Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[NH:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:40][C:41]([CH3:46])([CH3:45])[C:42](Cl)=[O:43]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[N:14]([C:42](=[O:43])[C:41]([CH3:46])([CH3:45])[CH3:40])[CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: c1ccc(COc2ccc3c(c2)CCNC3c2ccc(OCCN3CCCC3)cc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.5 %

Procedure:
A solution of 6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.015 g, 0.04 mmol) and Et3N (0.01 ml, 0.07 mmol) in anhydrous THF (0.35 ml) was added to a solution of trimethylacetyl chloride (0.04 mmol) in anhydrous THF (0.4 ml) at rt in a sealed reaction vessel. The resulting suspension was stirred at rt for 20 hr, then evaporated to dryness. The product was suspended in a mixture of H2O (0.4 ml) and saturated NaHCO3 solution (0.4 ml), then extracted with CH2Cl2 (3×0.75 ml). The combined extracts were evaporated to dryness to give the crude product. Purification by reverse-phase HPLC, eluting first with gradient. Purification by reverse-phase HPLC on a Primesphere (Phenomenex 2320 West 205th St. Torrance, Calif. 90501) C-18HC (50.0 mm×10.0 mm column with 5 m particle size) column, eluting with a linear gradient starting at time 0 min. of H2O:CH3CN:1% TFA/H2O (85:10:5), increasing to H2O:CH3CN:1% TFA/H2O (5:90:5) at 8 min., detected on a Micromass Platform 2 mass spectrometer (DAD 190-600 nM) gave material which, after evaporation to dryness, was purified by reverse-phase HPLC on a Primesphere C-18HC (3.0 mm×2.0 mm column with 5 m particle size) column, eluting with a linear gradient starting at time 0 min. of H2O:CH3CN:TFA (99.9:0:0.1), increasing to H2O:CH3CN:TFA (0:99.9:0.1) at 4 min., detected with a UV detector (300 nM +/−90 nM and 254 nM +/−25 nM), gave an eluent that was evaporated to dryness to give 0.012 g (56% yield) of the pure product. MS 513 m/e (M++1).
Reaction SMILES: [PH2:1](=[O:3])[O-:2].[NH4+].C[Si](C)(C)N[Si](C)(C)C.[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[CH2:14]([PH:1](=[O:2])[O:3][CH2:14][CH2:15][CH2:16][CH3:17])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[PH2][O-]
Reactant: ClCc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [NH4+]
Solvent: ClCCl
Product: CCCCO[PH](=O)Cc1ccccc1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A mixture of ammonium phosphinate (9.18 g) and hexamethyldisilazane (25 mL) was heated at 110° C. for 2 hours. The mixture was cooled in ice, dissolved in dry dichloromethane (120 mL), benzyl chloride (20 g; 14 mL) was added and the mixture allowed to warm to room temperature and stirred 18 hours. The solution was filtered, the solvent evaporated, the residue azeotroped with methanol (2×70 mL), dissolved in toluene (150 mL) containing n-butanol (30 mL) and the solution was boiled under reflux in a Dean and Stark water trap for 5 hours. The solvent was evaporated, the residue slurried with dichloromethane (120 mL), filtered and evaporated and the residue chromatographed on silica-gel in 1-2% methanol in dichloromethane to give the title compound as an oil.
Reaction SMILES: [CH:1]([CH:5]([CH2:9][C:10]([OH:12])=[O:11])[C:6]([OH:8])=[O:7])=[CH:2][CH2:3][CH3:4]>CO.[Pt]>[CH2:1]([CH:5]([CH2:9][C:10]([OH:12])=[O:11])[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCC=CC(CC(=O)O)C(=O)O
Agent: [Pt]
Solvent: CO
Product: CCCCC(CC(=O)O)C(=O)O

Procedure:
40 g. of the butenylsuccinic acid is hydrogenated in methanol over a platinum catalyst to yield n-butylsuccinic acid, m.p. 82°-83° C. Ring closure to n-butylsuccinic anhydride is achieved by mixing it with 100 g. of acetic anhydride and distilling acetic acid as it is formed. The resulting crude product is directly sulfonated by the procedure of (7) (b) using corresponding molar amounts of the n-butyl-succinic anhydride and SO3.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([N:9]1[CH:13]=[CH:12][CH:11]=[N:10]1)([CH3:8])([CH3:7])[CH3:6]>OS(O)(=O)=O>[C:5]([N:9]1[CH:13]=[C:12]([N+:1]([O-:4])=[O:2])[CH:11]=[N:10]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)n1cccn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)(C)n1cc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
HNO3 (11.7 g, 185 mmol) was added dropwise to a mixture of 1-tert-butyl-1H-pyrazole (23 g, 185 mmol) in cone. H2SO4 (30 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min and was poured onto crashed ice. The aqueous mixture was extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give 1-tert-butyl-4-nitro-1H-pyrazole (20 g, 64% yield). 1H NMR (400 MHz, DMSO-d6): δ8.85 (s, 1H), 8.23 (s, 1 H), 1.52 (s, 9 H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.Cl[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)[CH2:6][CH2:7]1
Reactant: Clc1ccc2ccccc2n1
Reactant: OCC1CCN(c2nccnc2C2CCNCC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: OCC1CCN(c2nccnc2C2CCN(c3ccc4ccccc4n3)CC2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of [1-(3-piperidin-4-yl-pyrazin-2-yl)-piperidin-4-yl]-methanol hydrochloride (156 mg, 0.5 mmol) and 2-chloro-quinoline (81.5 mg 0.5 mmol) in DMF (5 mL) was added Cs2CO3 (325 mg, 1 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (15 mL) and brine (15 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give {1-[3-(1-quinolin-2-yl-piperidin-4-yl)-pyrazin-2-yl]-piperidin-4-yl}-methanol (142 mg, 0.35 mmol, yield 70.47%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:12][Si:13]([CH3:40])([CH3:39])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2[N:23]=[CH:24][N:25]=[C:26]([C:27]3[CH:28]=[N:29][N:30]([C:32]4([CH2:36][C:37]#[N:38])[CH2:35][NH:34][CH2:33]4)[CH:31]=3)[C:21]=2[CH:20]=[CH:19]1.Cl[C:42]1[N:43]=[CH:44][C:45]([C:48]([NH:50][C@H:51]([CH3:56])[C:52]([F:55])([F:54])[F:53])=[O:49])=[N:46][CH:47]=1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[C:37]([CH2:36][C:32]1([N:30]2[CH:31]=[C:27]([C:26]3[C:21]4[CH:20]=[CH:19][N:18]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:39])([CH3:12])[CH3:40])[C:22]=4[N:23]=[CH:24][N:25]=3)[CH:28]=[N:29]2)[CH2:33][N:34]([C:42]2[N:43]=[CH:44][C:45]([C:48]([NH:50][C@H:51]([CH3:56])[C:52]([F:55])([F:54])[F:53])=[O:49])=[N:46][CH:47]=2)[CH2:35]1)#[N:38]
Reactant: C[C@@H](NC(=O)c1cnc(Cl)cn1)C(F)(F)F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1)C(F)(F)F
Temperature: 125 °C
Reaction time: 2 h

Procedure:
N,N-Diisopropylethylamine (0.11 mL, 0.62 mmol) was added to a mixture of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (110 mg, 0.22 mmol) and 5-chloro-N-[(1R)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide (52 mg, 0.21 mmol) in NMP (2.0 mL). The reaction mixture was stirred at 125° C. for 2 h. The reaction mixture was worked up with saturated aqueous NaHCO3, and extracted with dichloromethylene (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in dichloromethylene (0-70%) to afford the desired product. LCMS (M+H)+: m/z=627.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](C)[CH:10]=1)[C:5]([NH2:7])=[O:6].[CH3:12][O:13]C1C=C(C=C([N+]([O-])=O)C=1)C(O)=O.N>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][CH3:12])[CH:10]=1)[C:5]([NH2:7])=[O:6]
Reactant: Cc1cc(N)cc(C(N)=O)c1
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: N
Product: COc1cc(N)cc(C(N)=O)c1

Procedure:
Using a procedure analogous to that described for preparation of 89C, 93C was converted to an acid chloride, reacted with aqueous ammonia, and hydrogenated to give 93D. 1H NMR (400 MHz, CD3OD) δ ppm 3.76 (s, 3H) 6.45 (t, J=2.20 Hz, 1H) 6.71-6.74 (m, 1H) 6.77 (t, J=1.54 Hz, 1H); LC/MS 167 (M+H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[N:4]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]=[C:28]([C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33])[S:29][CH:30]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[N:27]=[C:28]([C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:14](=[O:16])[C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([C:5]4[N:4]=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=4)[N:13]=3)[S:29][CH:30]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(CN)c1nc(-c2ccc(Cl)cc2)cs1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)n1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)n1)c1nc(-c2ccc(Cl)cc2)cs1
Yield: 56 %

Procedure:
This compound was synthesized from 6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)picolinic acid and 2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropan-1-amine as described in example 8 step 6 (55 mg, yield 56%). 1H NMR (400 MHz, CDCl3) δ 8.87-8.85 (m, 1H), 8.43-8.41 (dd, J=7.8 Hz, 1 Hz, 1H), 8.27-8.24 (dd, J=7.8 Hz, 1.3 Hz, 1H), 8.10-8.06 (m, 1H), 7.89-7.87 (d, J=8.5 Hz, 2H), 7.41 (s, 1H), 7.32-7.29 (d, J=8.8 Hz, 2H), 3.91-3.89 (d, J=6.5 Hz, 2H), 1.56 (s, 6H). MS (ESI) m/z: Calculated for C22H17ClF3N6O2S: 507.07. found: 508.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[S:7](=[O:9])(=[O:8])[C@@H:6]2[CH2:10][C@H:11]([CH3:22])[O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C@@:5]2([CH3:23])[N:4]=[C:3]1[N:24]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].CO>[Pd].C(OCC)(=O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][C@@H:11]([CH3:22])[CH2:10][C@H:6]3[S:7](=[O:8])(=[O:9])[C:2]([CH3:39])([CH3:1])[C:3]([N:24]([C:25]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:31])[C:32](=[O:33])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[N:4][C@:5]3([CH3:23])[C:14]=2[CH:15]=1
Reactant: C[C@H]1C[C@@H]2[C@](C)(N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S2(=O)=O)c2cc([N+](=O)[O-])ccc2O1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H]1C[C@@H]2[C@](C)(N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S2(=O)=O)c2cc(N)ccc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Tert-butyl N-[(4aR,6S,11bR)-3,3,6,11b-tetramethyl-10-nitro-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (7.3 g, 12.86 mmol) and palladium on carbon (10%), wet (1 g, 0.470 mmol) were combined in ethyl acetate (60 ml) with 5 ml of MeOH under hydrogen atmosphere and stirred at room temp for 1 h. The solution was filtered thru celite, the Pd solids were washed with DCM and MeOH, then the organics were concentrated to afford tert-butyl N-[(4aR,6S,11bR)-10-amino-3,3,6,11b-tetramethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (6.5 g, 12.09 mmol, 94% yield) as a white solid. MS m/z=560 [M+Na].
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H-].[Na+].[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br.O>O1CCCC1>[CH3:1][N:2]([CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([Br:14])[CH:16]=1)[C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: BrCc1cccc(Br)c1
Reactant: CCCCCCCC(=O)NC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCC(=O)N(C)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
5 g (31.8 mmol) of N-methyloctanamide (1a) are added at 0° C. to a suspension of 1.4 g (35 mmol) of sodium hydride (60% in grease) in 60 mL of tetrahydrofuran. The reaction mixture is stirred for 30 minutes at room temperature and a solution of 8.9 g (35 mmol) of 3-bromobenzyl bromide in 15 mL of tetrahydrofuran is then added. The mixture is stirred for 16 hours at room temperature. The reaction is stopped by adding 100 mL of water and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (75/25 heptane/ethyl acetate). 7.4 g of N-methyl-N-(3-bromobenzyl)octanamide are obtained. Yield=71%.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CS(O[C:21]1[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][C:22]=1[C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)=O>N1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([O:13][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][C:22]=2[C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1
Reactant: CS(=O)(=O)Oc1ccc(C(=N)N)cc1C(=O)c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C=CC(=O)Oc2ccc(C(=N)N)cc2C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a mixture of 3.1 g of 4-acetyloxycinnamic acid and 50 ml of dried pyridine, while being cooled in ice, was added 3.7 g of DDC. To the mixture, after having been stirred for 30 minutes, was added 5.0 g of 4-amidino-2-benzoylphenol methanesulfonate. The mixture was stirred overnight at room temperature. The insolubles precipitated from the reaction mixture were collected by filtration and mixed with DMF. Ethyl ether was added to the supernatant to precipitate an insoluble substance which was recrystallized from ethanol, yielding 4.7 g of colorless crystals of 4-amidino-2-benzoylphenyl 4-acetyloxycinnamate methanesulfonate.
Reaction SMILES: [CH2:1]([C@H:8]1[NH:12][C:11](=[O:13])[C@@H:10]([CH2:14][CH2:15][C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CCOC(C)=O>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][N:12]1[C@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C@H:10]([CH2:14][CH2:15][C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)[C:11]1=[O:13])[CH3:43]
Reactant: CCOC(=O)CBr
Reactant: CC1(CC[C@H]2C[C@@H](Cc3ccccc3)NC2=O)OCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1C(=O)[C@@H](CCC2(C)OCCO2)C[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 12-3 (210 mg, 0.7257 mmol) and THF (5 mL) at −78° C. was added NaN(TMS)2 (0.943 mL, 0.943 mmol, 1.0 M in THF). After 30 min, ethyl bromoacetate (0.104 mL, 0.9434 mmol) was added and the reaction was warmed to 0° C. After 1.0 hour, the reaction mixture was diluted with EtOAc and then washed with sat NaHCO3, brine, dried (MgSO4), and concentrated to give 12-4 as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:32].[CH2:33]([N:35]([CH2:40][CH3:41])[CH2:36][CH2:37][CH2:38][NH2:39])[CH3:34]>ClCCl>[CH2:33]([N:35]([CH2:40][CH3:41])[CH2:36][CH2:37][CH2:38][NH:39][C:16]1[N:17]=[C:18]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:22]([OH:24])=[O:23])[C:13]2[CH:12]=[CH:11][C:10](=[O:32])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1)[CH3:34]
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CCN(CC)CCCN
Solvent: ClCCl
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (600 mg, 1.32 mmol) in dichloromethane (30 mL) was added N,N-diethyl-1,3-propanediamine (0.624 mL, 4.0 mol). The mixture was stirred at room temperature overnight. Solvent was removed by rotovap. Separation by HPLC with TFA afforded the title compound (695 mg, 85%). LC-MS m/z 522 (M+H)+.
Reaction SMILES: CC([CH:5]1[CH2:10][N:9]([CH2:11][CH:12]2[C:21]3[C:16](=[C:17]([C:22]#[N:23])[CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][O:13]2)[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[N:9]1([CH2:11][CH:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([C:22]#[N:23])[C:16]=3[CH2:15][CH2:14][O:13]2)[CH2:10][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)C1CN(CC2OCCc3c(C#N)cccc32)CCN1C(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1cccc2c1CCOC2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1,1-dimethylethyl4-[(5-cyano-3,4-dihydro-1H-isochromen-1-yl)methyl]piperazine-1-carboxylate (150 mg, 0.42 mmol) in 10 mL of DCM was added 5 mL of 4N HCl/dioxane, and the mixture was stirred at room temperature for 2 hours. The solvents was removed off under vacuum to afford 1-(piperazin-1-ylmethyl)-3,4-dihydro-1H-isochromene-5-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([OH:18])CCOC[CH2:13]3)[N:8]2[CH3:11])=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]2[CH3:25])[N:3]=1.O=C1C[N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([OH:18])[CH2:28][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:13]3)[N:8]2[CH3:11])=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]2[CH3:25])[N:3]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(O)CCOCC1)n2C
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(O)CN(C(=O)OC(C)(C)C)C1)n2C

Procedure:
This compound (c-1) was prepared in an analogous fashion to (S)-4-(2-chloro-9-methyl-6-(3-methylmorpholino)-9H-purin-8-yl)tetrahydro-2H-pyran-4-ol, using tert-butyl 3-oxoazetidine-1-carboxylate as the starting material. 1H NMR (CDCl3, 400 MHz) δ ppm 5.17 (broad d, 2H), 4.56 (dd, J=16.9, 9.48 Hz, 2H), 4.21 (dd, J=9.48. 2.56 Hz, 1H), 4.04 to 3.96 (m, 1H), 3.82 to 3.71 (m, 5H), 3.59 (td, J=11.6, 2.6 Hz, 1H), 3.47 (broad s, 1H), 2.02 (s, 1H), 1.43 (s, 9H), 1.40 to 1.36 (m, 4H); LC-MS (method A)=439/441 [M+H]+, RT=2.56 min.
Reaction SMILES: [C:1]1([CH:6]=[N:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([Li])[CH2:15][CH2:16][CH3:17].O>CCOCC>[CH2:14]([CH:6]([NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[C:1]1[S:5][CH:4]=[CH:3][CH:2]=1)[CH2:15][CH2:16][CH3:17]
Reactant: C(=Nc1ccncc1)c1cccs1
Reactant: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CCCCC(Nc1ccncc1)c1cccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 106.2 %

Procedure:
To a stirred, cooled (10°-20° C.) a solution of 3.77 grams of 4-(2-thenylideneamino)pyridine in 100 milliliters of dry ether, a solution containing 0.025 mole butyl lithium in 50 milliliters of dry ether was added dropwise. The resulting solution was stirred at room temperature for 4 hours, and then diluted with 150 ml dry ether before cautious addition of 50 ml. water. The organic phase was dried (MgSO4) and evaporated to dryness to give 5.24 grams of a brown oil. This brown oil was dissolved in toluene and extracted with 2 N hydrochloric acid. The extracts were basified with sodium hydroxide and extracted back into toluene. The resulting solution of the base in toluene was dried (MgSO4) and evaporated to dryness. The resulting oil was crystallised from petrol (100°-120° C.)/toluene affording 2.0 grams of a white solid. This material was dissolved in isopropanol and converted to the hydrochloride salt with ethereal hydrogen chloride and crystallised by addition of ether, yielding 1.153 grams of N-[α-butyl-2-thenyl]-4-pyridinamine hydrochloride of melting point 146.5°-148° C.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1>>[NH2:13][C:10]1[C:9]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:8][C:7]([Br:6])=[CH:12][N:11]=1
Reactant: O=S(=O)(O)Cl
Reactant: Nc1ccc(Br)cn1
Product: Nc1ncc(Br)cc1S(=O)(=O)Cl
Temperature: 25 °C
Yield: 77 %

Procedure:
To a cooled (0° C.) solution of chlorosulfonic acid (58 mL) under vigorous stirring was added 5-bromo-2-pyridinamine (86.7 mmol) portionwise. The reaction mixture was then heated at reflux for 3 hrs. Upon cooling to room temperature, the reaction mixture was poured over ice (˜100 g) with vigorous stirring. The resulting yellow precipitate was collected by suction filtration, washing with cold water and petroleum ether to provide the title compound as an orange-yellow solid (18.1 g, 77% yield). MS(ES)+ m/e 272.8 [M+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][C@@H:33]([C@H:45]([CH3:53])[CH2:46][CH:47]([CH3:52])[CH2:48][CH2:49][CH:50]=[CH2:51])[C:34]([N:36]1[CH2:40][C@H:39]([OH:41])[CH2:38][C@H:37]1[C:42](O)=[O:43])=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.[NH2:55][C@:56]1([C:61]([O:63][CH3:64])=[O:62])[CH2:58][C@H:57]1[CH:59]=[CH2:60].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:25]([O:29][C:30]([NH:32][C@@H:33]([C@H:45]([CH3:53])[CH2:46][CH:47]([CH3:52])[CH2:48][CH2:49][CH:50]=[CH2:51])[C:34]([N:36]1[CH2:40][C@H:39]([OH:41])[CH2:38][C@H:37]1[C:42]([NH:55][C@:56]1([C:61]([O:63][CH3:64])=[O:62])[CH2:58][C@H:57]1[CH:59]=[CH2:60])=[O:43])=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)OC)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
HATU (2.510 g, 6.60 mmol) was added to a solution of (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.269 g, 5.5 mmol), (1R,2S)-methyl 1-amino-2-vinylcyclopropanecarboxylate HCl (1.172 g, 6.60 mmol), and Hunig's Base (3.84 ml, 22.00 mmol) in DCM (20 ml) and was stirred at RT for overnight. The reaction was washed with 1N HCl (3×) and then brine and evaporated on rotovap, then purified via silica gel chromatography to get the product (1R,2S)-methyl 1-((2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate (2.68 g, 5.00 mmol, 91% yield) as a light orange foam. MS: MS m/z 558.16 (M++23).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:9]([C:10]([O-])=[O:11])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.O.[NH2:16][NH2:17]>C(O)C>[NH:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:9]([C:10]([NH:16][NH2:17])=[O:11])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1
Reactant: O=C([O-])c1ccc(-c2nnn[nH]2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(-c2nnn[nH]2)cc1
Temperature: 25 °C
Yield: 47.5 %

Procedure:
0.20 g (0.99 mmol) of the 4-(1H-tetrazol-5-yl)benzoate was heated with ethanol (3.2 ml) and 0.84 g (16.8 mmol) of hydrazine monohydrate under reflux for 8.5 hours, and then the reaction solution was cooled to room temperature, and the precipitated pale yellow solid was collected by filtration through a Kiriyama funnel, washed with methanol and dried under reduced pressure to obtain the desired product (0.096 g, yield 47%, purity 99%).