Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]1([C:8]2[C:13]([NH:14]C(=O)C)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1>[ClH:1].[C:2]1([C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cccnc1-c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cccnc1-c1ccccc1
Temperature: 0 °C
Yield: 897.8 %

Procedure:
To a solution of N-(2-phenyl-pyridin-3-yl)-acetamide hydrochloride (61.9 g, 24.9 mmol) in tetrahydrofuran (100 mL) was added concentrated hydrochloric acid (100 mL). The reaction mixture was heated to reflux overnight and concentrated to a low volume. Tetrahydrofuran was added (2000 mL) and the volume was reduced to about 1000 mL as, product started precipitating. The mixture was cooled to 0° C. and was granulated for two) hours. The solids were filtered to afford 2-phenyl-3-aminopyridine hydrochloride (46.2 g, 90%). M. p.=226-1227° C. 1H NMR (300 MHz, CDCl3) δ6.35 (bs, 3), 7.61-7.74 (m, 6), 7.82 (dd, 1, J=1.4, 8.6), 8.05 (dd, 1, J=1.5, 5.4). Analysis calculated for C11H11CIN2: C, 63.93; H, 5.36; N, 13.55. Found: C, 63.64; H, 5.20; N, 13.49.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[CH:12]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:11](=[O:24])[N:10]([CH2:25][C:26]([N:28]2[CH2:33][CH2:32][CH:31]([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]2)=[O:27])[CH2:9]1.[OH-].[Na+].Cl>C1COCC1.CO.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[CH:12]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:11](=[O:24])[N:10]([CH2:25][C:26]([N:28]2[CH2:29][CH2:30][CH:31]([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]2)=[O:27])[CH2:9]1
Reactant: CCOC(=O)C1CCN(C(=O)CN2CC(c3ccccc3Br)c3cc(Cl)ccc3C(CC(C)C)C2=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC1C(=O)N(CC(=O)N2CCC(C(=O)O)CC2)CC(c2ccccc2Br)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
24 mg of the compound from Example 22 (0.04 mol) are dissolved in 2.0 ml of THF/methanol (1:1). 0.1 ml of 1 N sodium hydroxide solution is added, and the reaction mixture is stirred at room temperature for 16 h. It is diluted with water and acidified with 1 N hydrochloric acid, and the mixture is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulphate, and the solvent is removed in a rotary evaporator. 23 mg (100% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[H-].[Na+].Cl[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=1>>[F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][O:4][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: OCC(F)(F)C(F)F
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccc(OCC(F)(F)C(F)F)nc1

Procedure:
In a similar manner to that described in Reference example 1(c), a reaction was carried out using 2,2,3,3-tetrafluoropropanol (5.23 ml), sodium hydride (55% suspension in oil, 1.91 g) and methyl 6-chloronicotinate (5.00 g) and treated to afford crude methyl 6-(2,2,3,3-tetrafluoropropoxy)nicotinate (5.42 g) as a colorless oil. In a similar manner to that described in Example 2, a reaction was carried out using the crude product described above (2.70 g) and aqueous sodium hydroxide solution (2N, 15 ml) and the reaction mixture was treated to afford crude title compound (1.60 g). This product was used in Example 102 and Example 150 without further purification.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]3[N:18]=[N:17][NH:16][N:15]=3)=[CH:12][C:11]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:10]([Cl:23])[CH:9]=2)[S:4][CH:5]=1.Cl[CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[CH2:27]([O:26][CH2:25][N:15]1[C:14]([C:13]2[C:8]([NH:7][CH2:6][C:3]3[S:4][CH:5]=[CH:1][CH:2]=3)=[CH:9][C:10]([Cl:23])=[C:11]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:12]=2)=[N:18][N:17]=[N:16]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NS(=O)(=O)c1cc(-c2nn[nH]n2)c(NCc2cccs2)cc1Cl
Reactant: ClCOCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cc(-c2nnnn2COCc2ccccc2)c(NCc2cccs2)cc1Cl

Procedure:
Azosemide can be reacted with benzyl chloromethyl ether, triethylamine and sodium iodide in DMF to yield 5-[1-(benzyloxymethyl)-1H-tetrazol-5-yl]-2-chloro-4-[(2-thienylmethyl)amino]benzenesulfonamide.
Reaction SMILES: [F:1][C:2]1[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:15]=[C:16]([C:20]#[C:21][C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:17]=[CH:18][CH:19]=2)=[C:12]2[C:7]([C:8]([C:33]([F:36])([F:35])[F:34])=[CH:9][CH:10]=[CH:11]2)=[N:6]1>CO>[F:1][C:2]1[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:15]=[C:16]([CH2:20][CH2:21][C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:17]=[CH:18][CH:19]=2)=[C:12]2[C:7]([C:8]([C:33]([F:34])([F:35])[F:36])=[CH:9][CH:10]=[CH:11]2)=[N:6]1
Reactant: CCOC(=O)c1cccc(C#Cc2cccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3c(F)cc(F)cc3F)c2)c1
Solvent: CO
Product: CCOC(=O)c1cccc(CCc2cccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3c(F)cc(F)cc3F)c2)c1
Reaction time: 24 h
Yield: 100.1 %

Procedure:
A mixture of ethyl 3-({3-[2-(2,4,6-trifluorobenzyl)-7-(trifluoromethyl)-2H-indazol-3-yl]phenyl}ethynyl)benzoate (0.035 g, 0.06 mmol) and palladium dimethylamine complex (3.5 mg) (ref. Sajiki et. al. JOC, 1998, 63, 7990) in 1 mL of methanol was hydrogenated at atmospheric pressure for 24 hours. The catalyst was filtered and washed with methanol. The combined filterates were evaporated to give 35 mg of product as an oil, which solidified on standing.
Reaction SMILES: [C:1]1([CH:7]2[CH2:9][CH:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([NH:20][C:21]([C:23]1[S:27][C:26]([NH2:28])=[N:25][C:24]=1[CH3:29])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:21]([C:23]1[S:27][C:26]([NH:28][C:10]([CH:8]2[CH2:9][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:11])=[N:25][C:24]=1[CH3:29])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)C1CC1c1ccccc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)C2CC2c2ccccc2)sc1C(=O)NCc1ccccc1
Yield: 73 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 2-phenylcyclopropanecarbonyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 73% yield; 1H NMR (DMSO-d6, 300 MHz) δ 7.38-7.03 (m, 10H), 5.87 (s, br, 1H), 4.56-4.50 (m, 2H), 2.70-2.63 (m, 1H), 2.41 (s, 3H), 1.81-1.73 (m, 2H), 1.52-1.23 (m, 1H); MS (ES+) m/z 391.8 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[NH2:20][CH2:21][C:22]([NH2:24])=[O:23]>>[C:22]([CH2:21][NH:20][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19])(=[O:23])[NH2:24]
Reactant: NCC(N)=O
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCC(N)=O)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and α-aminoacetamide to afford the title compound. MS: m/e=315 (M+H).
Reaction SMILES: N1CCCCC1.[CH:7]1([O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=2[O:21][CH3:22])[CH2:11][CH2:10][CH2:9][CH2:8]1.C([CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=[O:28])(O)=O.Cl>C1(C)C=CC=CC=1>[CH:7]1([O:12][C:13]2[CH:20]=[CH:19][C:16](/[CH:17]=[CH:26]/[C:27]([NH:29][C:30]3[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=3[C:32]([OH:34])=[O:33])=[O:28])=[CH:15][C:14]=2[O:21][CH3:22])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: COc1cc(C=O)ccc1OC1CCCC1
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC1CCCC1
Yield: 67.8 %

Procedure:
Piperidine (0.45 mL, 4.5 mmol) was added to a suspension of 4-cyclopentyloxy-3-methoxybenzaldehyde (1.0 g, 4.5 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.92 g, 4.1 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH/water providing (E)-2-{[3-(4-cyclopentyloxy-3-methoxyphenyl)-1-oxo-2-propenyl]amino}benzoic acid (1.06 g, 67%) as a pale yellow crystalline solid; mp 96-98° C.; δH (400 MHz, DMSO-d6) 1.46 (m, 2H, CH2), 1.67-1.71 (m, 4H, CH2), 1.90 (m, 2H, CH2), 3.81 (s, 3H, OCH3), 4.82 (t, J=5.6 Hz, 1H, OCH), 6.76 (d, J=15.6 Hz, 1H, CH═CHCO), 6.94 (d, J5′,6′=8.4 Hz, 1H, H5′), 7.15 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.19 (dd, J5′,6′=8.4, J5′,6′=1.6 Hz, 1H, H6′), 7.35 (d, J2′,6′=1.6 Hz, 1H, H2′), 7.54 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 HZ, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.28 (s, 1H, NH), 13.59 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 23.7, 32.3, 55.7, 79.5, 110.9, 114.0, 116.5, 119.7, 120.3, 122.5, 122.6, 127.0, 131.1, 134.0, 141.1, 141.7, 149.0, 149.6, 164.2, 169.5; HRMS (ESI) calculated for C22H23NO5 [M+Na]+ 404.1468. found 404.1468; vmax 747, 1261, 1506, 1584, 1659, 2964, 3524 cm−1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[CH3:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]=1[C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27](O)=[O:28])[CH:24]=1>>[CH3:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:10]=1[C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([NH:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:28])[CH:24]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccc2C(=O)O)cn1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccc2C(=O)NC2CCOCC2)cn1
Yield: 37 %

Procedure:
As described for Example 71, tetrahydro-pyran-4-ylamine was converted, using 2-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (47 mg, 37%) which was obtained as an off-white solid. MS: m/e=429.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)=[CH:4][CH:3]=1>P(OCC)(OCC)OCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:14][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(Br)cc1
Agent: CCOP(OCC)OCC
Product: Brc1ccc2c(c1)[nH]c1ccccc12
Yield: 40 %

Procedure:
Around bottom flask was charged with 4′-bromo-2-nitrobiphenyl (100 mmol) and triethyl phosphite (100 mL) and set to reflux under a nitrogen atmosphere for 24 hours. Upon cooling, the solvent was distilled off under vacuum, and the crude product was recrystallized from hot toluene to give 2-bromo-9H-carbazole in 40% yield.
Reaction SMILES: I[CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:13])[NH:4]1.[CH2:14]([O:21][C:22]1[CH:27]=[C:26](I)[CH:25]=[CH:24][C:23]=1[N:29]1[S:33](=[O:35])(=[O:34])[N:32]([CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:31](=[O:42])[CH2:30]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]1[CH:27]=[C:26]([CH:25]=[CH:24][C:23]=1[N:29]1[CH2:30][C:31](=[O:42])[N:32]([CH2:36][CH2:37][Si:38]([CH3:39])([CH3:40])[CH3:41])[S:33]1(=[O:34])=[O:35])[CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:13])[NH:4]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: O=C1N[C@H](CI)Cc2ccccc21
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@@H]3Cc4ccccc4C(=O)N3)cc2OCc2ccccc2)S1(=O)=O

Procedure:
The title compound is prepared from (S)-3-iodomethyl-3,4-dihydro-2H-isoquinolin-1-one and 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one analogous to the method used in Example 57, step B.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:21]>N1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:20]([O:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=3)=[O:21])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccc(C(F)(F)F)cc1
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: c1ccncc1
Product: CN1CCC(OC(=O)Oc2ccc(C(F)(F)F)cc2)N(c2nnc(C(C)(C)C)s2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C and 4-trifluoromethylphenyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(4-trifluoromethylphenoxycarbonyloxy)-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=1[CH2:23]Br>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([N:14]3[CH2:15][CH2:16][N:17]([CH2:23][C:22]4[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:21]=4[F:20])[CH2:18][CH2:19]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: Fc1ccc([C@H]2CC[C@H](N3CCNCC3)CC2)cc1
Product: Fc1ccc([C@H]2CC[C@H](N3CCN(Cc4cc(F)ccc4F)CC3)CC2)cc1

Procedure:
The title compound was prepared from trans 1-[4-(4-fluorophenyl)-1-cyclohexyl]piperazine and 2,5-difluorobenzyl bromide by the method described in example 15 to give the product (69%, mp: 85°-86° C.). Calc'd for C23H27F3N2 : C, 71.12%; H, 7.01%; N, 7.22%. Found: C, 71.11%; H, 7.01%; N, 7.19%.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=O)[CH2:10][C:11]([O:13]CC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]([C:20]1[CH:30]=[CH:29][C:23]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1)=[N+:18]=[N-:19].[O-]CC.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:27]([NH:26][C:24]([C:23]1[CH:29]=[CH:30][C:20]([N:17]2[C:9]([CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:10]([C:11]([OH:13])=[O:12])[N:19]=[N:18]2)=[CH:21][CH:22]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)CC(=O)CCc1ccccc1
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
Ethyl 5-phenyl-3-oxovalerate (1.27 g, 5.52 mmol, 1.25 eq.) obtained in Example 98a) and 4-azido-N-ethylbenzamide (0.842 g, 4.43 mmol) were dissolved in ethanol (25 ml), sodium ethoxide (417 mg, 5.52 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 80° C. for 3 hr. 2% Aqueous sodium carbonate solution (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with water (20 ml) and washed with ethyl acetate-hexane (2:1, 40 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid and extracted with ethyl acetate (35 ml×2). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and diethyl ether-ethyl acetate (2:1, about 8 ml) was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a pale-brown powder (1.56 g, 4.27 mmol, 96.4%).
Reaction SMILES: C[O-].[Na+:3].CCO.CN1[CH:15]=[CH:14][C:12](=[O:13])N(C)C1=O.[C:17]([CH2:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[S:21])#[N:18]>CO>[C:17]([C:19]1[CH:15]=[CH:14][C:12](=[O:13])[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]=1[S-:21])#[N:18].[Na+:3]
Reactant: N#CCC(=S)Nc1ccccc1
Reactant: Cn1ccc(=O)n(C)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: N#Cc1ccc(=O)n(-c2ccccc2)c1[S-]
Temperature: 25 °C

Procedure:
A solution of sodium methoxide in MeOH (30 wt %, 202.2 g) was added to absolute EtOH (360 mL) followed by 1,3-dimethyluracil (75 g) and 2-cyano-N-phenyl-thioacetamide (Adhikari et al, Australian J. Chem., 1999, 52, 63-67) (90 g). The resulting mixture was heated at reflux for 8 h and then allowed to cool to ambient temperature overnight. The reaction mixture was then cooled to +5° and maintained at this temperature for at least an hour when the product was recovered by filtration. The filter cake was washed with cold (+5°) absolute ethanol (450 mL) and then dried to constant weight under vacuum at 45° to give the title compound as a pale pink solid (130.0 g). The product thus obtained contains residual EtOH and MeOH, estimated at 12.2 wt % by 1H nmr, corresponding to a corrected yield of 114.1 g. δH (DMSO-d6) 7.32 (2H, m), 7.27-7.18 (1H, m), 7.16 (1H, d, J 9.1 Hz), 6.92 (2H, m), 5.63 (1H, d, J 9.1 Hz). LCMS (Conditions B) (ES+) RT 2.43 minutes, 229 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].C[C:14](=[O:18])[O:15]CC>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]([OH:6])[C:14]([OH:18])=[O:15]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CCOC(C)=O
Product: O=C(O)C(O)c1ccccc1C(F)(F)F

Procedure:
The 2-trifluoromethylbenzaldehyde (43.9 g, 252 mmol) was converted to product in a manner substantially analogous to Preparation 59 to yield 39.1 g. (70.5%). EA, MS(FD).
Reaction SMILES: [F-].[K+].[C:3]([C:5]1[C:6](OS(C(F)(F)F)(=O)=O)=[CH:7][C:8]2[C@@:15]3([CH3:18])[C@H:16]([CH3:17])[C@H:11]([N:12](C(=O)C(F)(F)F)[CH2:13][CH2:14]3)[CH2:10][C:9]=2[CH:25]=1)#[N:4].[OH-].[Na+]>O.O1CCCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:18][C@:15]12[C@H:16]([CH3:17])[C@H:11]([NH:12][CH2:13][CH2:14]1)[CH2:10][C:9]1[CH:25]=[C:5]([C:3]#[N:4])[CH:6]=[CH:7][C:8]2=1
Reactant: C[C@@H]1[C@H]2Cc3cc(C#N)c(OS(=O)(=O)C(F)(F)F)cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1[C@H]2Cc3cc(C#N)ccc3[C@]1(C)CCN2
Reaction time: 1 h

Procedure:
A solution of KF (76 mg) in water (1 mL) followed by polymethylhydrosiloxane (1.0 g) is added to a mixture of (2R,6R,11S)-trifluoro-methanesulfonic acid 9-cyano-6,11-dimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl ester (0.30 g) and Pd(OAc)2 (7 mg) in tetrahydrofuran (3 mL). The resulting mixture is stirred at room temperature overnight before 1 M NaOH (20 mL) is added. After stirring vigorously for 1 h, the organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water and brine and dried (MgSO4). The solvent is removed and the residue is taken up in 4 M NaOH (1 mL) and methanol (3 mL) and stirred at room temperature overnight. Then, the solution is neutralized with 1 M hydrochloric acid, filtered, concentrated and the residue is purified by HPLC on reversed phase (MeCN/water).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][O:32][CH2:33][CH3:34])[N:14]([CH2:15][C:16]3[CH:30]=[CH:29][C:19]([CH2:20][NH:21]C(=O)OC(C)(C)C)=[CH:18][CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)=[CH:5][C:4]=2[N:3]=1>Cl>[NH2:21][CH2:20][C:19]1[CH:29]=[CH:30][C:16]([CH2:15][N:14]2[C:10]3[C:9]4[CH:8]=[CH:7][C:6]([C:35]5[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=5)=[CH:5][C:4]=4[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[C:13]2[CH2:31][O:32][CH2:33][CH3:34])=[CH:17][CH:18]=1
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1Cc1ccc(CN)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
tert-Butyl {4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-ylmethyl]benzyl}carbamate (0.660 g) was added to ethanolic hydrogen chloride (4M, 10 mL) and the solution was heated at reflux temperature for 30 minutes. The reaction was cooled to room temperature and concentrated under reduced pressure. Diethyl ether and water were added to the oily residue and the layers were separated. The aqueous fraction was brought to pH 13 with 10% aqueous sodium hydroxide and then extracted sequentially with dichloromethane and dichloromethane containing 5% methanol. The organic fractions were combined, washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield 0.526 g of 1-(4-aminomethylbenzyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, mp 211.0-213.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1(Cl)[Cl:8].[CH3:10][O:11][P:12]([O-:16])([O:14][CH3:15])=[O:13].[Na+].C(#N)C>O>[CH3:10][O:11][P:12]([O-:16])([O:14][CH3:15])=[O:13].[CH3:1][NH+:2]1[CH2:6][CH2:5][N:4]([CH3:7])[CH:3]1[Cl:8]
Reactant: CN1CCN(C)C1(Cl)Cl
Agent: COP(=O)([O-])OC
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CN1CC[NH+](C)C1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.9 %

Procedure:
3.00 g (17.75 mmol) of 1,3-dimethyl-2,2-dichloroimidazolidine and 2.63 g (17.77 mmol) of sodium dimethylphosphate are mixed with 20 ml of acetonitrile and 2 ml of water. The reaction mixture is stirred for 12 hours at room temperature, and the precipitate NaCl is subsequently filtered off. The solvent is distilled off, and the residue is dried for 6 hours under a reduced pressure of 7 Pa and at an oil-bath temperature of 70-80° C., giving 4.39 g of 1,3-dimethyl-2-chloroimidazolidinium dimethylphosphate, corresponding to a yield of 95.6%.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16]2[NH:20][N:19]=[CH:18][CH:17]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]>CN(C=O)C>[Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16]2[CH:17]=[CH:18][N:19]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[N:20]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccnc1-c1ccn[nH]1
Reactant: COC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CCn1ccc(-c2ncccc2CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61 %

Procedure:
To a mixture of 3-((tert-butyldimethylsilyloxy)methyl)-2-(1H-pyrazol-5-yl)pyridine (140 mg, 0.48 mmol, 1 eq.) and Cs2CO3 (312 mg, 0.96 mmol, 2 eq.) in DMF (3 mL) was added methyl 3-bromopropanoate (122 mg, 0.73 mmol, 1.5 eq.). The mixture was stirred at rt for 6 h, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give methyl 3-(3-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate (110 mg, 61%). LRMS (M+H+) m/z 376.1.