Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:45](Cl)(=[O:48])[CH2:46][CH3:47].O>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:45](=[O:48])[CH2:46][CH3:47])[CH2:32][CH2:31]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CCC(=O)Cl
Reactant: Nc1ncnn2c(CCCN3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)N1CCN(CCCc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 50 °C
Yield: 42.5 %

Procedure:
5-(2-benzyl-2H-indazol-6-yl)-7-(3-piperazin-1-yl-propyl)pyrrolo-[2,1-f][1,2,4]triazin-4-ylamine (75 mg, 0.16 mmol) was dissolved in anhydrous DMF (3.2 mL) and treated with EtN(iPr)2 (44 μL, 0.32 mmol) followed by the addition of propionyl chloride (22 μL, 0.24 mmol). The mixture was heated to 50° C. for 18 h, cooled to rt and poured into water. The aqueous layer was extracted with 3×10 mL of EtOAc and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified via preparative HPLC. The product containing fractions were collected, and the TFA from the eluent was removed via filtration through an acidic resin followed by washing with acetonitrile. The product was then eluted with 2M NH3 in MeOH. The filtrate was concentrated and the residue was crystallized from DCM-ether to provide the title compound (35.5 mg, 42%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.88 (s, 1H), 7.79 (d, 1H), 7.57 (s, 1H), 7.36 to 7.28 (m, 5H), 7.13 (dd, 1H), 6.60 (s, 1H), 5.63 (s, 2H), 3.41-3.31 (m, 4H), 2.89 (t, 2H), 2.38 to 2.24 (m, 8H), 1.90 to 1.84 (m, 2H), 0.93 (t, 3H); ES-MS m/z 523.3 [M+H]+, RT (min) 2.15.
Reaction SMILES: [NH2:1][CH:2]([C:12]1[N:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[O:19])[C:15]([OH:29])=[C:14]([OH:30])[N:13]=1)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[Cl:38][CH2:39][CH:40]=O.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[CH2:5]([O:4][CH2:3][CH:2]([C:12]1[N:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[O:19])[C:15]([OH:29])=[C:14]([OH:30])[N:13]=1)[NH:1][CH2:40][CH2:39][Cl:38])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(COCc1ccccc1)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1
Reactant: O=CCCl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)c1nc(C(COCc2ccccc2)NCCCl)nc(O)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of compound of Step 3 in dry trimethylortoformiate, triethylamine (1.3 eq.) and 1.1 eq. of α-chloroacetaldehyde (1.1 eq.) were added. The resulting solution was aged for 2 hours at room temperature, the solvent was removed by rotary evaporation to afford a residue that was dissolved in MeOH, treated with acetic acid (pH=5) and NaBH3CN (1.1 eq.). The mixture was stirred overnight at room temperature then the solvent was removed by rotary evaporation and the resulting residue was taken in dry toluene and concentrated. This material was used without any purification for the next step. MS (ES) C23H24ClFN4O4 requires 474. Found: 475.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]([F:20])=[N:11][C:12]2[C:17]([C:18]=1F)=[CH:16][N:15]=[CH:14][CH:13]=2.[CH:21]([NH2:25])([CH2:23][CH3:24])[CH3:22]>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)C>[CH:21]([NH:25][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[N:15][CH:16]=2)[N:11]=[C:10]([F:20])[C:9]=1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])([CH2:23][CH3:24])[CH3:22]
Reactant: CCC(C)N
Reactant: Fc1cccc(Cl)c1-c1c(F)nc2ccncc2c1F
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCC(C)Nc1c(-c2c(F)cccc2Cl)c(F)nc2ccncc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Step 1 (0.10 g) was dissolved in DMF (2 ml). Sec-butylamine (0.1 ml) and DMAP (0.001 g) were added and the mixture was stirred in a sealed tube at ambient temperature for 18 hours. The brown reaction mixture was diluted with diethyl ether, washed with brine and dried over sodium sulphate. After evaporation of the solvent the resulting yellow gum was purified by flash column chromatography on silica gel (40-60) in ethyl acetate:hexane 1:3 to give N-sec-butyl-3-(2-chloro-6-fluorophenyl)-2-fluoro-1,6-naphthyridin-4-amine as a dark yellow solid (0.06 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[C:12](N1C=CN=C1)([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[S:13]>C(#N)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:9][C:12]([N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)=[S:13])[S:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2nc(N)sc2c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cc1ccc2nc(NC(=S)n3ccnc3)sc2c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
To 6-methylbenzo[d]thiazol-2-amine (1. g, 6.2 mmol) in acetonitrile (30 mL) was added 1,1′-thiocarbonyldiimidazole (1.44 g, 8.1 mmol). The reaction was stirred at 50° C. for 18 hours. The reaction was cooled to room temperature and the precipitate was filtered and washed with acetonitrile (2×50 mL). The yellow powder was dried in a vacuum oven (40° C.) for 1 hour to yield N-(6-methylbenzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide (1.06 g, 3.86 mmol, 62% yield) and then used in the next step without any further purification or characterization.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:14][C:15](=[O:22])[C:16]4[N:17]([CH:19]=[CH:20][CH:21]=4)[CH:18]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:25]([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>C(#N)C.O>[CH3:25][N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[NH:14][C:15](=[O:22])[C:16]4[N:17]([CH:19]=[CH:20][CH:21]=4)[CH:18]=3)=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: [BH3-]C#N
Reactant: O=c1[nH]c(-c2ccc(C3CCNCC3)cc2)cn2cccc12
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CN1CCC(c2ccc(-c3cn4cccc4c(=O)[nH]3)cc2)CC1
Reaction time: 0.08 h

Procedure:
3-(4-Piperidin-4-yl-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one (50.0 mg; 0.17 mmol) is dissolved in acetonitrile (1.5 mL), 35% aqueous formaldehyde solution (67.0 μl; 0.84 mmol) is added and the reaction mixture is stirred for 5 min. Sodium cyanoborohydride (21.2 mg; 0.34 mmol) is added in small portions and the reaction stirred for 2 h. The reaction mixture is diluted with water, treated with saturated NaHCO3 solution and extracted with ethylacetate (three times). The combined organic layers are washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude product is purified by preparative HPLC. The combined fractions are concentrated in vacuo, the aqueous residue is made basic with saturated NaHCO3 solution, treated with NaCl (solid) and extracted with ethylacetate (four times). The combined organic layers are washed with brine, dried over Na2SO4, filtered off by suction and evaporated to dryness to afford 3-[4-(1-methyl-piperidin-4-yl)-phenyl]-2H-pyrrolo[1,2-a]pyrazin-1-one as beige solid; HPLC/MS 1.28 min (A), [M+H] 308;
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH:55]([C:58]1[CH:63]=[CH:62][CH:61]=[C:60]([CH:64]([CH3:66])[CH3:65])[C:59]=1[NH2:67])([CH3:57])[CH3:56].S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Br:1][C:62]1[CH:63]=[C:58]([CH:55]([CH3:57])[CH3:56])[C:59]([NH2:67])=[C:60]([CH:64]([CH3:66])[CH3:65])[CH:61]=1
Reactant: [Br-]
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc(Br)cc(C(C)C)c1N
Reaction time: 2 h
Yield: 94.6 %

Procedure:
40.8 g (85 mmol) of tetra-n-butylammonium tribromide are added, at 0° C. and portionwise, to a solution of 15 g (85 mmol) of 2,6-diisopropylphenyl-amine in 200 ml of tetrahydrofuran. The medium is stirred for 2 h. It is then poured into a saturated aqueous solution of sodium thiosulphate and extracted with ethyl acetate. The organic phases are combined and washed with water. They are dried over sodium sulphate. The residue is purified by silica gel chromatography (80/20 heptane/ethyl acetate). 20.6 g of 4-bromo-2,6-diisopropylphenylamine are obtained in the form of a yellow oil (yield=95%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=O)(C)(C)C.[Br:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[OH:22].CCOC(/N=N/C(OCC)=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.FC(F)(F)C(O)=O>>[Br:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[OH:22].[Br:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[O:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Oc1cnccc1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccncc1OC[C@@H]1CCCN1

Procedure:
(S)-1-t-Butoxycarbonyl-2-pyrrolidinemethanol (792 mg, 3.94 mmol), 4-bromo-3-pyridinol (685 mg, 3.94 mmol), DEAD (485 uL, 4.33 mmol) and PPh3 (1.14 g, 4.33 mmol) were allowed to react as described in Example 2a The crude product was directly treated with trifluoroacetic acid (5 mL) at room temperature for 3 hours. The trifluoroacetic acid was removed under reduced pressure, and water (8 mL) was added. The mixture was extracted with EtOAc (2×20 mL), and the resultant aqueous layer was basified with excess solid sodium bicarbonate. The resultant slurry was washed extensively with EtOAc (4×10 mL). The combined organic layers were dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography on silica gel eluting with CHCl3 /MeOH/NH4OH (10:1.5:0.02 and 10:1.5:0.1) to provide 371 mg (37% yield from 4bromo-3-pyridinol) of the title compound. TLC Rf 0.16 (10:1:0.02 CHCl3 /MeOH/NH4OH). MS (DCI/NH3) m/e 257 with 79Br and 259 (M+H)+with 81Br. 1H NMR (CDCl3, 300 MHz) 8: 8.25 (s, 1H, ArH), 8.08 (d, J=6.6 Hz, 1H, ArH), 7.48 (d, J=6.6 Hz, 1H, ArH), 4.28 (dd, J =4.8, 10.2 Hz, 1H, OCHH), 4.17 (dd, J=6.3, 10.2 Hz, 1H, OCHH), 3.90-3.80 (m, 1H, NCH), 3.30-3.14 (m, 2H, NCR2), 2.18-1.80 (m, 4H, 2CH2).
Reaction SMILES: C(OCC)(=O)C.C(=O)([O-])O.[K+].[CH:12]#[C:13][CH:14]([OH:17])[CH2:15][CH3:16].[Br:18][C:19](Br)=[N:20][OH:21]>O>[Br:18][C:19]1[CH:12]=[C:13]([CH:14]([OH:17])[CH2:15][CH3:16])[O:21][N:20]=1
Reactant: C#CC(O)CC
Reactant: ON=C(Br)Br
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(O)c1cc(Br)no1

Procedure:
Added to 800 ml of ethyl acetate were 8 ml of water, 60.0 g (0.6 mol) of potassium hydrogencarbonate and 73.5 g (0.88 mol) of 1-pentyn-3-ol. Under stirring, 40.5 g (0.2 mol) of dibromoformaldoxime were added at room temperature over 3 hours. After the resultant mixture was stirred at room temperature for 16 hours, water was added and the reaction product was extracted with ethyl acetate. Subsequent to concentration, 3-bromo-5-(1-hydroxypropyl)isoxazole was obtained as oil. It was distilled to collect a fraction at 97°-102° C./2 mmHg. 102° C/2 mmHg.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[CH:7]=[CH:8][C:9]=1[CH3:10].O>C(O)(=O)C>[Br:1][C:7]1[CH:8]=[C:9]([CH3:10])[C:4]([CH3:3])=[CH:5][C:6]=1[NH:11][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc(C)c(C)c1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(C)c(C)cc1Br
Reaction time: 0.25 h

Procedure:
Bromine (5.08 mL, 99.1 mmol) was added over 1 h to a stirred solution of N-(3,4-dimethylphenyl)acetamide 1-6 (13.5 g, 82.6 mmol) in acetic acid (200 mL) at approximately 15° C. After 15 minutes, water (400 mL) was added until no further precipitation was observed. The resultant solid was filtered, washed with water (until white) and dried in vacuo to afford 1-7 as a white crystalline solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][C@H:17]([S:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][C@H:15]1[C:39]([NH:41][NH2:42])=[O:40])(=[O:13])=[O:12].[CH:43](=O)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(O)C>[CH:43](=[N:42][NH:41][C:39]([C@@H:15]1[CH2:16][C@@H:17]([S:19][C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:18][N:14]1[S:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:13])=[O:12])=[O:40])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=Cc1ccccc1
Reactant: NNC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Solvent: CCO
Product: O=C(NN=Cc1ccccc1)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 80 °C
Yield: 79.9 %

Procedure:
(step 10) To a suspension of 3.0 g (5.05 mmol) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid hydrazide in ethanol were added 0.56 ml (5.6 mmol, 1.1 eq) benzaldehyde at RT, and the reaction mixture was heated to 80° C. for 3 h. The solvent was evaporated and the residue was purified by flash chromatography on silica gel with ethyl acetate:hexane 1:1 as eluent yielding 2.75 g (80%) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid benzylidene-hydrazide as white foam, MS: 682 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:24]=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=4)[CH:19]=[O:20])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:25]([Mg]Br)#[C:26][CH3:27]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:24]=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:19]([OH:20])[C:25]#[C:26][CH3:27])[CH:21]=[CH:22][CH:23]=4)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC#C[Mg]Br
Reactant: O=Cc1cccc(-c2ccn3nc(-c4ccc(F)cc4)cc3c2)c1
Solvent: C1CCOC1
Product: CC#CC(O)c1cccc(-c2ccn3nc(-c4ccc(F)cc4)cc3c2)c1
Yield: 67.9 %

Procedure:
The procedure described in stage 2.5 is followed, starting with 0.300 g (0.95 mmol) of 3-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]benzaldehyde obtained according to the process described in 2.4, in solution in 10 ml of tetrahydrofuran, followed by addition of 5.70 ml (2.85 mmol) of a (propyn-1-yl)magnesium bromide solution (0.5M in tetrahydrofuran) and after chromatography on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (8/2), 0.23 g (67%) of the expected product is obtained in the form of a pale yellow powder.
Reaction SMILES: [C@H:1]12[CH2:26][C@H:4]([N:5]([CH2:7][C:8]3[N:12]([C:13]4[CH:14]=[C:15]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=4)[C:16]([NH2:18])=O)[N:11]=[N:10][N:9]=3)[CH2:6]1)[CH2:3][O:2]2.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C@H:1]12[CH2:26][C@H:4]([N:5]([CH2:7][C:8]3[N:12]([C:13]4[CH:14]=[C:15]([CH:19]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:21]=4)[C:16]#[N:18])[N:11]=[N:10][N:9]=3)[CH2:6]1)[CH2:3][O:2]2
Reactant: NC(=O)c1cc(-n2nnnc2CN2C[C@@H]3C[C@H]2CO3)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: N#Cc1cc(-n2nnnc2CN2C[C@@H]3C[C@H]2CO3)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
To a solution of 3-{5-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl]-1H-tetrazol-1-yl}-5-(trifluoromethyl)benzamide (Intermediate 32, 100 mg, 0.272 mmol) and triethylamine (0.076 ml, 0.543 mmol) in dichloromethane (5 ml) was added trifluoroacetic anhydride (0.038 ml, 0.272 mmol). The reaction was stirred at room temperature for 4 hours before the addition of trifluoroacetic anhydride (0.038 ml, 0.272 mmol). The reaction was stirred at room temperature for a further three hours. The reaction was partitioned between DCM (5 mL) and water (5 mL). The organic layer was collected via a hydrophobic frit and the solvent removed. The residue was purified by silica chromatography (Biotage SP4, eluting a gradient from 20-80% EtOAc in iso-hexane). The compound was further purified by high pH MDAP to yield the title compound as a white solid (36 mg)
Reaction SMILES: [ClH:1].[C:2]([CH:5](O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)([OH:4])=[O:3].S(Cl)([Cl:20])=O>>[ClH:20].[C:2]([CH:5]([Cl:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)([OH:4])=[O:3]
Reactant: O=C(O)C(O)CCCCCCn1ccnc1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: O=C(O)C(Cl)CCCCCCn1ccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 140 mg of 1-(7-carboxy-7-hydroxyheptyl)imidazole hydrochloride (prepared in Example 6(a)) was added dropwise 0.193 ml of thionyl chloride at from 0° C. to 3° C., and the mixture was stirred at room temperature overnight, and concentrated under reduced pressure. Ice was added to the obtained residue, and the mixture was stirred for 5 minutes, and concentrated under reduced pressure. A small amount of water was added to the residue, and insoluble materials were removed off, and the solution thus obtained was concentrated under reduced pressure to give 149 mg of the title compound having the following physical characteristics:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1.C1CCN2C(=NCCC2)CC1>CC#N>[O:16]1[CH2:17][CH2:18][CH:13]([O:12][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([NH:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]2)[N:11]=[CH:10]3)[CH2:14][CH2:15]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Clc1ncc2cccc(OC3CCOCC3)c2n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O[C@H]1CC[C@H](Nc2ncc3cccc(OC4CCOCC4)c3n2)CC1

Procedure:
2-chloro-8-(tetrahydro-2H-pyran-4-yloxy)quinazoline (1 g, 3.8 mmol), trans-4-amino-cyclohexanol (0.524 g, 4.56 mmol) and DBU (0.69 g, 4.56 mmol) were suspended in MeCN (10 mL). The mixture was heated at reflux for 10 h. TLC showed the reaction was complete. The mixture was concentrated in vacuo, the residue was purified by HPLC to yield the title compound (0.373 g, 28%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 10.817 (d, 1H), 9.120 (s, 1H), 7.351 (m, 2H), 7.210 (m, 1H), 4.630 (m, 1H), 4.118 (m, 1H), 4.041 (m, 2H), 3.712 (m, 1H), 3.524 (m, 2H), 2.001 (m, 8H), 1.620 (q, 2H), 1.419 (q, 2H)
Reaction SMILES: C(O[C@H](C)[C@H](NC(C1(CC2C=CC=CC=2)CCCN1)=O)C(OC)=O)(=O)C.C([O-])([O-])=O.[Na+].[Na+].[CH2:33]([O:40][C:41]([N:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[C:48]([OH:50])=O)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O=S(Cl)[Cl:53]>C(Cl)Cl.O>[Cl:53][C:48]([C@@H:44]1[CH2:45][CH2:46][CH2:47][N:43]1[C:41]([O:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:42])=[O:50]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: COC(=O)[C@@H](NC(=O)C1(Cc2ccccc2)CCCN1)[C@@H](C)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(Cl)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
To a stirred solution of compound 6 (1 g, 2.76 mmol) and Na2CO3 (732 mg, 6.90 mmol) in CH2Cl2:H2O (20 mL, 1:1) was added a solution of acid chloride [To a solution of (S)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (825 mg, 3.31 mmol) in CH2Cl2 (20 mL) was added SOCl2 (0.60 mL) drop wise at 0° C. and was refluxed for 2 h. The volatiles were removed under reduced pressure to yield (S)-benzyl 2-(chlorocarbonyl)pyrrolidine-1-carboxylate] in CH2Cl2 and the reaction mixture was stirred at RT for 2 h. The volatiles were evaporated under reduced pressure. The residue was diluted with CH2Cl2 (100 mL), filtered and the filtrate was concentrated under vacuum. The crude residue was purified by column chromatography using 60% EtOAc/Hexane as eluent to afford compound 7 (750 mg, 45%).
Reaction SMILES: O1CCCC1.[CH3:6][NH:7][CH3:8].Cl.Cl[C:11]([N:13]1[C:19]2[S:20][C:21]([CH2:23][CH3:24])=[CH:22][C:18]=2[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:16][CH2:15][CH2:14]1)=[O:12]>O>[CH2:23]([C:21]1[S:20][C:19]2[N:13]([C:11](=[O:12])[N:7]([CH3:8])[CH3:6])[CH2:14][CH2:15][N:16]=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:18]=2[CH:22]=1)[CH3:24]
Reactant: CNC
Reactant: CCc1cc2c(s1)N(C(=O)Cl)CCN=C2c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc2c(s1)N(C(=O)N(C)C)CCN=C2c1ccccc1

Procedure:
To 50 ml of 25%(W/V) tetrahydrofuran solution of dimethylamine is added 7.1 g of 1-chlorocarbonyl-7-ethyl-5-phenyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine hydrochloride by portions with cooling and stirring, and stirred at room temperature for 2 hours. The reaction mixtureis transferred to water and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue is treated with ethanolic hydrogen chloride to give 7-ethyl-1-dimethylcarbamoyl-5-phenyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine hydrochloric as yellow crystals, melting at 237°-238° C with decomposition.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=2)[C:5]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[N:9]=[C:8]([CH2:16][CH3:17])[C:6]=2[N:7]=1.[NH:26]1[CH2:34][CH2:33][CH:29]([C:30]([OH:32])=[O:31])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>C(OCC)(=O)C.O>[CH2:14]([O:13][CH2:12][CH2:11][N:10]1[C:5]2[C:4]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=3)=[N:3][C:2]([N:26]3[CH2:34][CH2:33][CH:29]([C:30]([OH:32])=[O:31])[CH2:28][CH2:27]3)=[N:7][C:6]=2[C:8]([CH2:16][CH3:17])=[N:9]1)[CH3:15]
Reactant: CCOCCn1nc(CC)c2nc(Cl)nc(Nc3cc(C)ccn3)c21
Reactant: O=C(O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOCCn1nc(CC)c2nc(N3CCC(C(=O)O)CC3)nc(Nc3cc(C)ccn3)c21
Temperature: 125 °C
Reaction time: 20 h
Yield: 7.3 %

Procedure:
A mixture of N-[5-chloro-1-(2-ethoxyethyl)-3-ethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-methylpyridin-2-ylamine from step 5 (5.42 g, 166 mmol), isonipecotic acid (85.9 g, 665 mmol), cesium carbonate (162 g, 498 mmol), and DMSO (55 mL) was heated, with stirring, at 125° C. After 20 h, the mixture was cooled to 20° C. and water (165 mL) was added. The mixture was stirred for 15 min and was then treated with ethyl acetate (55 mL). The layers were separated and the aqueous was treated with another portion of ethyl acetate (55 mL). The layers were separated again and the aqueous layer was taken to pH ˜5 using 6 M HCl. After stirring for 1 hour, the resulting solid was filtered, washed with water (20 mL) and dried in vacuuo, to give 5.5 g of the title compound. 1H NMR (400 MHz, DMSO-d6): 1.10 (t, 3 H), 1.30 (t, 3 H), 1.49-1.60 (m, 2 H), 1.84-1.95 (m, 2 H), 2.32-2.36 (m, 3 H), 2.52-2.57 (m, 1 H), 2.78 (q, 2 H), 2.99-3.08 (m, 2 H), 3.52 (q, 2 H), 3.78 (t, 2 H), 4.45-4.53 (m, 2 H), 4.56-4.64 (m, 2 H), 6.91 (d, 1 H), 8.05 (s, 1 H), 8.18 (d, 1 H), 9.63 (s, 1 H), 12.18 (s, 1 H). LCMS m/z 454.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:27]2[CH2:29][CH2:28]2)[C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:19]=[N:20][C:21]([O:24][CH2:25][CH3:26])=[CH:22][CH:23]=3)=[N:16][CH:17]=2)=[O:11])[CH2:5][CH2:4]1)#[N:2].[OH:30][NH:31][C:32](=N)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH:27]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:30][N:31]=[C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:2]=3)[CH2:8][CH2:7]2)[C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:19]=[N:20][C:21]([O:24][CH2:25][CH3:26])=[CH:22][CH:23]=3)=[N:16][CH:17]=2)=[O:11])[CH2:28][CH2:29]1
Reactant: CCOc1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(C#N)CC3)cn2)cn1
Reactant: N=C(NO)c1ccccc1
Product: CCOc1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(c4nc(-c5ccccc5)no4)CC3)cn2)cn1

Procedure:
The title compound is prepared from 2-(6-ethoxy-pyridin-3-yl)-pyrimidine-5-carboxylic acid (1-cyano-piperidin-4-yl)-cyclopropyl-amide and N-hydroxy-benzamidine following a procedure analogous to that described in Example 6. LC (method 3): tR=2.20 min; Mass spectrum (ESI+): m/z=512 [M+H]+.