C)=O>C(N)CN>[CH3:32][C@H:27]1[CH2:28][O:29][CH2:30][CH2:31][N:26]1[C:16]1[N:17]=[C:18]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]2[CH3:25])[C:13]2[CH:12]=[CH:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]4[C:3](=[O:2])[NH:46][CH2:43][CH2:44][NH:45][C:5]=4[CH:6]=3)=[N:33][C:14]=2[N:15]=1
Reactant: COC(=O)c1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1OC
Reactant: NCCN
Solvent: CC(=O)N(C)C
Product: C[C@H]1COCCN1c1nc(N2CCOC[C@@H]2C)c2ccc(-c3ccc4c(c3)NCCNC4=O)nc2n1

Procedure:
A solution of 4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzoic acid methyl ester (1 equiv) in ethylenediamine (0.35 M) was stirred at room temperature for 24 hours. DMA was added to the solution (ethylenediamine/DMA 1:1.25). The reaction vessel was sealed and exposed to microwave radiation (180° C., medium absorption setting) for 1 hour. The reaction mixture was diluted with CH2Cl2 and extracted with water and washed with brine. The organic layer was dried with magnesium sulphate, filtered and concentrated in vacuo to yield a yellow solid which was then purified by preparative HPLC to give the desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccccn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccccn1

Procedure:
A stirred solution of methyl 2-pyridylacetate (10.0 g, 66.0 mmol), N-bromosuccinimide (13.0 g, 73.0 mmol) and 2,2′-azobisisobutyronitrile (0.50 g, 3.04 mmol) in carbon tetrachloride (120 mL) was irradiated with a sunlamp source for approximately 15 h. After filtration, the filtrate was concentrated in vacuo and the crude residue was purified by flash chromatography on silica gel (gradient elution; 5-10% EtOAc/hexane as eluent) to afford the title compound 5i.
Reaction SMILES: [OH-].[Na+].COCCO.[Br:8][C:9]1[C:10](/[C:23](/[CH3:36])=[CH:24]/[C:25]2[CH:35]=[CH:34][C:28]([C:29]([O:31]CC)=[O:30])=[CH:27][CH:26]=2)=[CH:11][C:12]2[C:13]([CH3:22])([CH3:21])[CH2:14][CH2:15][C:16]([CH3:20])([CH3:19])[C:17]=2[CH:18]=1>CCOCC>[Br:8][C:9]1[C:10](/[C:23](/[CH3:36])=[CH:24]/[C:25]2[CH:35]=[CH:34][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[CH:11][C:12]2[C:13]([CH3:22])([CH3:21])[CH2:14][CH2:15][C:16]([CH3:19])([CH3:20])[C:17]=2[CH:18]=1
Reactant: CCOC(=O)c1ccc(/C=C(\C)c2cc3c(cc2Br)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: CCOCC
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1cc2c(cc1Br)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of sodium hydroxide, 2-methoxyethanol and ether was added to 50 mg (0.11 mmol) of ethyl 4-[(E)-2-(3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)propen-1-yl]benzoate (Compound 14) and the resulting mixture stirred at room temperature for 17 hours. Solvent was removed in-vacuo and the resulting solid taken-up in water, acidified using 2N HCl, and extracted with ether. The ether extracts were washed with water, brine and dried (MgSO4). The solvent was removed in-vacuo to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)C#N.C[Mg]Br.CCCCCC.CC[O:21][CH2:22][CH3:23]>>[F:1][C:2]1[CH:3]=[C:4]([C:22](=[O:21])[CH3:23])[CH:7]=[CH:8][N:9]=1
Reactant: CCOCC
Reactant: N#Cc1ccnc(F)c1
Agent: C[Mg]Br
Solvent: CCCCCC
Product: CC(=O)c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-fluoroisonicotinonitrile (10 g, 82 mmol) in anhydrous Et2O (250 mL) cooled in an ice-water bath was slowly added 3M methyl magnesium bromide in hexane (40 mL, 120 mmol). The mixture was stirred at 25° C. overnight. The reaction was quenched slowly with 1N aq. citric acid solution at 0° C. until all solids dissolved. Brine was added and the two phases were separated. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give 1-(2-fluoropyridin-4-yl)-ethanone (6.2 g) as a brown oil. The aqueous phase was stirred at 25° C. for 3 h, then extracted with CH2Cl2. The dichloromethane layer was dried over Na2SO4, filtered, and concentrated in vacuo to give an additional 1.1 g of the product, for a total of 7.3 g, used in the next step without further purification. MS m/z 139. 1H NMR (CDCl3): δ 8.25 (dd, 1H), 7.47 (d, 1H), 7.21 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:21]I>N1C=CC=CC=1>[CH3:21][NH:1][C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CI
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(N)c1
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(NC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.01 moles of ethyl 3-amino-4-cyclohexylphenylglyoxylate in 100 ml. of pyridine is added 0.1 moles of methyl iodide. The reaction mixture is stirred overnight at room temperature, filtered and concentrated. The residue is distilled to obtain ethyl 3-methylamino-4-cyclohexylphenylglyoxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH:47]([C:49](=[O:72])[CH2:50][CH2:51][C@@H:52]([NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68])[CH2:53][C:54]1[CH:55]=[N:56][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:58][CH:59]=1)[NH2:48]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:5]([NH:48][NH:47][C:49](=[O:72])[CH2:50][CH2:51][C@@H:52]([NH:64][C:65](=[O:71])[O:66][C:67]([CH3:68])([CH3:69])[CH3:70])[CH2:53][C:54]2[CH:55]=[N:56][C:57]([C:60]([F:61])([F:62])[F:63])=[CH:58][CH:59]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(=O)NN)Cc1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
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: CC(C)(C)OC(=O)N[C@H](CCC(=O)NNC(=O)c1ccc([N+](=O)[O-])c(F)c1)Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 262.3 %

Procedure:
A mixture of 3-fluoro-4-nitrobenzoic acid (130 mg, 701 μmol) (commercially available from 3B Scientific Corporation Product List (Order Number 3B3-068221)), HATU (267 mg, 701 μmol), and N,N-diisopropylethylamine (132 μL, 760 μmol) in DMF (4 mL) was stirred at room temperature for 1 hour. This mixture was added dropwise to a mixture of tert-butyl ((1R)-4-hydrazino-4-oxo-1-((6-(trifluoromethyl)-3-pyridinyl)methyl)butyl)carbamate (220 mg, 585 μmol), prepared as shown in Scheme 24, and N,N-diisopropylethylamine (132 μL, 760 μmol) in DMF (3 mL) and the resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the remaining residue partitioned between saturated aqueous NaHCO3 (20 mL) and DCM (20 mL). The layers were separated and the aqueous layer was extracted with DCM (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting colorless solid was dissolved in MeOH/DCM, absorbed onto silica gel and purified by flash chromatography (silica gel, 2% to 8% MeOH/DCM) to provide tert-butyl ((1R)-4-(2-((3-fluoro-4-nitrophenyl)carbonyl)hydrazino)-4-oxo-1-((6-(trifluoromethyl)-3-pyridinyl)methyl)butyl)carbamate (834 mg, 77%) as a light yellow solid. LCMS (API-ES) m/z: 566.0 (M+Na+).
Reaction SMILES: OC1C=CC([C:8]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)([C:14](OCC)=O)[C:9]([O:11]CC)=[O:10])=CC=1.[OH-:29].[K+]>>[OH:29][C:20]1[CH:25]=[CH:24][C:23]([CH2:14][CH:8]([O:19][C:20]2[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=2)[C:9]([OH:11])=[O:10])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(Oc1ccc(C(C)C)cc1)(C(=O)OCC)c1ccc(O)cc1
Reactant: [OH-]
Agent: [K+]
Product: CC(C)c1ccc(OC(Cc2ccc(O)cc2)C(=O)O)cc1

Procedure:
In a similar manner to that described in Reference example 2(b), a reaction was carried out using diethyl 2-(4-hydroxyphenyl)-2-(4-isopropylphenoxy)malonate (25.2 g), which is the product of Reference example 5(c), and potassium hydroxide (20.0 g) and the reaction mixture was treated to afford, via crystals of 3-(4-hydroxyphenyl)-2-(4-isopropylphenoxy)propionic acid, the desired compound (19.8 g) as a syrup.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:46])[CH2:19][CH2:20][C:21]1[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[CH:25][CH:24]=[CH:23][C:22]=1[O:38][CH2:39][CH2:40][CH2:41][C:42]([O:44]C)=[O:43]>>[C:42]([CH2:41][CH2:40][CH2:39][O:38][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])[C:21]=1[CH2:20][CH2:19][C:18]([OH:46])=[O:17])([OH:44])=[O:43]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)CCCOc1cccc(CCCCCCOS(C)(=O)=O)c1CCC(=O)OC
Product: CCCc1c(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 184, 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one was converted into the title compound by alkylation with 2-(4-methoxy-4-oxobutoxy)-6-[6-(methylsulfonyl)oxyhexyl]benzenepropanoic acid methyl ester from the preceding example, followed by saponification, in 40% overall yield. The product was a colorless solid, mp 116°-117.5° C., recrystallized from acetonitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=1.[Li]CCCC.CN([CH:21]=[O:22])C.O>C1COCC1>[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[N:5]1[CH:6]=[C:2]([CH:21]=[O:22])[CH:3]=[N:4]1
Reactant: CN(C)C=O
Reactant: Brc1cnn(C2CCCCO2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cnn(C2CCCCO2)c1
Reaction time: 0.75 h
Yield: 61 %

Procedure:
4-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (61 g, 0.264 mol) was dissolved in THF (400 mL). Then 1.6 M n-BuLi (181 mL) was added to the solution which was at −95° C. The reaction mixture was stirred over a period of 45 minutes at the same temperature. Then DMF (22.4 mL, 0.29 mol) was added (the same temperature was maintained). The mixture was allowed to heat up to room temperature before addition of water (100 mL). The organic layer was separated, and the aqueous phase was extracted with ether (3×50 mL). The combined organic extracts were dried over Na2SO4, filtered and evaporated. The residue was purified by chromatography (EtOAc/hexane, 1:4) to afford 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde (29 g, 57%).
Reaction SMILES: [CH2:1]([N:5]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]I)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:5]([C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:13][NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:15])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CI)C(=O)O)cc1
Reactant: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CNc2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-iodoacetyl-L-lysine (200 mg, 0.38 mmol, product of step B above) by following the indications of general procedure H using DIEA (0.19 mL, 1.09 mmol) and aniline (0.16 mL, 1.76 mmol). The crude material was purified by preparative HPLC. The product was isolated as a solid (90 mg, 48% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[C:22]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)(=[O:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C(Cl)c1ccncc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3ccncc3)CC1)O2

Procedure:
Compound 57 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, isonicotinoyl chloride and conditions outlined in procedure AC. M.p.=267-269° C.; 400 MHz 1H NMR (CDCl3) δ: 8.74-8.70 (m, 2H), 8.06-8.10 (m, 1H), 7.73-7.76 (m, 1H), 7.66-7.70 (m, 1H), 7.49-7.55 (m, 1H), 7.30-7.33 (m, 2H), 4.65-4.71 (m, 1H), 3.62-3.69 (m, 1H), 3.45-3.56 (m, 1H), 3.34-3.45 (m, 1H), 2.96-3.04 (m, 2H), 2.26-2.32 (m, 1H), 2.12-2.18 (m, 1H), 1.85-1.97 (m, 1H), 1.68-1.78 (m, 1H); LCMS: 407 [M+H].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:32])=[C:21]([NH:25][S:26]([CH:29]3[CH2:31][CH2:30]3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH3:33].CO>C(Cl)Cl>[NH2:33][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:32])=[C:21]([NH:25][S:26]([CH:29]3[CH2:31][CH2:30]3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)C1CC1
Reactant: N
Solvent: CO
Solvent: ClCCl
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)C3CC3)c2F)n1
Temperature: 80 °C

Procedure:
A suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}cyclopropanesulfonamide (125 mg, 0.252 mmol) and 7M ammonia in MeOH (7 mL, 0.49 mmol) was heated in a sealed tube to 80° C. for 2 days. The reaction was diluted with DCM and added silica gel and concentrated. The crude product was chromatographed on silica gel eluting with 100% DCM to 1:1 [DCM:(9:1 EtOAc:MeOH)]. The clean fractions were concentrated to yield the crude product as a yellow solid (62 mg). The crude product was repurified by reverse phase HPLC (a gradient of acetonitrile:water with 0.1% TFA in both). The combined clean fractions were concentrated then partitioned between DCM and saturated NaHCO3. The DCM layer was separated and dried over Na2SO4. The title compound was obtained as a yellow solid (26 mg, 21% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.67 (s, 1H), 7.86 (d, J=5.4 Hz, 1H), 7.49 (td, J=7.4, 2.2 Hz, 1H), 7.11-7.38 (m, 2H), 6.53 (s, 2H), 5.84 (d, J=5.3 Hz, 1H), 3.68 (t, J=4.7 Hz, 4H), 3.43 (t, J=4.7 Hz, 4H), 2.53-2.68 (m, 1H), 0.74-0.92 (m, 4H). MS (ESI): 477.0 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][C:2]=1[NH:11][C@H:12]1[CH2:15][C@H:14]([NH:16][C:17]2[C:22]([NH2:23])=[CH:21][N:20]=[CH:19][N:18]=2)[CH2:13]1.C(N(CC)CC)C.[CH:31]1([C:34](Cl)=O)[CH2:33][CH2:32]1>O1CCCC1>[CH:31]1([C:34]2[N:16]([C@H:14]3[CH2:15][C@H:12]([NH:11][C:2]4[N:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)[CH2:13]3)[C:17]3[C:22]([N:23]=2)=[CH:21][N:20]=[CH:19][N:18]=3)[CH2:33][CH2:32]1
Reactant: Nc1cncnc1N[C@H]1C[C@H](Nc2ncc3ccccc3n2)C1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1ccc2nc(N[C@H]3C[C@H](n4c(C5CC5)nc5cncnc54)C3)ncc2c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
N4-(Trans-3-(quinazolin-2-ylamino)cyclobutyl)pyrimidine-4,5-diamine (0.045 g, 0.146 mmol) and triethylamine (0.50 ml, 3.59 mmol) were dissolved in dry tetrahydrofuran (10 mL) and treated with cyclopropanecarbonyl chloride (0.050 ml, 0.546 mmol). The reaction was stirred at room temperature for 14 hours. The mixture was evaporated to dryness under reduced pressure and the residue dissolved in acetic acid (20 mL). It was sealed in a microwave vessel and heated at 125° C. for 20 minutes then to 145° C. for 1 hour. The solution was evaporated to dryness under reduced pressure. Purification using silica chromatography (0-4% methanol in dichloromethane gradient) gave the desired N-(trans-3-(8-cyclopropyl-9H-purin-9-yl)cyclobutyl)quinazolin-2-amine (0.025 g, 0.070 mmol, 47.8% yield). M+1: 358.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.15-1.24 (m, 2 H) 1.24-1.33 (m, 2 H) 2.02-2.12 (m, 1 H) 2.69-2.80 (m, 2 H) 3.68-3.81 (m, 2 H) 4.89 (m, J=7.70, 7.70, 4.10 Hz, 1 H) 5.54 (quin, J=8.36 Hz, 1 H) 5.92 (br. s, 1 H) 7.23-7.35 (m, 1 H) 7.59-7.67 (m, 1 H) 7.67-7.76 (m, 2 H) 8.95 (s, 1 H) 8.91 (s, 1 H) 9.03 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH:22]=O>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22][N:13]1[CH2:14][CH2:15][C:16]2[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=3[O:9][C:10](=[O:17])[C:11]=2[CH2:12]1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Product: COc1ccc2c3c(c(=O)oc2c1)CN(Cc1ccc(Cl)c(Cl)c1)CC3
Yield: 65 %

Procedure:
Prepared by the procedure of Example 3 from 8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one and 3,4-dichlorobenzaldehyde. Yield 65%, mp 144°-146° C.