Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH:7]1[C:9]2([CH2:12][N:11]([C:13]([C:15]3[C:20]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=4[F:29])=[C:19]([F:30])[C:18]([F:31])=[CH:17][CH:16]=3)=[O:14])[CH2:10]2)[O:8]1.[N-:32]=[N+:33]=[N-:34].[Na+].C(OCC)(=O)C>CN(C)C=O>[N:32]([CH:7]([C:9]1([OH:8])[CH2:10][N:11]([C:13]([C:15]2[CH:16]=[CH:17][C:18]([F:31])=[C:19]([F:30])[C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[O:14])[CH2:12]1)[CH2:6][CH:2]1[O:3][CH2:4][CH2:5][O:1]1)=[N+:33]=[N-:34]
Reactant: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC2(C1)OC2CC1OCCO1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC(CC1OCCO1)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reaction time: 22 h
Yield: 73.7 %

Procedure:
6-{[2-(1,3-Dioxolan-2-ylmethyl)-1-oxa-5-azaspiro [2.3]hex-5-yl]carbonyl}-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline (31 mg, 0.057 mmol) was dissolved in dimethylformamide (0.5 mL) and sodium azide (20 mg, 0.308 mmol) was added. The mixture was stirred at ambient for 22 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with water, brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 50% ethyl acetate in hexanes) gave 3-[1-azido-2-(1,3-dioxolan-2-yl)ethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (25 mg, 0.042 mmol, 74% yield): MS (EI) for C21H19F3IN5O4: 590 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[C:6]3[CH2:18][CH2:19][N:20]([CH3:22])[CH2:21][C:5]=3[C:4]=2[CH:3]=1.[CH:23]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([NH:28][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:15])[C:6]3[CH2:18][CH2:19][N:20]([CH3:22])[CH2:21][C:5]=3[C:4]=2[CH:3]=1
Reactant: NC1CCCC1
Reactant: CCOC(=O)CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCC(=O)NC2CCCC2)C1
Temperature: 120 °C

Procedure:
A mixture of ethyl 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)propanoate (CD17) (100 mg) and cyclopentylamine (1 ml) was heated at 120° C. for 15 h to obtain 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-N-cyclopentylpropanamide (CD32) after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[NH2:14][C:15]1[N:20]=[C:19]([CH3:21])[C:18]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:31])[CH:24]=2)=[CH:17][CH:16]=1.N1C=CC=CC=1>ClCCCl.C1COCC1>[CH3:21][C:19]1[C:18]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:31])[CH:24]=2)=[CH:17][CH:16]=[C:15]([NH:14][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])[N:20]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)C(N)=O
Reactant: Cc1nc(N)ccc1Oc1ccnc(NC(=O)N2CCCC2)c1
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)NC(=O)C(C)(C)C)ccc1Oc1ccnc(NC(=O)N2CCCC2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 17.4 %

Procedure:
A suspension of 2,2,2-trimethylacetamide (0.297 g, 2.94 mmol) in DCE (5 mL) was treated with oxalyl chloride (0.236 mL, 2.79 mmol), heated at 100° C. for 1 h, cooled to RT, added drop-wise to a solution of N-(4-((6-amino-2-methylpyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide (0.658 g, 2.100 mmol) and pyridine (0.237 mL, 2.94 mmol) in THF (10 mL) and stirred at RT for 2 h. The mixture was concentrated to dryness, treated with satd. NaHCO3, extracted with EtOAc (4×) and the combined organics were dried over Na2SO4 and concentrated to dryness. The residue was treated with MeCN, sonicated and the resulting solid was removed via filtration. The filtrate was concentrated to dryness, suspended in MeCN, sonicated, allowed to stand for 3 h and the resulting solid collected via filtration to afford N-(4-((2-methyl-6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide (161 mg, 17%). 1H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 10.41 (s, 1H), 8.70 (s, 1H), 8.09 (d, J=5.7 Hz, 1H), 7.90 (m, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.38-7.37 (m, 1H), 6.55 (dd, J=5.7, 2.4 Hz, 1H), 3.31 (m, 4H), 2.23 (s, 3H), 1.78 (m, 4H), 1.21 (s, 9H); MS (ESI) m/z: 441.2 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@@H:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[CH2:29]=O>C(O)=O>[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@@H:18]3[CH2:22][CH2:21][N:20]([CH3:29])[CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCNC1
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C)C1
Temperature: 85 °C
Yield: 59 %

Procedure:
4-(3-chloro-2-fluoroanilino)-6-[(3R)-pyrrolidin-3-yloxy]-7-methoxyquinazoline hydrochloride (0.24 g, 0.56 mmole; prepared as described in Example 29-preparation of starting materials) was dissolved in formic acid (4 ml) and formaldehyde (37% w/v in water) (2 ml) was added. The mixture was heated to 85° C. for one hour and then evaporated under vacuum and azeotroped with toluene. The residue was partitioned between ethyl acetate and saturated aqueous NaFfCO3. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (94/6). The fractions containing the expected product were combined, evaporated and the residue triturated with isohexane/diethylether, filtered and dried under vacuum to give the title product as a white solid (0.13 g; 59%); 1H NMR Spectrum: (DMSO d6) 1.70-1.9 (m, 1H); 2.27 (s, 3H); 2.30-2.50 (m, 2H); 2.55-2.75 (na, 2H); 2.91-3.00 (m, 1H); 3.91 (s, 3H); 4.90-5.10 (m, 1H); 7.18 (s, 1H); 7.20-7.35 (m, 1H); 7.40-7.58 (m, 2H); 7.64 (s, 1H); 8.35 (s, 1H); 9.57 (s, 1H); Mass Spectrum: (M−H)− 401.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:13]([O-:15])=[O:14])=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4]([N+:13]([O-:15])=[O:14])=[CH:5][C:6]([CH3:12])=[C:7]([C:8]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[O:10])[CH:11]=1
Reactant: C1COCCN1
Reactant: COc1cc(C(=O)O)c(C)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)N2CCOCC2)c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.2 %

Procedure:
To 5-methoxy-2-methyl-4-nitrobenzoic acid (2.0 g, 9.47 mmol) in DCM (50 mL) was added DIPEA (8.3 mL, 47 mmol) and HATU (3.96 g, 10.4 mmol) followed by morpholine (0.83 mL, 9.47 mmol). The mixture was allowed to stir at RT for 5 h and then water (50 mL) and DCM (50 mL) were added. The aqueous phase was extracted with DCM (3×25 mL) and the combined organic phases were passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-100% EtOAc in iso-hexane) gave (5-methoxy-2-methyl-4-nitrophenyl)(morpholino)methanone (2.5 g, 94%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]+=281 at 3.17 min. 1H NMR (400 MHz, CDCl3): δ 7.72 (s, 1H), 6.90 (s, 1H), 3.94 (s, 3H), 3.85-3.76 (m, 4H), 3.61 (dd, 2H), 3.23 (dd, 2H), 2.30 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])=[CH:17][CH:16]=1)=O)(C)(C)C.Cl.CCOCC>CO>[ClH:29].[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccc(Cl)cc2Cl)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Clc1ccc(COc2ccc(OC[C@H]3CCCN3)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 205.8 %

Procedure:
To a 25 mL vial which contained a solution of the product from step 2 (120 mg, 0.26 mmol) in MeOH (2 mL) was added HCl (2 N in ether, 4 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 24 h. The ether (10 mL) was added to the mixture and the solid which formed was filtered out to provide the crude which was further purified by recrystallization with MeOH-ether to yield the title product, (104 mg, 95%); LCMS; 100% APCI+, Calcd: 352.3. Found m/z 352.3 (M). 1H NMR (400 MHz, DMSO-d6); δ 1.68-1.75 (m, 1H), 1.84-2.02 (m, 2H), 2.07-2.16 (m, 1H), 3.13-3.26 (m, 2H), 3.80-3.90 (m, 1H), 4.05-4.10 (m, 1H), 4.18 (dd, J1=10.4 Hz, J2=3.6 Hz, 1H), 5.09 (s, 2H), 6.94-7.01 (m, 4H), 7.48 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.68 (d, 1H, J=2.0 Hz):
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.[Si:7]([O:24][CH2:25][CH2:26][C:27]#[N:28])([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)Cl>C1(C)C=CC=CC=1.C1C=CC=CC=1>[Si:7]([O:24][CH2:25][CH2:26][C:27]([NH2:1])=[NH:28])([C:20]([CH3:22])([CH3:23])[CH3:21])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: [NH4+]
Reactant: CC(C)(C)[Si](OCCC#N)(c1ccccc1)c1ccccc1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCC(=N)N)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of NH4Cl (5.35 g, 0.1 mol) in 60 mL of dry benzend at 0° C. was slowly added 50 mL of 2M solution of trimethylaluminum in toluene. After the addition was complete, the reaction mixture was allowed to warm up to room temperature and was stirred for 2 h until gas evolution had ceased. A solution of 3-(tert-butyldiphenylsilyloxy)propanenitrile (9.27 g, 0.03 mol) in 20 mL of dry benzene was added to the aluminum amide reagent and the resulting mixture was heated up to 80° C. for 20 h. The reaction mixture was slowly cooled to room temperature and then carefully poured into a slurry of 300 mL of DCM and 200 g of silica gel. It was then filtered and washed thoroughly with MeOH/DCM (1:2). After concentration, flash chomatography (SiO2, EtOAc to EtOAc/MeOH=100:20 to 100:30 to EtOAc/2M NH3 in MeOH=100:30) gave the product as a white solid.
Reaction SMILES: [ClH:1].CO[C:4](=O)[CH:5]([NH2:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12].[N:15]#[C:16][NH2:17]>>[ClH:1].[CH2:6]([C:5]1[N:13]=[C:16]([NH2:17])[NH:15][CH:4]=1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12]
Reactant: N#CN
Reactant: C#CCCCCCC(N)C(=O)OC
Agent: Cl
Product: C#CCCCCCc1c[nH]c(N)n1
Yield: 53 %

Procedure:
2-Amino-non-8-ynoic acid methyl ester hydrochloride (2.02 g, 9.20 mmol) was treated to an Akabori reduction followed by a cyanamide condensation employing conditions previously reported to produce 4-Hept-6-ynyl-1H-imidazol-2-ylamine hydrochloride (1.04 g, 53%) as a pale yellow solid (Olofson et al., Journal of Organic Chemistry 1997, 62, (23), 7918-7919). 1H NMR (300 MHz, CD3OD) δ 6.17 (s, 1H), δ 2.19 (t, 2H), δ 1.90 (t, 1H), δ 1.86 (m, 2H), δ 1.24-1.13 (m, 6H) ppm; 13C NMR (75 MHz, CD3OD) δ 147.5, 128.3, 108.8, 83.8, 65.5, 28.4, 28.3, 28.2, 24.5, 17.8 ppm; HRMS (ESI) calcd for C10H16N3 (M+) 178.1338. found 178.1337.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:36])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:36][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[N:28]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2)cc1

Procedure:
The title compound is prepared as described in Example 1 but using (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 7.1) and 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine (see J. Med. Chem. 45, 2994-3008 (2002)). Title compound: ES-MS: 465.5 [M+H]+; 1H NMR (CDCl3) 8.55 (d, J=3.9 Hz, 1H), 8.38 (s, 1H), 8.24 (d, J=8.2 Hz), 7.83 (d, J=8.2 Hz, 2H), 7.52-7.48 (m, 1H), 7.45 (d, J=8.2 Hz, 2H), 7.42-7.40 (m, 1H), 7.39 (s, 1H, NH), 7.16 (d, J=8.2 Hz, 2H), 7.13 (d, J=8.2 Hz, 2H), 6.66 (s, 1H), 3.81 (s, 2H), 2.13 (s, 3H), 1.36 (s, 9H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[ClH:6].[C:7]1([C:13]2([CH2:19][C:20](=O)[CH3:21])[CH:18]=[CH:17][CH2:16][CH:15]=[CH:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([BH3-])#N.[Na+]>CO>[ClH:6].[CH3:21][CH:20]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:19][C:13]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:18]=[CH:17][CH2:16][CH:15]=[CH:14]1
Reactant: CC(=O)CC1(c2ccccc2)C=CCC=C1
Reactant: CCNCC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(CC)C(C)CC1(c2ccccc2)C=CCC=C1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To 27.5 ml. (about 6 equivalents) of diethylamine and 10 g. of molecular sieve 3A in 200 ml. of methanol are added at 0° C. 17.6 ml. of 5 N methanolic hydrochloric acid (2 equivalents) and then 9.4 g. of (1-phenyl-2,5-cyclohexadien-1-yl)-2-propanone in a small amount of methanol and finally 1.95 g. (0.7 equivalents) of sodium cyanoborohydride. The mixture is stirred at room temperature for 5 days and then worked-up in exactly the same manner as described in Example 16. There is obtained an oily residue which is chromatographed on a silica gel thick-layer plate with ethyl acetate/triethylamine (15:1). Two products are scratched off and eluted with methylene chloride/methanol (4:1). The product of RF 0.32 is α-methyl-N-ethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine. The other product (RF 0.54) is the desired product, namely, α-methyl-N,N-diethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine. This is converted as usual into the hydrochloride and recrystallized from methylene chloride/ether. According to melting point and mixed melting point, the product is identical with that obtained in accordance with Example 18.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].C1(C(C2C=CC=CC=2)[N:18]2[CH2:21][CH:20]([O:22][C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=3[F:33])[CH2:19]2)C=CC=CC=1>C(Cl)Cl>[F:33][C:24]1[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:32])[F:31])=[CH:28][C:23]=1[O:22][CH:20]1[CH2:19][N:18]([C:1]([Cl:4])=[O:2])[CH2:21]1
Reactant: Fc1ccc(C(F)(F)F)cc1OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Cl)N1CC(Oc2cc(C(F)(F)F)ccc2F)C1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 163.3 %

Procedure:
A mixture of 10.8 g (0.11 mole) of phosgene and 14.2 g (0.11 mole) of potassium carbonate in 200 mL of methylene chloride was cooled to 5° C. in an ice bath while stirring undr nitrogen. After 30 min, the reaction mixture was treated with 40 g (0.1 mole) of 1-(diphenylmethyl)-3-[2-fluoro-5-(trifluoromethyl)phenoxy]azetidine in 100 mL of methylene chloride added dropwise. After stirring for 16 h, the reaction mixture was treated with small pieces of ice to destroy any excess phosgene. Then the reaction mixture was decanted from the inorganic paste and concentrated in vacuo to give 48.6 g of pale yellow oil. The residual oil was distilled at 0.15 mmHg to yield 3 fractions: #1, 12.7 g at 120°-128°; #2, 1.5 g at 128°, and #3 at 128°-132°; with total yield of 19.7 g (66.2%). A sample of fraction #2 was submitted for analysis.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19](=[O:20])[CH:18]=[CH:17][C:16]3[N:15]=[CH:14][C:13]([C:21]#[N:22])=[CH:12][C:11]2=3)[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.CO.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)(Cl)[Cl:52]>>[ClH:52].[ClH:52].[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19](=[O:20])[CH:18]=[CH:17][C:16]5[N:15]=[CH:14][C:13]([C:21]#[N:22])=[CH:12][C:11]4=5)[CH2:6][CH2:7]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: N#Cc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: ClC(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: Cl
Product: N#Cc1cnc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
A solution of 5-[2-(4-amino-1-piperidinyl)ethyl]-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carbonitrile (44 mg, 0.148 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (24.5 mg, 0.148 mmol) and 3A molecular sieves in chloroform (1 ml) and MeOH (1 ml) was heated at 65° C. for 5 h, cooled and then NaBH(OAc)3 (63 mg, 0.30 mmol) was added. The reaction was stirred at rt for 18 h, filtered through Celite and evaporated. The residue was treated with sat. aq NaHCO3 solution and a 4:1 DCM:MeOH mixture. The aqueous phase was extracted twice with a 4:1 DCM:MeOH mixture and then the combined organic phases were dried and the solvent was removed under reduced pressure. The residue was subjected to column chromatography on silica gel using a DCM, MeOH and aqueous ammonia gradient to provide the free base of the title compound (0.061 g, 92%).
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:30]=3)[C:25](O)=[O:26])=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:30]=3)[C:25]([NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)=[O:26])=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: CN1CC[C@H](Oc2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(C(=O)O)c2)C1=O
Reactant: Nc1ccccn1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CC[C@H](Oc2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(C(=O)Nc3ccccn3)c2)C1=O
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 46.9 %

Procedure:
1-Chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.077 mL, 0.58 mmol) was added to a solution of 3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoic acid (Intermediate 30) (200 mg, 0.49 mmol) in DCM (5 mL) and stirred at ambient temperature for 50 minutes. 2-Amino-pyridine (93 mg, 0.98 mmol) and pyridine (0.080 mL, 0.98 mmol) were added and the reaction stirred for 16 hours. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (40 mL), washed with water (10 mL), and brine (10 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography, eluting with a gradient of 0-100% methanol in DCM to afford the product (112 mg, 47%). 1H NMR δ (300 MHz, CDCl3) 2.12-2.26 (m, 1H), 2.35 (quintet, 2H), 2.53-2.66 (m, 1H), 2.93 (s, 3H), 3.34-3.57 (m, 2H), 4.25 (t, 2H), 4.70 (t, 2H), 4.93 (t, 1H), 6.97 (s, 1H), 7.08 (t, 1H), 7.22 (s, 1H), 7.38 (d, 1H), 7.45 (s, 1H), 7.75 (t, 1H), 8.11 (d, 1H), 8.29 (d, 1H), 8.33 (q, 2H), 8.68 (s, 1H); m/z 488 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][C:13]([N:17]4[C:21]5=[N:22][CH:23]=[CH:24][CH:25]=[C:20]5[NH:19][C:18]4=[O:26])=[CH:14]3)=[N:9]2)=[N:6][CH:7]=1.I[CH2:28][CH3:29].O>CN(C=O)C>[CH2:28]([N:19]1[C:20]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[N:17]([C:13]2[CH:12]=[CH:11][C:10]3[C:15](=[CH:16][N:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=4)[N:9]=3)[CH:14]=2)[C:18]1=[O:26])[CH3:29]
Reactant: Cc1ccc(-n2cc3cc(-n4c(=O)[nH]c5cccnc54)ccc3n2)nc1
Reactant: CCI
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc3nn(-c4ccc(C)cn4)cc3c2)c2ncccc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 16.1 %

Procedure:
A mixture of 3-[2-(5-methylpyridin-2-yl)-2H-indazol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (31 mg) and iodoethane (15.5 mg) in DMF (2 mL) was stirred at 50° C. for 3 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/Hexane. The product was crystallized from AcOEt/Hexane to give the title compound as white crystals (5.4 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[F:7][C:8]([F:17])([F:16])[C:9]([C:11]1[S:12][CH:13]=[CH:14][N:15]=1)=[O:10]>>[CH3:1][C:2]1[N:3]=[C:4]([C:9]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)([OH:10])[C:8]([F:17])([F:16])[F:7])[S:5][CH:6]=1
Reactant: Cc1cscn1
Reactant: O=C(c1nccs1)C(F)(F)F
Product: Cc1csc(C(O)(c2nccs2)C(F)(F)F)n1

Procedure:
From 4-methylthiazole and 2-trifluoroacetylthiazole using the general method of Example 6. M.p. 89°-90° C.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4([CH2:24][O:25]C)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[C:27]([NH:29][C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=3)[C:33]([OH:35])=[O:34])=[O:28])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.B(Br)(Br)Br.O>C(Cl)Cl>[C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4([CH2:24][OH:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[N:15][C:14]=3[C:27]([NH:29][C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=3)[C:33]([OH:35])=[O:34])=[O:28])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COCC1(c2nc(C(=O)Nc3cccc(C(=O)O)c3)c(CCC34CC5CC(CC(C5)C3)C4)[nH]2)CCCCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1cccc(NC(=O)c2nc(C3(CO)CCCCC3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.8 %

Procedure:
To a suspension of 3-{[5-(2-adamantan-1-yl-ethyl)-2-(1-methoxymethyl-cyclohexyl)-1H-imidazole-4-carbonyl]-amino}-benzoic acid (Example 203) (300 mg, 0.58 mmol) in DCM (10 ml) was added 1 M solution of boron tribromide in DCM (1.72 ml, 1.72 mmol) at 0° C. The mixture was stirred at room temperature for 16 h, cooled to 0° C., and water (20 ml) was added slowly. The product was extracted with DCM/MeOH (3×20 ml of 9:1 mixture), the organic phase was dried (MgSO4) and the solvent was evaporated. The crude product was purified by flash column chromatography (silica, DCM/MeOH, 95:5) to afford the title compound as a white solid (40.5 mg, 14%). 1H NMR (300 MHz, d6-DMSO) 9.51 (1H, s), 8.38 (1H, s), 7.92 (1H, d), 7.60 (1H, d), 7.40 (1H, t), 3.41 (2H, s), 2.87 (2H, m), 2.05 (2H, m), 1.94 (3H, br s), 1.65 (6H, m), 1.52 (11H, m), 1.34 (5H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 60.86; H, 8.33; N, 7.76%. C37H56N4O9.1.6 H2O requires: C, 60.86; H, 8.18; N, 7.67%.