Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N:12]([CH2:14][CH2:15][O:16][CH3:17])[CH3:13])=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.C(O)(=O)/C=[CH:20]/[C:21](O)=[O:22]>C(O)C>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[N:6]=[C:2]([NH:1][C:21](=[O:22])[CH3:20])[S:3][C:4]=1[N:12]([CH2:14][CH2:15][O:16][CH3:17])[CH3:13]
Reactant: COCCN(C)c1sc(N)nc1-c1ccco1
Reactant: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: COCCN(C)c1sc(NC(C)=O)nc1-c1ccco1
Yield: 21.4 %

Procedure:
In a manner similar to that in Example 2, a free form of the entitled Compound was obtained from 2-amino-4-(2-furyl)-5-[N-(2-methoxyethyl)-N-methylamino]thiazole (160 mg, 0.63 mmol) obtained in Step 1 of Example 77, in place of Compound a. The resulting free form was dissolved in ethanol (5 mL), and fumaric acid (146 mg, 1.26 mmol) was added thereto, and the precipitated solid was collected by filtration to afford the entitled Compound 83 (39.8 mg, 18%).
Reaction SMILES: Br.[CH2:2]([NH:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10]Br)[CH2:3][CH2:4][CH3:5].[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO.O>[CH2:2]([NH:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Nc1ccccc1
Reactant: CCCCNc1cc(CBr)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: Br
Solvent: O
Solvent: CO
Product: CCCCNc1cc(CNc2ccccc2)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A solution of 3-n-butylamino-4-phenoxy-5-sulfamylbenzyl bromide hydrobromide (2.5 g; prepared as described in Example 67) and aniline (10 ml) in methanol (20 ml) is refluxed for 16 hours. After cooling the mixture is diluted with water (about 80 ml); the resulting semi-solid precipitate is washed twice with water, which is decanted, and is then crystallized from aqueous ethanol. After filtration and recrystallization from ethanol, (3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)aniline is obtained with a melting point of 142°-143° C.
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(N1CCOC(COC2C=CC=CC=2)C1)(=O)=O.[Br:42][C:43]1[CH:44]=[C:45]2[C:49](=[CH:50][CH:51]=1)[N:48](S(C1C=CC=CC=1)(=O)=O)[C:47]([C:61](OCC)=[O:62])=[C:46]2[S:66]([N:69]1[CH2:74][CH2:73][O:72][CH:71]([CH2:75][O:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[CH2:70]1)(=[O:68])=[O:67]>>[Br:42][C:43]1[CH:44]=[C:45]2[C:49](=[CH:50][CH:51]=1)[NH:48][C:47]([C:61]([NH2:7])=[O:62])=[C:46]2[S:66]([N:69]1[CH2:74][CH2:73][O:72][C@@H:71]([CH2:75][O:76][C:77]2[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=2)[CH2:70]1)(=[O:68])=[O:67]
Reactant: CCOC(=O)c1c(S(=O)(=O)N2CCOC(COc3ccccc3)C2)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)N2CCOC(COc3ccccc3)C2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Product: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)N1CCO[C@@H](COc2ccccc2)C1

Procedure:
Using the same procedures described for Example 23, replacing the product from Step A of Example 22, ethyl(±)-5-chloro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate, with ethyl(±)-5-bromo-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate, the second-eluting enantiomer of ethyl 5-bromo-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate was converted to the titled compound after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 493.85 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[N:31]3[CH:32]=[CH:33][C:34]([C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)=[CH:35][C:30]3=[N:29][CH:28]=2)[CH:22]=1)=[O:19])(C)(C)C>C(Cl)Cl>[NH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[N:31]3[CH:32]=[CH:33][C:34]([C:36]4[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=4)=[CH:35][C:30]3=[N:29][CH:28]=2)[CH:22]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)Nc1cccc(-c2cnc3cc(-c4ccc(F)cc4)ccn23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCNC(=O)Nc1cccc(-c2cnc3cc(-c4ccc(F)cc4)ccn23)c1
Yield: 15.1 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a stirred solution of [2-(3-{3-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-ureido)-ethyl]-carbamic acid tert-butyl ester (85 mg, 0.17 mmol) in CH2Cl2 (2 ml) at 0° C. After 1 h the volatiles were removed in vacuo and the residue was purified by preparative HPLC to give the title compound (10 mg, solid).
Reaction SMILES: [CH2:1]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:22]([O-])(=[O:24])[CH3:23].[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)(Cl)Cl>[OH:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:20][C:19]=1[C:22](=[O:24])[CH3:23]
Reactant: CCCCCCCCCCCCCCc1ccc(O)cc1
Reactant: CC(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCc1ccc(O)c(C(C)=O)c1
Temperature: 120 °C

Procedure:
A 900 mg portion of 4-tetradecylphenol, acetate was heated at 70° C. under argon and 720 mg of aluminum trichloride was added portionwise. After 2 hours the temperature was raised to 120° C. and the mixture was heated at this temperature for 45 minutes. The mixture was then cooled, diluted with chloroform, washed with 50% aqueous hydrochloric acid then water and dried. The solvents were removed and the residue recrystallized from ether-methanol, giving 850 mg of the desired compound, mp 38.5°-39.5° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11](I)=[CH:12][N:13]=[C:7]2[CH:6]=1)=O.O.[NH2:16][NH2:17]>C(O)C>[N:13]1[CH:12]=[CH:11][N:8]2[CH:9]=[CH:10][C:5]([C:3]([NH:16][NH2:17])=[O:2])=[CH:6][C:7]=12
Reactant: NN
Reactant: COC(=O)c1ccn2c(I)cnc2c1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccn2ccnc2c1
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a suspension of methyl-3-Iodo-imidazo[1,2-a]pyridine-7-carboxylate (0.3 g, 1.7 mmol, 1.0 equiv) in ethanol (3 ml) was added hydrazine hydrate (0.414 ml, 8.52 mmol). The mixture was heated to 70 deg C. for 1 h then allowed to cool. The solid was filtered off and washed with ethyl acetate and ether then dried to afford 0.209 g of product. 1H NMR (400 MHz, DMSO-d6): 9.95 (1H, s), 8.60 (1H, d), 8.05 (2H, d), 7.70 (1H, d), 7.30 (1H, dd), 4.58 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([OH:13])[C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:6].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C@H:4]([OH:13])[C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH:6][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: COC(=O)[C@H](O)[C@@H](N)c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](O)[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (2R,3S)-β-phenyl isoserine methyl ester (2) (Preparation 1, 2 mM) in pyridine containing a small amount of DMAP is cooled in an ice bath and treated with benzyl chloroformate (0.8 ml). After stirring at room temperature overnight, the reaction is diluted with ethyl acetate, washed with 5% aqueous sodium bisulfate, dried and evaporated. The product is obtained pure by silica gel chromatography in ethyl acetate-hexane mixtures. Mp 120-121° C. NMR(CDCl3, TMS): δ3.26 (m, 1H); 3.79 (s, 3H); 4.47 (m, 1H); 5.06 (m, 2H); 5.27 (d, 1H); 5.75 (m, 1H); 7.20-7.50 (m, 10 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:5]=[C:4]([CH:19]([OH:22])CO)[N:3]=1.I([O-])(=O)(=O)=O.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:5]=[C:4]([CH:19]=[O:22])[N:3]=1
Reactant: OCC(O)c1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: O=Cc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Reaction time: 16 h
Yield: 92.8 %

Procedure:
To a mixture of 1-{4-chloro-6-[2-(2,4-dichloro-phenyl)-ethylamino]-pyrimidin-2-yl}-ethane-1,2-diol (320 mg, 0.88 mmol) in MeOH (5 mL) and water (5 mL) is added sodium meta-periodate (567 mg, 2.65 mmol) and stirred for 16 hours before adding water (50 mL), and extracted thrice with EtOAc (30 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 4-chloro-6-[2-(2,4-dichloro-phenyl)-ethylamino]-pyrimidine-2-carbaldehyde (270 mg, 93%) as a solid.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[N:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[N:5]=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2cccc(CCOCCC(=O)OC(C)(C)C)c2)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1cc(-c2cccc(CCOCCC(=O)O)c2)nn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl 3-(3-(1-ethyl-1H-1,2,3-triazol-4-yl)phenethoxy)propanoate [Example 4, Step iii)] (382 mg), DCM (5 mL) and TFA (5 mL) was stirred at 25° C. for 30 min and concentrated under vacuum to give the subtitled compound as a gum (625 mg). 1H NMR (300 MHz, CDCl3) δ 7.92 (s, 1H), 7.75 (s, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.24 (s, 1H), 4.53 (q, J=7.4 Hz, 2H), 3.76 (t, J=5.9 Hz, 2H), 3.76 (t, J=6.0 Hz, 2H), 2.93 (t, J=6.0 Hz, 2H), 2.63 (t, J=5.9 Hz, 2H), 1.67 (t, J=7.4 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[C:11]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:9]=[N:8][CH:7]=[C:6]([Cl:10])[C:3]=2[C:4]#[N:5])=[CH:21][CH:20]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(c1ccccc1)c1ccc(B(O)O)cc1
Reactant: N#Cc1c(Cl)cncc1Cl
Product: N#Cc1c(Cl)cncc1-c1ccc(C(=O)c2ccccc2)cc1
Yield: 80 %

Procedure:
Following conditions described in Step 1 of Example 50, 3,5-dichloroisonicotinonitrile was reacted with 4-benzoylphenylboronic acid to give 3-(4-benzoylphenyl)-5-chloroisonicotinonitrile (˜80% pure). MS (ES+) m/z: 351 (M+H); LC retention time: 3.980 min (analytical HPLC Method A). Step 2:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([NH2:7])[CH2:5][CH3:6].[C:8](#N)[CH3:9]>[Ni]>[CH3:8][CH:9]1[NH:7][CH:4]([CH2:5][CH3:6])[CH2:3][CH2:2][NH:1]1
Reactant: CCC(N)CCN
Reactant: CC#N
Agent: [Ni]
Product: CCC1CCNC(C)N1
Temperature: 90 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
Ninety grams (96.8% purity, 0.854 mole) 1,3-diaminopentane, 60 g acetonitrile (1.46 moles) and 3 g powdered nickel on alumina catalyst were charged to a 300 ml autoclave described in Example 1. The mixture was stirred and heated at 90° C. and 650 psig pressure for 6 hours followed by cooling to 25° C. Analysis of the filtered product on a capillary GC column showed a 42.9% conversion of 1,3-diaminopentane and 94% yield of 2-methyl-4-ethylhexahydropyrimidine.
Reaction SMILES: I[C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([NH2:18])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>>[CH3:15][N:14]1[C:5]2[C:4]3[N:3]=[C:2]([NH:26][CH:23]4[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]4)[N:11]=[CH:10][C:9]=3[CH2:8][CH2:7][C:6]=2[C:12]([C:16]([NH2:18])=[O:17])=[N:13]1
Reactant: CN1CCC(N)CC1
Reactant: Cn1nc(C(N)=O)c2c1-c1nc(I)ncc1CC2
Product: CN1CCC(Nc2ncc3c(n2)-c2c(c(C(N)=O)nn2C)CC3)CC1
Yield: 0 %

Procedure:
8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (0.10 g, 0.28 mmol) and 1-methylpiperidin-4-amine (0.19 g, 1.7 mmol) were heated at 80° C. under nitrogen for 3 hours. The mixture was concentrated under reduced pressure and the residue was purified by chromatography on a silica gel column (eluant: dichloromethane/ethanol/ammonium hydroxide 90/10/1) to give 0.047 mg of 1-methyl-8-[(1-methylpiperidin-4-yl)amino]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (50% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[CH:7]=O)[CH3:2].[NH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])/[CH:7]=[N:16]/[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)[CH3:2]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCOc1cc(C=O)ccc1OC(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1cc(/C=N/c2ccc(C#N)cc2)ccc1OC(C)C
Yield: 86.9 %

Procedure:
A mixture of 3-ethoxy-4-isopropoxybenzaldehyde (1.78 g, 8.55 mmol), 4-aminobenzonitrile (1.01 g, 8.55 mmol), and 5 g 4 A molecular sieves in 20 mL toluene was refluxed with azeotropic removal of water for 2 h. The mixture was filtered and concentrated to afford 2.29 g of Intermediate 1.1 as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12](O)[CH3:13]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
First, 17.24 g of 4-chlorophenylacetic acid was dissolved in 200 ml of ethanol, to which a catalytic amount of p-toluenesulfonic acid was added, and the mixture was heated under reflux for 10 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated. The residue was poured into water and extracted with ethyl acetate, and the organic layer was dried and then concentrated. The residue was subjected to silica gel chromatography, which afforded 19.0 g of ethyl 4-chlorophenylacetate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>C(O)C.CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][CH2:14][CH2:12][OH:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: NCCO
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CO
Solvent: CCO
Product: O=[N+]([O-])c1cnc(Cl)nc1NCCO
Reaction time: 18 h
Yield: 81 %

Procedure:
19.40 g (0.1 mole) of 2,4-dichloro-5-nitropyrimidine was completely dissolved in 60 ml of ethanol and maintained below 15° C. To this solution, a solution of 12.22 g (0.2 mole) of ethanolamine in 20 ml of methanol was added slowly while maintaining the temperature of a reactor below 20° C. The mixture was stirred below 15° C. for 18 hours. After completion of the reaction, the reaction product was maintained below 5° C., and the resulting crystal was filtered, washed and dried, thereby giving 17.71 g (81% yield) of light yellow-colored 2-chloro-4-(2-hydroxyethylamino)-5-nitropyrimidine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]([Cl:13])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:4]=1.C(N(CC)C(C)C)(C)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>CN(C)C=O>[C:30]([NH:1][CH2:2][C:3]1[C:12]([Cl:13])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:4]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(Cl)c(CN)nc1-c1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(CNC(C)=O)nc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 6-(aminomethyl)-5-chloro-2-(3-fluorophenyl)nicotinate (0.35 g, 1,2 mmol) was stirred in N,N-dimethylformamide (5 mL) with N,N-diisopropylethylamine (0.41 mL, 2.4 mmol) and acetic anhydride (0.17 mL, 1.8 mmol) was added. The mixture was stirred for 30 minutes at room temperature. Evaporation gave the crude material which was contaminated with the corresponding dechlorinated byproduct (0.4 g, 100%). LCMS calculated for C16H15ClFN2O3 (M+H)+: m/z=337.1. found 336.9.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[F:19][C:20]1[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=1[C:22]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)=[O:23]>>[F:19][C:20]1[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=1[C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=2)=[CH:26][CH:25]=1)=[O:23]
Reactant: O=C(c1ccc(O)cc1)c1ccccc1F
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccccc3F)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 2-fluoro-4′-hydroxybenzophenone and cleavage from the resin (Standard Procedure G) gave an oily solid (7%). 1H-NMR (200.15 MHz, CDCl3): δ 7.81 (dd, 2H, J=8.8, 1.3), 7.54–7.45 (m, 2H), 7.28–7.09 (m, 4H), 6.94 (d, 2H, J=8.6), 6.83 (d, 2H, J=8.6), 4.24 (t, 2H, J=6.2), 4.14 (t, 2H, J=6.2), 3.98 (dd, 1H, J=7.0, 4.6), 3.40 (s, 3H), 3.09 (dd, 1H, J=14.2, 4.6), 2.96 (dd, 1H, J=14.2, 7.0), 2.28 (q, 2H, J=6.2).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:18][C@@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]([NH:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:4][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.[F:31][C:32]1[CH:66]=[CH:65][C:35]([C:36](/[N:38]=[C:39]2/N([C@H]3CC[C@@H](C(=O)NC(C)C)CC3)C3C=C(OCCOC)N=CC=3N/2)=[O:37])=[CH:34][CH:33]=1.FC1C=CC(C(N=C=S)=O)=CC=1>>[F:31][C:32]1[CH:33]=[CH:34][C:35]([C:36](/[N:38]=[C:39]2/[N:18]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([C:25](=[O:26])[NH:27][CH:28]([CH3:30])[CH3:29])[CH2:21][CH2:20]3)[C:3]3[CH:4]=[C:5]([O:8][CH2:9][CH2:10][CH2:11][N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)[N:6]=[CH:7][C:2]=3[NH:1]/2)=[O:37])=[CH:65][CH:66]=1
Reactant: COCCOc1cc2c(cn1)[nH]/c(=N\C(=O)c1ccc(F)cc1)n2[C@H]1CC[C@@H](C(=O)NC(C)C)CC1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCCN3CCOCC3)ncc2N)CC1
Agent: O=C(N=C=S)c1ccc(F)cc1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3cnc(OCCCN4CCOCC4)cc32)CC1

Procedure:
The title compound was prepared from cis-4-(5-amino-2-(3-morpholinopropoxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide using a procedure analogous to that used to prepare (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide with 1.3 equivalents of 4-fluorobenzoyl isothiocyanate. Isolated as an off-white solid (98 mg, 104% yield). M/Z calc'd for C30H39FN6O4: 566.67. found 567 [M+H].
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.[Br:14][C:15]1[S:19][C:18]2=[N:20][C:21]([C:23](O)=[O:24])=[CH:22][N:17]2[CH:16]=1>>[Br:14][C:15]1[S:19][C:18]2=[N:20][C:21]([C:23]([NH:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:9][CH:8]=3)=[O:24])=[CH:22][N:17]2[CH:16]=1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using (4-(trifluoromethoxy)phenyl)methanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>C1COCC1.[Na+].[Cl-]>[Br:13][C:14]1[C:15]([Si:23]([CH3:26])([CH3:25])[CH3:24])=[C:16]([F:21])[C:17]([F:20])=[CH:18][CH:19]=1
Reactant: C[Si](C)(C)Cl
Reactant: Fc1ccc(Br)cc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)c1c(Br)ccc(F)c1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Diisopropylamine (2.62 g, 25.9 mmol) was added drop wise to a solution of n-BuLi (2.5 M in hexane, 10.4 mL, 26.0 mmol) in anhydrous THF (19 mL) at −78° C., then the solution was stirred at −78° C. for 15 minutes. To this solution was added 4-bromo-1,2-difluorobenzene (5.00 g, 25.9 mmol), then the mixture was stirred at −78° C. for 2 hours. Freshly distilled chlorotrimethylsilane (2.81 g, 25.9 mmol) was added, then the mixture was allowed to warm to room temperature slowly over two hours. The mixture was diluted with saturated NaCl (aq) then extracted with EtOAc (3×40 mL). The combined organic layers were dried over MgSO4, filtered, then concentrated to afford the title compound as a light yellow oil. This material was used directly in the next step without further purification. 1H NMR (500 MHz, CDCl3): δ 7.27 (ddd, J=8.7, 4.0, 1.7 Hz, 1H); 7.00 (q, J=8.9 Hz, 1H); 0.47 (s, 9H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=1)[CH3:4].C1OCCOCCOCCOCCOCCOC1.Br[CH2:35][CH2:36][CH2:37][CH2:38]Br>CN(C=O)C.O>[CH2:3]([O:5][C:6]([C:7]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:15])[CH3:4]
Reactant: CCOC(=O)Cc1cccc(Br)c1
Reactant: BrCCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2cccc(Br)c2)CCCC1
Reaction time: 0.42 h
Yield: 91.2 %

Procedure:
Sodium hydride (60% in oil, 1.07 g, 26.8 mmol) is added to a solution of (3-bromo-phenyl)-acetic acid ethyl ester [2.59 g, 10.7 mmol] and 18-crown-6 (catalytic amount) in N,N′-dimethylformamide (50 mL). The mixture is stirred for 25 minutes and 1,4-dibromobutane (1.41 mL, 11.8 mmol) is added dropwise via syringe. The mixture is stirred for 18 hours at ambient temperature, diluted with water (100 mL) and extracted thrice with EtOAc (60 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 1-(3-bromo-phenyl)-cyclopentanecarboxylic acid ethyl ester [2.9 g, 91%] as an oil, which is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([CH3:15])[CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])=[C:4]([CH2:15][Br:16])[CH:3]=1
Reactant: Cc1cc(Br)ccc1NC(=O)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Nc1ccc(Br)cc1CBr)C(F)(F)F
Yield: 67.5 %

Procedure:
A solution of Example 478A (2.5 g, 8.9 mmol) and N-bromosuccinimide (1.58 g, 8.9 mmol) in carbon tetrachloride (25 mL) was irradiated with a 100-watt incandescent bulb overnight. The solution was filtered and the filtrate was concentrated. The concentrate was purified by flash chromatography on silica gel using 3–4% ethyl acetate/hexanes to give 2.17 g (68% yield) of the desired product. MS (ESI(−)) m/e 360, 362 (M−H)−.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:19])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=1.Br[C:21]1[N:25]([CH3:26])[N:24]=[N:23][N:22]=1>C(O)C>[CH3:26][N:25]1[C:21]([NH:1][CH2:2][CH:3]([OH:19])[CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:7]=2)=[N:22][N:23]=[N:24]1
Reactant: Cn1nnnc1Br
Reactant: NCC(O)COc1cccc(CN2CCCCC2)c1
Solvent: CCO
Product: Cn1nnnc1NCC(O)COc1cccc(CN2CCCCC2)c1
Reaction time: 0.25 h
Yield: 53.2 %

Procedure:
A solution of 1-amino-3-[3-(1-piperidinylmethyl)phenoxy]-2-propanol (1.19 g) and 5-bromo-1-methyl-1H-tetrazole (0.735 g) in absolute ethanol (6 ml) was heated in an autoclave at 125° for 18 h. The mixture was cooled, evaporated, saturated with sodium carbonate solution (30 ml) and ethyl acetate (30 ml) added. The mixture was stirred for 15 min. and filtered to give a white solid (830 mg) which was recrystallised from ethyl acetate (20 ml) to give the title compound (0.58 g) as white micro-crystals, m.p. 156°-7°.