Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]1[N:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=2)[C:18]2[C:13](=[CH:14][C:15]([C:32]3[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][N:33]=3)=[CH:16][CH:17]=2)[N:12]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:19]2[C:18]3[C:13](=[CH:14][C:15]([C:32]4[C:37]([C:38]([F:40])([F:41])[F:39])=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:16][CH:17]=3)[N:12]=[C:11]([CH2:10][N:6]3[CH2:7][CH2:8][CH2:9][C@H:5]3[C:3]([OH:4])=[O:2])[N:20]=2)=[CH:27][CH:26]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)[C@@H]1CCCN1Cc1nc(Nc2ccc(C(C)(C)C)cc2)c2ccc(-c3ncccc3C(F)(F)F)cc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(Nc2nc(CN3CCC[C@H]3C(=O)O)nc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a mixture of (S)-1-[4-(4-tert-butyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-ylmethyl]-pyrrolidine-2-carboxylic acid methyl ester (140 mg, 0.248 mmol) in THF (20 ml) and H2O (20 ml), add LiOH (18 mg, 0.745 mmol). Stir the mixture for 2 hours at 50° C. Concentrate, add water, extract with ether, acidify the aqueous layer to pH 6-7, extract with EtOAc, and concentrate to give (S)-1-[4-(4-tert-butyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-ylmethyl]-pyrrolidine-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH:4](Br)Br.C(O)=[O:13].Cl>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH:4]=[O:13]
Reactant: O=CO
Reactant: Fc1ccc(C(Br)Br)c(Cl)c1
Agent: Cl
Product: O=Cc1ccc(F)cc1Cl
Temperature: 25 °C
Yield: 107.2 %

Procedure:
In a flask were placed 30.25 g (0.100 mole) of 2-chloro-4-fluorobenzal bromide, 45 ml (1.2 mole) of formic acid, and 15 ml of concentrated hydrochloric acid. This mixture was heated at 100°-105° C. overnight. After cooling to room temperature, the reaction mixture was poured into 200 ml of an ice/water mixture which was then extracted twice with diethyl ether. The combined extracts were washed successively with a saturated, aqueous, sodium bicarbonate solution and water. After being dried over anhydrous magnesium sulfate, the extract was filtered, and the solvent was evaporated under reduced pressure,, leaving 17 g of 2-chloro-4-fluorobenzaldehyde as a residue.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=[O:7].[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([Cl:33])[C:24]=1[NH:34][NH2:35].O>C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:26]=[C:25]([Cl:33])[C:24]=1[NH:34][N:35]=[C:10]([OH:12])[C:9]1[CH:13]=[CH:14][CH:15]=[N:16][C:8]=1[C:6](=[O:7])[C:5]1[CH:17]=[CH:18][CH:19]=[C:3]([C:2]([F:1])([F:21])[F:20])[CH:4]=1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=C(O)c1cccnc1C(=O)c1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1cccc(C(F)(F)F)c1)c1ncccc1C(O)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 9 %

Procedure:
A suspension of 2-(3-trifluoromethylbenzoyl)nicotinic acid (1.5 g) and 2,6-dichloro-4-trifluoromethylphenylhydrazine (1.87 g) in toluene was stirred at reflux with azeotropic removal of water (using a Dean Stark apparatus) for 6.5 hours. The mixture was cooled to room temperature and then washed with 2N hydrochloric acid and water. The organic phase was dried and evaporated. The crude product was purified by column chromatography to yield a yellow gum which was triturated in hexane to yield the title compound as a pale yellow solid (0.24 g), m.p. 92°-96° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[N:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:21][CH2:20]1)=[O:18])[C:13](=[O:14])[N:46]1[CH2:45][CH2:44][N:43]([C:40]2[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=2)[CH2:48][CH2:47]1)[CH3:2]
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Reactant: c1cc(N2CCNCC2)ccn1
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(c3ccncc3)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 170 mg (1.04 mmol) 1-pyridin-4-yl-piperazine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=1.C(N(C(C)C)C(C)C)C.[CH2:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:31].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:8][C:6]1[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=[C:2]([N:35]2[CH2:36][CH2:37][N:32]([CH2:30][CH3:31])[CH2:33][CH2:34]2)[N:7]=1
Reactant: COC(=O)c1c(Cl)nc(Cl)nc1Nc1cccc(C)c1
Reactant: CCN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN1CCN(c2nc(Cl)c(C(=O)OC)c(Nc3cccc(C)c3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 24.3 %

Procedure:
A mixture of methyl 2,4-dichloro-6-(m-tolylamino)pyrimidine-5-carboxylate (502.6 mg, 1.610 mmol), N-ethyldiisopropylamine (0.3 mL, 1.718 mmol) and N-ethylpiperazine (0.21 mL, 1.653 mmol) in THF (8 mL) was stirred at RT for 12 h. Saturated aq NaHCO3 was added and the resulting mixture was extracted with EtOAc. The organic layers were washed with saturated aq NaHCO3, water, and brine, were dried over anhydrous Na2SO4, and then filtered through SiO2. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, hexanes/EtOAc=4/1) to give the title compound (152.6 mg, 24%). 1H NMR (500 MHz, CDCl3) δ ppm 1.12 (t, J=6.5 Hz, 3H), 2.35 (s, 3H), 2.48 (br s, 6H), 3.82-3.97 (m, 7H), 6.92-6.93 (m, 1H), 7.21-7.22 (m, 1H), 7.37-7.42 (m, 2H), 10.45 (s, 1H). [M+H] calc'd for C19H25ClN5O2, 390. found, 390.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=C(C(O)=O)[CH:16]=2)[C:11]([Cl:21])=[CH:10][N:9]=1>C(Cl)Cl.CN(C=O)C>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:1]([C:2]([Cl:4])=[O:3])[CH:16]=2)[C:11]([Cl:21])=[CH:10][N:9]=1
Reactant: O=C(O)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc2c(Cl)cnc(Cl)c2c1

Procedure:
Anal. Found: C, 49.59; H, 2.08; N, 5.74. Calc for C10H5Cl2NO2 : C, 49.62; H, 2.08; N, 5.78. ##STR170## Oxalyl chloride (144 μL, 1.65 mmol) was added to a suspension of 1,4-dichloro-7-isoquinolinecarboxylic acid (200 mg, 0.83 mmol) at room temperature in CH2Cl2 (10 mL), followed by DMF (1 drop). After 30 min the resultant clear solution was evaporated in vacuo to afford 1,4-dichloro-7-isoquinolinecarbonyl chloride which was used without further purification.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[CH:19]=[C:18]([NH2:20])[N:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[N:29]=[C:30]=[O:31]>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[NH:29][C:30]([NH:20][C:18]1[CH:19]=[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)[N:15]=[CH:16][N:17]=1)=[O:31]
Reactant: O=C=Nc1c(F)cccc1F
Reactant: Nc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Product: O=C(Nc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1)Nc1c(F)cccc1F

Procedure:
The title compound is prepared analogously as described in Example 105B from N-(4-morpholin-4-yl-phenyl)-pyrimidine-4,6-diamine and 2,6-difluorophenyl isocyanate. Slightly pink solid, HPLC: tR=3.53 min (purity: 100%, gradient F), ESI-MS: 427.4 [MH]+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[N:7][C:2]([N:26]4[CH2:27][CH2:28][O:24][C:25]4=[O:29])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)nn3)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)nn3)CC2)c(C)c1
Yield: 25.1 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (152 mg) described in Preparation Example 230 and oxazolidin-2-one (40 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (44 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:35][O:36][CH2:37][CH2:38]Br>C(#N)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:38][CH2:37][O:36][CH3:35])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1
Reactant: COCCBr
Reactant: Fc1cccnc1[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COCCN1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3ncccc3F)CC2)C1
Temperature: 70 °C

Procedure:
A mixture of trans-8-chloro-1-[4-(3-fluoro-pyridin-2-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50.0 mg, 0.126 mmol), cesium carbonate (81.9 mg, 0.251 mmol) and 2-bromoethyl methyl ether (0.024 ml, 0.25 mmol) in acetonitrile (0.6 ml) was heated at 70° C. for 20 h. The reaction mixture was partitioned between a water-brine mixture (1:1) (2 ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with two 5-ml portions of ethyl acetate. The combined organic layers were concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (13 mg, 23%) as light yellow solid. MS m/e: 456 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.FC1C=C(C(O)C)C=C(F)C=1B1O[C:29](C)(C)[C:28](C)(C)[O:27]1>>[F:10][C:4]1[CH:5]=[C:6]([CH:28]([OH:27])[CH3:29])[CH:7]=[C:2]([F:1])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Reactant: CC(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: CC(O)c1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with 1-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol (Intermediate 106) gave the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[N:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:15]=3[N:16]=2)=[CH:24][CH:23]=1
Reactant: CCc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3-nitrobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH2:14][CH3:15])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1.[Br:24]Br.C(=O)([O-])[O-].[Na+].[Na+]>Br>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH2:14][CH3:15])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[C:23]=1[Br:24]
Reactant: CCC1N=C(c2ccccc2Cl)c2cc(N)ccc2N(C)C1=O
Reactant: BrBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCC1N=C(c2ccccc2Cl)c2c(ccc(N)c2Br)N(C)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9.6 g (0.029 M) of rac-7-amino-3-ethyl-5-(o-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one dissolved in 50 ml of concentrated aqueous hydrobromic acid are treated slowly at between 0°-5° C. with 5.2 g (1.65 ml) of bromine and the mixture is stirred at 0° C. for 1 hour. The mixture is then poured on to a mixture of ice and sodium carbonate solution, extracted with methylene chloride and the extract is dried over sodium sulphate, filtered and concentrated. After crystallisation from methylene chloride/ether/petroleum ether, there is obtained rac-7-amino-3-ethyl-6-bromo-5-(o-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one which melts at 251° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[C:4]([N:8]2[C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([NH2:25])[CH:19]=3)([OH:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:26])[CH:5]=[CH:6][CH:7]=1.[C:28](N1C=CN=C1)(N1C=CN=C1)=[S:29]>O1CCCC1>[Cl:1][C:2]1[C:3]([F:27])=[C:4]([N:8]2[C:16]([OH:17])([C:18]3[CH:23]=[CH:22][C:21]4[NH:24][C:28](=[S:29])[NH:25][C:20]=4[CH:19]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:26])[CH:5]=[CH:6][CH:7]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(C2(O)c3ccccc3C(=O)N2c2cccc(Cl)c2F)cc1N
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(O)(c2ccc3[nH]c(=S)[nH]c3c2)N1c1cccc(Cl)c1F
Reaction time: 4 h
Yield: 83.5 %

Procedure:
To a solution of 2-(3-chloro-2-fluorophenyl)-3-(3,4-diaminophenyl)-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (575 mg, 1.49 mmol) in tetrahydrofuran (2.0 mL) was added 1,1′-thiocarbonyldiimidazole (400 mg, 2.25 mmol) at room temperature and stirred for 4 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (SiO2, hexanes/ethyl acetate) to afford 2-(3-chloro-2-fluorophenyl)-3-hydroxy-3-(2-thioxo-2,3-dihyro-1H-benzimidazol-5-yl)-2,3-dihyro-1H-isoindol-1-one (530 mg, 84%) as an off-white powder. 1H NMR (400 MHz, d6-DMSO): 12.58 (s, 1H), 12.50 (s, 1H), 7.90 (s, 1H), 7.89 (s, 1H), 7.70-7.60 (m, 2H), 7.51 (t, 1H), 7.32 (d, 1H), 7.30 (t, 1H), 7.19 (t, 1H), 7.14 (s, 1H), 7.05 (d, 1H), 6.94 (d, 1H); MS (EI) for C21H13ClFN3O2S: 426 (MI).
Reaction SMILES: [NH:1]1[CH:5]=[C:4](/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])[N:3]=[CH:2]1.Cl[C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[C:13]1([C:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:1]2[CH:5]=[C:4](/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])[N:3]=[CH:2]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)/C=C/c1c[nH]cn1
Solvent: CN(C)C=O
Product: O=C(O)/C=C/c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
(E)-3-(imidazol-4-yl)acrylic acid was reacted with chlorotriphenylmethane in N,N-dimethylformamide to obtain (E)-3-(N-triphenylmethylimidazol-4-yl)acrylic acid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:17])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2([CH3:16])[CH2:15][CH2:14]2)[CH:8]=1.[C:18](N1C=CN=C1)([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:19]>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]([NH:17][C:18]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[O:19])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2([CH3:16])[CH2:15][CH2:14]2)[CH:8]=1
Reactant: Cc1nc(N)sc1-c1ccnc(C2(C)CC2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccnc(C2(C)CC2)c1
Reaction time: 14 h
Yield: 94.2 %

Procedure:
A mixture of 4-methyl-5-[2-(1-methyl-cyclopropyl)-pyridin-4-yl]-thiazol-2-ylamine (Step 40.2) (211 mg, 0.86 mmol) and 1,1′-carbonyldiimidazole (210 mg, 1.3 mmol, 1.5 eq) in DCM (10 mL) is stirred for 14 h at reflux and allowed to cool. The resulting precipitate is collected by filtration to provide 275 mg of the title compound as white solid: ESI-MS: 338.2 [M−H]−.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:19]([O:21][P:22]([C:27]([P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH2:28])(=[O:26])[O:23][CH2:24][CH3:25])[CH3:20]>C1COCC1>[CH2:31]([O:30][P:29]([CH:27]([P:22](=[O:26])([O:21][CH2:19][CH3:20])[O:23][CH2:24][CH3:25])[CH2:28][C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:36])[O:33][CH2:34][CH3:35])[CH3:32]
Reactant: C#Cc1ccccc1
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(CC#Cc1ccccc1)P(=O)(OCC)OCC
Reaction time: 0.5 h

Procedure:
Phenylacetylene (IX, 4.4 g) is dissolved in THF (43 ml), cooled to -78°, and treated with lithium hexamethyldisilazide (1M in THF, 43 ml). The reaction is stirred for 30 min, then a solution of ethenylidenebisphosphonic acid tetraethyl ester (10.7 g) in THF (36 ml) is added and the reaction warmed to 22° for 1 hour. The reaction is quenched with water, extracted thrice with ethyl acetate. The organics were then washed with water, hydrochloric acid (10%), saturated sodium bicarbonate, and saline, dried with magnesium sulfate, and concentrated. The concentrate is purified by distillation, bp 0.1 195°-200°.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([NH:33][C:34]([NH:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[O:35])[CH:30]=[CH:31][CH:32]=2)O1>O.O1CCOCC1>[N:4]1[CH:3]=[C:2]([C:31]2[CH:30]=[C:29]([NH:33][C:34]([NH:36][CH2:37][C:38]([F:39])([F:40])[F:41])=[O:35])[CH:28]=[CH:27][CH:32]=2)[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: CC1(C)OB(c2cccc(NC(=O)NCC(F)(F)F)c2)OC1(C)C
Reactant: Brc1cnc2ccccn12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3ccccn23)c1
Temperature: 90 °C

Procedure:
To a stirred solution of 3-Bromoimidazo[1,2-a]pyridine (commercially available, ex Bionet, 394 mg, 2 mmol) was added a solution of K3PO4 (1.27 g, 6 mmol) in H2O (2 mls). 1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (905 mg, 2.5 mmol) dissolved in dioxane (8 ml) was added to the reaction mixture and the reaction deoxygenated by evacuation and refill of the flask with N2 (×2). PdCl2dppf (150 mg, 0.2 mmol) was added and the reaction mixture was deoxygenated (×3). The reaction mixture was heated at 90° C. for 16 h, cooled to RT and partitioned between CH2Cl2 and H2O, then filtered. The layers were separated and the aqueous layer further extracted with CH2Cl2. The organic fractions were combined and passed through a phase separating cartridge, then the solvent removed in vacuo. The residue was purified using a SCX cartridge, washing with MeOH and eluting with 2M NH3/MeOH. The resulting solid was further purified by silica column chromatography (0-3% 2M NH3/MeOH in CH2Cl2) to afford a beige solid (335 mg). MS: [M+H]+=335.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[C:13]([C:17]([OH:20])([CH3:19])[CH3:18])[CH:14]=[N:15][CH:16]=3)[N:10]=2)[CH:7]=1.[Cl:21]N1C(=O)CCC1=O>C(#N)C>[Cl:21][C:8]1[N:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[C:11]1[CH:12]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:14]=[N:15][CH:16]=1
Reactant: CC(C)(O)c1cncc(-c2cn3cc(F)ccc3n2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(C)(O)c1cncc(-c2nc3ccc(F)cn3c2Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the title compound from Example 2 Step E (0.068 g, 0.251 mmol) in acetonitrile (1.25 ml) was added N-chlorosuccinimide (0.040 g, 0.301 mmol). The resulting mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. The resulting residue was diluted with dichloromethane, washed with saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (100% ethyl acetate) provided the title compound: LCMS m/z 306.08 [M+H]+; 1H NMR (500 MHz, CDCl3) 9.23 (d, J=1.7 Hz, 1H), 8.78 (d, J=2.1 Hz, 1H), 8.51 (t, J=2.0 Hz, 1H), 8.08 (t, J=2.5 Hz, 1H), 7.65 (dd, J=9.3, 4.9 Hz, 1H), 7.24-7.20 (m, 1H), 2.02 (br s, 1H), 1.69 (s, 6H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:15])=[C:9]([CH3:14])[C:10]=1[C:11](=[O:13])[CH3:12])=[O:5])C.[OH-].[K+]>C(O)C>[C:11]([C:10]1[C:9]([CH3:14])=[C:8]([CH3:15])[NH:7][C:6]=1[C:4]([OH:5])=[O:3])(=[O:13])[CH3:12]
Reactant: CCOC(=O)c1[nH]c(C)c(C)c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)c1c(C(=O)O)[nH]c(C)c1C
Yield: 81.7 %

Procedure:
A mixture of pyrrole ester 34 (8.2 g, 0.0392 mol), in ethanol and 100 mL of 10% potassium hydroxide were refluxed for 1 h. The mixture was cooled and concentrated in vacuo to an oil. Water was added to the oil, the mixture acidified with dilute HCl and extracted with ether. The organic phase was dried with anhy. sodium sulfate and concentrated in vacuo to a solid residue. The compound was recrystallized in 80 mL of ethanol to give 5.8 g of pure 3-acetyl-4,5-dimethyl-2-pyrrole carboxylic acid 35 as a solid. 1H NMR (DMSO-d6) d 2.5 (s,3H), 2.2 (s,3H), 2.0 (s,3H) ppm.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:13]([CH3:14])=[C:12](O)[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>O1CCCC1>[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([C:21](=[O:24])[CH2:22][CH3:23])[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1
Reactant: CCC(=O)Cl
Reactant: Cc1nc2c(F)cc(C(C)(C)C)cc2c(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=O)c1c(C)c(C)nc2c(F)cc(C(C)(C)C)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In tetrahydrofuran (3 ml) was suspended 60% sodium hydride (20 mg). The compound 1 (124 mg) was added to the suspension under ice cooling, and the mixture was stirred for 30 min. Further, propionyl chloride (200 μl) was added thereto, and the mixture was stirred for 3 hr. The reaction solution thus obtained was poured into ice water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed under the reduced pressure. The crude product was purified by chromatography on silica gel (Wako Gel C-200, elution solvent: n-hexane-ethyl acetate (3:1)) to give 2,3-dimethyl-6-t-butyl-8-fluoro-4-propionylquinoline (compound 3, 21 mg). 1H-NMR data on this compound in deutro-chloroform were as shown below.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][NH:25][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][N:25]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=1[F:16])[CH2:26]2
Reactant: Brc1cccc2c1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4cccc(Br)c4C3)c(F)cc2c1=O
Yield: 18.6 %

Procedure:
142 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 149 mg of 4-bromoisoindoline, 114 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 43 mg of the target compound.