Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([Cl:25])[C:7]2[C:8]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13][C:9]=3[NH:10][C:11]=2[CH:12]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([Cl:25])[C:7]2[C:8]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13][C:9]=3[N:10]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:11]=2[CH:12]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Cl)cc(Cl)c3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3c(Cl)cc(Cl)cc31)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.33 h
Yield: 75.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.3 mmol) was added to a solution of tert-butyl 8,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.5 g, 4.2 mmol) in DMF (15 mL). After 20 min, ethyl bromoacetate (0.94 mL, 8.4 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 1.5 h and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M) with heptane/EtOAc (3:1) followed by crystallization from MeOH/EtOAc to give 1.4 g (78%) of a white solid: mp 144.5-147.0° C.; IR (diffuse reflectance) 2982, 2972, 1748, 1690, 1456, 1411, 1373, 1366, 1352, 1252, 1222, 1202, 1159, 1115, 824 cm; MS (EI) m/z 440 (M+), 442, 440, 386, 384, 310, 300, 298, 86, 84, 57; Anal. Calcd for C21H26Cl2N2O4: C, 57.15; H, 5.94; N, 6.35; found: C, 57.15; H, 6.04; N, 6.37.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:7]1[C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]2[O:3][CH2:2][O:1][C:5]=2[CH:6]=1)([O-:16])=[O:15]
Reactant: COC(=O)c1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])O
Product: COC(=O)c1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of methyl 1,3-benzodioxole-5-carboxylate (9.3 g, 51 mmol) acetic acid (25 mL) and fuming nitric acid (50 mL) was stirred approximately 15 minutes and then poured into ice-water (600 mL). The mixture was allowed to stand 1 hour in an ice-bath and the solids were collected, stirred with water and recollected to give methyl 6-nitro-1,3-benzodioxole-5-carboxylate.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([C:7](=O)[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=O)=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:27])[C:23]([NH2:26])=[N:24][CH:25]=1.C1(C2N=C3CCCN(CCC/C=C/CC(O)=O)C3=NC=2C2C=CC=CC=2)C=CC=CC=1>C(O)(=O)C>[Cl:19][C:20]1[CH:25]=[N:24][C:23]2=[N:26][C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:18])=[CH:2][CH:3]=3)[N:27]=[C:22]2[CH:21]=1
Reactant: Cc1ccc(C(=O)C(=O)c2ccc(C)cc2)cc1
Reactant: Nc1cc(Cl)cnc1N
Agent: O=C(O)C/C=C/CCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Solvent: CC(=O)O
Product: Cc1ccc(-c2nc3cc(Cl)cnc3nc2-c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from 1,2-dip-tolylethane-1,2-dione and 5-chloro-pyridine-2,3-diamine analogously to 2,3-dip-tolylpyrido[2,3-b]pyrazine (Intermediate E step 1). Acetic acid is not used in this reaction.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[CH:4][C:3]=1[NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+].[C:28]1([CH3:37])[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:18][C:17]([CH3:20])([CH3:19])[C:16]([NH:15][C:3]1[CH:4]=[N:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:7][C:2]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH3:37])=[O:21]
Reactant: Cc1ccccc1B(O)O
Reactant: CN1CCN(c2cc(I)c(NC(=O)C(C)(C)C)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1NC(=O)C(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of 54 g (134 mmol) N-[4-iodo-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-2,2-dimethyl-propionamide, 420 ml toluene, 150 ml 2 N sodium carbonate solution, 4.63 g (3.9 mmol) tetrakis(triphenylphosphine)palladium(0) and 20.16 g (147 mmol) o-tolylboronic acid was heated under argon at 80° C. for 12 h. After cooling to room temperature, the aqueous phase was separated and washed twice with toluene. The combined organic layers were washed with 50 ml brine, dried (sodium sulfate), evaporated and dried in vacuo to yield 49 g (quantitative) of the title compound as a brown oil.
Reaction SMILES: C(N(CC)CC)C.O=C1CCC(=O)N1[O:15][C:16](=O)[CH2:17][C:18]#[N:19].[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28]2[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]3[C:36](=[O:41])[NH:37][CH:38]=[CH:39][CH:40]=3)[N:29]=2)[CH2:22]1>ClCCl>[O:15]=[C:16]([N:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28]2[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]3[C:36](=[O:41])[NH:37][CH:38]=[CH:39][CH:40]=3)[N:29]=2)[CH2:22]1)[CH2:17][C:18]#[N:19]
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Reactant: O=c1[nH]cccc1Nc1nccc(N[C@@H]2CCCNC2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@@H](Nc2ccnc(Nc3ccc[nH]c3=O)n2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 13.5 %

Procedure:
Triethylamine (33 μL, 0.24 mmol) and 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropane nitrile (prepared as described in BE875054(A1), 51 mg, 0.28 mmol) were added to a solution of (R)-3-(4-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridin-2(1H)-one (Preparation 19c, 67 mg, 0.23 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at ambient temperature for 24 hours and solvent was evaporated. Water was added and the mixture was extracted with dichloromethane. The organic layer was dried (MgSO4), evaporated under reduced pressure and the residue was purified by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (11 mg, 12%) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>>[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1)=[O:13]
Reactant: O=c1cc(O)cc[nH]1
Reactant: O=C(Cl)c1ccccc1Cl
Product: O=C(Oc1cc[nH]c(=O)c1)c1ccccc1Cl
Yield: 68 %

Procedure:
The general procedure of Example 12 was followed using 1.00 g of 4-hydroxy-2-pyridone and 1.36 ml of 2-chlorobenzoyl chloride to produce 1.42 g of the title compound in a yield of 68%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH:10]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)=O.[BH4-].[Na+].O>CO>[N:15]1[CH:16]=[C:12]([CH2:10][NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[O:2][CH3:1])[NH:13][CH:14]=1
Reactant: O=Cc1c[nH]cn1
Reactant: COc1ccccc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccccc1NCc1cnc[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a solution of 2-methoxyaniline (0.62 g, 5 mmol) in methanol (5 ml) was added 4-formylimidazole (0.48 g, 5 mmol). After stirring the mixture overnight at 60° C. the solution was cooled and sodium borohydride (0.28 g, 7.5 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours. Then water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by recrystallisation from heptane/ethyl acetate to yield off-white crystals (0.85 mg, 84%); MS (ISP): 204.3 ((M+H)+.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[Br:15][C:16]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2[N+:33]([O-:35])=[O:34])=[CH:21][C:17]=1[C:18](Cl)=[O:19].O>CN(C)C=O>[Br:15][C:16]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2[N+:33]([O-:35])=[O:34])=[CH:21][C:17]=1[C:18]([N:10]1[C:11](=[O:12])[C:6]2=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=[C:7]2[C:8]1=[O:9])=[O:19]
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: O=C(Cl)c1cc(Oc2ccc(Br)cc2[N+](=O)[O-])ccc1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cc(Oc2ccc(Br)cc2[N+](=O)[O-])ccc1Br)N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of 4-nitrophthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-bromo-5-(2-nitro-4-bromophenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-bromo-5-(2-nitro-4-bromophenoxy)benzoyl]-4-nitrophthalimide.
Reaction SMILES: C([O-])(=O)C(C)(C)C.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Zn+])=[CH:11][CH:10]=1.Br[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=[O:22]>>[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH:21]=[O:22])=[CH:11][CH:10]=1
Reactant: COc1ccc(C=O)cc1Br
Reactant: Fc1ccc(C[Zn+])cc1
Agent: CC(C)(C)C(=O)[O-]
Product: COc1ccc(C=O)cc1Cc1ccc(F)cc1
Yield: 82 %

Procedure:
(4-Fluorobenzyl)zinc pivalate (11) shows a clean coupling reaction with 3-bromo-4-methoxybenzaldehyde (5m) and afford 3-(4-fluorobenzyl)-4-methoxybenzaldehyde (6s) in 82% yield without observance of any addition products towards the aldehyde functionality (entry 19).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:19]3=[O:43])=[CH:15][CH:14]=2)=[CH:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:43])=[CH:15][CH:14]=2)=[CH:2]1
Reactant: O=C1SC(Cc2ccc(OCCc3c[nH]c4ccccc34)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC(=O)C(Cc2ccc(OCCc3c[nH]c4ccccc34)cc2)S1
Yield: 62.9 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 1.77 g of 5-{4-[2-(indol-3-yl)ethoxy]benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 11), 53 ml of methylene chloride and 0.3 ml of trifluoroacetic acid were used, to give 0.67 g of the title compound, melting at 42.6-44.5° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]2([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]3[CH2:13][NH:14][CH2:15][CH2:16][N:11]3[C:10](=[O:17])[O:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:25][C:26]1[CH:35]=[CH:34][C:29]([CH2:30][N:31]=[C:32]=[O:33])=[CH:28][CH:27]=1>O1CCCC1>[C:19]1([CH2:18][C:8]2([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:12]3[CH2:13][N:14]([C:32]([NH:31][CH2:30][C:29]4[CH:34]=[CH:35][C:26]([F:25])=[CH:27][CH:28]=4)=[O:33])[CH2:15][CH2:16][N:11]3[C:10](=[O:17])[O:9]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1OC(Cc2ccccc2)(Cc2ccccc2)C2CNCCN12
Reactant: O=C=NCc1ccc(F)cc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(F)cc1)N1CCN2C(=O)OC(Cc3ccccc3)(Cc3ccccc3)C2C1
Temperature: 50 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
To 1,1-bis(phenylmethyl)-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one (0.16 g, 0.50 mmol) were added tetrahydrofuran (10 mL) and 4-fluorobenzyl isocyanate (0.30 g, 2.0 mmol), and the mixture was stirred at 50° C. for 4 hours. The reaction solution was concentrated, and then the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate). The fractions were collected and concentrated. To the residue was added diisopropyl ether, and the obtained solid matter was collected by filtration and washed with diisopropyl ether to obtain the title compound (0.17 g, yield 70%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:18]=[C:19]([NH2:20])[CH:21]=[CH:22][CH:23]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Reactant: C#Cc1cccc(N)c1
Product: CC(C)(C)c1cc2ncc(C#Cc3cccc(N)c3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=291.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 3-ethynylaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4]Br.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C)C=O>[N:11]([CH2:4][C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1cccc(Cl)c1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1c(Cl)cccc1Cl
Temperature: 55 °C
Yield: 87.9 %

Procedure:
To a solution of 2,6-dichlorobenzylbromide (0.50 g) in dimethylformamide (5 mL) is added sodium azide (0.41 g). The reaction is heated to 55° C. overnight. The resulting solution is cooled to room temperature and is concentrated under reduced pressure. The residue is dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.37 g). 1H NMR (400 MHz, CDCl3) δ 7.45-7.40 (d, 2H), 7.30-7.25 (t, 1H), 4.73 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH2:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.F[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[N:30][N:29]=[N:28]4)=[CH:23][N:22]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: Fc1ccc(-n2cnnn2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1cnc(N2CCC([C@H]3C[C@H]3CCNc3ccc(-n4cnnn4)cn3)CC2)nc1
Temperature: 70 °C

Procedure:
2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanamine (50 mg, 0.18 mmol) from Example 5 step 3 and 2-fluoro-5-(1H-tetrazol-1-yl)pyridine (35.6 mg, 0.20 mmol) from step 1 were added in NMP (0.89 mL), then potassium carbonate (73.8 mg, 0.53 mmol) was added and the reaction was heated to 70° C. 6.5 hours. The reaction was cooled to room temperature, water (10 mL) was added, extracted with ethyl acetate (20 mL), second wash with brine (10 mL). The organic phase was dried by magnesium sulfate, filtered and concentrated and purified by column chromatography through a 25 gram Biotage SNAP KP-Sil™ silica gel cartridge eluting with 40% ethyl acetate/hexane to give the title compound as a white-solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:21]3[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1c(F)cccc1Cl
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3c(F)cccc3Cl)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-6-fluoro-phenyl)-acrylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([OH:1])[CH:11]=[CH:10]2
Reactant: BrBr
Reactant: Oc1ccc2ccccc2n1
Solvent: CC(=O)O
Product: Oc1ccc2cc(Br)ccc2n1

Procedure:
2-Hydroxyquinoline (ex. Aldrich) was treated with bromine in acetic acid to give 6-bromo-2-hydroxyquinoline (Paolo and Gianlorenzo, Chem. Abs., 63, 5602C, 1965). The latter was treated with phosphorous oxychloride and phosphorous pentachloride at 90° to give 6-bromo-2-chloroquinoline. The latter was converted to the title compound by analogy with compound 33.
Reaction SMILES: [CH3:1][CH:2]([C:5](=O)[CH3:6])[C:3]#[N:4].C(O)C.[CH3:11][NH:12][NH2:13].[ClH:14]>O>[ClH:14].[NH2:4][C:3]1[N:12]([CH3:11])[N:13]=[C:5]([CH3:6])[C:2]=1[CH3:1]
Reactant: CC(=O)C(C)C#N
Reactant: CNN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1nn(C)c(N)c1C

Procedure:
2-Methyl-3-keto-butyronitrile (J. Am. Chem. Soc. 79, 723, 1957) (25.25 g.) in 120 ml. ethanol was treated with 15 g. methylhydrazine while cooling. The solution was refluxed 3 hours then concentrated in vacuum, benzene added and the solution concentrated again. Ether was added to give 29.12 g. mp 70-106 of base (contained H2O). This was converted to the hydrochloride with HCl in isopropyl alcohol. HCl had mp 286°-288°.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@H:12]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=2[O:14][B:13]1[OH:25].[OH-:26].[Na+].Cl>CO.O>[C:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:2]([NH:3][C@H:12]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=2[O:14][B:13]1[OH:25])=[O:1])([OH:26])=[O:11]
Reactant: O=C(O)c1cccc2c1OB(O)[C@@H](N1C(=O)c3ccccc3C1=O)C2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccccc1C(=O)N[C@H]1Cc2cccc(C(=O)O)c2OB1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 20 mg of (R)-3-(1,3-dioxoisoindolin-2-yl)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid in a mixture of methanol and H2O (2 mL, 1:1) was added 1 N NaOH (0.5 mL) and the resulting reaction mixture was stirred at room temperature for 3 hr. 1N HCl was added to adjust the pH of the solution to 3. The product was then purified by reverse phase HPLC and dried using lyophilization. ESI-MS m/z 356 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:29][C:28]1[CH:30]=[CH:31][C:25]([C:2]2[N:7]=[C:6]([NH:8][C@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH:5]=[N:4][CH:3]=2)=[CH:26][CH:27]=1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1ccccc1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](Nc1cncc(-c2ccc(N)cc2)n1)c1ccccc1

Procedure:
A mixture of 6-chloro-N-[(1S)-1-phenylethyl]pyrazin-2-amine (1.10 g, 4.71 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1.10 g, 5.02 mmol), (PPh3)4Pd (580 mg, 0.5 mmol) and a Na2CO3 solution (2.6 ml, 2M solution) in toluene (20 ml) was heated under reflux for 40 h. Upon cooling, the mixture was diluted with water (30 mL) and the product extracted with ethyl acetate (3×40 ml). The organic layers were combined, washed with brine (30 ml), dried (Na2SO4), and the solvent removed in vacuo. The residue was purified by column chromatography, eluting with a hexane-ethyl acetate (2:3) to furnish the desired product from the polar fractions (0.86 g, 63%).
Reaction SMILES: FC(F)(F)C(O)=[O:4].[CH3:8][N:9]([CH3:33])[CH:10]([CH2:12][C:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH:18]=C)[CH3:11].O=[O+][O-].CSC>CO>[CH3:8][N:9]([CH3:33])[CH:10]([CH2:12][C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]=[O:4]
Reactant: C=CCCCC(=O)C(CC(C)N(C)C)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: O=[O+][O-]
Solvent: CSC
Solvent: CO
Product: CCCCC(=O)C(CC(C=O)N(C)C)(c1ccccc1)c1ccccc1
Temperature: -20 °C

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution of 2-dimethylamino-4,4-diphenyl-9-decene-5-one (270 mg) in methanol (5 ml) to adjust the pH to 2.0. The solution was rotary evaporated, and the residue was taken up in methanol. A gentle stream of ozone was passed through the solution at -78° C., until the color turned to sky blue. The reaction was warmed to -20° C., and dimethyl sulfide (3 ml) was added. Rotary evaporation of the solution gave a crude material which was flash-chromatographed over silica gel. Elution with chloroform/methanol (30:1) yielded 80 mg of 2-dimethylamino-4,4-diphenyl-5-oxo-nonanal.
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([CH3:14])[C:11]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([O:18]C)=[O:17])=[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([C:8]1[N:13]=[C:12]([CH3:14])[C:11]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([OH:18])=[O:17])=[C:10]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cc2ccccc2)nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCC(C(=O)O)c1c(C)nc(Cc2ccccc2)nc1-c1ccccc1
Yield: 40.8 %

Procedure:
A solution of methyl 2-(2-benzyl-4-methyl-6-phenylpyrimidin-5-yl)pentanoate (67 mg; 0.17 mmol) in ethanol (1 mL), tetrahydrofuran (1 mL) and 2N sodium hydroxide solution (0.895 mL; 1.789 mmol) was stirred for 40 h at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with water and acidified with a 6N hydrochloric acid solution. The suspension was extracted twice with ethyl acetate and the organic layers were washed with water and dried by filtration over a phase separater filter (PS1). The crude material was purified first by flash chromatography on silica gel using a linear gradient of methanol (1-10%) in dichloromethane and then by preparative thick layer chromatography on silica gel eluting with 10% methanol in dichloromethane to give 25 mg (37%) of the title compound as a colorless oil. ESI/APCI(+): 361 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:22][C:21]([C:23]([O:25]CC)=[O:24])=[N:20][N:19]=2)[CH2:14][CH2:13]1)=[O:10].[OH-].[Li+].O.Cl>O1CCOCC1>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:22][C:21]([C:23]([OH:25])=[O:24])=[N:20][N:19]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: CCOC(=O)c1nnc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1[nH]c(C(=O)NC2CCN(c3nnc(C(=O)O)s3)CC2)c(Cl)c1Cl
Yield: 5.2 %

Procedure:
Ethyl 5-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3,4-thiadiazole-2-carboxylate (Example 219; 0.530 g, 1.2 mmol) and lithium hydroxide (0.117 g, 4.9 mmol) were stirred in dioxane (5 ml) and water (0.5 ml) and heated to 50° C. for thirty minutes. The solution was acidified (pH 4) using 1 N HCl resulting in a precipitate. The solids were collected and purified using semi-preparative HPLC to give the title compound (0.025 g).