Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[C:26]2[C:27]3=[C:28]4[C:23](=[CH:24][CH:25]=2)[CH:22]=[CH:21][CH:20]=[C:19]4[CH:18]=[CH:17][C:16]3=[CH:15][CH:14]=1.[B:29](OC)([O:32]C)[O:30]C.Cl>O1CCCC1>[C:13]1([B:29]([OH:32])[OH:30])[C:26]2[C:27]3=[C:28]4[C:23](=[CH:24][CH:25]=2)[CH:22]=[CH:21][CH:20]=[C:19]4[CH:18]=[CH:17][C:16]3=[CH:15][CH:14]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Temperature: 0 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
An excess of 1.6 M n-BuLi in hexane (50 mL, 80 mmol) was added to a solution of 1-bromopyrene (20.4 g, 72.6 mmol) in 500 ml dry tetrahydrofuran at −78° C. under N2. The reaction mixture was then maintained at 0° C. for 1 h before cooling to −78° C. Trimethyl borate (10.4 g, 100 mmol) was added dropwise; the solution was then warmed slowly to room temperature and stirred for 24 h. 2N HCl (150 ml) was added and then the mixture was stirred for a further 1 h. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuo, and the residue was crystallized (n-hexane) to give the pyren-1-ylboronic acid 12.5 g as a yellow solid (70%)
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:8]=1[N+:17]([O-])=O)[C:4]([NH2:6])=[O:5])#[N:2]>C(O)C.[Pd]>[NH2:17][C:8]1[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:7]=1[CH:3]([C:1]#[N:2])[C:4]([NH2:6])=[O:5]
Reactant: COC(=O)c1ccc(C(C#N)C(N)=O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(C(C#N)C(N)=O)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
5% Palladium-activated carbon (80 mg) was added to a solution of 2-cyano-2-(4-methoxycarbonyl-2-nitrophenyl)acetamide (Reference compound 1-5, 1.0 g, 3.8 mmol) in ethanol (10 mL), and the mixture was stirred at room temperature overnight under hydrogen atmosphere (3 kgf/cm2). After the reaction mixture was filtered throught Celite®, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title reference compound (0.42 g) as a brown solid (yield 47%).
Reaction SMILES: [C:1]([CH:8]([NH2:19])[C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([Cl:18])[CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[Cl:18][C:11]1[CH:10]=[C:9]([CH:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[NH2:19])[CH:17]=[CH:16][C:12]=1[C:13]([NH:25][C:24]1[CH:26]=[CH:27][C:21]([Cl:20])=[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH:23]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)C(N)c1ccc(C(=O)O)c(Cl)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CC(C)(C)OC(=O)C(N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
General procedure G was used to couple 4-(BOC-aminomethyl)-2-chloro-benzoic acid and 4-chloro-3-(pyridin-2-yl)aniline to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)-phenyl)-4-(BOC-aminomethyl)-benzamide with. The crude reaction mixture was treated to TFA and trace water for 1 h prior to concentrating to dryness to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)-phenyl)-4-(aminomethyl)-benzamide.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.Cl[C:13]1[N:18]=[CH:17][C:16]([N:19]2[CH2:23][CH2:22][C:21]3([CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:20]2=[O:29])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:13]2[N:14]=[CH:15][C:16]([N:19]3[CH2:23][CH2:22][C:21]4([CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:20]3=[O:29])=[CH:17][N:18]=2)[CH2:8]1
Reactant: C[C@H]1CCCN1[C@H]1CCNC1
Reactant: O=C1N(c2cnc(Cl)nc2)CCC12CCOCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H]1CCCN1[C@H]1CCN(c2ncc(N3CCC4(CCOCC4)C3=O)cn2)C1
Temperature: 70 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
To a solution of (2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl (0.072 g, 0.315 mmol) in acetonitrile (25 mL) was added 2-(2-chloro-pyrimidin-5-yl)-8-oxa-2-aza-spiro[4.5]decan-1-one (0.07 g, 0.262 mmol), and powdered potassium carbonate (0.145 g, 1.05 mmol) and stirred at 70° C. for 16.0 hours. Additional (2S,3′S)-2-Methyl-[1,3′]bipyrrolidinyl (0.1 g) was added and reaction mixture stirred for 4 hours at 70° C. The reaction mixture was then allowed to cool to room temperature, quenched with water (2 mL) diluted with ethyl acetate (10 mL). The aqueous phase was extracted with 10% methanol in dichloromethane (10 ml, 3×), combined organics washed with brine, dried over Na2SO4, concentrated under vacuum. Purification by column chromatography on silica gel (0-100%) eluting with methanol in dichloromethane (0-10%) afforded 0.0732 g (72%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([N+:9]([O-])=O)[CH:3]=1.[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:19]([CH3:20])=[N:9][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: CC(=O)Nc1ccccc1
Product: Cc1nc2cc(Cl)ccc2n1-c1ccccc1
Yield: 56 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 4-Chloro-1-bromo-2-nitrobenzene (118 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol), as starting materials to yield the title compound as yellow solid (68 mg, 56% yield). mp 109-111° C. 1H NMR (DMSO) δ 2.52 (s, 3 H), 7.22 (d, J=8.6 Hz, 1 H), 7.34 (d, J=8.6 Hz, 1 H), 7.48-7.59 (m, 5 H), 7.86 (s, 1 H); 13C NMR δ 13.5, 112.2, 116.4, 123.9, 126.9, 127.9, 129.7, 130.1, 133.9, 138.5, 154.0, 157.0. HRMS (FAB): cal. for C14H12N2Cl [M+H+]: 243.0689; found: 243.0684.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]([CH3:10])=[C:6]([CH3:11])[C:5]1=[O:12].[Cl:13][CH2:14][C:15](O)=[O:16].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[Cl:13][CH2:14][C:15]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]([CH3:10])=[C:6]([CH3:11])[C:5]1=[O:12])=[O:16]
Reactant: O=C(O)CCl
Reactant: CC1=C(C)C(=O)N(CCO)C1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=C(C)C(=O)N(CCOC(=O)CCl)C1=O
Yield: 83.9 %

Procedure:
With stirring, 169.2 g (1 mole) of N-(2-hydroxyethyl)dimethylmaleimide, 113.4 g (1.2 moles) of chloroacetic acid and 11.8 g of concentrated sulfuric acid are heated to reflux in 1000 ml of toluene using a water separator. The formation of water ceases after about 2 hours and 18 ml have separated. The reaction solution is washed with saturated sodium bicarbonate solution and water. The organic phase is dried over magnesium sulfate and concentrated in a rotary evaporator at 40° C. The residue is dried for 2 hours at 60° C./0.1 mm, affording 206 g of a colourless liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:9][C:19]1[CH:18]=[CH:17][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(N)Cc1ccccc1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)Nc1ccc2ccccc2c1
Temperature: 50 °C
Yield: 49 %

Procedure:
A mixture of N-benzyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 27; 1.21 g, 5.44 mmol), 2-naphthaleneboronic acid (Lancaster; 1.00 g, 5.8 mmol), copper(II) acetate (990 mg, 5.45 mmol) and triethylamine (1.9 mL, 13.6 mmol) in 1,2-dichloroethane (30 mL) was heated in an oil bath at 50° C. for 1.5 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 120 g column, eluting with 15-30% ethyl acetate/hexanes, to give N-benzyl-N′-naphthalen-2-yl-hydrazinecarboxylic acid tert-butyl ester (929 mg, 49%) as a yellow oil that solidified on standing.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[CH3:11][O:12][N:13]=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]Br)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][O:12][N:13]=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CON=C(C(=O)OC)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CON=C(C(=O)OC)c1ccccc1COc1ccc(C(C)=O)cc1
Yield: 73.9 %

Procedure:
3.0 g (0.022 mol) of 4-hydroxyacetophenone and 6.0 g (0.021 mol) of methyl 2-bromomethylphenylglyoxylate O-methyloxime are dissolved in 30 ml of dimethylformamide, and 5.5 g (0.040 mol) of potassium carbonate are added. The mixture is stirred at room temperature for 24 hours, hydrolyzed with water and extracted with methyl tert-butyl ether. The organic phase is washed with water, dried and concentrated. 5.3 g (78%) of methyl 2-(4-acetylphenoxymethyl)phenylglyoxylate O-methyloxime are obtained as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:11])[C:4]([CH:12]=O)=[C:3]1Cl.C([O-])([O-])=O.[K+].[K+].[SH:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]>>[Cl:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[C:3]1[S:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:12][C:4]2=1
Reactant: Cn1c(Cl)c(C=O)c2cccc(Cl)c21
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc2c3cccc(Cl)c3n(C)c2s1
Yield: 83 %

Procedure:
Prepared from (47) (6.5 g), K2CO3 (11.17 g) and methyl 2-mercaptoacetate (4.46 ml) yielding (50) 6.62 g (83%). M.p. 166°-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:11]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:12]=[C:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]3)[CH:5]=[CH:6][C:7]=1[F:8].[CH:26]1([N:32]=[C:33]=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CCN(CC)CC>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:10]2[N:11]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[N:12]=[C:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]3)[C:33]([NH:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:34])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C=NC1CCCCC1
Reactant: Fc1ccc(Nc2c3ccccc3nn2-c2ccc(Cl)cc2)cc1Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)N(c1ccc(F)c(Cl)c1)c1c2ccccc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 1.2, (3-chloro-4-fluoro-phenyl)-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 4 d under reflux conditions to give the title compound as yellow oil. MS: m/e=496.9 [M+H+].
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[CH2:1]([NH:9][C:10](=[O:12])[CH3:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1ccccc1
Product: CC(=O)NCCc1ccccc1

Procedure:
In close analogy to the procedure described above, phenethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:9][CH2:8]2)[C:5]2[CH:28]=[CH:29][CH:30]=[CH:31][C:4]=2[NH:3]1.NN.O>C(O)C>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:9][CH2:8]2)[C:5]2[CH:28]=[CH:29][CH:30]=[CH:31][C:4]=2[NH:3]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
Batch size: 11.5 g (27.4 mmol) 2-{4-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-butyl}-isoindolin-1,3-dione and 2.7 ml (55 mmol) hydrazine.hydrate in 60 ml ethanol. The accumulated crude product is further processed without further purification: Yield 5.1 g (64%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>ClCCl.O>[NH:11]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of alpha-bromo-4-tolunitrile (86.6 g) in dichloromethane (1000 mL) is mixed with imidazole (68.0 g). The mixture is stirred at ambient temperature for 15 hours and then diluted with water (1000 mL). Any undissolved solid is removed by filtration and the separated organic solution is then repeatedly washed with water (5×200 mL) to remove excess imidazole, and then dried (MgSO4). The crude product obtained upon evaporation of the solvent can be purified by trituration with cold diethyl ether (200 mL) to obtain 4-(1-imidazolylmethyl)-benzonitrile, m.p. 99°-101°; HCl salt, m.p. 142°-144°.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[Cl:5][CH2:6][C:7]1([CH3:10])[CH2:9][O:8]1>O>[Cl:5][CH2:6][C:7]1([CH3:10])[O:8][C:2](=[O:1])[NH:3][CH2:9]1
Reactant: CC1(CCl)CO1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Product: CC1(CCl)CNC(=O)O1
Reaction time: 15 h

Procedure:
Potassium cyanate (7.61 g) was dissolved in 350 ml of water, and 2-(chloromethyl)-2-methyloxirane was slowly added (5.00 g). The solution was stirred overnight (15 h) at reflux. The reaction mixture was then extracted while still moderately warm with ethyl acetate (5×200 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide the title compound an off-white solid (3.32 g, 47%). Mass spectrum (ESI) 150.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 5.23 (bs, 1H), 3.70 (d, J=8.7 Hz, 1H), 3.68 (d, J=11.0 Hz, 1H), 3.56 (d, J=11.2 Hz, 1H), 3.34 (d, J=8.9 Hz, 1H), 1.59 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7].C(=O)([O-])[O-:19].[Ca+2].O>O1CCOCC1>[OH:19][CH2:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: CON(C)C(=O)c1cccc(CBr)c1[N+](=O)[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: CON(C)C(=O)c1cccc(CO)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture of Intermediate 37B (3.7 g, 4.88 mmol) and calcium carbonate (2.93 g, 29.3 mmol) in dioxane (25 mL)/water (25 mL) was stirred at reflux for 5 h. The mixture was then cooled to room temperature, the solid was removed by filtration and the filtrate was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to dryness. The crude residue was purified by flash chromatography (SiO2, 80 g column, EtOAc/hexane=20-100%) to afford Intermediate 37C (1.079 g, 78%). HPLC: RT=0.75 min (CHROMOLITH® SpeedROD column 4 6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm), MS(ES): m/z=241.0 [M+H+].
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:24])[CH3:23])[NH2:21]>>[CH3:17][O:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:24])[CH3:23])[NH:21][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1ccccc1)C(C)C

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (fromo Example B1 above) and L-valine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid (mp=112-115° C.). The reaction was monitored by tlc (Rf=0.33 in 50% EtOAc/hexanes) and the product was not purified.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[C:9]([CH2:10]Cl)=[CH:8][CH:7]=[C:6]([Cl:12])[N:5]=1>C(#N)C>[Cl:3][C:4]1[C:9]([CH2:10][NH:2][CH3:1])=[CH:8][CH:7]=[C:6]([Cl:12])[N:5]=1
Reactant: CN
Reactant: ClCc1ccc(Cl)nc1Cl
Solvent: CC#N
Product: CNCc1ccc(Cl)nc1Cl
Yield: 83.7 %

Procedure:
In 50 ml of acetonitrile was dissolved 7.8 g (0.1 mole) of 40% aqueous methylamine and with stirring and ice-cooling, a solution of 3.9 g (0.02 mole) of 2,6-dichloro-3-pyridylmethyl chloride in 10 ml of acetonitrile was added dropwise over 5 minutes. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours and, then, concentrated. The residue was extracted with ether (30 ml×3 ) and dried over MgSO4. Finally, the solvent was distilled off to give 3.2 g of the title compound as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[C:28]([C:35]([F:38])([F:37])[F:36])[CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)=[C:28]([C:35]([F:36])([F:37])[F:38])[CH:27]=1
Reactant: COc1ccc(B(O)O)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and 4-methoxy-2-(trifluoromethyl)phenylboronic acid (248 mg, 1.0 mmol) to afford after chromatographic purification the title compound (196 mg, 83%). 1H NMR (CDCl3, 300 MHz) δ 7.21-7.26 (m,2H), 7.01-7.05 (m, 1H), 6.86 (s, 1H), 6.82 (s, 1H), 3.90-4.30 (m, 3H), 3.86 (s, 3H), 3.3.64-3.75 (m, 1H), 3.25-3.50 (m, 4H), 3.05-3.12 (m, 1H), 2.85-2.95 (m, 1H), 1.80-1.90 (m, 2H), 1.47 (s, 9H) ppm. MS-ApCI: 475 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[N:16]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[N:15]=[C:14]([Cl:24])[CH:13]=3)[O:8][C:7](=[O:25])[C:6]=2[CH:5]=[C:4](I)[CH:3]=1.[Cu][C:28]#[N:29]>O1CCCC1.C(OCC)(=O)C.[Cu]I>[Cl:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[N:16]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[N:15]=[C:14]([Cl:24])[CH:13]=3)[O:8][C:7](=[O:25])[C:6]=2[CH:5]=[C:4]([C:28]#[N:29])[CH:3]=1
Reactant: O=c1oc(-c2cc(Cl)nn2-c2ncccc2Cl)nc2c(Cl)cc(I)cc12
Reactant: N#C[Cu]
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cc(Cl)c2nc(-c3cc(Cl)nn3-c3ncccc3Cl)oc(=O)c2c1

Procedure:
To a solution of 8-chloro-2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-iodo-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Step B) (575 mg, 1.1 mmol) in tetrahydrofuran (15 mL) was added copper(I) iodide (840 mg, 0.44 mmol), tetrakis(triphenyphosphine)palladium(0) (255 mg, 0.22 mmol) and copper(I) cyanide (500 mg, 5.5 mmol) sequentially at room temperature. The reaction mixture was then heated at reflux overnight. The reaction turned black in color, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The reaction was diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by washing three times with 10% aqueous sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure to afford 375 mg of the title compound as a crude yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19]C)=[C:11]([C:21]([O:23]C)=[O:22])[CH:10]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.CO.Br>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([OH:19])=[C:11]([C:21]([OH:23])=[O:22])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(Cc2ccc(Cl)nc2)c2ccccc2c1OC
Agent: Br
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(O)c1cc(Cc2ccc(Cl)nc2)c2ccccc2c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-[(6-chloropyridin-3-yl)methyl]-1-methoxy-2-naphthoate (see Example 3, 0.200 g, 0.585 mmol) in 5 mL of dichloromethane at −78° C. was added boron tribromide (1.0 M in dichloromethane, 1.76 mL, 1.76 mmol) dropwise. After 1 hour, the reaction was warmed to 0° C., treated with 6 mL of MeOH and warmed to room temperature overnight. To this reaction was added hydrobromic acid (33% in acetic acid, 2.50 mL, 15.2 mmol) dropwise, and the mixture was heated to 65° C. for 60 hours. Addition hydrobromic acid (33% in acetic acid, 1.50 mL, 9.14 mmol) was added, and the reaction was heated to 90° C. for 4 hours, cooled to room temperature, azeotroped 2× with toluene, and concentrated in vacuo to provide 4-[(6-chloropyridin-3-yl)methyl]-1-hydroxy-2-naphthoic acid that gave a mass ion (ES+) of 314.2 for [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11].[Cl-].Cl[CH2:16][CH2:17][NH2+:18][CH2:19][CH2:20]Cl>C(O)CCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:5][C:4]=1[C:10]([F:11])([F:12])[F:13]
Reactant: COc1ccc(N)cc1C(F)(F)F
Reactant: ClCC[NH2+]CCCl
Agent: [Cl-]
Solvent: CCCCO
Product: COc1ccc(N2CCNCC2)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 4-methoxy-3-trifluoromethylphenylamine (12 g; 0.0627 mol) and bis(2-chloroethyl) ammonium chloride (11.2 g; 0.0627 mol) in n-butanol (120 ml) was refluxed for 10 hours. The reaction mixture was cooled at room temperature and the crude title compound precipitated as hydrochloride salt overnight. The solid was collected and crystallized from acetone. 7 g; m.p. 244-245° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([NH:23][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[O:34][CH:33]=[CH:32][C:31]=23)=[O:25])[CH2:18]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH:19]([NH:23][C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[C:30]4[O:34][CH:33]=[CH:32][C:31]=34)=[O:25])[CH2:18]2)=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: O=C(NC1CCCNC1)c1cccc2occc12
Product: Cc1nc(C(=O)N2CCCC(NC(=O)c3cccc4occc34)C2)c(-c2ccc(F)cc2)s1

Procedure:
prepared by reaction of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid with (RS)-benzofuran-4-carboxylic acid piperidin-3-ylamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)[CH2:33][CH2:32]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Reactant: Clc1cccc(N2CCNCC2)c1
Product: COc1ccc2nc(NC(=O)N3CCN(c4cccc(Cl)c4)CC3)c(OC)nc2c1
Yield: 85 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 85%). 1H NMR (300 MHz, CDCl3): δ 2.29 (s, 4H), 3.74 (s, 4H), 3.90 (s, 3H), 4.13 (s, 4H), 6.78-6.89 (m, 3H), 7.15-7.27 (m, 4H), 7.73 (d, J=9.7 Hz, 1H).