Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:61])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([C@@H:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:60])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:62]OC(NC(C1C=CC=CC=1C)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:61])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:60])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=6[CH3:62])=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Reactant: COC(=O)NC(C(=O)O)c1ccccc1C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1C
Yield: 50 %

Procedure:
This compound was prepared following the procedure for [1-(2-{5-[6-(4-{2-[1-(2S)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using Methoxycarbonylamino-o-tolyl-acetic acid (0.03 g, 0.12 mmol, 1.75 equiv.) to provide [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-o-tolyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.03 g, 50%) as a white powder. LCMS-ESI+: calc'd for C48H52N8O6: 836.4 (M+). Found: 837.4 (M+H+). 1H-NMR: 400 MHz, (CDCl3) δ: (Mixture of diastereomers) 7.61-8.00 (m, 16H), 7.18-7.41 (m, 12H), 7.10 (s, 2H), 5.28-5.63 (m, 10H), 4.36 (t, 2H), 3.72-3.86 (m, 4H), 3.68 (s, 6H), 3.66 (s, 6H), 2.79-3.07 (m, 8H), 2.50 (s, 3H), 2.44 (s, 3H), 2.38 (m, 4H), 1.86-2.28 (m, 8H), 0.88-0.94 (m, 12H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[O:5][N:4]=1.C(N(C(C)C)C(C)C)C.Br[CH2:34][C:35]1[C:36]([CH2:41]Br)=[CH:37][CH:38]=[CH:39][CH:40]=1>CN(C)C=O>[CH2:41]1[C:36]2[C:35](=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:34][N:1]1[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[O:5][N:4]=1
Reactant: CN1Cc2c(-c3nc(CN)no3)ncn2-c2ccccc2C1=O
Reactant: BrCc1ccccc1CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1Cc2c(-c3nc(CN4Cc5ccccc5C4)no3)ncn2-c2ccccc2C1=O
Yield: 23.1 %

Procedure:
1.28 g (4.1 mmol) of 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 25 ml of N,N-dimethylformamide, 2 ml (11.7 mmol) of N-ethyldiisopropylamine and 1.19 g (4.5 mmol) of α,α'-dibromo-o-xylene were stirred at room temperature for 4 hours. After evaporating the solvent the residue was chromatographed on 180 g of silica gel while eluting with ethyl acetate. The uniform fractions were evaporated. There was obtained 0.39 g (23%) of 5,6-dihydro-3-(3-isoindolin-2-ylmethyl-1,2,4-oxadiazol-5-yl)-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 155°-160°.
Reaction SMILES: C([O:4][CH2:5][C:6]([C:8]1[N:16]2[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]2)=[CH:10][C:9]=1[C:17]([O:19]C)=O)=O)(=O)C.[NH2:21][NH2:22]>C(O)C>[OH:4][CH2:5][C:6]1[C:8]2[N:16]3[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]3)=[CH:10][C:9]=2[C:17](=[O:19])[NH:22][N:21]=1
Reactant: NN
Reactant: COC(=O)c1cc2ccccn2c1C(=O)COC(C)=O
Solvent: CCO
Product: O=c1[nH]nc(CO)c2c1cc1ccccn12

Procedure:
Following the procedure of Example 3, reaction of 2-carbomethoxyindolizine with acetoxyacetyl chloride gave 3-acetyloxyacetyl-2-carbomethoxyindolizine (IX). Reaction of IX with 1.5 equiv of anhydrous hydrazine in dry ethanol gave 4-hydroxymethylpyridazino[4,5-b]indolizin-1-one which upon refluxing with excess POCl3 gave 1-chloro-4-chloromethylpyridazino[4,5-b]indolizine (X). Compound X (1.0 g, 4.0 mmol) was combined with excess N,N-diethylaminopropylamine (2.68 mL, 17 mmoL) in N-methylpyrrolidinone (2 mL) containing TEA (0.74 mL, 1.2 equiv.) and 1.2 equiv. of ammonium chloride (vigorous initial reaction with gas evolution). When the reaction subsided the stirred reaction mixture was heated at 100° C. overnight. After cooling to room temperature, the volatiles were removed by vacuum distillation. The residue was dissolved in methylene chloride and extracted with water (3 times), dried (MgSO4), and the solvent evaporated. The residue was purified by flash column chromatography on silica gel eluting with 20% methanol in methylene chloride containg 2% ammonium hydroxide. The isolated free base was converted to the tetra hydrochloride salt using ethereal HCl in ether m.p. 120°-123° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:26]#[C:27][CH3:28])[CH2:21][C:22]([O:24]C)=[O:23])=[CH:16][CH:15]=1)[C:7](=[O:29])[CH2:6][C:5]2([CH3:31])[CH3:30].[Li+].[OH-].OS(O)(=O)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:26]#[C:27][CH3:28])[CH2:21][C:22]([OH:24])=[O:23])=[CH:16][CH:15]=1)[C:7](=[O:29])[CH2:6][C:5]2([CH3:31])[CH3:30]
Reactant: CC#CC(CC(=O)OC)c1ccc(OCN2C(=O)CC(C)(C)c3cc(Br)ccc32)cc1
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC#CC(CC(=O)O)c1ccc(OCN2C(=O)CC(C)(C)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
91 mg of methyl 3-[4-(6-bromo-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethoxy)-phenyl]hex-4-ynoate were dissolved in 1.4 ml of tetrahydrofuran, and 1N LiOH solution was added. The experiment was stirred at room temperature for 2 hours and left to stand at room temperature overnight. Subsequently, 2N H2SO4 was used to adjust the pH to 1 and the mixture was extracted with 80 ml of ethyl acetate. The organic phase was removed and dried over MgSO4, filtered and then concentrated under reduced pressure. The residue was purified by means of RP-HPLC. This gave 27.0 mg of 3-[4-(6-bromo-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethoxy)phenyl]hex-4-ynoic acid,
Reaction SMILES: O1CCOCC1.Cl.[NH2:8][C:9]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1)=[O:16])=[O:12]>CO>[NH2:8][C:9]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]1)=[O:16])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)CNC(=O)c2cc(Cl)ccc2N)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ccc(Cl)cc1C(=O)NCC(=O)NCC1CCNCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 4 M dioxane solution of HCl (9.5 mL) was added to a methanol (20 mL) solution of 4-[[(N-(2-amino-5-chlorobenzoyl)glycyl)amino]methyl]-1-(tert-butoxycarbonyl)piperidine (1.63 g, 3.84 mmol), and the resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated, and a 2 M aqueous solution of NaOH (20 mL) was added to the resulting residue. The obtained mixture was extracted with dichloromethane (20 mLX 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to thereby afford 4-[[(N-(2-amino-5-chlorobenzoyl)glycyl)amino]methyl]piperidine (1.19 g, 95%). 1H NMR (CDCl3, 270 MHz) δ 1.10-1.76 (m, 4H), 2.55 (td, J=2.4 and 12.2 Hz, 2H), 3.00-3.10 (m, 2H), 3.17 (t, J=6.2 Hz, 2H), 3.48 (s, 2H), 4.03 (d, J=4.9 Hz, 2H), 5.50 (br. s, 2H), 6.11-6.23 (m, 1H), 6.60 (d. J=8.8 Hz, 1H), 6.85-7.02 (m, 1H), 7.15 (dd, J=2.7 and 8.8 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H). ESI/MS m/e 325.2 (M++H, C15H23ClN4O2).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NCCN1CCOCC1
Solvent: c1ccncc1
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
35 G. of p-chlorobenzoyl chloride are added dropwise to a solution of 26 g. of N-(2-aminoethyl)-morpholine in 200 ml. of pyridine, while stirring and cooling with ice-water. Thereafter, the mixture is stirred overnight at room temperature and subsequently evaporated to dryness. Then, the residue is evaporated twice more with 200 ml. of toluene each time. The solid residue is taken up in 300 ml. of ice-water and 300 ml. of methylene chloride and rendered basic with 3-N sodium hydroxide solution. The phases are separated and the methylene chloride extract is washed with water, dried over sodium sulfate and evaporated to dryness. The residue is recrystallized from isopropanol and 41.5 g. of p-chloro-N-(2-morpholinoethyl)-benzamide, melting point 137° C., are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[CH3:10][N:11]([CH3:36])[C:12]([C:14]1[N:19]=[CH:18][C:17]([O:20][C:21]2[C:26]3[CH:27]=[C:28]([CH3:30])[O:29][C:25]=3[CH:24]=[C:23]([C:31](OCC)=[O:32])[CH:22]=2)=[CH:16][N:15]=1)=[O:13]>>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:31]([C:23]2[CH:22]=[C:21]([O:20][C:17]3[CH:18]=[N:19][C:14]([C:12]([N:11]([CH3:10])[CH3:36])=[O:13])=[N:15][CH:16]=3)[C:26]3[CH:27]=[C:28]([CH3:30])[O:29][C:25]=3[CH:24]=2)=[O:32])=[N:7][CH:8]=1
Reactant: CCOC(=O)c1cc(Oc2cnc(C(=O)N(C)C)nc2)c2cc(C)oc2c1
Reactant: COc1cnc(N)cn1
Product: COc1cnc(NC(=O)c2cc(Oc3cnc(C(=O)N(C)C)nc3)c3cc(C)oc3c2)cn1

Procedure:
The title compound (3) was prepared by a method analogous to that described in Example 1 using 5-methoxypyrazin-2-amine and ethyl 4-(2-(dimethylcarbamoyl)-pyrimidin-5-yloxy)-2-methylbenzofuran-6-carboxylate (I-2a).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.C(C1NC(C=O)=C(C)N=1)C.[CH:23]1([C:28]2([CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4([C:49]#[N:50])[CH2:48][CH2:47][CH2:46][CH2:45]4)=[C:40]([F:51])[CH:39]=3)[CH2:33][C:32](=[O:34])[CH2:31][C:30](=[O:35])[O:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1.C1(C2(CCC3C=CC(C(C)(C)C#N)=C(F)C=3)CC(O)=CC(=O)O2)CCCC1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH2:11][C:31]3[C:30](=[O:35])[O:29][C:28]([CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([C:44]5([C:49]#[N:50])[CH2:45][CH2:46][CH2:47][CH2:48]5)=[C:40]([F:51])[CH:39]=4)([CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:33][C:32]=3[OH:34])[N:10]=2)[CH:7]=1
Reactant: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CCCC1
Reactant: O=Cc1nc2ncc(Cl)cn2n1
Agent: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(O)=CC(=O)O2)cc1F
Agent: CCc1nc(C)c(C=O)[nH]1
Product: N#CC1(c2ccc(CCC3(C4CCCC4)CC(O)=C(Cc4nc5ncc(Cl)cn5n4)C(=O)O3)cc2F)CCCC1

Procedure:
The title compound was prepared analogously to Example A(97) where 6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde and 1-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopentanecarbonitrile (Example A(189) (was substituted in place of 2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile. 1H NMR (400 MHz, CDCl3) δ: 1.41-1.98 (m, 17H), 2.30-2.68 (m, 6H), 3.62 (d, J=16 Hz, 1H), 3.71 (d, J=16 Hz, 1H), 6.99-7.03 (m, 2H), 7.21-7.25 (m, 1H), 8.74 (s, 1H), 9.45 (s, 1H), 10.8 (s, 1H). Anal. Calcd. For C30H31ClFN5O3: C, 63.88; H, 5.54; N, 12.42. Found: C, 63.73; H, 5.71; N, 12.17. MS (ESI): 564 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][O:8][C:9]([CH:11](P(OCC)(OCC)=O)[N:12]=[CH:13][S:14][CH2:15][C:16](=O)[CH3:17])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[CH3:17][C:16]1[CH2:15][S:14][CH:13]=[N:12][C:11]=1[C:9]([O:8][CH2:7][C:6]1[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:10]
Reactant: CCOP(=O)(OCC)C(N=CSCC(C)=O)C(=O)OCc1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(C)CSC=N2)cc1
Yield: 92.3 %

Procedure:
A solution of 2-oxo-propyl N-(p-methoxybenzyloxycarbonyl-diethylphosphonomethyl)thioformimidate (59 mg.) in acetone (0.5 ml.) is stirred with powdered potassium carbonate (25 mg.) for 21 hours at room temperature and under a nitrogen atmosphere. The resulting mixture is diluted with methylene chloride and filtered. Evaporation of the filtrate in vacuo yields an oil which is dissolved in carbon tetrachloride (4 ml.), washed with water (2 × 2 ml.) and saturated brine (4 ml.), dried over magnesium sulfate, and evaporated in vacuo to yield p-methoxybenzyl 5-methyl-6H-1,3-thiazine-4-carboxylate (35 mg.) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C:15](OCC)=[N:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[C:29]([NH:31][NH2:32])=O>C(O)CCC>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]2[C:29]([C:21]3[S:20][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]=3)=[N:31][N:32]=[C:15]2[CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)c1nc2ccccc2s1
Reactant: CCOC1=NCCN(C(=O)OCc2ccccc2)C1
Solvent: CCCCO
Product: O=C(OCc1ccccc1)N1CCn2c(nnc2-c2nc3ccccc3s2)C1
Temperature: 25 °C

Procedure:
A mixture of 5-ethoxy-3,6-dihydro-2H-pyrazine-1-carboxylic acid benzyl ester (prepared according to the method of Example 259, Step A, 490 mg, 1.87 mmol) and benzothiazole-2-carboxylic acid hydrazide (360 mg, 1.87 mmol; J. Org. Chem. 1958, 23, 1344) in n-butanol (2 mL) was stirred at reflux overnight, cooled to room temperature, concentrated, and purified by flash column chromatography (1% methanol/chloroform) to give 580 mg of the title compound of Example 259, Step B (contaminated with an equimolar amount of benzothiazole-2-carboxylic acid hydrazide which was removed in the subsequent step) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[S:26][CH:27]=[CH:28][N:29]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([NH:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
A solution of 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid (1.01 g, 3.39 mmol) in methylene chloride (8.5 mL) was treated with 2 drops of dry N,N-dimethylformamide. The reaction mixture was cooled to 0° C. and then treated with oxalyl chloride (3 mL, 33.98 mmol). The reaction mixture was stirred at 0° C. for 10 min and then stirred at 25° C. for 15 h. The reaction mixture was concentrated in vacuo. The resulting yellow oil was dissolved in a small amount of methylene chloride and slowly added to a cooled solution (0° C.) of 2-aminothiazole (680.6 mg, 6.79 mmol) and N,N-diisopropylethylamine (1.2 mL, 6.79 mmol) in methylene chloride (17 mL). The resulting reaction mixture was stirred at 0° C. for 10 min and then at 25° C. for 15 h. The reaction mixture was concentrated in vacuo to remove methylene chloride. The resulting residue was diluted with ethyl acetate (200 mL). The organic phase was washed with a 10% aqueous hydrochloric acid solution (2×100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×100 mL), and washed with a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(4-bromo-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (1.23 g, 95%) as an orange solid which was used in subsequent reactions without further purification. An analytical sample was recrystallized from ethyl acetate to provide a cream solid: mp 201-202° C.; EI-HRMS m/e calcd for C17H19BrN2OS (M+) 378.0401, found 378.0405.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1[CH:20]=[C:19]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[O:18][N:17]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt]>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]2[O:18][N:17]=[C:16]([CH2:15][NH:14][C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[N:6]=[CH:5][C:4]=3[NH2:1])[CH:20]=2)[CH:22]=1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCc1cc(-c2cccnc2)on1
Agent: [Pt]
Product: Nc1cnc2ccccc2c1NCc1cc(-c2cccnc2)on1
Yield: 89.8 %

Procedure:
3-Nitro-N-[(5-pyridin-3-ylisoxazol-3-yl)methyl]quinolin-4-amine (1.17 g, 3.37 mmol) was hydrogenated in the presence of 5% platinum on carbon (0.120 g) according to the method described in Part G of Example 35 to provide 0.96 g of N4-[(5-pyridin-3-ylisoxazol-3-yl)methyl]quinoline-3,4-diamine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)[CH3:2].[CH3:13][C:14]1[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:20][C:19]2[C:14]([CH3:13])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: Cc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Oc2cccnc2C)cc1
Temperature: 150 °C
Reaction time: 1.33 h

Procedure:
A reaction tube containing a magnetic stirrer bar was charged with ethyl-4-fluorobenzoate (1 mmol), 2-methyl-3-pyridol (1.0 mmol), potassium carbonate (1.08 mmol) and DMF (2 ml). The reaction tube was then sealed and heated by microwave irradiation (100 W, 4 mins) to 150° C. and held at that temperature for 80 mins. The solution was filtered to remove the insoluble potassium carbonate and then concentrated in vacuo. The residue was purified by preparative HPLC and freeze dried to give 4-(2-Methyl-pyridin-3-yloxy)-benzoic acid ethyl ester as a white solid which was hydrolysed by 6N aqueous HCl solution heated by microwave irradiation (200 W) for 3 mins at 150° C. The solution was freeze dried to give to 63 mg of hydrochloride salt of the title compound as a white powder m/z=229 in MS ES+, which was characterised by HPLC and MS.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([C@@H:12]2[CH2:16][C@@H:15]([F:17])[CH2:14][N:13]2[CH3:18])=O)=[N:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C@@H:12]3[CH2:16][C@@H:15]([F:17])[CH2:14][N:13]3[CH3:18])=[N:9][N:8]=2)[CH:7]=1
Reactant: CN1C[C@H](F)C[C@H]1C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1C[C@H](F)C[C@H]1c1nnc2ccc(F)cn12
Reaction time: 4 h
Yield: 113.7 %

Procedure:
A solution of Intermediate 91b (189 mg, 0.79 mmol), Ph3P (416 mg, 1.59 mmol) and Et3N (0.44 mL, 3.17 mmol) in THF (10 mL) at RT was added hexachloroethane (375 mg, 1.59 mmol) portion wise and the mixture stirred for 4 h. The solution was diluted with water and extracted with DCM. The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound as light yellow powder (214 mg, 63%). LCMS (Method 3): Rt 0.42 min, m/z 239 [MH+].
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[CH:9][CH:8]=1.[C:22](O)(=O)C>>[Br:6][C:7]1[CH:8]=[C:9]2[C:10]([CH2:13][CH2:14][N:15]([C:16](=[O:21])[C:17]([F:19])([F:20])[F:18])[CH2:22]2)=[CH:11][CH:12]=1
Reactant: O=C(NCCc1ccc(Br)cc1)C(F)(F)F
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Into acetic acid (42 ml) were added dropwise under ice cooling sulfuric acid (28 ml), subsequently N-(2-(4-bromophenyl)ethyl)trifluoroacetamide (7.8 g) and paraformamide (1.27 g) and the resulting mixture was stirred overnight under a nitrogen atmosphere. The reaction mixture was poured into ice water and was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium hydrogen carbonate, water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 7-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (8.1 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[Li]CCCC.CON(C)[C:30](=[O:34])[CH2:31][CH2:32][CH3:33]>C1COCC1>[Si:15]([O:14][CH:13]1[C:6]2=[CH:5][C:4]3[CH:3]=[C:2]([C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[CH:10]=[CH:9][C:8]=3[N:7]2[CH2:11][CH2:12]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OC1CCn2c1cc1cc(Br)ccc12
Reactant: CCCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(=O)c1ccc2c(c1)cc1n2CCC1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of 7-bromo-1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indole (4.1 g, 11.2 mmol) in THF (60 mL), cooled to −78° C., was added n-BuLi (7.7 mL, 1.6M, 12.3 mmol) dropwise. The reaction mixture was allowed to stir at −78° C. for 5 minutes before N-methoxy-N-methylbutyramide (1.6 g, 12.3 mmol) was added. The resulting orange solution was allowed to slowly warm to room temperature then quenched with the addition of a saturated solution of NH4Cl. The reaction mixture was poured into H2O (100 mL) and extracted with Et2O (2×100 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound as a white solid (4.0 g, 99%).
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(CN2C(=O)C3=CC=CC=C3C2=O)C(=O)N(CC(C)C)N=1.[C:32]([C:35]1[C:36](=[O:53])[N:37]([CH2:49][CH:50]([CH3:52])[CH3:51])[N:38]=[C:39]([C:41]2[CH:46]=[CH:45][C:44]([S:47][CH3:48])=[CH:43][CH:42]=2)[CH:40]=1)(O)=[O:33]>>[OH:33][CH2:32][C:35]1[C:36](=[O:53])[N:37]([CH2:49][CH:50]([CH3:51])[CH3:52])[N:38]=[C:39]([C:41]2[CH:46]=[CH:45][C:44]([S:47][CH3:48])=[CH:43][CH:42]=2)[CH:40]=1
Reactant: CSc1ccc(-c2cc(C(=O)O)c(=O)n(CC(C)C)n2)cc1
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN2C(=O)c3ccccc3C2=O)c1=O
Product: CSc1ccc(-c2cc(CO)c(=O)n(CC(C)C)n2)cc1
Yield: 35.3 %

Procedure:
Following the procedure of Example 1 (8), 4-carboxy-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one was reacted to yield the title compound as a yellow oil (yield: 35.3%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O-:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].O.[CH:13]([Cl:16])(Cl)Cl>CN(C)C=O>[Cl:16][C:13]1[CH:5]=[CH:6][C:1]([C:7]2[CH2:8][O:9][C:8](=[O:10])[C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:2][CH:3]=1
Reactant: O=C([O-])Cc1ccccc1
Reactant: ClC(Cl)Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OCC(c2ccc(Cl)cc2)=C1c1ccccc1
Reaction time: 4 h

Procedure:
2-bromine-1-(4-chlorophenyl)-ethanone (2, 102.6 g, 0.44 mol) and potassium phenylacetate (1, 104.5 g, 0.6 mol) are heated to 80° C. in dimethyl formamide (600 mL) while being stirred for 4 hours and are then cooled. After the addition of water (1 L), chloroform is used for extraction (3 times 300 mL), and the chloroform extract is washed with water and then dried (Na2SO4) and concentrated to dryness. For crystallization, diisopropyl ether is added (500 mL) and the crystals, which are formed in the cold [and have] a melting point of 111-113° C., are collected (yield 92 g, 78% with reference to 2).