Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:16]1[O:18][CH2:17]1>C1(C)C=CC=CC=1>[CH:2]1([CH3:1])[CH2:3][CH2:4][CH:5]([CH:9]([CH3:11])[CH3:10])[CH:6]([O:8][CH:17]([OH:18])[CH3:16])[CH2:7]1
Reactant: C1CO1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC1CCC(C(C)C)C(OC(C)O)C1
Temperature: 5 °C
Yield: 96 %

Procedure:
At first, 100.0 g (0.64 mol) of l-menthol and 42.7 g (0.32 mol) of anhydrous aluminum chloride were added into a reaction vessel and after replacement with nitrogen, 500 ml of toluene was further added to the vessel and stirred with the mixture under the ice-cooling condition to cool the resulting mixture to 5° C. And while the temperature of the solution being kept at 5 to 10° C., 57 g of ethylene oxide was further added. On completion of the supply, the mixture was stirred for one more hour at a room temperature to complete the reaction. Next, the reaction solution was cooled again and washed with 150 ml of 10% aqueous hydrochloric acid while being kept at 20° C. or lower. After the reaction solution was washed again with 50 ml of saturated sodium hydrogen carbonate aqueous solution and then with 100 ml of saturated brine, water therein was removed with sodium sulfate and the solvent was recovered under reduced pressure to obtain 123.1 g of crude l-menthyloxyethanol. The obtained product was distilled to isolate and recover 45.7 g of an unreacted raw material, l-menthol, and refine and isolate 60.8 g of an aimed product, l-menthyloxyethanol. Theoretical yield: 47.4% based on l-menthol.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:26])=[C:8](C(O)=O)[NH:9][C:10]=1[CH:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Br:21])[CH:19]=2)[NH:14][C:13]1=[O:22])([OH:3])=[O:2].[OH-].[K+].O.Cl>C(O)CO>[Br:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:22])[C:12]2=[CH:11][C:10]1[NH:9][CH:8]=[C:7]([CH3:26])[C:6]=1[CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: Cc1c(C(=O)O)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1CCC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1c[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1CCC(=O)O
Temperature: 90 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
4-(2-carboxyethyl)-3-methyl-5-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid (380 mg) suspended in ethylene glycol (5 mL) was held in a sealed tube in a pre-heated oil bath at 200° C. for 2 hours. The reaction mixture was cooled to 90° C. and potassium hydroxide (1 pellet) was added. It was then stirred at 90° C. for 30 minutes. The reaction mixture was cooled, poured into water, and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and purified using silica gel column chromatography to give 168 mg (49% yield) of 3-[2-(5-bromo -2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrol-3-yl]-propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[CH:27]1[C:32]([CH:33]=O)=[CH:31][C:30]2[O:35][CH2:36][O:37][C:29]=2[CH:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:33][C:32]4[CH:27]=[CH:28][C:29]5[O:37][CH2:36][O:35][C:30]=5[CH:31]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccc4c(c3)OCO4)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.045 mmol) was reacted with piperonal to provide 21 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1)[C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].[N:21]#[C:22][NH2:23]>C(O)C>[ClH:1].[CH3:2][CH:3]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:22]([NH2:23])=[NH:21])[CH:15]=1)[C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: CC(Cc1cccc(N)c1)C(=O)Oc1ccccc1
Reactant: N#CN
Agent: Cl
Solvent: CCO
Product: CC(Cc1cccc(NC(=N)N)c1)C(=O)Oc1ccccc1

Procedure:
In 200 ml of ethanol were dissolved 24.3 g of the phenyl α-methyl-β-(m-aminophenyl)-propionate hydrochloride obtained and 4.2 g of cyanamide, and the solution was subjected to reaction at 70° C. for 5 hours. After the reaction, the solvent was removed by distillation under reduced pressure to obtain phenyl α-methyl-β-(m-guanidinophenyl)-propionate hydrochloride in the form of an oily matter. This was dissolved in 50 ml of ethanol and then added to saturated aqueous NaHCO3 solution, upon which colorless crystals precipitated. The crystals were collected by filtration and washed with water and acetone, to obtain phenyl α-methyl-β-(m-guanidinophenyl)-propionate carbonate. Yield: 22.6 g (75%); melting point: 97°-98° C.; IR (cm-1): 3500-2500, 1745, 1682, 1625; MS: M+= m/e 297 (M.W.-H2CO3).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([I:11])=[CH:4][N:3]=1.Cl.[NH2:13][C:14]([CH3:20])([CH3:19])[C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C>C(O)C>[CH3:18][O:17][C:15](=[O:16])[C:14]([NH:13][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([I:11])=[CH:4][N:3]=1)([CH3:20])[CH3:19]
Reactant: COC(=O)C(C)(C)N
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)C(C)(C)Nc1ncc(I)cc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 78 %

Procedure:
2-Chloro-5-iodo-3-nitro-pyridine (1.61 g) was dissolved in ethanol. Methyl α-aminoisobutyrate HCl was added (2.4 eq) followed by triethylamine (2.4 eq). The reaction mixture was heated to 150° C. in a microwave oven for 30 minutes. The reaction mixture was concentrated to dryness and triturated with H2O, Silica gel chromatography of the resulting brown solid afforded the title compound as a bright yellow crystalline solid (78% yield based on recovered starting material). M.p. 121-122° C., 1H-NMR (CDCl3, 400 MHz) δ 1.56 (s, 3H), 1.66 (s, 3H), 3.67 (s, 3H), 8.53 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.68 (d, J=2.3 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1.[C:25](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Br:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:25])[C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1
Reactant: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Br

Procedure:
using 3-(4-bromo-2-fluoro-5-isopropoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with potassium carbonate and methyl iodide in acetonitrile there is obtained 3-(4-bromo-2-fluoro-5-isopropoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 79° C.;
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:21]([C:22](OC(C)(C)C)=[O:23])[CH2:20][CH:19]([CH2:29][Cl:30])[C:12]2=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](C(O)=O)=[CH:37]2.CCN=C=NCCCN(C)C>O1CCOCC1.CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:21]([C:22]([C:38]3[NH:39][C:40]4[C:36]([CH:37]=3)=[CH:35][C:34]([O:33][CH3:32])=[CH:42][CH:41]=4)=[O:23])[CH2:20][CH:19]([CH2:29][Cl:30])[C:12]2=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(OCc1ccccc1)c1ncccc21
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: COc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc(OCc3ccccc3)c3ncccc43)cc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
A suspension of 14 (0.10 g, 0.24 mmol) in dioxane (15 mL) was saturated with HCl, stirred at r.t. for 5 h and evaporated. 5-Methoxy-1-H-indole-2-carboxylic acid (0.054 g, 0.28 mmol), EDCI (0.23 g, 1.17 mmol) and DMA (5 mL) were added to the remaining yellow solid, and the red mixture was stirred at r.t. for 52 h. The mixture was partitioned between CH2Cl2 and cold 5% KHCO3 solution. The aqueous layer was extracted with CH2Cl2 (×3). The CH2Cl2 extracts were dried (brine, Na2SO4). Flash chromatography (EtOAc/petroleum ether, 7:3) gave 5-(benzyloxy)-1-(chloromethyl)-3-[(5-methoxy-1H-indol-2-yl)carbonyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline (17d) (0.11 g, 98%) as a yellow solid: mp 186–189° C.; 1H NMR (CDCl3) δ 9.55 (s, 1 H), 8.88 (dd, J=4.2, 1.7, 1 H), 8.37 (s, 1 H), 7.99 (dd, J=8.3, 1.6, 1 H), 7.56 (d, J=7.3, 2 H), 7.42 (dd, J=8.3, 4.1, 1 H), 7.33 (m, 4 H), 7.10 (d, J=2.3, 1 H), 6.99 (m, 2 H), 5.48 (d, J=12.5, 1 H), 5.42 (d, J=12.6, 1 H), 4.74 (dd, J=10.9, 2.0, 1 H), 4.61 (dd, J=10.6, 8.7, 1 H), 4.05 (m, 1 H), 3.85 (s, 3 H), 3.84 (dd, J=11.2, 4.1, 1 H), 3.45 (dd, J=11.0, 10.5, 1 H); 13C NMR (CDCl3) δ 160.7, 155.4, 154.7, 147.9, 142.4, 138.4, 136.4, 131.4, 130.5, 130.2, 128.6, 128.2, 128.0, 127.7, 125.2, 122.4, 117.0, 115.4, 112.7, 106.2, 102.5, 102.4, 70.9, 55.7, 55.2, 45.9, 42.6.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=O)=[CH:29][C:30]=1[CH3:31])=[O:25])[CH3:18]>>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])=[CH:29][C:30]=1[CH3:31])=[O:25])[CH3:35]
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: CCN(CC)CCCNC(=O)c1[nH]c(C=O)cc1C
Product: CCN(CC)CCCNC(=O)c1[nH]c(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)cc1C

Procedure:
6-Phenyl-1,3-dihydroindol-2-one (105 mg, 0.5 mmol) was condensed with 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide to give 67.8 (30%) of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@:9]2([OH:23])[C:13]3=[C:14]([F:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][CH2:3]1.NC1CCN(C[C@]2(O)C3=C([F:45])C=NC4C=CC(=O)N(C=43)C2)CC1>>[NH2:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][C@@:9]2([OH:23])[C:13]3=[C:14]([F:22])[CH:15]=[N:16][C:17]4[CH:18]=[C:19]([F:45])[C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:6][CH2:7]1
Reactant: NC1CCN(C[C@]2(O)Cn3c(=O)ccc4ncc(F)c2c43)CC1
Reactant: NC1CCN(C[C@@]2(O)Cn3c(=O)ccc4ncc(F)c2c43)CC1
Product: NC1CCN(C[C@]2(O)Cn3c(=O)c(F)cc4ncc(F)c2c43)CC1

Procedure:
A portion of this material (740 mg, estimated ratio of E1:E2 ca. 3:1) was resolved by preparative chiral HPLC into the two enantiomers E1 and E2, using a Chiralpak AD column, eluting with 50:50:0.1-CH3CN:isopropylalcohol:isopropylamine affording 553 mg of the desired E1 (4S) enantiomer (>99.5% ee) as the first eluting enantiomer.
Reaction SMILES: C[O:2][C:3]1[C:8](OC)=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=[CH:5][C:4]=1[C:15]1[N:20]=[CH:19][N:18]=[C:17]([O:21][C:22]2[C:27]3[N:28]=[C:29]([NH2:31])[S:30][C:26]=3[CH:25]=[CH:24][CH:23]=2)[CH:16]=1.B(F)(F)F.CCOCC>ClCCl>[NH2:31][C:29]1[S:30][C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([O:21][C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:4]4[CH:5]=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][C:3]=4[OH:2])[CH:16]=3)[C:27]=2[N:28]=1
Reactant: COc1c(-c2cc(Oc3cccc4sc(N)nc34)ncn2)ccc(C(F)(F)F)c1OC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4O)ncn3)cccc2s1
Temperature: -78 °C

Procedure:
To a 100-mL, round-bottomed flask containing a solution of 4-[6-(2-methoxy-methoxy-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 135(c)), (1.8 g, 3.9 mmol) in dichloromethane (39 mL) was added boron trifluoride diethyl etherate (1.5 mL, 12 mmol, Aldrich) with stirring at −78° C. The reaction mixture was then stirred at 0° C. for 1 h and at room temperature for 3 h. The mixture was quenched with satd sodium bicarbonate at 0° C. and extracted with dichloromethane (2×100 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuum. The crude material was purified by silica gel chromatography (gradient: 0-3% 2 N ammonia in methanol/dichloromethane) to yield the title compound as an amorphous, white solid. MS (ESI, pos. ion.) m/z: 406 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][C:14]1[CH:41]=[CH:40][C:17]([CH2:18][N:19]([CH2:30][C:31]2[NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=3[N:32]=2)[CH:20]2[C:29]3[N:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.CCN(CC)CC>O=S(Cl)Cl.CN(C1C=CN=CC=1)C>[NH:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=[C:31]1[CH2:30][N:19]([CH2:18][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][NH:12][C:4](=[O:6])[C:3]2[C:7]([CH3:11])=[CH:8][CH:9]=[N:10][C:2]=2[CH3:1])=[CH:41][CH:40]=1)[CH:20]1[C:29]2[N:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:23][CH2:22][CH2:21]1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: Cc1ccnc(C)c1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1ccnc(C)c1C(=O)NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
A solution of 2,4-dimethyl-nicotinic acid (54 mg, 0.35 mmol) in SOCl2 (˜2 mL, excess) was heated to 80° C. for 4 hours. The condenser was removed and the mixture was flushed with N2 at 80° C. for ˜5 minutes and then dried in vacuo for 10 minutes. The resulting syrup was dissolved in CH2Cl2 (2.4 mL) and added to a stirring mixture of (4-aminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (187 mg, 0.47 mmol), Et3N (0.33 mL, 2.35 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred overnight at room temperature. Purification of the crude yellow foam (240 mg) by radial chromatography on silica gel (2 mm plate, CH2Cl2/MeOH/NH4OH, 100:2:1) followed by radial chromatography on silica gel (1 mm plate, EtOAc/MeOH/NH4OH, 400:3:3) afforded the desired amide (61 mg, 33%) as a white foam.
Reaction SMILES: [Na].[C:2]1([CH:9]=[CH:8][C:6]([OH:7])=[CH:5][CH:4]=1)[OH:3].Cl.[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15]Cl>CO.Cl>[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][O:3][C:2]1[CH:9]=[CH:8][C:6]([O:7][CH2:15][CH2:14][CH2:13][N:12]([CH3:17])[CH3:11])=[CH:5][CH:4]=1
Reactant: Oc1ccc(O)cc1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CN(C)CCCOc1ccc(OCCCN(C)C)cc1
Yield: 10.7 %

Procedure:
First, to a solution of 2.3 g of metallic sodium dissolved in 35 ml of absolute methanol, a solution of 2.2 g of hydroquinon in 15 ml of absolute methanol and a solution of 7.9 g of 3-dimethylaminopropyl chloride hydrochloride in 10 ml absolute methanol were added, and the mixture was heated to reflux for 5 hours. After the reaction was completed, the mixture was evaporated under a reduced pressure, and after adding water to the resulting residue, alkalized with 10% sodium hydroxide, salted-out with sodium chloride and extracted with 100 ml of chloroform, the extract was washed with a saturated sodium chloride, and dried over magnesium sulfate. The solvent was removed under a reduced pressure to obtain a reddish liquid, which was dissolved in 1N hydrochloric acid, the solution was washed with chloroform, alkalized with 1N sodium hydroxide and extracted with 100 ml of chloroform. The extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate, and the solvent was evaporated off under a reduced pressure to obtain 0.60 g of a desired compound as a reddish brown liquid.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][N:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][N:41]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc(CCl)nc1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: Cc1ccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)nc1
Yield: 80.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 2-(chloromethyl)-5-methylpyridine (0.43 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.71 g) was obtained.
Reaction SMILES: N1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7](O)(=O)[CH2:8][C:9]([OH:11])=[O:10].S(=O)(=O)(O)O>N1C=CC=CC=1>[CH:2]1[C:6]2[C:6](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:5]=[CH:4][C:3]=1[CH:7]=[CH:8][C:9]([OH:11])=[O:10]
Reactant: C1CCNCC1
Reactant: O=C(O)CC(=O)O
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc2ccccc2c1

Procedure:
A solution of 2-naphthylaldehyde (3 g), piperidine (0.49 ml) and malonic acid (4.0 g) in pyridine (15 ml) was stirred for 2 hrs at 120° C. After cooling, the solution was acidified with conc. sulphuric acid. The solution was extracted with EtOAc. The oily layer was washed, dried, and evaporated to give the title compound (3.6 g) having the following physical data:
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]2[CH2:9][CH2:10][O:11][C:7]=2[CH:6]=1)([CH3:3])[CH3:2].[N-:14]=[C:15]=[O:16].[Na+]>C(O)(=O)C>[CH:1]([N:4]([C:5]1[CH:13]=[CH:12][C:8]2[CH2:9][CH2:10][O:11][C:7]=2[CH:6]=1)[C:15]([NH2:14])=[O:16])([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccc2c(c1)OCC2
Reactant: [N-]=C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)N(C(N)=O)c1ccc2c(c1)OCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 12.2 g. of N-isopropyl-2,3-dihydro-6-benzofuranamine in 250 ml. of glacial acetic acid, cooled to 15°±5°C. is added 24.0 g. of sodium isocyanate. The mixture is stirred at room temperature for 18 hours and then concentrated in vacuo. The residue is treated with 200 ml. of 2N sodium hydroxide solution and then extracted twice with chloroform. The combined chloroform extracts are dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo to obtain an oil of 1-isopropyl-1-(2,3-dihydro-6-benzofuranyl)urea.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[C:14]([NH2:20])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[N:30]=[C:31]=S.CI>CO>[CH3:1][N:2]([CH3:21])[C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]3[N:18]([CH3:19])[C:31]([NH:30][C:24]4[C:23]([F:22])=[CH:28][CH:27]=[CH:26][C:25]=4[F:29])=[N:20][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: Fc1cccc(F)c1N=C=S
Reactant: CNc1ccc(Oc2ccnc(C(=O)N(C)C)c2)cc1N
Solvent: CI
Solvent: CO
Product: CN(C)C(=O)c1cc(Oc2ccc3c(c2)nc(Nc2c(F)cccc2F)n3C)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the 4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carboxylic acid dimethylamide (1 eq) in methanol was treated with 2,6-difluorophenylisothiocyanate (1 eq) and stirred overnight. To the reaction mixture, methyl iodide (1 eq) was added and stirred overnight at 60° C. The reaction was cooled down to room temperature, evaporated, and the residue purified by reverse phase HPLC. HPLC, 1.66 min; MS: MH+=424.1
Reaction SMILES: [C:1]1([C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:8]2[CH:12]=[C:11]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([F:23])[CH:16]=3)=[O:14])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36][Mg+].[Br-]>C1COCC1.CCOCC>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:13]([C:11]2[N:10]=[CH:9][N:8]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:12]=2)([OH:14])[CH3:36])=[CH:16][C:17]=1[F:23])#[N:22]
Reactant: N#Cc1ccc(C(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1F
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)(c1ccc(C#N)c(F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 1 h

Procedure:
To a solution of 4-cyano-3-fluorophenyl 1-(triphenylmethyl)imidazol-4-yl ketone from Step E (7.0 g, 15.3 mmol) in dry THF (280 mL), under argon, at −78° C., was added MeMgBr (5.3 mL of a 3.0 M solution in Et2O, 15.9 mmol), dropwise. After 1 hr, the reaction mixture was quenched with sat. aq. NH4Cl (100 mL) and extracted with CH2Cl2 (2×150 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexane—30% to 50% EtOAc, to yield the titled product as pale solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:6](=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:8][C:9]=2[S:11][CH2:12][CH2:13][CH3:14])[CH2:5][CH2:4][CH2:3]1.[Br:20]Br>C(Cl)(Cl)Cl>[Br:20][CH:3]1[CH2:4][CH2:5][C:6]2=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:8][C:9]([S:11][CH2:12][CH2:13][CH3:14])=[C:10]2[C:2]1=[O:1]
Reactant: BrBr
Reactant: CCCSc1sc(C(=O)OCC)c2c1C(=O)CCC2
Solvent: ClC(Cl)Cl
Product: CCCSc1sc(C(=O)OCC)c2c1C(=O)C(Br)CC2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 90.9 %

Procedure:
Ethyl 4,5,6,7-tetrahydro-4-oxo-3-propylthiobenzo[c]thiophene-1-carboxylate (25.29 g) was dissolved in chloroform (380 ml); a solution of bromine (13.81 g) in chloroform (20 ml) was added dropwise at room temperature over a period of 20 minutes. After the reaction mixture was stirred at room temperature for 40 minutes, it was washed with a 2% aqueous solution of sodium sulfite (400 ml), water, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and dried (MgSO4), after which the solvent was distilled off to yield ethyl 5-bromo-4,5,6,7-tetrahydro-4-oxo-3-propylthiobenzo[c]thiophene-1-carboxylate (29.07 g, 90.9%), which was then recrystallized from ethyl acetate-hexane. Light-yellow prisms. Melting point 93-94° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([F:52])[CH:48]=[CH:47][C:46]=1[F:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:46]([F:53])=[CH:47][CH:48]=[C:49]([F:52])[C:50]=3[Cl:51])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(F)c(CBr)c1Cl
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3c(F)ccc(F)c3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-3-chloro-1,4-difluorobenzene and isolated as white solid (8.0 mg, 44%). MS(m/e): 443.4 (MH+).