Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[N:2].[NH2:12][C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[C:20]([OH:27])[C:19]=1[CH2:28][CH2:29][CH3:30].C(N(CC)CC)C>ClCCl>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:15]2[CH:14]=[C:13]([NH:12][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[CH:33]=[CH:32][CH:31]=2)=[C:19]([CH2:28][CH2:29][CH3:30])[C:20]=1[OH:27])(=[O:26])[CH3:25]
Reactant: CCCc1c(OCc2cccc(N)c2)ccc(C(C)=O)c1O
Reactant: N#Cc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(OCc2cccc(NC(=O)c3cccc(C#N)c3)c2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
Add a solution of 3-cyanobenzoyl chloride (553 mg, 3.34 mmol) in dichloromethane (10 mL) to a solution of 1-[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (1.00 g, 3.34 mmol) in dichloromethane (10 mL), and triethyl amine (1.4 mL) at 0° C. Stir to room temperature for one hour. Partition the mixture between dichloromethane (20 mL) and 2N hydrochloric acid (30 mL). Wash the organic layer with 2N hydrochloric acid (20 mL), saturated sodium bicarbonate, brine, dry, filter, and concentrate to afford the title compound as a light yellow powder (1.33 g, 93%): 1H NMR (CDCl3) δ 0.96 (t, 3H), 1.59 (sextet, 2H), 2.55 (s, 3H), 2.72 (t, 2H), 5.19 (s, 2H), 6.47 (d, 1H), 7.26 (d, 1H), 7.42 (t, 1H), 7.54-7.59 (m, 2H), 7.65 (t, 1H), 7.77 (s, 1H), 7.84 (d, 1H), 7.88 (s, 1H), 8.11 (d, 1H), 8.17 (s, 1H), 12.75 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C@H:11]2[CH2:17][O:16][C@@H:13]([CH:14]=[O:15])[C@@H:12]2[OH:18])=[CH:5][CH:4]=1.[BH4-].[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C@@H:11]2[C@@H:12]([OH:18])[C@H:13]([CH2:14][OH:15])[O:16][CH2:17]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CS[C@H]2CO[C@@H](C=O)[C@@H]2O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(CS[C@H]2CO[C@@H](CO)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a room temperature solution, under argon, of 10.9 g of product from Example 322 in 115 ml of absolute ethyl alcohol is added 1.57 g of sodium borohydride. The reaction is stirred at room temperature for 1 hour. Water is added dropwise with stirring and the minute is concentrated in vacuo. The residue is extracted with methylene chloride, washed with water, dried and concentrated in vacuo to give after chromatography (Silica gel: 50-75% ethyl acetate/hexane) 7.68 g of the desired product.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=O)[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[Br:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[CH2:22][NH:23][CH3:24].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH2:11]([N:6]1[CH2:7][CH:8]([N:23]([CH2:22][C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([Br:18])[CH:20]=2)[CH3:24])[CH2:9][CH:5]1[C:3]([OH:2])=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNCc1cccc(Br)c1
Reactant: COC(=O)C1CC(=O)CN1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(Cc1cccc(Br)c1)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reaction time: 3 h
Yield: 64.8 %

Procedure:
To a solution of 1-benzyl-4-oxo-pyrrolidine-2-carboxylic acid methyl ester (1 mmol), (3-bromo-benzyl)-methyl-amine (1 mmol) in 2 mL of CH2Cl2 were added NaBH(OAc)3 (2 mmol) and 5 drops of AcOH, and the resulting mixture was stirred for 3 h. The mixture was treated with aq. NaHCO3, extracted by CH2Cl2 (3×5 mL), and the combined extracts were washed by brine (10 mL), dried over Na2SO4, and concentrated to give 261.3 mg of crude product in 65% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:16])=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[N:13]=2)=[CH:4][CH:3]=1.[NH:17](C1C=CC(C2C(C)CC(=O)NN=2)=CC=1)N>>[NH:1]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:16])=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[N:13]=2)=[CH:4][CH:3]=1)[NH2:17]
Reactant: CC1CC(=O)NN=C1c1ccc(NN)cc1
Reactant: Cc1cc(=O)n(C)nc1-c1ccc(N)cc1
Product: Cc1cc(=O)n(C)nc1-c1ccc(NN)cc1

Procedure:
The title compound was prepared from 6-(4-aminophenyl)-2,5-dimethyl-2H-pyridazin-3-one similarly as 6-(4-hydrazinophenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one.
Reaction SMILES: [Na+].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]([O:14][CH3:15])[C:11]([O-:13])=[O:12])=[CH:5][CH:4]=1.[CH3:16]S(O)(=O)=O>CO>[CH3:16][O:12][C:11](=[O:13])[C@H:10]([O:14][CH3:15])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1
Reactant: CO[C@H](Cc1ccc(O)cc1)C(=O)[O-]
Reactant: CS(=O)(=O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](Cc1ccc(O)cc1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Compound (a), (R)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid sodium salt, (Example 2, Step 5) (5.00 g, 22.9 mmol) is dissolved in methanol (125 mL) and treated with methanesulfonic acid (7.44 mL, 114.6 mmol). The reaction is stirred at room temperature for 1 h. The reaction is concentrated in vacuo and the resulting residue taken up in diethyl ether. The organic portion is washed with water (2×) and saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated in vacuo to yield 4.00 g (83%) of an off-white solid. The material is used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.06 (dd, J=2.2, 6.4 Hz, 2H), 6.72 (dd, J=2.2, 6.4 Hz, 2H), 5.38 (bd s, 1H), 3.95 (dd, J=5.3, 7.1 Hz, 1H), 3.71 (s, 3H), 3.35 (s, 3H), 2.95 (m, 2H); MS (electrospray), 209.2 (ES−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16]N=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.CC1[N:30]=[CH:29]C(NN)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:29]=[N:30][C:17]([CH3:16])=[CH:18][CH:19]=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Reactant: Cc1ccc(NN)cn1
Agent: Cl
Product: Cc1ccc(-n2nc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)cn1

Procedure:
785 g (2.25 mmol) of the compound of Example 1A is reacted analogously to the synthesis of the compound of Example 20A with 599 mg (3.38 mmol) of 6-methylpyridin-3-yl-hydrazine hydrochloride. After hydrolysis, 60 mg (8% of theory) of the title compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>CO>[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Agent: Cl
Solvent: CO
Product: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Yield: 75.4 %

Procedure:
The tert-butyl N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate (4.3 g, 10.0 mmol) was dissolved in methanol (15 mL) and 1 N hydrochloric acid (100 mL) and then heated at reflux for 2 hours. The reaction mixture was concentrated under vacuum to a volume of about 50 mL. Addition of concentrated ammonium hydroxide to pH 12 did not produce a precipitate. The pH was adjusted to 7 with 1 N hydrochloric acid. The mixture was extracted with dichloromethane and then with ethyl acetate. The aqueous layer was concentrated to dryness. The residue was dissolved in water (50 mL) and then extracted continuously with refluxing chloroform for 36 hours. The chloroform extract was concentrated under vacuum to provide a light tan solid. This material was recrystallized from acetonitrile to provide 2.5 g of 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as an off white solid, m.p. 175-177° C. Analysis: Calculated for C20H21N5: %C, 72.48; %H, 6.39; %N, 21.13; Found: %C, 72.72; %H, 6.32; %N, 20.71.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:6]=1>C(O)C>[NH2:1][C:2]1[S:3][C:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:6]=1
Reactant: CCCCCc1nc(N)sc1Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CCCCCc1nc(N)sc1Cc1ccc(N)cc1
Yield: 111.2 %

Procedure:
3.0 g of 2-amino-5-(4-nitrobenzyl)-4-pentylthiazole (9.8 mmol) in 100 ml of ethanol are hydrogenated according to Example 25 to give 3 g of 2-amino-5-(4-aminobenzyl)-4-pentylthiazole in the form of a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]([CH2:21][NH2:22])[CH2:16][CH2:15][CH2:14]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]=[C:25]=[O:26]>>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][NH:22][C:25]([NH:24][CH3:23])=[O:26])[CH2:16][CH2:15][CH2:14]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Reactant: CN=C=O
Product: CNC(=O)NC[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21

Procedure:
(R)-1-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-3-methyl-urea was prepared by treatment of C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine with methyl isocyanate according to the procedure of Najer et al.; Bull. Soc. Chim. Fr.; 1069-1071 (1957).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:11][C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[C@@H:4]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[C@@H:3]1[OH:18].ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:19])[O:11][C:10]2[CH:9]=[CH:8][N+:7]([O-:28])=[CH:6][C:5]=2[C@@H:4]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[C@@H:3]1[OH:18]
Reactant: CC1(C)Oc2ccncc2[C@@H](N2CCCC2=O)[C@@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC1(C)Oc2cc[n+]([O-])cc2[C@@H](N2CCCC2=O)[C@@H]1O

Procedure:
The compound of example 1 (102mgm) and m-chloroperbenzoic acid (134mgm) were heated under reflux in chloroform (10 mL) for 2hr. The reaction mixture was cooled and evaporated and the resulting gum was chromatographed (chromatotron; chloroform ->10% methanol-chloroform in a gradient elution), and chromatographically homogenous fractions were combined and recrystallised from ethyl acetate-methanol to give the N-oxide of (E2) as a solid (54mgm) of m.p. 284°-285° C.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].I[CH2:21][CH2:22][CH3:23]>CN(C=O)C.O>[C:1]([C:5]1[C:6]([O:13][CH2:21][CH2:22][CH3:23])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCI
Reactant: CC(C)(C)c1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1c(C=O)cccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.6 %

Procedure:
To a solution of 3-tert-butyl-2-hydroxy-benzaldehyde (2.04 g, 11.5 mmol) and K2CO3 (7.91 g, 57.3 mmol) in anhydrous DMF (23 ml) was added 1-iodopropane (2.34 ml, 24.0 mmol). The reaction mixture was left to stir for 48 h at room temperature. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (3×50 ml). Combined organic layers were washed with water (50 ml) and brine (50 ml), dried over MgSO4, filtered and the solvent was removed in vacuo to give a yellow oil. Purification by column chromatography (silica gel, gradient elution of hexanes to 20% EtOAc/hexanes) gave 3-tert-butyl-2-propoxy-benzaldehyde (2.55 g, 99%) as a yellow oil: 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 7.62 (s, 1H), 7.61 (s, 1H), 7.19 (t J=8.0, 1H), 3.89 (t, J=8.0 Hz, 2H), 1.91-1.82 (m, 2H), 1.37 (s, 9H), 1.03 (t, J=8.0 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[N:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[N:10]=[C:11]([CH3:12])[C:3]=12.[CH2:22]([NH:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25]>CS(C)=O>[CH2:22]([NH:26][CH2:27][CH2:28][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[N:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[N:10]=[C:11]([CH3:12])[C:3]=12)[CH2:23][CH2:24][CH3:25]
Reactant: Cc1cc(C)c(-n2nc(C)c3c(Cl)cc(C)nc32)c(C)c1
Reactant: CCCCNCC
Solvent: CS(C)=O
Product: CCCCNCCc1cc(C)nc2c1c(C)nn2-c1c(C)cc(C)cc1C
Temperature: 177.5 °C

Procedure:
A mixture of 4-chloro-3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridine (98 mg, 0.33 mmol), N-butylethylamine (1 ml) in DMSO (2 ml) was heated in an oil bath at 175-180° C. for 20 hours. The reaction mixture was quenched with saturated ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, dried, and concentrated to give a brown oil. The oil residue was purified through silica gel column chromatography using EtOAc/Hexane in a ratio of 1/9 as eluent to give a colorless oil. 1H NMR (CDCl3) 6.92 (s, 2H), 6.29 (s, 1H), 3.42 (q, 2H), 3.27 (t, 2H), 2.65 (s, 3H), 2.44 (s, 3H), 2.30 (s, 3H), 1.91 (s, 6H), 1.57 (m, 2H), 1.33 (m, 2H), 1.13 (t, 3H), 0.90 (t, 3H) ppm. IR (neat) 2960, 2920, 1570 cm−1. High MS, calc. 364.2627, found 364.26306.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][CH:22]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[N:25]=2)[CH3:23])=[CH:19][CH:18]=1>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:30][C:26]4[N:25]=[C:24]([CH:22]([O:21][C:20]5[CH:31]=[CH:32][C:17]([Cl:16])=[CH:18][CH:19]=5)[CH3:23])[CH:29]=[CH:28][N:27]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CC(Oc1ccc(Cl)cc1)c1ccnc(N)n1
Solvent: c1ccncc1
Product: CC(Oc1ccc(Cl)cc1)c1ccnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)n1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.2 mmol) in pyridine (2 mL) was added 4-(1-(4-chlorophenoxy)ethyl)pyrimidin-2-amine (50 mg, 0.2 mmol) and the reaction mixture was stirred at 115° C. for 15 hours. The solvent was evaporated to dryness and the residue redissolved in DMF, filtered and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product. ESI-MS m/z calc. 437.9. Found 438.1 (M+1)+. Retention time 3.16 minutes.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([OH:14])=[CH:3][CH:2]=1.[H-].[Na+].[CH2:17](I)[CH3:18]>CN(C=O)C>[CH2:17]([O:14][C:4]1[C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=[CH:2][CH:3]=1)[CH3:18]
Reactant: CCI
Reactant: Oc1cccc2c1oc1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cccc2c1oc1ccccc12
Yield: 82.4 %

Procedure:
A solution of Dibenzo[b,d]furan-4-ol (1 g, 5.43 mmol) in DMF (5 ml) was added to a stirred and cooled (0° C.) suspension of 60% sodium hydride (326 mg, 8.12 mmol) in DMF (20 ml). The mixture was stirred at 0° C. for 5 min and ethyl iodide (1.18 g, 10.86 mmol) in DMF (5 ml) was added dropwise over a period of 10 min. The cooling bath was removed and the mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with ice-cold water (100 ml) and extracted with EtOAc (3×50 ml). The combined organic extracts were washed with water (2×100 ml), brine (100 ml) and dried (Na2SO4), to give 0.95 g (82%) of the product as viscous liquid,
Reaction SMILES: [Br:1]Br.O.[NH2:4][C:5]1[C:12]([F:13])=[CH:11][C:8]([C:9]#[N:10])=[C:7]([F:14])[CH:6]=1>CC(O)=O>[NH2:4][C:5]1[C:12]([F:13])=[CH:11][C:8]([C:9]#[N:10])=[C:7]([F:14])[C:6]=1[Br:1]
Reactant: N#Cc1cc(F)c(N)cc1F
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cc(F)c(N)c(Br)c1F
Reaction time: 16 h
Yield: 71 %

Procedure:
A mixture of 1.65 mL of Br2, 2 mL of H2O and 5 g of 4-amino-2,5-difluorobenzonitrile in 50 mL of AcOH is stirred at 20°-25° for 16 hours. The solvents are removed in vacuo and the residue partitioned between 100 mL of H2O and 3×200 ml of CH2Cl2. The CH2Cl2 extracts are washed with H2O, saturated NaHCO3, H2O (100 mL each), dried with Na2SO4 and evaporated in vacuo to give 6.89 g of crude 4-amino-3-bromo-2,5-difluorobenzonitrile. This is purified by dry-column chromatography using SiO2 to give 5.38 g (71% yield). Recrystallization from CH2Cl2 /hexane affords analytically pure material, m.p. 106°-108° C.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:15]>O1CCCC1>[C:4]([CH:5]([CH2:13][C:14](=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:11]
Reactant: O=C(CBr)c1ccccc1Oc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)c1ccccc1Oc1ccccc1)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
A mixture of sodium hydride (60% oil dispersion, 0.157 g, 3.92 mmol) and tetrahydrofuran (6.1 mL) was cooled to 0° C., treated dropwise with ethyl 3-oxobutanoate (0.413 mL, 3.27 mmol) and stirred at 0° C. for 30 minutes. A solution of 2-bromo-1-(2-phenoxyphenyl)ethanone (1.05 g, 3.6 mmol) in tetrahydrofuran (2 mL) was added dropwise and stirring was continued for 5.5 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution and washed with saturated aqueous sodium chloride. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 2-20% ethyl acetate in hexanes) to give 1.1 g (100%) of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[N:15]1([C:20]2[CH:21]=[C:22]([N:26]3[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[C:27]3=[O:34])[CH:23]=[CH:24][CH:25]=2)[CH:19]=[CH:18][CH:17]=[CH:16]1.N1(C2C=C(N3CCC(C(O)=O)C3=O)C=CC=2)C=CC=C1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:15]1([C:20]2[CH:21]=[C:22]([N:26]3[CH2:30][CH2:29][CH:28]([C:31]([NH:14][CH2:13][CH2:12][C:6]4[C:5]5[C:9](=[CH:10][CH:11]=[C:3]([Cl:2])[CH:4]=5)[NH:8][CH:7]=4)=[O:32])[C:27]3=[O:34])[CH:23]=[CH:24][CH:25]=2)[CH:19]=[CH:18][CH:17]=[CH:16]1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C1CCN(c2cccc(-n3cccc3)c2)C1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2cccc(-n3cccc3)c2)C1=O
Yield: 30 %

Procedure:
This compound was prepared according to method E with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), 1-(3-(1H-pyrrol-1-yl)phenyl)-2-oxopyrrolidine-3-carboxylic acid 1-(3-(1H-pyrrol-1-yl)phenyl)-2-oxopyrrolidine-3-carboxylic acid (0.117 g; 0.433 mmol), PyBOP (0.225 g; 0.433 mmol), N,N diisopropylethylamine (0.186 mL; 1.08 mmol) in DMF (3 mL). The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane and 2 to 20% ethyl acetate in dichloromethane) to yield 0.058 g (30%) of 1-(3-(1H-pyrrol-1-yl)phenyl)-N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Cl:13]Cl>C(Cl)Cl>[Cl:13][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCl
Agent: [K]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1Cl
Temperature: 0 °C
Yield: 88 %

Procedure:
To 800 ml. of methylene chloride were added 50 grams (270 mmoles) of potassium phthalimide. The resulting slurry was chilled to 0° C. To a jacketed flask maintained immediately above the main reaction vessel were added 200 ml. of methylene chloride. The methylene chloride was saturated with chlorine and was maintained at a temperature of -5° C. to 0° C. The flask containing the chlorinesaturated methylene chloride was equipped with a dry-ice trap to ensure that none of the reagent escaped. The chlorine-saturated methylene chloride then was added to the potassium phthalimide mixture as rapidly as possible by means of a tube which extended below the surface of the potassium phthalimide slurry. Addition was completed in less than 30 seconds. During addition, the temperature of the mixture increased from 0° C. to 10° C. The resulting mixture had a greenish-yellow color which persisted. The mixture was allowed to warm to 20° C. over a two hour period. Some undissolved lumps of potassium phthalimide were noted in the mixture. The resulting potassium chloride percipitate was removed by filtration, and the filtrate was evaporated in vacuo to a slush. Heptane (about 400 ml.) was added, and the mixture was filtered. The collected N-chlorophthalimide was reslurried in about 500 ml. of water and vacuum-dried to afford 42.9 grams (88% yield) of N-chlorophthalimide.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[N:20]1([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27](O)=[O:28])[CH:24]=[CH:23][CH:22]=[N:21]1>>[N:20]1([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:28])[CH:24]=[CH:23][CH:22]=[N:21]1
Reactant: O=C(O)c1ccccc1-n1cccn1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1ccccc1-n1cccn1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-Pyrazol-1-yl-benzoic acid. LC-MS (basic): tR=1.20 min; [M+H]+=447.1.
Reaction SMILES: [OH-].[K+].[CH3:3][S:4]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[C:11]([CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:30][CH2:29]1)=[C:10]2[C:40]([O:42]C)=[O:41])(=[O:6])=[O:5]>CO.O>[CH3:3][S:4]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=1)[C:11]([CH2:27][N:28]1[CH2:29][CH2:30][CH:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[CH2:32][CH2:33]1)=[C:10]2[C:40]([OH:42])=[O:41])(=[O:6])=[O:5]
Reactant: COC(=O)c1c(CN2CCC(N3CCOCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)O)c2c1
Yield: 93.2 %

Procedure:
Potassium hydroxide (1.42 g, 25.4 mmol) was added to a solution of methyl 6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (3.0 g, 5.07 mmol) in methanol (60 mL) and water (20 mL), and the resulting mixture was heated to reflux for 5 h. The solvent was removed under reduced pressure, and the residue was adjusted to pH˜5-6 with 2N HCl and extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (2.73 g, 81% yield). MS (m/z) 578.2 (M+H+).