Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:16][C:17](=[O:19])[CH3:18])C=CC=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:16][C:17](=[O:19])[CH3:18])[CH:2]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccnc1
Solvent: Cc1ccccc1
Product: CC(=O)C=Cc1cccnc1

Procedure:
Pyridine-3-carboxaldehyde (18.9 ml) and 1-triphenylphosphoranylidene-2-propanone (70 g) were heated at reflux in toluene for 2 hr. The solvent was evaporated and the residue was distilled at reduced pressure to give 1-(3-pyridyl)but-1-en-3-one as an oil. Pmr spectrum (CDCl3 ; δ in ppm): 2.41 (3H, s); 6.79 (1H, d); 7.2-8.77 (4H, m); 7.52 (1H, d).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[CH2:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH3:20]>>[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:7]3[CH:8]=[CH:9][S:10][C:6]=3[CH:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:3]=2)[CH2:23][CH2:22]1)[CH3:20]
Reactant: COc1ccc(-c2cc3sccc3c(Cl)n2)cc1
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2nc(-c3ccc(OC)cc3)cc3sccc23)CC1
Temperature: 130 °C
Yield: 61.5 %

Procedure:
A mixture of 4-chloro-6-(4-methoxyphenyl)thieno[3,2-c]pyridine (6.6 g) and N-ethylpiperazine (30 ml) was heated at 130° C. for 2 hr. The reaction mixture was evaporated, and to the resulting residue were added potassium carbonate and water. The resulting mixture was extracted with ethyl acetate, and the resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was removed, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the title compound as a pale brown oil (5.2 g, yield; 61.5%).
Reaction SMILES: [Cl-].Cl[C:3](=[O:8])[CH2:4][NH+:5]([CH3:7])[CH3:6].[CH3:9][C:10]1[CH:14]=[C:13]([CH3:15])[NH:12][C:11]=1/[CH:16]=[C:17]1\[C:18](=[O:28])[N:19]([CH2:26][OH:27])[C:20]2[C:25]\1=[CH:24][CH:23]=[CH:22][CH:21]=2>>[CH3:6][N:5]([CH2:4][C:3]([O:27][CH2:26][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)/[C:17](=[CH:16]/[C:11]2[NH:12][C:13]([CH3:15])=[CH:14][C:10]=2[CH3:9])/[C:18]1=[O:28])=[O:8])[CH3:7]
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(CO)c3ccccc32)[nH]1
Reactant: C[NH+](C)CC(=O)Cl
Agent: [Cl-]
Product: Cc1cc(C)c(/C=C2\C(=O)N(COC(=O)CN(C)C)c3ccccc32)[nH]1

Procedure:
Following the procedure of Example 2, the title compound was prepared from 2-chloro-N,N-dimethyl-2-oxoethanaminium chloride and (3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)-methylidene]-1-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (1).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][CH3:12])[S:4]([N:7]=[C:8]=[S:9])(=[O:6])=[O:5])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:23][NH:22][N:21]=2)=[CH:16][CH:15]=1>ClCCl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:23][N:22]([C:8](=[S:9])[NH:7][S:4]([N:3]([CH2:1][CH3:2])[CH2:10][CH2:11][CH3:12])(=[O:6])=[O:5])[N:21]=2)=[CH:18][CH:19]=1
Reactant: CCCN(CC)S(=O)(=O)N=C=S
Reactant: Clc1ccc(C2=NNCC2c2ccccc2)cc1
Solvent: ClCCl
Product: CCCN(CC)S(=O)(=O)NC(=S)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Reaction time: 1.5 h
Yield: 55.6 %

Procedure:
Part A: To a stirred solution of ((ethyl)propylamino)sulfonyl isothiocyanate (5.98 gram, 25.4 mmol) in dry dichloromethane in a nitrogen atmosphere is added of 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (6.52 gram, 25.4 mmol). After stirring for 90 minutes the resulting solution is concentrated in vacuo and purified by column chromatography (CH2Cl2, silicagel, Rf˜0.45). The resulting solid is recrystallized from diethyl ether to give 3-(4-chlorophenyl)-N-(((ethyl)propylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-thiocarboxamide (6.57 gram, 56% yield). Melting point: 144-146° C.
Reaction SMILES: [CH:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH:12]1[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[N:14]=[CH:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C>[CH3:20][O:19][C:17]([C:15]1[N:14]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH:13]=[N:12][CH:16]=1)=[O:18]
Reactant: OC1CCCc2ccccc21
Reactant: COC(=O)c1c[nH]cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1CCCc2ccccc21
Reaction time: 16 h

Procedure:
To a solution of 1,2,3,4-tetrahydro-1-naphthol (CAS#529-33-9, 1.00 g, 6.74 mmol), which can be prepared as described in Ollivier, R.; et al. Journal of Medicinal Chemistry, 1997, 40, 952-960, in THF (60 mL), at 0° C. is added methyl 4-imidazolecarboxylate (CAS#17325-26-7, 0.85 g, 6.74 mmol) and triphenylphosphine, followed by diisopropyl azodicarboxylate (1.36 g, 6.74 mmol). The cooling bath is then removed. After 16 hours, the solvent is evaporated in vacuo and the residue is purified by silica gel flash chromatography (elution with ethyl acetate) to give a partially purified product, which is dissolved in ethyl acetate and extracted with 1M aqueous HCl. The aqueous layer is basified to a pH of ca. 9 with 2M aqueous NaOH, and then extracted three times with dichloromethane. The organic layers are combined, dried with MgSO4, filtered, and concentrated to furnish 3-(1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid methyl ester; MS: (ESI) m/z 257.2 (M+H)+. The HNO3 salt of the title compound is prepared by dissolving the free base in methanol, followed by treatment with an excess of a 1:1 solution of HNO3—H2O. Concentration and trituration with diethyl ether and methanol, provides the nitric acid salt of 3-(1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid methyl ester; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.87 (m, 2 H), 2.11-2.33 (m, 2 H), 2.81 (dt, J=17.2, 6.5 Hz, 1 H), 2.93 (dt, J=17.2, 6.0 Hz, 1 H), 3.87 (s, 3 H), 6.33 (t, J=5.9 Hz, 1 H), 6.99 (d, J=7.6 Hz, 1 H), 7.10-7.21 (m, 1 H), 7.21-7.35 (m, 2 H), 8.34 (s, 1 H), 8.58 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][C:11]2(OCC[O:18]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:5][N:4]=[N:3]1.O.Cl>C(O)(=O)C>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:18])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCCCC1(c2ccccn2)OCCO1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cn1nnnc1SCCCC(=O)c1ccccn1
Yield: 83.4 %

Procedure:
1-Methyl-5-[4,4-ethylenedioxy-4-(2-pyridyl)butyl]thio-1,2,3,4-tetrazole (0.7 g) is dissolved in acetic acid (5 ml). Water (2.5 ml) and conc. hydrochloric acid (0.5 ml) are added to the solution and the mixture is heated on a water bath for 1 hour. Water is added to the reaction mixture and the mixture is extracted with chloroform. The chloroform solution is washed with water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by silica gel column chromatography (Kieselgel 60). The column is eluted with benzene-ether (10:1) and the product is recrystallized from hexane-ether to obtain 1-methyl-5-[3-(2-pyridylcarbonyl)propyl]thio-1,2,3,4-tetrazole, (0.5 g) as colorless needles, m.p. 73°-75° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl:21][CH2:22][C:23](=O)[CH2:24][OH:25]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([CH2:24][OH:25])[CH2:22][Cl:21])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: O=C(CO)CCl
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: C1CCOC1
Product: OCC(CCl)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1-chloro-3-hydroxypropanone under nitrogen to give 7-chloro-2-[[2-chloro-1-(hydroxymethyl)ethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][CH:11]=1.Cl[C:17]1[N:22]=[C:21]([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([CH3:30])[CH2:25][CH2:24]2)[CH:20]=[N:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([N:23]3[CH2:29][CH2:28][CH2:27][N:26]([CH3:30])[CH2:25][CH2:24]3)[N:22]=2)[CH:7]=1
Reactant: CN1CCCN(c2cncc(Cl)n2)CC1
Reactant: COC(=O)/C=C/c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1cccc(-c2cncc(N3CCCN(C)CC3)n2)c1
Temperature: 120 °C
Yield: 61.7 %

Procedure:
[3-(E-3-methoxy-3-oxo-1-propen-1-yl)phenyl]boronic acid (125 mg, 0.61 mmol) and bistriphenylphosphinepalladium(II)chloride (30 mg, 0.057 mmol) were combined in a microwave reaction tube. Subsequently 1-(6-chloro-pyrazin-2-yl)-4-methyl-[1,4]diazepane (130 mg, 0.57 mmol) was added as a solution in DMF (8 mL) followed by an aqueous solution of Na2CO3 (2M, 3 mL, 6 mmol). The tube was sealed and the reaction mixture was heated in the microwave at 120° C. for 20 min. The reaction mixture was then filtered through a plug of celite, and purified by flash chromatography to provide the title compound (124 mg 61%); MS analysis electrospray, 353 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][C:3]=1[CH3:16].[H-].[Na+].Cl[CH2:20][C:21]#[N:22].O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]2[CH2:20][C:21]#[N:22])=[CH:4][C:3]=1[CH3:16]
Reactant: N#CCCl
Reactant: CCOC(=O)c1cc2cc(C)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C)c(Cl)cc2n1CC#N
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of ethyl 6-chloro-5-methylindole-2-carboxylate (1.5 g, 6.3 mmol) in DMF (30 mL) was added dropwise to a stirred suspension of sodium hydride (60%, 0.39 g, 10 mmol) in DMF (20 mL) at room temperature under Ar. The reaction was then cooled to 0° C. and stirred for 45 min then chloroacetonitrile (0.81 mL, 13 mmol) was added in one portion. The reaction was heated to 75° C. and stirred for 1 h. After allowing to cool to room temperature the mixture was poured into water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (1×100 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuum to leave the crude product which was used immediately.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]1)=[O:18])[CH:11]1[CH2:12][CH2:13][N:14]([CH3:34])[CH2:15][CH2:16]1)=[O:4]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCNCC1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from step V (5.340 g) in 1,2-dichloroethane (60 mL) is added formaldehyde (1.94 mL of 37% aqueous solution, 23.88 mmol), followed by sodium triacetoxyborohydride (2.403 g, 11.34 mmol) in portions over 20 min. The mixture is stirred at room temperature overnight, then water is added to the mixture, and it is extracted with CH2Cl2. Organic fraction is washed with aqueous NaHCO3 and brine, dried over Na2SO4, concentrated and purified by column chromatography on silica gel eluting with 0-10% of MeOH in CH2Cl2 to give 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:27][C:28](=[O:39])/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][N:32]=1)(C)(C)C.[OH-].[K+]>CCO>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20](=[O:22])/[CH:21]=[CH:37]/[C:34]3[CH:35]=[CH:36][C:31](/[CH:30]=[CH:29]/[C:28]([OH:39])=[O:27])=[N:32][CH:33]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cn1
Reactant: CC(=O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C/c1ccc(/C=C/C(=O)c2ccc(N3CCN(Cc4ccccc4)CC3)cc2)cn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
A mixture of 1-[4-(4-benzyl-piperazin-1-yl)-phenyl]-ethanone (319 mg, 1.085 mmol), (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester (described in Example 11 STEP A-D, 253 mg, 1.08 mmol) and KOH 1.7 M (0.638 ml) in EtOH (10 ml) was stirred at 0° C. overnight. The resulting precipitate was filtered washing with hot EtOH and the powder was dissolved in DCM (10 ml) and treated with TFA (2 ml) for 6 h. The solvent was then removed in vacuo to give 388 mg of (E)-3-(5-{(E)-3-[4-(4-benzyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-acrylic acid as its bis-trifluoroacetate salt.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:9][C:10]1[C:11]([F:21])=[C:12]([F:20])[C:13](F)=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:9][C:10]1[C:11]([F:21])=[C:12]([F:20])[C:13]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[F:1])=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16]
Reactant: Nc1ccccc1F
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 2-fluoroaniline (10.2 mL, 105.8 mmol) and 5-bromo-2,3,4-trifluorobenzoic acid (13.51 g, 52.9 mmol) in THF (120 mL) was added LiHMDS (158.7 mL, 1 M in THF, 158.7 mmol) dropwisely at −78° C. under nitrogen atmosphere. The mixture was allowed to slowly warm to room temperature and stirred at this temperature overnight. The reaction was quenched with 10% HCl (aq., 100 mL) and extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with water (200 mL×3) and brine (200 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product (pale yellow solid, 13.73 g, 75% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 8.01 (d, 1H), 7.26 (m, 1H), 7.01-7.16 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([OH:8])[CH:7]=1.CCOC(C)=O>CCO>[NH2:9][C:5]1[CH:4]=[C:3]([S:12]([CH3:15])(=[O:14])=[O:13])[C:2]([CH3:1])=[CH:7][C:6]=1[OH:8]
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1S(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(O)c(N)cc1S(C)(=O)=O
Yield: 53 %

Procedure:
5-Methyl-4-(methylsulfonyl)-2-nitrophenol (D86, 103 mg, 0.45 mmol) was dissolved in EtOH:EtOAc (20 mL, 1:1) and was reduced using an H-Cube (full H2 mode, 25° C., 1 mL/min). The reaction was concentrated by rotary evaporation and the crude residue was purified via flash column chromatography (silica, DCM to 0.5% NH3/9.5% MeOH/90% DCM) to give 2-amino-5-methyl-4-(methylsulfonyl)phenol (D87, 48 mg, 41%) as a yellow solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([N+:15]([O-])=O)=[C:13]([O:18][CH3:19])[CH:12]=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[N:23]#[C:24]Br>CO.[Pt]=O>[NH2:23][C:24]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2[C:10]([O:20][CH3:21])=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[C:14]=2[N:15]=1
Reactant: COc1ccc(OC)c([N+](=O)[O-])c1NCc1ccccc1
Reactant: N#CBr
Agent: O=[Pt]
Solvent: CO
Solvent: O
Product: COc1ccc(OC)c2c1nc(N)n2Cc1ccccc1

Procedure:
2-Benzylamino-3-nitro-1,4-dimethoxybenzene (10.0 g, 0.03 mole) is suspended in methanol and hydrogenated in the presence of platinum oxide catalyst at 50 psi for about twelve hours. After this time the solution changes color from red to colorless. The methanol is then removed in vacuo. To the residue is added approximately 250 ml water and 3.50 g (0.03 mole) of cyanogen bromide. The flask containing this mixture is stoppered, shaken, and stirred overnight at room temperature. After treatment with activated charcoal, the solution is filtered into excess 1N NaOH, causing the precipitation of the product. The amorphous white powder melts at 191°-193° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([OH:10])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)([CH3:37])[CH3:36]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([N:41]2[CH2:42][CH2:43][N:38]([CH:35]([CH3:37])[CH3:36])[CH2:39][CH2:40]2)=[O:10])=[CH:11][CH:12]=1
Reactant: O=C(O)/C=C/c1ccc(F)cc1
Reactant: CC(C)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)/C=C/c2ccc(F)cc2)CC1
Reaction time: 15.5 h
Yield: 73.2 %

Procedure:
To a solution of E-4-fluorocinnamic acid (1.18 g, 7. 10 mmol), which is commercially available from Sigma-Aldrich, and TBTU (3.42 g, 10.6 mmol) in DMF (50 mL) was added 1-isopropylpiperazine (1.12 mL, 7.81 mmol) at ambient temperature. The reaction was stirred for ca. 15.5 h before being concentrated under reduced pressure, wherein the crude residue was dissolved in EtOAc (70 mL) and partitioned with sat. aq. NaHCO3 (25 mL). The aq. layer was separated and further extracted with EtOAc (2×30 mL). The combined organic layers were then washed with sat. aq. NaHCO3 (2×20 mL) and brine (35 mL), then concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2—40 g; gradient elution: 100% DCM for 5 min, then 0% to 2% MeOH/DCM over 5 min; hold for 5 min, 2% to 4% over 5 min, hold for 5 min, 4% to 10% over 5 min, hold 10% MeOH/DCM for 5 min at 40 mL/min) to give 1.58 g 10A (80% yield) as a pale orange solid. m/z (ES+) M+1=277.4; HPLC tR=1.50 min. 1H NMR (500 MHz, CDCl3) δ 7.62 (d, J=15.6 Hz, 1H), 7.50 (dd, J=8.9, 5.5 Hz, 2H), 7.11-6.99 (m, 2H), 6.80 (d, J=15.6 Hz, 1H), 3.85-3.54 (m, 4H), 2.73 (quintet, J=6.7 Hz, 1H), 2.55 (d, J=5.2 Hz, 4H), 1.05 (d, J=6.4 Hz, 6H).
Reaction SMILES: CS(O[CH2:6][C:7]1([F:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)(=O)=O.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C)C=O.C(OCC)(=O)C>[F:13][C:7]1([CH2:6][N:18]2[C:14](=[O:24])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17]2=[O:19])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OCC1(F)CCOCC1
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC1(F)CCOCC1

Procedure:
A mixture of EXAMPLE 138A (1.8 g) and potassium phthalimide (2.356 g) in N,N-dimethylformamide (30 mL) was heated at 150° C. overnight, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, concentrated and chromatographed on silica gel eluting with 30% ethyl acetate in hexanes to give the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:6]=[CH:5]2.CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N(Br)C(=[O:34])C1.C([O-])(O)=O.[Na+]>O.C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]=[O:34])[N:8]=[C:7]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:6]=[CH:5]2
Reactant: Cc1cc2nc(-c3ccccc3)ccc2cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1cc2nc(-c3ccccc3)ccc2cc1Cl
Temperature: 90 °C
Reaction time: 3 h

Procedure:
The CCl4 (45 ml) solution of 6-chloro-7-methyl-2-phenylquinoline (753.3 mg, 2.969 mmol), AIBN (48.8 mg, 0.1 eq.) and NBS (898.4 mg, 1.7 eq.) was heated at 80° C. under N2 for 8 h. After that time, the reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (60 ml), washed successively with H2O (30 mL), saturated NaS2O3 (30 mL), H2O (30 mL), and brine (30 mL). The organic extract was then dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in DMSO (105 mL), and then NaHCO3 (2495 mg, 10 eq.) was added. The reaction mixture was stirred at 90° C. for 3 h. Water (140 mL) was added and the mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were washed with H2O (4×60 mL) and brine (60 mL), and dried (MgSO4), filtered, and concentrated in vacuo. The residue was recrystallized from CHCl3/hexane (20:80, 10 mL) to give 6-chloro-2-phenylquinoline-7-carbaldehyde as pale-yellow solid; 1H NMR (CDCl3, 400 MHz) δ 7.51-7.58 (m, 3H), 7.93 (s, 1H), 8.03 (d, 1H, J=8.8 Hz), 8.18-8.20 (m, 3H), 8.75 (s, 1H), 10.63 (s, 1H); MS(ES+): 268.1/270.0 (M/M+2).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH2:6][NH2:7].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O>C(Cl)Cl.[OH-].[Na+]>[C:13]([NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:10]([F:11])=[C:3]([Br:2])[CH:4]=1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCc1ccc(F)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(F)c(Br)c1
Reaction time: 16 h

Procedure:
To a solution of 3-bromo-4-fluorobenzylamine hydrochloride (10 g, 42 mmol) and TEA (10.5 g, 103 mmol) in 200 mL of CH2Cl2 was added BOC2O (9.1 g, 42 mmol) at RT. The resulting solution was stirred for 16 h. The solution was diluted with aq. 1 N NaOH and CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give N-Boc-(3-bromo-4-fluoro-benzyl)amine. MS (ES+): 305 (M+H)+; (ES−): 303 (M−H). Calc'd C12H15BrFNO2-304.16.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([I:11])=[N:9][NH:10][C:4]=2[CH:3]=1.CS(O)(=O)=O.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1>C(Cl)Cl.O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([I:11])=[N:9][N:10]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[C:4]=2[CH:3]=1
Reactant: Clc1cc2[nH]nc(I)c2cn1
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Clc1cc2c(cn1)c(I)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
At r.t. to a suspension of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (0.55 g, 2.0 mmol) in methylene chloride (6 mL) and tetrahydrofuran (3 mL) was added methanesulfonic acid (20 μL, 0.4 mmol), followed by dihydropyran (0.54 mL, 5.9 mmol) (Aldrich, Cat. #: D106208). The mixture was stirred at r.t. overnight. Then, it was stirred at 60° C. for 4 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.72 g).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31][OH:32]>>[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31][O:32][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1
Reactant: OCc1ccc(F)c(F)c1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3ccc(F)c(F)c3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and 3,4-difluorobenzyl alcohol (108 mg; 0.736 mmol), example 86 was prepared analogously to the procedure for the preparation of example 42.