Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:30]=1)[C:25](O)=[O:26]>>[N:31]1([C:29]2[CH:28]=[C:24]([CH:23]=[C:22]([F:21])[CH:30]=2)[C:25]([NH:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)=[O:26])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)c1cc(F)cc(N2CCCCCC2)c1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cc(F)cc(N2CCCCCC2)c1

Procedure:
Compound is prepared from [4-(2-morpholin-4-ylethoxy)-1-naphthyl]amine (0.11 g, 0.40 mmol) and 3-fluoro-5-azepan-1-ylbenzoic acid (0.40 mmol) according to conditions described in general procedures E and F. A pink solid is produced (78 mg). Mp: 142-144° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.48 (bs, 4H), 1.74 (bs, 4H), 3.33 (bs, 2H), 3.51 (t, J=5.7 Hz, 4H), 3.53-3.76 (m, 6H), 4.01 (bs, 2H), 4.56 (t, J=4.2 Hz, 2H), 6.67 (d, J=13.2 Hz, 1H), 6.99-7.01 (m, 1H), 7.07 (d, J=8.1Hz, 1H), 7.17 (s, 1H), 7.46 (d, J=8.1Hz, 1H), 7.56-7.61 (m, 2H), 7.85-7.88 (m, 1H), 8.30-8.33 (m, 1H), 10.22 (s, 1H); MS 492 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH:3]1[O:5][CH2:4]1.[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]>>[CH2:13]([NH:14][CH2:4][CH:3]([OH:5])[CH:2]([CH3:6])[CH3:1])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][CH2:4][CH:3]([OH:5])[CH:2]([CH3:6])[CH3:1]
Reactant: NCCCCCCN
Reactant: CC(C)C1CO1
Product: CC(C)C(O)CNCCCCCCNCC(O)C(C)C

Procedure:
Condensation of 3-methyl-1-butene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxy-3-methylbutylamine] (I: R= (CH3)2CH, R' = H, X= (CH2)6, Z= H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:41])[C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[NH2:40])=[N:29][CH:30]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([NH:40][C:34]1[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:33]=1[C:32]([NH:31][C:28]1[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][N:29]=1)=[O:41])=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CSc1ccc(C(=O)O)c(OCCCNC(=O)OC(C)(C)C)c1
Product: CSc1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)c(OCCCNC(=O)OC(C)(C)C)c1

Procedure:
2-[2-(3-tert-Butoxycarbonylaminopropoxy)-4-(methylthio)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide was prepared by methods described in Example 4-E from 2-(3-tert-butoxycarbonylaminopropoxy)-4-(methylthio)benzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide (1.63 g, 49%).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[C:5](=[O:15])[NH:4][CH2:3]1.[H-].[Na+].[CH:18]1([CH2:21]Br)[CH2:20][CH2:19]1.O>CN(C=O)C>[CH:18]1([CH2:21][N:4]2[CH:3]=[C:2]([CH3:1])[C:11]3[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=3)[C:5]2=[O:15])[CH2:20][CH2:19]1
Reactant: CC1CNC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(CC2CC2)c(=O)c2cc([N+](=O)[O-])ccc12
Reaction time: 1 h
Yield: 19.5 %

Procedure:
To 4-methyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (0.90 g) in DMF (30 ml), sodium hydride (0.212 g, 60% suspension in oil) was added in portions. The mixture was stirred for 1 h then treated with cyclopropylmethyl bromide (0.72 g). The mixture was stirred for 4 h, poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried (Na2SO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, DCM) to give the sub-title compound (0.22 g) as a yellow solid. 1H NMR δ: 0.43-0.54 (4H, m), 1.26 (1H, m), 2.30 (3H, s), 3.84 (2H, d, J 7.2 Hz), 7.70 (1H, s), 7.91 (1H, d, J=9.0 Hz), 8.50 (1H, dd, J=2.5, 8.9 Hz), 8.98 (1H, d, J=2.5 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:15][C:16]1([CH3:23])[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1.[H-].[Na+]>C1COCC1>[CH3:15][C:16]1([CH3:23])[CH2:21][CH2:20][CH:19]([O:22][C:2]2[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1cccc2c(Cl)nccc12
Reactant: CC1(C)CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CCC(Oc2nccc3c([N+](=O)[O-])cccc23)CC1
Yield: 62.4 %

Procedure:
The title compounds were prepared following the procedure described in step-1, Intermediate-10 using 1-chloro-5-nitroisoquinoline (Intermediate-1, step-1, 200 mg, 0.96 mmol) and 4,4-dimethylcyclohexanol (135 mg, 1.05 mmol) and NaH (42 mg, 1.05 mmol, 60% in mineral oil) in THF (10 mL) to afford 180 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.65 (d, J=7.8 Hz, 1H), 8.47 (d, J=7.8 Hz, 1H), 8.18 (d, J=6.6 Hz, 1H), 7.94 (d, J=6.3 Hz, 1H), 7.06 (d, J=7.8 Hz, 1H), 5.33 (m, 1H), 2.04-1.96 (m, 2H), 1.87-1.80 (m, 2H), 1.43-1.39 (m, 4H), 1.02 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: [C:1]1(=[O:27])[N:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[C:14]([C:19](O)=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:4](=[O:22])[C:3]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]12.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:40]([NH2:48])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:40]([NH:48][C:19]([C:14]1[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]2[C:1](=[O:27])[C:2]3=[CH:26][CH:25]=[CH:24][CH:23]=[C:3]3[C:4]2=[O:22])=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:20])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O
Reactant: NCCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(NCCc1ccccc1)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O

Procedure:
From 2′-phthalimidomethylbiphenyl-2-carboxylic acid (precursor 2), after activation with CDI and reaction with phenethylamine, 2′-phthalimidomethylbiphenyl-2-carboxylic acid phenethylamide was obtained; m.p. 156° C.
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][SH:7])[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].O.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][C:17]=1[S:25](=[O:28])(=[O:27])[NH2:26]>CCOCC>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([S:7][CH2:6][C@@H:2]([CH3:1])[C:3]([OH:5])=[O:4])=[O:21])=[CH:18][C:17]=1[S:25](=[O:27])(=[O:28])[NH2:26]
Reactant: C[C@H](CS)C(=O)O
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: C[C@H](CSC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
3 g of 2(S)-methyl-3-mercaptopropionic acid is added to a mixture of 3.5 g of potassium carbonate, 60 ml of water and 30 ml of ether with stirring atroom temperature under a nitrogen atmosphere whereupon 6.3 g of 4-chloro-3-sulfamoylbenzoyl chloride is added, and the resulting mixture is stirred at room temperature for 5.5 hours. The aqueous layer is then collected and made acidic with dilute hydrochloric acid, and the separatedoil is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Isopropyl ether is added to the residual oil. The crystals thus obtained are recrystallized from a mixture of ethyl acetate and hexane to give 3-(4-chloro-3-sulfamoylbenzoylthio)-2(S)-methylpropionic acid as white crystalline powder, melting at 152°-153° C. (sinteringat 145° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20](OC)=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.Cl.Cl.CN(C)CCO[C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44]>>[NH2:7][CH:6]1[CH2:8][C:41]2[CH:42]=[C:43]([NH:44][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:22]=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]6[S:27][CH:28]=[CH:29][CH:30]=6)[CH:20]=[CH:19][CH:18]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:45]=[CH:46][C:47]=2[CH2:4][CH2:5]1
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)Cc1cccs1
Reactant: CN(C)CCOc1cccc(N)c1
Agent: Cl
Product: NC1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)Cc6cccs6)c5)nn5ccccc45)n3)cc2C1
Yield: 64.4 %

Procedure:
N-[5-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-(methyloxy)phenyl]-2-(2-thienyl)acetamide (119 mg, 0.25 mmol) and 3-{[2-(dimethylamino)ethyl]oxy}-aniline dihydrochloride (127 mg, 0.50 mmol) were coupled according to the procedure of Example 56, Step H to give the title compound (46 mg, 30%). 1H NMR (400 MHz, d6-DMSO) δ 8.80 (s, 1H), 8.48 (d, J=7.2 Hz, 1H), 8.35 (d, J=9.2 Hz, 1H), 8.16 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.49 (s, 1H), 7.28-7.24 (m, 4H), 7.22-7.18 (m, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.04-7.03 (m, 2H), 6.89-6.86 (m, 2H), 6.61-6.59 (m, 2H), 4.09 (m, 2H), 3.95 (s, 2H), 3.81 (s, 3H), 2.76 (m, 2H), 2.35 (s, 6H) ppm. ES-LC/MS m/z=620 [M+H]+.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][N:7]([C:9]3[CH:10]=[C:11]([CH2:19][C:20]([NH2:22])=[O:21])[C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:6][CH2:5][NH:4]2)[CH2:2]1.C[O:24][C:25](=O)[C:26]([C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]([CH3:37])[CH:29]=1)=O.CC([O-])(C)C.[K+]>C1COCC1>[CH2:2]1[C:3]2([CH2:8][N:7]([C:9]3[CH:10]=[C:11]([C:19]4[C:20](=[O:21])[NH:22][C:25](=[O:24])[C:26]=4[C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]([CH3:37])[CH:29]=4)[C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:6][CH2:5][NH:4]2)[CH2:1]1
Reactant: NC(=O)Cc1cc(N2CCNC3(CC3)C2)cc2ccccc12
Reactant: COC(=O)C(=O)c1cn(C)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1cc(C2=C(c3cc(N4CCNC5(CC5)C4)cc4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 0.08 h

Procedure:
2-[3-(4,7-Diaza-spiro[2.5]oct-7-yl)-naphthalen-1-yl]-acetamide (100 mg, 0.30 mmol) and (1-methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (97 mg, 0.44 mmol) are azeotroped three times with dry THF and then dissolved in dry THF (3 ml). A solution of 1.0 M KOtBu In THF (1.2 ml) is added dropwise over 20 minutes at RT. After 5 minutes, TLC analysis indicates complete conversion of starting materials. The reaction is quenched by the addition of water (5 ml). The mixture is diluted with EtOAc and washed twice with saturated aq. NH4Cl. The aqueous layers are back extracted twice with EtOAc. The combined organic layers are dried over Na2SO4 and the solvent is evaporated. The residue is purified by FCC (EtOAc/AcOH/H2O 800:55:45) to afford the title compound as its acetate salt. The compound is dissolved in MeOH/TFA and the solvent is removed to yield the title compound as its trifluoroacetate salt. 1H NMR (DMSO, 400 MHz) δ 0.95 (M, 4H), 3.39 (br, 4H), 3.49 (br, 2H), 3.86 (s, 3H), 6.16 (d, J=7.9 Hz, 1H), 6.46 (dd, J=6.6/7.9 Hz, 1H), 7.00 (dd, J=6.6/7.9 Hz, 1H), 7.13 (dd, J=7.6/7.6 Hz, 1H), 7.40 (m, 4H), 7.55 (d, J=8.5 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 8.14 (s, 1H), 9.10 (br, 2H), 11.17 (s, 1H); ES-MS: 463 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[C:37]([CH3:38])=[CH:36][N:35]=[C:34]([CH3:39])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][C:34]1[CH:33]=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:40])[NH:21][C:9]4[CH:10]=[C:11]([C:17]([F:18])([F:19])[F:20])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[C:37]([CH3:38])=[CH:36][N:35]=1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)ncc3C)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)ncc3C)c1)=N2

Procedure:
The title compound was prepared from [2-{3-[3-(2,5-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M124) (0.25 g, 0.44 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (170 mg, 86%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([OH:11])[C:5]=1[OH:12].Br[CH2:15][CH2:16][CH2:17]Br.C([O-])([O-])=O.[K+].[K+]>CC(=O)C>[Cl:10][C:8]1[CH:9]=[C:4]([C:3]([O:2][CH3:1])=[O:13])[C:5]2[O:12][CH2:17][CH2:16][CH2:15][O:11][C:6]=2[CH:7]=1
Reactant: COC(=O)c1cc(Cl)cc(O)c1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)cc2c1OCCCO2
Yield: 94.8 %

Procedure:
A mixture of 5-chloro-2,3-dihydroxy-benzoic acid methyl ester (0.3 mol), 1,3-dibromopropane (0.42 mol) and K2CO3 (0.66 mol) in 2-propanone (500 ml) was stirred and refluxed for 20 hours, then filtered hot and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM). The desired fractions were collected and the solvent was evaporated. Toluene was added and azeotroped on the rotary evaporator, yielding 69 g of methyl 8-chloro-3,4-dihydro-2H-1,5-benzodioxepin-6-carboxylate (intermediate 5).
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4](=[CH:9][N:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[N:11]=2)[CH:5]=[N+:6]([O-])[CH:7]=1.P(Br)(Br)([Br:22])=O>ClCCCl>[Br:22][C:5]1[C:4]2=[CH:9][N:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[N:11]=[C:3]2[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: O=P(Br)(Br)Br
Reactant: [O-][n+]1cc(Br)c2nn(-c3c(Cl)cccc3Cl)cc2c1
Solvent: ClCCCl
Product: Clc1cccc(Cl)c1-n1cc2c(Br)ncc(Br)c2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
To a cooled (0° C.) suspension of 7-bromo-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-5-oxide (1.7 g, 4.7 mmol) in DCE (30 mL) was added phosphorus oxybromide (4.0 g, 14.1 mmol). The reaction mixture was stirred at 0° C. for 15 minutes, warmed to room temperature, and stirred for a further 2.25 hours. The reaction mixture was partitioned between DCM and sodium carbonate (sat. aq.). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-20% ethyl acetate in cyclohexane) to afford the title compound as a white solid (1.07 g, 54% yield). LCMS (Method D): RT=3.93 min, m/z: 422 [M+H+].
Reaction SMILES: CN1CCN(CCCNC2N=CN=C3N(C4C=CC([OH:27])=CC=4)N=CC=23)CC1.[H-].[Na+].[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[NH:39][C:40]([C:42]1[CH:43]=[CH:44][CH:45]=[C:46]2[C:51]=1[CH2:50][N:49]([C:52]1[N:57]=[C:56]([C:58]([O:60]C(C)(C)C)=[O:59])[C:55]([CH2:65][CH2:66][CH2:67]I)=[CH:54][CH:53]=1)[CH2:48][CH2:47]2)=[O:41]>CN(C=O)C>[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[NH:39][C:40]([C:42]1[CH:43]=[CH:44][CH:45]=[C:46]2[C:51]=1[CH2:50][N:49]([C:52]1[N:57]=[C:56]([C:58]([OH:60])=[O:59])[C:55]([CH2:65][CH2:66][CH2:67][OH:27])=[CH:54][CH:53]=1)[CH2:48][CH2:47]2)=[O:41]
Reactant: CN1CCN(CCCNc2ncnc3c2cnn3-c2ccc(O)cc2)CC1
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1ccc(CCCO)c(C(=O)O)n1)CC2
Reaction time: 0.17 h

Procedure:
To a solution of compound 84A (60 mg, 0.163 mmol) in DMF (5 ml) was added sodium hydride (32.7 mg, 0.816 mmol)(60%). The reaction was stirred for 10 min and compound 96D (107 mg, 0.163 mmol) was added. The resulting mixture was stirred for 3 hour and purified by reverse phase HPLC (mobile phase: 0%-50% acetonitrile in 0.1% TFA aqueous solution during 70 min) to provide the title compound 99: 1H NMR (400 MHz, DMSO-D6) δ ppm 12.81 (1H, s), 8.04 (1H, dd), 7.79 (1H, d), 7.60 (1H, d), 7.53 (1H, d), 7.45-7.50 (1H, m), 7.39-7.43 (1H, m), 7.32-7.38 (2H, m), 6.95 (1H, d), 4.92 (2H, s), 3.86 (2H, t), 3.37 (2H, t), 2.99 (2H, t), 2.63-2.70 (2H, m), 1.58-1.69 (2H, m), LCMS (APCI) 489 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH:26]2[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]2)[S:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1.[BH4-].[Na+].CC(C)=O>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C@H:26]2[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]2)[S:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1
Reactant: CC(C)c1nnc2ccc(-c3sc(C4CCC(=O)CC4)nc3-c3ccc(F)cc3F)nn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: CC(C)c1nnc2ccc(-c3sc([C@H]4CC[C@H](O)CC4)nc3-c3ccc(F)cc3F)nn12
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
The 4-(4-(2,4-difluorophenyl)-5-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiazol-2-yl)cyclohexanone (0.495 g, 1.09 mmol) was dissolved in MeOH (5 mL) then cooled to about −5° C. Sodium borohydride (0.041 g, 1.09 mmol) was added and the mixture was stirred for about 5 min. Acetone was added, the solvents were concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel with DCM/MeOH (95:5) as an eluent then by RP-HPLC (Table 1, Method f) to give the title compound (0.209 g, 42%): LC/MS (Table 1, Method a) Rt=2.29 min; MS m/z: 456.2 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=1[I:14])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:16][O:15][C:11]1[N:10]=[CH:9][C:8]([NH2:7])=[C:13]([I:14])[CH:12]=1
Reactant: COc1cc(I)c(NC(=O)OC(C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(I)c(N)cn1
Yield: 78.4 %

Procedure:
A solution of (6-methoxy-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (18 g, 51 mmol) in DCM (50 mL) and TFA (50 mL) was stirred at ambient temperature for 1 h and then evaporated in vacuo. The resultant residue was treated with saturated aqueous sodium hydrogen carbonate solution (25 mL), diluted with water (100 mL) and extracted into ethyl acetate (2×100 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound as a brown foam (10 g, 60%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[C:16]([C:22]3[CH:30]=[CH:29][C:25]4[O:26][CH2:27][O:28][C:24]=4[CH:23]=3)[C:17]=1[C:18]([O:20][CH3:21])=[O:19])[C:11]1[O:12][CH2:13][O:14][C:10]=1[CH:9]=[CH:8]2)=[O:4].[OH-].[K+]>CO>[CH3:21][O:20][C:18]([C:17]1[C:16]([C:22]2[CH:30]=[CH:29][C:25]3[O:26][CH2:27][O:28][C:24]=3[CH:23]=2)=[C:15]2[C:7]([CH:8]=[CH:9][C:10]3[O:14][CH2:13][O:12][C:11]=32)=[CH:6][C:5]=1[C:3]([OH:4])=[O:2])=[O:19]
Reactant: COC(=O)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1C(=O)OC)OCO3
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1c(C(=O)O)cc2ccc3c(c2c1-c1ccc2c(c1)OCO2)OCO3
Yield: 55.8 %

Procedure:
Compound 30 (20 mg, 0.05 mmol) was refluxed with 1 M solution of KOH in MeOH (10 mL) for 2 h. The solution was cooled, and the solvent was removed under reduced pressure. The remaining solid was dissolved in water (10 mL) and then acidified to pH 1-2 with 10% aqueous HCl solution. The precipitate was collected by filtration, washed with water, and dried. The product was purified by column chromatography on silica gel using CH2Cl2/MeOH (20:1 to 10:1, v/v) to give 31 (11 mg, 56%) as a pale yellow powder. mp 273-275° C.; 1H NMR (CDCl3) δ 8.54 (s, 1H, H4), 7.49 (d, 1H, H5, J=8.1 Hz), 7.20 (d, 1H, H6, J=8.1 Hz), 6.76-6.82 (m, 3H, H2′+H5′+H6′), 6.03 (AB, 2H, 3′,4′-OCH2O—, Δδ=11.1 Hz), 5.88 (AB, 2H, 7,8-OCH2O—, Δδ=7.2 Hz), 3.62 (s, 3H, OCH3); MS (FAB, positive) m/z 395 [M+H]+.
Reaction SMILES: C(Cl)Cl.[C:4](Cl)(=[O:8])[C:5]([CH3:7])=[CH2:6].[CH2:10]([N:17]([CH2:24][CH2:25][OH:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N(CC)CC)C>[CH2:10]([N:17]([CH2:24][CH2:25][O:26][C:4](=[O:8])[C:5]([CH3:7])=[CH2:6])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCCN(Cc1ccccc1)c1ccccc1
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCN(Cc1ccccc1)c1ccccc1

Procedure:
1000 ml of dried methylene chloride are placed in a 4 l sulfonating vessel at 0° C. together with 334 g of methacrylic acid chloride. A mixture of 500 ml of dried methylene chloride, 323 of dried triethylamine and 454 of N-benzyl-N(β-hydroxyethyl)aniline, (the compound of formula 1a) are added drop by drop to this mixture at 0°-10° C. The reaction mixture is allowed to rise to room temperature slowly and is controlled on a thin layer chromatograph (silica gel) solvent: toluene/acetic acid ester 2:1. After the end of the reaction (after standing overnight), the reaction mixture is filtered and washed three times with one liter of a 10% aqueous NaOH solution and finally four times each time with 1 l of water. The organic phase is then dried over sodium sulphate and the solvent is removed in a rotary evaporator. 482 g of the product of formula 1d ##STR15## results.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=O)[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)[CH:5]=[C:4]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:3]=1.Cl.[NH2:30][OH:31]>>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[N:30][OH:31])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)[CH:5]=[C:4]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:3]=1
Reactant: NO
Reactant: COC1(c2cc(OCc3ccc4c(c3)OCCC4=O)nc(N)n2)CCOCC1
Agent: Cl
Product: COC1(c2cc(OCc3ccc4c(c3)OCCC4=NO)nc(N)n2)CCOCC1
Yield: 79 %

Procedure:
Using an analogous procedure to that described in Example 43, 7-[2-amino-6-(4-methoxytetrahydropyran-4-yl)pyrimidin-4-yloxymethyl]chroman-4-one was reacted with hydroxylamine hydrochloride to give 7-[2-amino-6-(4-methoxytetrahydropyran-4-yl)pyrimidin-4-yloxymethyl]chroman-4-one oxime in 79% yield, m.p. 224°-228° C.;
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]([CH:56]2[CH2:58][CH2:57]2)[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]([CH:56]3[CH2:58][CH2:57]3)[C:52]([F:55])([F:54])[F:53])=[O:49])=[N:46][CH:47]=2)[CH2:35]1)#[N:38]
Reactant: O=C(N[C@@H](C1CC1)C(F)(F)F)c1cnc(Cl)cn1
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[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5cnc(C(=O)N[C@@H](C6CC6)C(F)(F)F)cn5)C4)c3)ncnc21
Temperature: 125 °C
Reaction time: 2 h
Yield: 58.4 %

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-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]pyrazine-2-carboxamide (58 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 (0-65%) to afford the desired product (80 mg, 59%). LCMS (M+H)+: m/z=653.2.