Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[C:9]([O:11]C)=[O:10].CO.O.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2ccc([N+](=O)[O-])cc2)ccc1C(=O)O
Temperature: 50 °C

Procedure:
Methyl 3-methoxy-4′-nitrobiphenyl-4-carboxylate (0.35 g, 0.97 mmol) was suspended in THF (6 mL), MeOH (6 mL) and water (3 mL), and NaOH (0.19 g, 4.9 mmol) was added. The reaction mixture was heated at 50° C. for 3 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure and acidified with 2N HCl. The resulting solid was collected by filtration and dried in a 40° C. vacuum oven, yielding 0.28 g (quantitative) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 3.90 (s, 3H), 7.35-7.41 (m, 2H), 7.77 (d, 1H), 8.03 (d, 2H), 8.36 (d, 2H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.FC(F)(F)[C:19](O)=[O:20].C1N2CN3CN(C2)CN1C3.OS(O)(=O)=O>O>[OH:14][C:11]1[CH:10]=[CH:9][C:8]([N:7]2[C:3]([C:2]([F:1])([F:15])[F:16])=[N:4][N:5]=[N:6]2)=[CH:13][C:12]=1[CH:19]=[O:20]
Reactant: Oc1ccc(-n2nnnc2C(F)(F)F)cc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Solvent: O
Product: O=Cc1cc(-n2nnnc2C(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
To a 2 L nitrogen purged round bottom flask fitted with a condenser was charged 67.7 g (0.29 mol) of 4-(5-trifluoromethyl-tetrazol-1-yl)-phenol, 540 mL trifluoroacetic acid, and 86.3 g (0.62 mol, 2.1 eq) of hexamethylenetetramine. The solution was heated to reflux and refluxed for 4 h. An additional 10 g (0.07 mol, 0.24 equiv) of hexamethylenetetramine was added and the solution refluxed overnight. The reaction was cooled and poured slowly into 3 L of 1N H2SO4. The suspension was diluted with an additional 500 mL of water and aged at room temperature for 30 min and at 0° C. and for additional 30 min. The yellow suspension was filtered and the cake washed with water until the filtrate was neutral. The cake was dissolved in methylene chloride and filtered through 300 g of Silica Gel 60 (70-230 mesh) and flushed with 6 L of methylene chloride. The solvent was removed in vacuo and the residue flushed with hexanes. The resulting slurry was cooled to room temperature and filtered. The white crystalline product that was obtained was dried yielding 50.4 g (66.4% yield) of the title compound. An additional 6.9 g (9.1%, for a combined yield of 57.3 g, 75.5% yield) was obtained by extracting the aqueous filtrate with ether and chromatographing (Silica Gel 60, methylene chloride): 1H NMR (CDCI3) δ 7.23 (d, J=9 Hz, 1H), 7.62 (dd, J=9, 2 Hz, 1H), 7.73 (d, J=2.5 Hz, 1H), 9.96 (s, 1H). MS (EI) m/z 258. Anal. Calcd for C9H5F3N4O2: C, 41.87; H, 1.95; F, 22.08; N, 21.70. Found: C, 41.87; H, 1.98; F, 22.61; N, 21.74.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[CH:16]=2)[C:11]([N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])=[O:13])=[CH:26][CH:27]=1)#[N:2]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Reactant: CCNCC
Product: CCN(CC)C(=O)c1cc(Oc2ccc(C#N)cc2)cc(Oc2ccc(C#N)cc2)c1
Yield: 72.3 %

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.2 g (3.36 mmol) and diethyl-amine (0.245 g, 3.36 mmol) were used to afford 1.0 g of the required product. 1H NMR (DMSO-d6): δ 1.15 (6H, m), 3.22 (2H, m), 3.40 (2H, m), 6.94 (2H, d), 7.05 (1H, t), 7.25 (2H, d), 7.88 (2H, d).
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]>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
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.3 %

Procedure:
To a solution of 2-fluoroaniline (4.27 ml, 44.3 mmol) in THF (30 ml) at −78° C. was added LIHMDS (66.6 ml, 1 M in THF, 66.6 mmol) dropwise. The reaction mixture was stirred for 10 min and a solution of 5-bromo-2,3,4-trifluorobenzoic acid (5.63 g, 22.2 mmol) in THF (40 ml) was added to the mixture. The reaction was slowly warmed to room temperature and stirred at this temperature for 4 h. The mixture was concentrated, quenched with 10% HCl solution (70 ml), and extracted with EtOAc (2×200 ml). The combined organic solution was dried over MgSO4 and concentrated to dryness. Purification by trituration with boiling CH2Cl2 gave 4.40 g (57%) of 5-bromo-3,4-difluoro-2-(2-fluorophenylamino)benzoic acid as a yellow solid.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[K+].S(O)(O)(=O)=O.[NH2:17]O>O>[NH2:9][C:8]1[CH:7]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[O:6][N:17]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1cc(N)no1
Reaction time: 0.05 h
Yield: 124.7 %

Procedure:
To a suspension of pivaloylacetonitrile (1.252 g) and 86% potassium hydroxide (0.717 g) in water (20 ml) is added hydroxylamine sulfate (0.903 g) at 25° C. and the mixture is stirred for 3 minutes. pH 8.30. The reaction mixture is treated as in Example 2 to give 3-amino-5-t-butylisoxazole (1.204 g). Yield, 85.9%. Purity, 95.8%.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1.O[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=3)=[CH:10][CH:9]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: Cc1cc(-c2ccccc2)nn1Cc1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CCc1ccc(OCc2ccc(Cn3nc(-c4ccccc4)cc3C)cc2)cc1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
To a mixture of {4-[(5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl]phenyl}methanol (278 mg, 1.0 mmol), methyl 3-(4-hydroxyphenyl)propanoate (180 mg, 1.0 mmol), triphenylphosphine (393 mg, 1.5 mmol) and dichloromethane (5 mL) was added dropwise diethyl azodicarboxylate (40% toluene solution, 650 mg, 1.5 mmol) with stirring at room temperature, and the mixture was stirred at room temperature for 1 hr. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography (hexane:ethyl acetate=19:1-1:2) to give the title compound (263 mg, yield 90%) as a yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:50][C:51]1[CH:52]=[C:53]([CH:59]=[C:60]([C:62]([F:65])([F:64])[F:63])[CH:61]=1)[O:54][CH:55]1[CH2:58][NH:57][CH2:56]1>CN(C=O)C>[F:50][C:51]1[CH:52]=[C:53]([CH:59]=[C:60]([C:62]([F:64])([F:63])[F:65])[CH:61]=1)[O:54][CH:55]1[CH2:58][N:57]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]2[N:18]=[CH:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:22])[CH2:56]1
Reactant: Fc1cc(OC2CNC2)cc(C(F)(F)F)c1
Reactant: O=C(O)CNC(=O)c1cn(-c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CC(Oc2cc(F)cc(C(F)(F)F)c2)C1)c1cn(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 31.4 %

Procedure:
DIPEA (143 mg, 1.1 mmol) was added to a stirred solution of [(1-phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acid (prepared from Intermediate 68 by means of Step 3 of the General Scheme) (68 g, 0.27 mmol) in DMF (2 mL) followed by HOBt (39 mg, 0.29 mmol) and EDCI (56 mg, 0.29 mmol). After 2 minutes of stirring, 3-(3-fluoro-5-trifluoromethyl-phenoxy)-azetidine hydrochloride (prepared by the method used for the synthesis of Intermediate 71) (75 mg, 0.27 mmol) was added and it was stirred overnight at ambient temperature. Partitioning with cold water and ethyl acetate and concentration of the organic layer after drying over sodium sulfate afforded a residue which was purified by preparative HPLC to give 40 mg (31.4% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[3-(3-fluoro-5-trifluoromethyl-phenoxy)-azetidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 463, 99.18%. 1H NMR (300 MHz, DMSO-d6): δ 8.44 (d, 1H), 8.34 (d, 1H), 8.2 (t, 1H), 7.8 (d, 2H), 7.56 (t, 2H), 7.44 (m, 1H), 7.34 (d, 1H), 7.12 (m, 2H), 5.25 (m, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 4.3 (m, 1H), 3.9 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl.[NH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:15]1[CH2:16][CH2:17][NH:12][CH2:13][CH:14]=1
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reaction time: 8 h

Procedure:
A mixture of 15.1 g of 5-chloro-1H-indole, 30.7 g of the hydrate of 4-piperidone hydrochloride and 150 ml of 2 N methanolic potassium hydroxide solution was refluxed under an inert atmosphere for 71/2 hours and was allowed to stand overnight at room temperature. The mixture was poured into 1.5 liters of water and the mixture was extracted with ethyl acetate. The organic phase was washed with water, aqueous sodium chloride solution, was dried over magnesium sulfate and evaporated to dryness. The 20.5 g of residue were dissolved in 1 liter of refluxing benzene and the solution was filtered hot. The solution was cooled to induce crystallization and after 3 hours, the mixture was vacuum filtered. The recovered product was rinsed with benzene to obtain 10.2 g of 5-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole melting at 177° C. The mother liquors were concentrated and crystallization induced to obtain 2.49 g of the said product melting at 175°-177° C. for a total yield of 12.69 g. For analysis, the product was purified by salification with an acid and then return to the basis.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)[CH2:8]2)[CH2:4][CH2:3]1.C(O)C.[ClH:28].N>CCOCC.[Zn]>[ClH:28].[ClH:28].[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2([CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH2:8]1
Reactant: CN1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1ccccc12
Agent: Cl
Agent: N
Agent: [Zn]
Solvent: CCOCC
Solvent: CCO
Product: CN1CCC2(CC1)CN(c1ccccc1N)c1ccccc12

Procedure:
A large excess, about 20-25 g, of zinc dust is added portionwise to a vigorously stirring solution, at about 0° C., of 10.7 g of 1'-methyl-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine] (Example 15), in a combined solvent of 75 ml of ethanol and 5 ml of concentrated hydrochloric acid. After total addition, an additional 15 ml of concentrated hydrochloric acid is carefully added to maintain the temperature of the reaction mixture below 70° C. The reaction mixture is basified with concentrated ammonia, and the alkaline mixture is filtered and concentrated to dryness. The residue is partitioned between 400 ml of methylene dichloride and 400 ml of 10% sodium hydroxide. The organic portion is successively washed thrice with 400 ml portions of 10% sodium hydroxide and then once with a 400 ml portion of water, dried and concentrated to dryness, leaving a black glassy product. The product is converted to its hydrochloride in ether which is recrystallized from a methanol-ether mixture to leave the salt, mp 243° C., dec. of 1-(2-aminophenyl)-1'-methylspiro[indoline-3,4'-piperidine]-dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:21]=[CH:22][CH2:23][OH:24])[CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:21]=[CH:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1c[nH]c2ccc(C=CCO)cc2c1=O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCN2CCOCC2)c2ccc(C=CCO)cc2c1=O
Temperature: 90 °C

Procedure:
A mixture of N-(4-chlorobenzyl)-1,4-dihydro-6-[3-hydroxy-1-propenyl]-4-oxo-3-quinolinecarboxamide from Preparations No. 11 and 12 (0.52 g) is dissolved in DMF (4 mL), and potassium carbonate (0.78 g) and N-(2-chloroethyl)morpholine hydrochloride (0.52 g) are added. The mixture is heated at 90° C. for 2 h and then partitioned between water and chloroform. The organic layer is concentrated in vacuo to give a brown oil. Column chromatography (elution with 1-7% MeOH/CHCl3) followed by crystallization from EtOAc/hexane gave the title compound as a mixture of isomers. The mixture is then purified by HPLC chromatography on a 0.46×25 cm Chiralcel OD-H column eluting with EtOH at a rate of 0.5 mL/min. This gave 0.161 g of the alkene mixture as approximately a 2:1 mixture of the trans:cis isomers, which is crystallized from ethyl acetate to give 0.13 g of the title compound as a hydrate.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=3)=[O:18])[CH2:15][CH2:16]2)=[CH:30][CH:31]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)C2CCN(CCOc3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(C(=O)C2CCN(CCOc3ccc(N)cc3)CC2)cc1
Yield: 66.4 %

Procedure:
The compound of Example 1 (2.00 g, 4.47 mmol) and tin (II) chloride dihydrate (8.06 g, 35.75 mmol) were stirred together in ethanol (30 mL) at 70° C. for 6 hours. The solvent was removed in vacuo and the residue was partitioned between 10% aqueous sodium bicarbonate and 4:1 dichloromethane/isopropanol. The organic phase was dried (MgSO4) and concentrated to afford 1.24 g (66%) of N-[4-[[1-[2-(4-aminophenoxy)ethyl]-4-piperdinyl]carbonyl]phenyl]methanesulfonamide as a white foam which was used directly in the next step. 1H NMR (CDCl3): δ 7.85 (d, J=6 Hz, 2H), 7.23 (d, J=6 Hz, 2H), 6.63 (m, 4H), 4.21 (br s, 2H), 4.00 (m, 2H), 3.18 (m, 3H), 3.00 (s, 3H), 2.79 (m, 2H), 2.20 (m, 2H), 1.80 (m, 4H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([CH:23]=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:16][CH:17]=1
Reactant: OCC1(c2ccc(Cl)cc2)CCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CC1(c2ccc(Cl)cc2)CCCC1

Procedure:
This compound is prepared in a manner analogous to that of Step B of Example 4, using 7.0 grams (0.055 mole) of oxalyl chloride, 9.5 grams (0.120 mole) of dimethyl sulfoxide, 10.5 grams (0.050 mole) of [1-(4-chlorophenyl)-1-cyclopentyl]methanol, and 25.5 grams (0.250 mole) of triethylamine in 175 mL of methylene chloride, yielding 1-(4-chlorophenyl)-1-cyclopentanecarboxaldehyde.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][CH2:13]Cl.Cl.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>C(O)C>[CH2:16]([N:20]1[C:2]2[N:7]3[N:8]=[CH:9][N:10]=[C:6]3[N:5]=[C:4]([CH3:11])[C:3]=2[CH2:12][CH2:13]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN
Reactant: Cc1nc2ncnn2c(Cl)c1CCCl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCN1CCc2c(C)nc3ncnn3c21

Procedure:
A mixture of 2g of 7-chloro-6-(2-chloroethyl)-5-methyl-s-triazolo[1,5-a]pyrimidine, 0.95g of n-butylamine hydrochloride, 4 ml of triethylamine and 20 ml of ethanol was stirred under reflux for 1 hour. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in chloroform and purified by an column chromatography of alumina. The crystals thus obtained were recrystallized from isopropyl ether affording 1.35g of pale yellow needles of m.p. 72° - 75° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17](O)=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[NH2:21][C:22]1[CH:23]=[C:24]([CH:28]2[N:33]([CH3:34])[CH2:32][CH2:31][N:30]([CH3:35])[C:29]2=[O:36])[CH:25]=[CH:26][CH:27]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([NH:21][C:22]4[CH:23]=[C:24]([CH:28]5[N:33]([CH3:34])[CH2:32][CH2:31][N:30]([CH3:35])[C:29]5=[O:36])[CH:25]=[CH:26][CH:27]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: CN1CCN(C)C(c2cccc(N)c2)C1=O
Product: CN1CCN(C)C(c2cccc(Nc3ncc4ccc(-c5cccc(S(C)(=O)=O)c5)n4n3)c2)C1=O

Procedure:
3-{3-[7-(3-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-1,4-dimethyl-piperazin-2-one was prepared from 7-(3-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 3-(3-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1052a. Product isolated as an orange foam (69 mg, 46%). LCMS (m/e) 491 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.75 (s, 1H), 8.59 (d, 1H, J=8.0 Hz), 8.52 (s, 1H), 7.91 (d, 1H, J=7.8 Hz), 7.84 (d, 1H, J=8.1 Hz), 7.75-7.66 (m, 1H), 7.41-7.33 (m, 1H), 7.10 (s, 1H), 7.12-7.04 (m, 2H), 6.89-6.81 (m, 2H) 3.76-3.66 (m, 2H), 3.27-3.18 (m, 1H), 3.09 (s, 3H), 3.06-2.96 (m, 1H), 2.98 (s, 3H), 2.74-2.62 (m, 1H), 2.19 (s, 3H).
Reaction SMILES: [Mg+2].[Br-].[Br-].CCOCC.C(N(C(C)C)CC)(C)C.[C:18]([C:21]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH:22]=1)([CH3:20])=[CH2:19].C[O:28][C:29](=O)[CH:30]=[CH2:31]>C(Cl)Cl>[CH3:19][C:18]1[CH2:20][CH2:31][C@@H:30]2[C@@H:22]3[C:21]=1[CH2:25][CH2:24][C@@H:23]3[O:26][C:29]2=[O:28]
Reactant: C=CC(=O)OC
Reactant: C=C(C)C1=C[C@@H](O)CC1
Agent: [Br-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C2CC[C@@H]3OC(=O)[C@H](CC1)[C@H]23
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
Anhydrous MgBr2.Et2O (759.2 mg, 2.940 mmol) was suspended in DCM (3.5 mL), treated with Diisopropylethylamin (1.0, 760 mg, 5.880 mmol) and stirred for 15 minutes until the suspension turns magenta. Then compound (7a) (182.4 mg, 1.469 mmol) dissolved in DCM (11.5) was added slowly within 15 minutes. After stirring for 1 hour Methylacrylate (0.27 mL, 257.9 mg, 2.995 mmol) was added dropwise. The resulting mixture was stirred for 5½ hours before it was quenched with saturated aqueous NH4Cl. For a better phase separation potassium sodium tartrate was added and the solution extracted with DCM (4×). The combined extracts were dried (Na2SO4) and concentrated in vacuo. Purification by chromatography (hexane/EtOAc 6/1) furnished 194.3 mg of compound (8a) as white solid with 74% yield.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH2:10][NH:11][CH2:12][CH2:13][C:14]=3[N:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:20][C:21](=[O:31])[CH:22]([CH2:26][S:27](Cl)(=[O:29])=[O:28])[CH:23]([CH3:25])[CH3:24])(C)(C)C.C(N(CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:24][CH:23]([CH3:25])[CH:22]([CH2:26][S:27]([N:11]1[CH2:12][CH2:13][C:14]2[N:15]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:8][C:9]=2[CH2:10]1)(=[O:29])=[O:28])[C:21]([OH:31])=[O:20]
Reactant: CC(C)C(CS(=O)(=O)Cl)C(=O)OC(C)(C)C
Reactant: c1ccc(-c2nc3c(s2)CNCC3)cc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(CS(=O)(=O)N1CCc2nc(-c3ccccc3)sc2C1)C(=O)O
Reaction time: 2 h
Yield: 74.8 %

Procedure:
2-Phenyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine (0.11 g) was added to a solution of 2-chlorosulfonylmethyl-3-methyl-butyric acid tert-butyl ester (0.14 g) and triethylamine (0.3 ml) in DCM (20 ml) at room temperature. The solution was stirred for 2 h, then TFA (5 ml) was added and the mixture stirred for 1 h. The mixture was evaporated in vacuo and the residue partitioned between diethyl ether (10 ml) and saturated sodium bicarbonate (30 ml). The aqueous layer was acidified with citric acid to pH 5 and extracted with ethyl acetate (3×20 ml). The solvent was dried (MgSO4) and evaporated to give the title compound as pale yellow solid (0.15 g).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C@H:2]1[CH2:5][O:6][C:7]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:8]=1[C:9](/[N:11]=[C:12]1/[N:13]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[N:14]([CH3:21])[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:16]/1)=[O:10].C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].O>C(Cl)Cl>[C:17]([C:15]1[N:14]([CH3:21])[N:13]([CH2:22][CH:23]2[CH2:24][CH2:25]2)/[C:12](=[N:11]/[C:9](=[O:10])[C:8]2[CH:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=[CH:29][C:7]=2[O:6][CH2:5][C@@H:2]2[CH2:3][CH2:4][N:1]2[S:42]([CH3:41])(=[O:44])=[O:43])/[CH:16]=1)([CH3:19])([CH3:18])[CH3:20]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OC[C@@H]2CCN2)n1CC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OC[C@@H]2CCN2S(C)(=O)=O)n1CC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
To a solution of Example 63B (220 mg, 0.474 mmol) and triethylamine (0.132 ml, 0.947 mmol) in CH2Cl2 (6 ml) was added methanesulfonyl chloride (0.055 ml, 0.710 mmol) dropwise. The mixture was stirred at ambient temperature for 2 hours then portioned between CH2Cl2 and water. The organic extract was washed with brine and concentrated. Purification by chromatography (silica gel, MeOH/Et3N (9:1) in CH2Cl2 in 0-30% gradient) provided 160 mg (62% yield) of the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 0.41-0.68 (m, 4H), 1.01-1.18 (m, 1H), 1.41-1.49 (m, 9H), 2.25-2.45 (m, 2H), 2.91 (s, 3H), 3.71-3.80 (m, 1H), 3.83 (s, 3H), 3.93-4.07 (m, 1H), 4.14-4.33 (m, 4H), 4.59-4.80 (m, 1H), 6.95-7.06 (m, 2H), 7.50 (dd, J=8.82, 1.70 Hz, 1H), 7.92 (d, J=2.37 Hz, 1H); MS (DCI/NH3) m/z 543 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][CH2:15][O:16][CH3:17])[C:7]=2[CH:18]=1>[O-2].[O-2].[Mn+4].ClCCl>[CH3:17][O:16][CH2:15][CH2:14][CH2:13][N:8]1[C:7]2[CH:18]=[C:3]([CH:2]=[O:1])[CH:4]=[CH:5][C:6]=2[O:11][CH2:10][C:9]1=[O:12]
Reactant: COCCCN1C(=O)COc2ccc(CO)cc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COCCCN1C(=O)COc2ccc(C=O)cc21
Reaction time: 8 h

Procedure:
The solution of 6.08 g of 6-hydroxymethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one and 300 ml of dichloromethane is admixed with 20.9 g of manganese dioxide and stirred over 8 hours. The reaction mixture is filtered and the filtrate is concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.59 (4:1 EtOAc-heptane); Rt=3.24.