Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[N:7]([CH3:11])/[C:6](=[CH:12]\[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)/[C:5]1=[O:21])(=O)C.[H-].[Na+].[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.C(OCC)(=O)C>[CH:24](=[C:9]1/[C:8](=[O:10])[N:7]([CH3:11])/[C:6](=[CH:12]\[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)/[C:5](=[O:21])[NH:4]/1)\[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(/C=C2/C(=O)N(C(C)=O)CC(=O)N2C)cc1
Reactant: O=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(/C=c2/c(=O)[nH]/c(=C\c3ccccc3)c(=O)n2C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (3Z)-1-Acetyl-3-(4-methoxybenzylidene)-4-methyl-2,5-piperazinedione (10) (200 mg, 0.69 mmol) and sodium hydride (60% dispersion in oil, 28 mg, 0.69 mmol) in dry DMF (10 ml) was stirred at room temperature for 18 h. Benzaldehyde (71 μl, 0.69 mmol) was then added and the reaction mixture stirred at room temperature for 18 h. It was then diluted with ethyl acetate (100 ml) and washed with brine (4×50 ml). The organic phase was separated, dried (MgSO4), and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, dichloromethane containing 1% MeOH) to give 48 mg (21 w) of a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:13][C:14]3[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=3)[N:8]=[C:9]2O)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:22]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:13][C:14]3[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=3)[N:8]=[C:9]2[Cl:22])=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(Nc2cc3ccc(Br)cc3c(O)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccc(Br)cc3c(Cl)n2)n[nH]1

Procedure:
Similar procedure as described in example 9B was used, starting from 7-Bromo-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol and POCl3 to give (7-Bromo-1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 337 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.C[O-].[Na+].[C:14]1([C:20]2[O:21][C:22]([CH3:29])=[C:23]([C:25](=[O:28])[CH2:26]Br)[N:24]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:14]1([C:20]2[O:21][C:22]([CH3:29])=[C:23]([C:25]([C:26]3[O:10][C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=4[CH:7]=3)=[O:28])[N:24]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)CBr
Reactant: O=Cc1cc(Br)ccc1O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1C(=O)c1cc2cc(Br)ccc2o1
Temperature: 780 °C
Reaction time: 0.33 h

Procedure:
To a slurry of 294 g of 5-bromosalicylaldehyde in 3 liters of dry ethanol was added 79.06 g of sodium methoxide and the mixture allowed to stir for 20 minutes. To the resulting yellow slurry was added 410 g of 2-phenyl-4-bromoacetyl-5-methyloxazole and the slurry heated to 780° C. for 2 hours. An additional 250 mg of sodium methoxide was added and heating continued overnight under a nitrogen atmosphere. The reaction was cooled and the solids filtered and washed with ethanol, 393 g, mp 212°-213° C.
Reaction SMILES: C(OC([NH:8][C:9]([CH3:48])([CH3:47])[C:10]([O:12][CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:22]=[C:17]2[C:16]([C:30](=[O:46])[C:31]2[C:36]([F:37])=[CH:35][CH:34]=[C:33]([NH:38][S:39]([CH2:42][CH2:43][CH3:44])(=[O:41])=[O:40])[C:32]=2[F:45])=[CH:15]1)=[O:11])=O)(C)(C)C.Cl>CCOC(C)=O>[ClH:29].[NH2:8][C:9]([CH3:47])([CH3:48])[C:10]([O:12][CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:22]=[C:17]2[C:16]([C:30](=[O:46])[C:31]2[C:36]([F:37])=[CH:35][CH:34]=[C:33]([NH:38][S:39]([CH2:42][CH2:43][CH3:44])(=[O:40])=[O:41])[C:32]=2[F:45])=[CH:15]1)=[O:11]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)C(C)(C)NC(=O)OC(C)(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)C(C)(C)N)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Yield: 145.5 %

Procedure:
A mixture of (5-(4-chlorophenyl)-3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (339 mg, 0.48 mmol) and a saturated solution of HCl in EtOAc (3 mL) was stirred at rt for 5 h. The resulting mixture was filtered to afford the title compound as a white solid (224 mg, 72.6%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:19]([CH3:20])=[CH:18][C:17]([NH:21][CH2:22][C:23]([O:25]CC)=[O:24])=[CH:16][C:15]=3[CH3:28])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2].Cl>O1CCOCC1.[OH-].[Na+]>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:19]([CH3:20])=[CH:18][C:17]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:16][C:15]=3[CH3:28])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)CNc1cc(C)c(Oc2ccc3[nH]cc(C(C)C)c3c2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(NCC(=O)O)cc(C)c1Oc1ccc2[nH]cc(C(C)C)c2c1
Yield: 98.3 %

Procedure:
56 mg of ethyl N-{4-[(3-isopropyl-1H-indol-5-yl)oxy]-3,5-dimethylphenyl}glycinate (Example 3) are stirred in 7 ml of dioxane with 1.5 ml of IN sodium hydroxide for 2 hours at room temperature. The mixture is poured onto water, rendered acidic using 1N hydrochloric acid, extracted with ethyl acetate, the extract is dried and the solvent is removed in vacuo. 51 mg of N-{4-[(3-isopropyl-1H-indol-5-yl)oxy]-3,5-dimethyl-phenyl}glycine are obtained 1H-NMR (300 MHz, CDCl3): δ=1.29, d, 6H; 2.10, s, 6H; 3.07, sept., 1H; 3.70, s, 2H; 6.41, s, 2H; 6.73, m, 1H; 6.91, m, 2H; 7.21, d, 1H; 7.77, s, broad, 1H.
Reaction SMILES: [Cl-].[Li+].C([Mg]Cl)(C)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1.[O:16]=[C:17]1[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18]1>C1COCC1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:17]2([OH:16])[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18]2)=[CH:11][CH:10]=1
Reactant: Clc1ccc(I)cc1
Reactant: O=C1CC(C(=O)O)C1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)C1CC(O)(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
While under argon, isopropylmagnesium chloride lithium chloride complex (1.3 M solution in THF, 160 mL, 0.208 mol) was added dropwise over 15 minutes to a solution of p-chloroiodobenzene (54.3 g, 0.227 mol) in 100 mL of dry THF at −78° C. After 1 h, 3-oxocyclobutanecarboxylic acid (7.42 g, 0.065 mol) in 40 mL of dry THF was added and the reaction mixture was allowed to warm to room temperature and stir overnight. The reaction was quenched with 1 M HCl to pH-3, and stirred 2 h. Diethyl ether was added, the solution was stirred vigorously and the phases separated. The product was leached from organic layer with 1 M NaOH, reacidified to pH-3 with 6 M HCl and extracted with diethyl ether (2×). The combined organic layers were dried over MgSO4 filtered and concentrated to give the crude product as an off-white solid. Recrystallization from diethyl ether and n-heptane afforded the subject compound as a white solid 4.03 g (27.3%). 1H NMR (DMSO-d6, 600 MHz) δ 12.25 (bs, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.45 (d, J=8.7 Hz, 2H), 5.86 (bs, 1H), 2.74-2.80 (m, 1H), 2.62-2.65 (m, 2H), 2.53-2.57 (m, 2H). ESI MS found for C11H11ClO3 m/z [225.1/227.1 (M−1)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[N:12]([CH2:15]O)[C:11](=[O:17])[O:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][Cl:20])[C:11](=[O:17])[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2oc(=O)n(CO)c2=O)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-n2oc(=O)n(CCl)c2=O)cc1

Procedure:
2-(4-Methoxyphenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione (0.03 mole) dissolved in chloroform (40 ml) and thionyl chloride (0.06 mole) dissolved in chloroform (10 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the reaction mixture is stripped of solvent under reduced pressure, leaving a residue. This residue is dissolved in toluene, and the toluene solution is stripped of solvent and unreacted starting materials to yield the desired product 2-(4-methoxyphenyl)-4-chloromethyl-1,2,4-oxadiazolidin-3,5-dione as the residue.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][CH2:7][C:6]=2[CH:12]=1.[O-]CC.[Na+].[Na].[C:18]1([S:24][CH2:25][CH2:26][CH2:27][CH2:28]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[C:18]1([S:24][CH2:25][CH2:26][CH2:27][CH2:28][O:1][C:2]2[CH:3]=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][CH2:7][C:6]=3[CH:12]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1Nc2ccc(O)cc2CO1
Reactant: BrCCCCSc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: O=C1Nc2ccc(OCCCCSc3ccccc3)cc2CO1

Procedure:
An amount of 4.95 gm (0.03 mol) of 6-hydroxy-4H-3,1-benzoxazin-2-one is added to an ethanolic sodium ethoxide solution prepared from 150 ml of ethanol and 0.92 gm (9.04 mol) of sodium, and the mixture is refluxed. Ten grams (0.04 mol) of 4-phenylmercapto-butylbromide (prepared from thiophenol and excess 1,4-di-bromo-butane, Bp 0.03 mb :=95°-104° C.) are added to the hot solution, and the mixture is refluxed for a further two hours. After cooling, the reaction solution is poured onto ice water and extracted with ethyl acetate. The extract is washed with water and dried with sodium sulfate, and the ethyl acetate is distilled off in vacuo. The residue is recrystallized from cyclohexane/ethyl acetate.
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(#N)C>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][N:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1)[CH3:31]
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCCn1nc(C(=O)OCC)cc1C(=O)OCC
Yield: 93.8 %

Procedure:
Diethyl 3,5-pyrazoledicarboxylate (50 g, 0.236 mol) was dissolved in acetonitrile (500 ml) under a nitrogen atmosphere. Potassium carbonate (33 g, 0.236 mol) was added followed by ethyl 5-bromovalerate (37.7 ml, 0.235 mol) and the mixture heated under reflux for 2 hours. The solvent was removed in vacuo leaving a clear oil which was partitioned between ethyl acetate and water. The organic phase was separated and the aqueous phase further extracted with ethyl acetate (×2). The organic extracts were combined, dried (MgSO4), filtered and concentrated under reduced pressure to give 75 g of the title product.
Reaction SMILES: [N+:1]([C:4]1[CH:42]=[CH:41][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][C:32]5[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][CH:33]=5)=[CH:27][CH:26]=4)[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.O.[H][H]>O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3([C:25]4[CH:26]=[CH:27][C:28]([CH2:31][C:32]5[CH:33]=[CH:34][C:35]([NH2:38])=[CH:36][CH:37]=5)=[CH:29][CH:30]=4)[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[CH:41][CH:42]=1
Reactant: CCCCC1CCC(c2ccc(Cc3ccc([N+](=O)[O-])cc3)cc2)(c2ccc(Cc3ccc([N+](=O)[O-])cc3)cc2)CC1
Reactant: [H][H]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC1CCC(c2ccc(Cc3ccc(N)cc3)cc2)(c2ccc(Cc3ccc(N)cc3)cc2)CC1
Yield: 41.9 %

Procedure:
1,1-Bis[4-(4-nitrobenzyl)phenyl]-4-butylcyclohexane 38.0 g was dissolved in 500 ml of tetrahydrofuran, a Pd--C catalyst (5% purity, water content 55.9%) 4.0 g was added, and the mixture was cooled with water at atmospheric pressure and contacted with hydrogen gas with stirring. After the absorption of hydrogen stopped, the catalyst was filtered off and the solution was concentrated. The concentrate was recrystallized with mixture solvent of ethanol 87% and methanol 13% to obtain 1,1-bis[4-(4-aminobenzyl)phenyl]-4-butylcyclohexane 14.22 g which is a diamino compound of the present invention. The melting point was 58.5°-60.1° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:28]=2[N:29]2[CH2:34][CH2:33][CH2:32][C@H:31]([NH:35]C(=O)OC(C)(C)C)[CH2:30]2)=[O:21])=[N:4][C:5]([C:8]2[CH:13]=[C:12](/[CH:14]=[CH:15]\[CH:16]([CH3:18])[CH3:17])[CH:11]=[CH:10][C:9]=2[F:19])=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:1][C:2]1[C:3]([C:20]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:28]=2[N:29]2[CH2:34][CH2:33][CH2:32][C@H:31]([NH2:35])[CH2:30]2)=[O:21])=[N:4][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])[CH:11]=[CH:10][C:9]=2[F:19])=[CH:6][CH:7]=1
Reactant: CC(C)/C=C\c1ccc(F)c(-c2ccc(N)c(C(=O)Nc3cnccc3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CCc1ccc(F)c(-c2ccc(N)c(C(=O)Nc3cnccc3N3CCC[C@H](N)C3)n2)c1
Yield: 35 %

Procedure:
Method 2 of Example 49 was followed using (S,Z)-tert-butyl 1-(3-(3-amino-6-(2-fluoro-5-(3-methylbut-1-enyl)phenyl)picolinamido)pyridin-4-yl)piperidin-3-ylcarbamate which after Boc deprotection with 25% TFA/CH2Cl2 yielded (S)-3-amino-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-(2-fluoro-5-isopentylphenyl)picolinamide (35%). LCMS (m/z): 477.3 (MH+); LC Rt=2.91 min.
Reaction SMILES: [CH2:1]([N:3]1[CH2:12][C:11]([CH3:14])([CH3:13])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-])=O)=[CH:8][CH:9]=2)[C:4]1=[O:18])[CH3:2].C([O-])=O.[NH4+]>CN(C=O)C.[Pd]>[NH2:15][C:7]1[CH:6]=[C:5]2[C:10]([C:11]([CH3:13])([CH3:14])[CH2:12][N:3]([CH2:1][CH3:2])[C:4]2=[O:18])=[CH:9][CH:8]=1
Reactant: CCN1CC(C)(C)c2ccc([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCN1CC(C)(C)c2ccc(N)cc2C1=O
Yield: 41.6 %

Procedure:
Palladium/Carbon (10% wt) (12 mg, 0.04 mmol) was added to a stirred solution of 2-ethyl-4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (110 mg, 0.44 mmol) and ammonium formate (137 mg, 2.21 mmol) in anhydrous DMF (6 ml) at room temperature. The resulting suspension was heated at reflux for lhr, then cooled and filtered through a pad of celite. The solvent was evaporated in vacuo and the crude residue purified by flash column chromatography (60% ethyl acetate in dichloromethane) to afford the title compound as a pale yellow solid (40 mg, 98%). HPLC retention time 2.99 min. Mass spectrum (ES+) m/z 219 (M+H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[N:11]O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Ni]>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: ON=C1CCC2(CC1)OCCO2
Agent: [Ni]
Solvent: CCO
Product: NC1CCC2(CC1)OCCO2
Yield: 91.4 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-one oxime (68 g, 400 mmol) in ethanol (200 mL) was added Raney Nickel as a suspension in ethanol (52 mL). The resulting mixture was shaken at 50 psi of hydrogen for 18 hours. The reaction was filtered and concentrated in vacuo to give 57.5g of 1,4-dioxaspiro[4.5]dec-8-ylamine.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)[C:3]([CH3:6])([CH3:5])[CH3:4].[C:18](=[O:20])=[O:19]>>[C:3]([CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)[C:18]([OH:20])=[O:19])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: O=C=O
Product: CC(C)(C)C(C(=O)O)c1ccc(OC(F)(F)F)cc1

Procedure:
The neopentyl chloride prepared in Example 25 is converted to the Grignard reagent and subsequent carbonation with carbon dioxide according to the procedure of Weinstein and Morse [Journal of the American Chemical Society 74, 1133 (1952)] gives the desired acid as a white solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][OH:8])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:3]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[O:33]1[CH:38]=[CH:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[Br:1][C:2]1[S:6][C:5]([CH2:7][O:8][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][O:33]2)=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: OCc1sc(Br)cc1-c1ccc(Cl)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Clc1ccc(-c2cc(Br)sc2COC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 250-mL round-bottom flask, was placed [5-bromo-3-(4-chlorophenyl)thiophen-2-yl]methanol (4.8 g, 15.81 mmol, 1.00 equiv), dichloromethane (100 mL), PPTS (100 mg, 0.40 mmol, 0.03 equiv), 3,4-dihydro-2H-pyran (2.67 g, 31.74 mmol, 2.01 equiv). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 5.0 g (82%) of 2-[[5-bromo-3-(4-chlorophenyl)thiophen-2-yl]methoxy]oxane as yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1.S(Cl)([Cl:18])(=O)=O>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:18])=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(O)c1ccc(-c2cccs2)cc1
Reactant: O=S(=O)(Cl)Cl
Product: O=C(Cl)c1ccc(-c2cccs2)cc1

Procedure:
A mixture of 3 g of 4-(2-thienyl)benzoic acid and 30 ml of sulfonyl chloride is refluxed for 45 minutes and the solvent removed. The residue is dissolved in carbon tetrachloride and the solvent removed under vacuum (2-times) to give 4-(2-thienyl) benzoyl chloride. To a cooled (0° C.) solution of 2.0 g of 5,11-dihydro-10H-dibenz[b,e][1,4]diazepine and 7 ml of N,N-diisopropylethylamine in 30 ml of dichloromethane is added dropwise a solution of 3.15 g of 4-(2-thienyl)benzoyl chloride in 30 ml of dichloromethane. The mixture is stirred at room temperature for 16 hours and diluted with 50 ml of chloroform. The solution is washed with 30 ml each of water, 2N HCl, saturated NaHCO3, water and dried (Na2 SO4). The solvent is removed under vacuum and the residue (3.1 g) chromatographed on silica gel (column) with hexane-ethyl acetate (2:1) as eluent to give 1.8 g of solid, m.p. 114° C.-116° C.
Reaction SMILES: [F:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:20]([O-])=O)[CH:3]=1>[Ni].C1COCC1>[F:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([CH:3]=1)[NH2:20]
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: CNc1cc(N2CCC(C(F)(F)F)CC2)c(F)cc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-fluoro-N-methyl-2-nitro-5-(4-trifluoromethyl-piperidin-1-yl)aniline (200 mg, 0.62 mmol), Ra—Ni (4 mg, 0.062 mmol) and THF (30 mL) was shaken under H2 atmosphere (1 atm) at rt for 1 h. The mixture was filtered through celite and the celite pad was further washed with THF. Concentration and crystallization from Et2O/PE gave the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[N:24][C:25]([CH3:29])=[C:26]([CH3:28])[N:27]=2)=[CH:18][C:17]=1[NH2:30]>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:30][C:17]1[CH:18]=[C:19]([C:22]2[N:23]=[N:24][C:25]([CH3:29])=[C:26]([CH3:28])[N:27]=2)[CH:20]=[CH:21][C:16]=1[Cl:15])=[O:8])=[O:5]
Reactant: Cc1nnc(-c2ccc(Cl)c(N)c2)nc1C
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Solvent: CC#N
Product: Cc1nnc(-c2ccc(Cl)c(NC(=O)NC(=O)c3cc(F)c(F)cc3Cl)c2)nc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The solution of equivalent amounts of 2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the solution of 75 mg of 2-chloro-5-(5,6-dimethyl-[1,2,4]triazin-3-yl)phenylamine in 8 ml of acetonitrile and the mixture was stirred at room temperature for 30 minutes. The solid was filtered off with suction and dried under reduced pressure.
Reaction SMILES: O1CCCO[B:2]1[C:7]1[CH:37]=[CH:36][C:10]([C:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][S:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:19]([N+:33]([O-:35])=[O:34])[CH:18]=2)(=[O:16])=[O:15])=[O:12])=[CH:9][CH:8]=1.[OH-].[K+]>C1COCC1>[BH2:2][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][S:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:19]([N+:33]([O-:35])=[O:34])[CH:18]=2)(=[O:15])=[O:16])=[O:12])=[CH:36][CH:37]=1
Reactant: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(B2OCCCO2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Bc1ccc(C(=O)NS(=O)(=O)c2ccc(NCCSc3ccccc3)c([N+](=O)[O-])c2)cc1
Reaction time: 16 h

Procedure:
A solution of Example 214D (26.26 g, 48.5 mmol) in THF (250 mL) at room temperature was treated with 2M KOH (225 mL), stirred for 16 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 70-100% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:13]2[C:12](=O)[N:11]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[C:10](=[O:22])[C:9]=2[CH:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:23]1[C:24](=[O:38])[NH:25][CH:26]=[CH:27][C:28]=1[NH:29][CH:30]([CH3:37])[CH2:31][C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[NH:6]2>CC(O)=O.CO.[Zn]>[Cl:1][C:2]1[C:13]2[CH2:12][N:11]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[C:10](=[O:22])[C:9]=2[CH:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:23]1[C:24](=[O:38])[NH:25][CH:26]=[CH:27][C:28]=1[NH:29][CH:30]([CH3:37])[CH2:31][C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[NH:6]2
Reactant: CC(Cc1cccs1)Nc1cc[nH]c(=O)c1-c1nc2c(Cl)c3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CC(Cc1cccs1)Nc1cc[nH]c(=O)c1-c1nc2c(Cl)c3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3
Temperature: 90 °C

Procedure:
4-Chloro-6-(1-methyl-piperidin-4-yl)-2-[4-(1-methyl-2-thiophen-2-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-1H-1,3,6-triaza-s-indacene-5,7-dione (49 mg, 0.089 mmol) was mixed with zinc dust (196 mg, 1.0 mmol) in HOAc (10 mL). After it was heated at 90° C. for 40 min, the reaction mixture was cooled to 50° C. and diluted with a mixed solvent of MeOH:DCM (45 mL/5 mL) and filtered. The filtrate was evaporated at 95° C. (the bath temperature) under reduced pressure to dryness. The residue was diluted with a mixed solvent of DCM/MeOH (1:5) and basified with 28% aqueous NH4OH solution and concentrated. Chromatography of the residual crude with a mixed solvent of CH3CN/CH2Cl2/MeOH/28% aqueous NH4OH (63:10:37:1) followed by HPLC re-purification afforded the title compound in TFA salt form (6.2 mg, 11%). 1H NMR (DMSO-d6) δ 1.37 (d, J=6 Hz, 3H, CH3), 1.95-2.13 (4H), 2.52 (m, 2H), 2.80 (s, 3H, CH3), 3.15 (m, 2H), 3.50-3.65 (4H), 4.05 (m, 1H), 4.31 (m, 1H), 4.50 (br s, 2H), 6.18 (d, J=8 Hz, 1H), 6.89 (m, 1H), 7.01 (m, 1H), 7.29 (m, 1H), 7.37 (m, 1H), 7.99 (s, 1H), 9.60 (br s, 1H), 11.22 (d, J=6 Hz, 1H), 11.30 (d, J=6 Hz, 1H); ESI-MS m/z 537.3 (MH+).