Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([NH:17][CH2:18][C:19]([OH:21])=O)=[O:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[N:45]1([C:51]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:59]([F:62])([F:61])[F:60])=[O:52])[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>CN(C=O)C.O>[O:21]=[C:19]([N:48]1[CH2:49][CH2:50][N:45]([C:51](=[O:52])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:59]([F:62])([F:60])[F:61])[CH2:46][CH2:47]1)[CH2:18][NH:17][C:15]([C:11]1[O:10][CH:14]=[CH:13][CH:12]=1)=[O:16]
Reactant: O=C(O)CNC(=O)c1ccco1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
DIPEA (0.143 mL, 0.83 mmol) was added to a stirred solution of [(furan-2-carbonyl)-amino]-acetic acid (40 mg, 0.24 mmol) in DMF (1 mL). HOBT (38 mg, 0.28 mmol), EDCI.HCl (54 mg, 0.28 mmol) were added, followed by the addition of piperazine-1-yl-(2-trifluoromethyl-phenyl)-methanone hydrochloride (0.2602 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (using silica gel, 60-120 A° and 10% methanol in chloroform as the eluent) afforded furan-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazine-1-yl]-ethyl}-amide in 33% yield. LC-MS purity: 83%, 1H NMR (CDCl3): δ 7.74 (d, 1H), 7.60 (m, 2H), 7.56 (d, 2H), 7.48 (s, 1H), 7.12 (t, 1H), 6.50 (q, 1H), 4.30 (m, 2H), 4.08-3.82 (m, 2H), 3.78-3.64 (m, 2H), 3.62-3.48 (m, 2H), 3.22 (m, 2H).
Reaction SMILES: Cl[CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])C.[SH:9][CH2:10][CH2:11]O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:8][CH2:7][CH2:6][C:2]1[S:9][CH2:10][CH2:11][O:5][CH:3]=1
Reactant: CC(=O)C(Cl)CCCl
Reactant: OCCS
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: ClCCC1=COCCS1
Yield: 60 %

Procedure:
A mixture of the 3,5-dichloro-2-pentanone (39 g., 0.24 mole) and 2-mercaptoethanol (20 g., 0.26 mole) in toluene (250 ml) was stirred, and triethylamine (27 g., 0.27 mole) added dropwise thereto. After stirring overnight at ambient temperature, the mixture was washed with dilute hydrochloric acid and subsequently refluxed with p-toluenesulfonic acid (0.5 g.) with azeotropic removal of water for 4 hours. Upon cooling, the reaction mixture was washed with aqueous sodium bicarbonate, dried (magnesium sulfate), and the toluene removed to leave the product 3-(2-chloroethyl)-5,6-dihydro-1,4-oxathiin (bp. 62°-70°/0.025 mm) in 60% yield and 98% purity (G.C.). N.M.R. spectrum (Deuterchloroform) gave lambda values: 1.85 (3H,S) 2.3-2.65 (2H,t); 2.9-3.5 (2H,t); 3.95-3.7 (2H,t); 4.1-4.25 (2H,t).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19]2)=[N:2]1.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH2:29].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:22]=[CH:21][C:20]([CH2:23][NH:29][CH2:28][CH2:27][N:26]([CH3:30])[CH3:25])=[CH:19]2)=[N:2]1
Reactant: CN(C)CCN
Reactant: O=Cc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CN(C)CCNCc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.7 %

Procedure:
Compound 167 (0.06 g, 0.19 mmol) was dissolved in dichloroethane (2.0 mL) and the solution was added with N,N-dimethylethylenediamine (62 μL, 0.57 mmol), acetic acid (63 μL, 0.57 mmol) and sodium triacetoxyborohydride (0.12 g, 0.57 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with water, extracted with ethyl acetate and the organic layer was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=9/1) to obtain Compound 186 (0.01 g, 14%).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([CH2:11][OH:12])[CH2:2]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:12][CH2:11][C@H:3]1[O:4][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[O:1][CH2:2]1)(=[O:23])=[O:22]
Reactant: OC[C@H]1COc2cccnc2O1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1COc2cccnc2O1
Temperature: 0 °C
Yield: 88.6 %

Procedure:
A mixture of intermediate (2-a) (0.023 mol) and triethylamine (0.046 mol) in DCM (40 ml) was stirred at 0° C. A mixture of methanesulfonyl chloride (0.035 mol) in DCM (10 ml) was added dropwise. The mixture was stirred on an ice bath for 2 hours and then washed with H2O/NaCl. The organic layer was dried, filtered and the solvent was evaporated. The residue (oil) was solidified in DIPE. The precipitate was filtered off and dried, yielding 5 g of (S)-2,3-dihydro-1,4-dioxino[2,3-b]pyridine-3-methanol methanesulfonate (ester) (intermediate 3) ([α]D20−27.89°; c=25.10 mg/5 ml in methanol; mp. 136° C.).
Reaction SMILES: [CH3:1][C:2]([CH:5]=O)([CH3:4])[CH3:3].[CH2:7]([O:9][C:10](=[O:14])[CH2:11][C:12]#[N:13])[CH3:8].C(O)(=O)C.N1C=CC=CC=1>Cl>[CH2:7]([O:9][C:10](=[O:14])[C:11]([C:12]#[N:13])=[CH:1][C:2]([CH3:5])([CH3:4])[CH3:3])[CH3:8]
Reactant: CC(C)(C)C=O
Reactant: CCOC(=O)CC#N
Agent: Cl
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CCOC(=O)C(C#N)=CC(C)(C)C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
A mixture of pivaldehyde (5.00 g, 58 mmol), ethylcyanoacetate (6.60 g, 58.3 mmol), acetic acid (3.50 g, 58.3 mmol) and pyridine (4.60 g, 58.2 mmol) was heated at reflux for 1 h. A second portion of pivaldehyde (5.00 g, 58 mmol) was added. The refluxing of the mixture was continued for 18 h. After cooling, the mixture was poured into 1N aqueous HCl (50 mL). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with 1N aqueous HCl, dried (MgSO4) and concentrated to give a colorless oil. The oil was purified by flash chromatography on SiO2 using hexane-EtOAc (9:1) as the eluant to give 2-cyano-4,4-dimethyl-2-pentenoic acid ethyl ester as a colorless oil (7.69 g, 73% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][OH:14].[H-].[Na+].[H][H].Cl[C:20]1[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][CH:21]=1>O1CCCC1.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:20]1[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cccc(Cl)n1
Reactant: [H][H]
Reactant: Cc1oc(-c2ccccc2)nc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCc2nc(-c3ccccc3)oc2C)n1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
To a mixture of (5-methyl-2-phenyl-4-oxazolyl)methanol (8.51 g) and tetrahydrofuran (100 mL) was added sodium hydride (60%, oil, 1.80 g) at room temperature and the reaction mixture was stirred at room temperature until generation of hydrogen ended. The mixture was added to a solution of methyl 6-chloropyridine-2-carboxylate (7.72 g) in tetrahydrofuran (75 ml) at room temperature and the obtained mixture was further stirred at 40° C. for 5 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals of methyl 6-(5-methyl-2-phenyl-4-oxazolyl)methoxy-2-pyridinecarboxylate from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave pale-yellow plate crystals (7.41 g, 51%). melting point: 97-98° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[CH2:27]([O:34][CH2:35][CH2:36][CH2:37][C:38](Cl)=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[Na+]>C1COCC1>[CH2:27]([O:34][CH2:35][CH2:36][CH2:37][C:38]1[N:6]=[C:4]([OH:5])[C:3]2[C:2](=[CH:10][C:9]([C:11]3[C:16]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:8][CH:7]=2)[N:1]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)CCCOCc1ccccc1
Reactant: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Oc1nc(CCCOCc2ccccc2)nc2cc(-c3ncccc3C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide (3.56 mmol), and pyridine (3.91 mmol) in THF (20 ml) add 4-benzyloxy-butyryl chloride (3.91 mmol). Stir the mixture 20 minutes at room temperature, add 20 ml of 20% NaOH, stir for 60 minutes at 50° C. Concentrate, add water, filter, acidify to pH=6, collect the precipitate to obtain 2-(3-benzyloxy-propyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ol.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[CH3:13][C:14]1[CH:15]=[C:16]([C:25](=[O:27])[CH3:26])[CH:17]=[CH:18][C:19]=1[C:20]1[N:21]=[CH:22][S:23][CH:24]=1.Cl>COC(C)(C)C>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:26][C:25]([C:16]1[CH:17]=[CH:18][C:19]([C:20]2[N:21]=[CH:22][S:23][CH:24]=2)=[C:14]([CH3:13])[CH:15]=1)=[O:27]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(-c2cscn2)c(C)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Product: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1-c1cscn1
Reaction time: 20 h
Yield: 99 %

Procedure:
To a stirred solution of ethyl trifluoroacetate (500 mg, 3.52 mmol) in tert-butyl methyl ether (4 ml) was added sodium methoxide (28 wt. % solution in methanol; 0.9 ml, 4.0 mmol) over 2 min. A solution of 1-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone from step 4 (714 mg, 3.33 mmol) in t-butylmethylether (6 ml) was added dropwise over 5 minutes, and the mixture was stirred for 20 hours. 2N HCl (10 ml) was added, and the whole was extracted with ethyl acetate. The organic layer was washed with brine, dried_over MgSO4, and concentrated in vacuo, and the residue was used for next reaction without further purification. (1.05 g, 99% yield).
Reaction SMILES: [H-].[Li+].[O:3]=[C:4]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=C[CH:7]=[CH:6][NH:5]1.Br[CH2:15][CH:16]1[CH2:18][CH2:17]1.C[N:20](C=O)C>CCOC(C)=O>[CH:18]1([CH2:17][N:5]2[CH:6]=[CH:7][N:20]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:4]2=[O:3])[CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc[nH]c1=O
Reactant: BrCC1CC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: COC(=O)c1nccn(CC2CC2)c1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
LiH (7.7 mg, 0.97 mmol) was added to the solution of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (0.10 g, 0.65 mmol) in DMF (3 mL) at 0° C. After stirring for 30 minutes, (bromomethyl) cyclopropane (0.18 g, 1.30 mmol) was added to the reaction mixture at the temperature, and the reaction was warmed to 50° C. After stirring for 3 days at 50° C., the reaction mixture was diluted with EtOAc, quenched with ice water, extracted with EtOAc, dried over MgSO4, and concentrated. The crude was purified by silica gel flash column chromatography (2% MeOH in CH2Cl2) to afford 87 mg (64%) of the desired product.
Reaction SMILES: [CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6]2.[CH2:24]([S:27](Cl)(=[O:29])=[O:28])[CH2:25][CH3:26].[OH2:31]>ClCCl>[C:21]([OH:28])(=[O:31])[CH3:22].[CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH:23][S:27]([CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28])[CH:20]=[CH:21][CH:22]=2)[CH:3]2[CH:7]1[CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4]2
Reactant: O
Reactant: CC1(c2cccc(N)c2)C2CN(CCCc3ccccc3)CC21
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(=O)O
Product: CCCS(=O)(=O)Nc1cccc(C2(C)C3CN(CCCc4ccccc4)CC32)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 4 %

Procedure:
To a solution of 3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine (Preparation 8, 200 mg, 0.65 mmol) in pynidine (2 ml) under nitrogen at 0° C. was added n-propanesulfonyl chloride (140 mg, 0.98 mmol), then the mixture was stirred at room temperature for 16 hours. Water (5 ml) and dichloromethane (5 ml) were added, and the mixture was stirred for 30 minutes. The organic phase was washed further with water (5 ml) for 30 minutes, separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica (10 g) column chromatography eluting with ethyl acetate:hexane:ammonia solution (0.880) (20:80:1 then 50:50:1). Product-containing fractions were combined and concentrated in vacuo. The residue was further purified by preparative HPLC (condition 4). Combination and evaporation of appropriate fractions gave the title compound as a pale brown solid (11 mg, 4%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][C:10](=[O:16])[NH:11]2.[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=O)[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18].N1CCCCC1>C(O)C>[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[NH:11][C:10]2=[O:16])[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2ccccn2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccccn4)c32)c1CCCN1CCN(C)CC1
Temperature: 70 °C

Procedure:
A mixture of 4-pyridin-2-yl-1,3-dihydroindol-2-one (31.5 mg, 0.15 mmol), 5-formyl-2-methyl-4-[3-(4-methylpiperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (48.2 mg, 0.15 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 70° C. for 6 hours. The reaction was concentrated and the residue was re-crystallized from ethyl acetate and hexane to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.CS(O[CH2:18][CH:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH3:20])(=O)=O.[Br:29]N1C(=O)CCC1=O.Br>CN(C)C(=O)C.C(Cl)(Cl)(Cl)Cl>[Br:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][CH:19]([O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:20])=[CH:7][CH:6]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(COS(C)(=O)=O)Oc1ccc(F)cc1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Product: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(F)cc2)cc1

Procedure:
As described in Example 68, 46 g of methyl p-hydroxyphenylacetate is reacted with 2-(p-Fluorophenoxy)-1-propanol O-methane-sulfonate in 400 ml of N,N-dimethylacetamide at 100° C. for 18 hrs. The product is dissolved in 1250 ml of carbon tetrachloride and N-bromosuccinimide added. Anhydrous HBr is added and the mixture is stirred and refluxed for 24 hrs. The mixture is filtered through a short column of silica gel and the solvent removed to give the product as a viscous oil.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:13][CH2:14][CH:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[OH:16].[BH4-].[Na+]>CO.O.CCOC(C)=O>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCC(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)c1ccc(CNCC(O)c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.32 ml of 4-tert-butylbenzaldehyde (1.8 mmol) and 250 mg of [rac]-2-amino-1-(3,4-dichloro -phenyl)-ethanol (1.2 mmol) were dissolved in 10 ml methanol at rt, and after stirring for 5 min at rt, were refluxed for 2 h. After cooling down to rt, 68 mg (1.8 mmol) of sodium borohydride were added and after stirring for 15 min at rt, the reaction mixture was then refluxed for 2 h. After cooling down to rt, the residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was stirred with diethylether/heptane, filtered and the solid dried under high vacuo, leading to 147 mg of [rac]-(4-tert-butyl-benzyl)-[2-(3,4-dichloro-phenyl)-2-hydroxy-ethyl]-amine as a light yellow solid (35%). MS (ISP) 352.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=1>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([NH:30][CH2:29][C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: NCc1ccncc1
Reactant: COc1ccccc1CN
Reactant: Clc1ccc2c(Br)cccc2n1
Product: COc1ccccc1CNc1ccc2c(NCc3ccncc3)cccc2n1

Procedure:
The title compound, MS: m/e=371.4 (M+H+), was prepared in accordance with the general method of example 1 from 5-bromo-2-chloroquinoline, 2-methoxybenzylamine and 4-picolylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[N+:17]([O-])([OH:19])=[O:18]>>[Br:1][C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(Br)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Temperature: -2.5 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of 5-bromo-2-methylbenzoic acid (5.0 g, 23 mmol) in concentrated H2SO4 (27 ml, 512 mmol) was cooled to 5° C. in an acetone/ice bath. A mixture of concentrated nitric acid (1.9 ml, 30 mmol) and concentrated H2SO4 (2.8 ml, 52 mmol) was added dropwise to the reaction mixture at −5 to 0° C. over 15 minutes. The yellow reaction mixture was stirred at −5 to 0° C. for 2 hours during which time a yellow precipitate formed. The reaction mixture was poured onto ice (150 g) and the precipitate was then collected by filtration. The precipitate was air dried to give the title compound (5.5 g, 52%) as a pale yellow solid. LC-MS 57%, 1.82 min (3.5 minute LC-MS method), no ionization; 1H NMR (500 MHz, DMSO-d6) δ ppm 8.29 (s, 1H) 8.13 (d, J=1.58 Hz, 1H) 2.43 (s, 3H).
Reaction SMILES: C[Si]([C:5]#[CH:6])(C)C.FC(F)(F)C1C=CC([C:15]#[C:16][C:17]2[CH:18]=[C:19]([CH:34]=[C:35](C#CC3C=CC(C(F)(F)F)=CC=3)[CH:36]=2)[CH2:20][O:21][C:22]2[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[C:24]([CH3:33])[CH:23]=2)=CC=1.[C:51](=O)([O-])[O-].[K+].[K+].CO>C(N(CC)CC)C.[Cu]I.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.ClCCl>[C:16]([C:17]1[CH:18]=[C:19]([CH:34]=[C:35]([C:5]#[CH:6])[CH:36]=1)[CH2:20][O:21][C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([O:30][CH3:51])=[O:29])=[C:24]([CH3:33])[CH:23]=1)#[CH:15]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(OCc2cc(C#Cc3ccc(C(F)(F)F)cc3)cc(C#Cc3ccc(C(F)(F)F)cc3)c2)ccc1OCC(=O)O
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: C#Cc1cc(C#C)cc(COc2ccc(OCC(=O)OC)c(C)c2)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Trimethylsilylacetylene (420 μL, 3.0 mmol) was added to a mixture of methyl [4-(3,5-dibromobenzyloxy)-2-methylphenoxy]acetate (444 mg, 1.0 mmol; prepared as described in example 15), copper(I) iodide (13 mg, 0.07 mmol) and tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol) in dry triethylamine (8 mL). The reaction mixture was stirred for 3 h at 70° C. and then at ambient temperature overnight. The resulting mixture was evaporated in vacuo, the residue was dissolved in ether/ethyl acetate mixture (1:1, 20 mL) and the formed precipitate was filtered off. The filtrate was evaporated in vacuo to yield red-brown oil. Potassium carbonate (23 mg, 0.17 mmol), dry methanol (2 mL) and dry dichloromethane (2 mL) were added to the oil under nitrogen and the resulting mixture was stirred for 3 h. Dichloromethane (15 mL) was added and the mixture was washed with brine (15 mL). The aqueous layer was extracted with dichloromethane (2×10 mL); the combined organic layers were dried with anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 90:10-80:20) yielding methyl [4-(3,5-diethynylbenzyloxy)-2-methylphenoxy]acetate.
Reaction SMILES: [C:1]([C:3]1[C:11]([CH2:12]/[CH:13]=[C:14](\[CH3:21])/[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[C:10]([CH2:22][CH3:23])[C:9]([CH3:24])=[C:8]2[C:4]=1[C:5](=[O:25])[O:6][CH2:7]2)#N.[OH-:26].[Na+].C[OH:29]>O>[C:1]([C:3]1[C:11]([CH2:12]/[CH:13]=[C:14](\[CH3:21])/[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[C:10]([CH2:22][CH3:23])[C:9]([CH3:24])=[C:8]2[C:4]=1[C:5](=[O:25])[O:6][CH2:7]2)([OH:29])=[O:26]
Reactant: CO
Reactant: CCc1c(C)c2c(c(C#N)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CCc1c(C)c2c(c(C(=O)O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2

Procedure:
A mixture of 4.0 g of methyl (E)-6-(4-cyano-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate and 1.86 g of sodium hydroxide in 100 ml of 3:2 water:methanol is heated at reflux for 2 hours. The resulting homogenous solution is distilled until 30 ml of distillate is recovered. An additional 0.6 g (15 mmol) of sodium hydroxide is added to the reaction solution and it is refluxed for 2 days. Upon cooling the solution is partitioned between 1N aqueous HCl and ethyl acetate. The organic phase is washed twice with water, once with brine, and then dried over magnesium sulfate. The solvent is evaporated under reduced pressure to give (E)-6-(4-carboxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:15][CH:16]=2)[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:10]([C:31]#[N:32])[N:9]=1>CCCCO.C(Cl)(Cl)Cl>[F:30][C:26]1[CH:25]=[C:24]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[CH:13]=3)[C:8]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[N:9][C:10]=2[C:31]#[N:32])[CH:29]=[CH:28][CH:27]=1
Reactant: N#Cc1nc(Cl)c2ccc(-c3ccccn3)cc2c1-c1cccc(F)c1
Reactant: C1COCCN1
Solvent: CCCCO
Solvent: ClC(Cl)Cl
Product: N#Cc1nc(N2CCOCC2)c2ccc(-c3ccccn3)cc2c1-c1cccc(F)c1
Temperature: 220 °C

Procedure:
Morpholine (36 mg, 0.42 mmol) was added to a solution of 1-chloro-4-(3-fluorophenyl)-6-pyridin-2-ylisoquinoline-3-carbonitrile (15 mg, 0.04 mmol) in n-BuOH (1.0 mL) in a microwave tube. The tube was sealed and heated to 220° C. for 1 h in the microwave. The reaction was diluted with CHCl3 and washed with sat'd NaHCO3, brine, dried (MgSO4), filtered and concentrated. The residue was purified via flash chromatography (1:3-1:1 EtOAc/hexanes) to yield the title compound as a beige solid.