Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:4][CH:5]1[NH:8][C:7](=[O:9])[CH:6]1[CH2:10][CH3:11])[CH:2]=[CH2:3].Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([S:4][CH:5]1[N:8]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:7](=[O:9])[CH:6]1[CH2:10][CH3:11])[CH:2]=[CH2:3]
Reactant: COC(=O)CBr
Reactant: C=CCSC1NC(=O)C1CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCSC1C(CC)C(=O)N1CC(=O)OC
Reaction time: 18 h

Procedure:
To a vigorously stirred solution of 2.34 g of 4-allylthio-3-ethylazetidin-2-one in 20 ml of dimethylformamide were added 1.37 ml of methyl bromoacetate and 4.16 g of finely ground potassium carbonate. After 18 hours, the mixture was poured into 75 ml of water, was extracted into ethyl acetate (5×20 ml) and the combined organic extracts were washed with water (6×15 ml), dried over MgSO4 and evaporated in vacuo to dryness. Chromatography over silica gel, eluting with hexane-ethyl acetate mixtures, afforded the title compound as a yellow oil (3 g).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH2:18])[CH3:14].[C:21]1([S:27]([CH2:29][CH2:30][NH:31][CH:32]([CH3:34])[CH3:33])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH:18][C:1](=[O:2])[N:31]([CH:32]([CH3:34])[CH3:33])[CH2:30][CH2:29][S:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:28])[CH3:14]
Reactant: CC(C)NCCS(=O)c1ccccc1
Reactant: CCN(CC)CCN
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)N(CCS(=O)c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
A mixture of 4.70 g (0.029 mole) of 1,1'-carbonyldiimidazole- and 3.07 g (0.0265 mole) of N,N-diethylethylenediamine in 400 ml of tetrahydrofuran was stirred at room temperature for 1 hr. A solution of 8.00 g (0.0245 mole) of N-[2-(phenylsulfinyl)ethyl]-2-propanamine in 50 ml of tetrahydrofuran was added, and the mixture was refluxed for 16 hr. The solvent was removed in vacuo, and the residue was dissolved in ether. The ether solution was extracted with several portions of water. The aqueous extract was extracted with ether and then with methylene chloride; these organic extracts were combined with the original ether solution. The organic solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil. Flash chromatography on silica gel (methanol) gave 4.84 g (55.9%) of oil:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][CH2:9][C:10]=2[CH:11]=1.[CH2:14]([Li])CCC.[C:19](=[O:21])=[O:20]>CCOCC.CCCCCC>[CH3:14][O:20][C:19]([CH:6]1[C:5]2[N:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:10]=2[CH2:9][CH2:8][C:7]1([CH3:13])[CH3:12])=[O:21]
Reactant: [Li]CCCC
Reactant: Cc1cnc2c(c1)CCC(C)(C)C2
Reactant: O=C=O
Solvent: CCOCC
Solvent: CCCCCC
Product: COC(=O)C1c2ncc(C)cc2CCC1(C)C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
3,7,7-Trimethyl-5,6,7,8-tetrahydroquinoline (17.5 g., 0.1 m.) was dissolved in dry ether (200 ml.) and treated with a solution of n-butyl lithium in hexane (15% solution, 56 ml.) under nitrogen. The reaction mixture was allowed to stand at room temperature for 30 minutes and then treated with CO2 gas until the intense red colour was discharged. The solvent was removed and the residual oily solid dissolved in water (20 ml.) then extracted with ether (3 × 50 ml.). The ethereal extracts were retained to recover unreacted starting material. The aqueous solution was evaporated to dryness, the residue treated with methanol previously saturated with dry HCl (100 ml.) and the solution allowed to stand at room temperature for 8 hours. The solvent was removed and the residual oil dissolved in water (50 ml.) and extracted with ether (3 × 50 ml.) and the extracts discarded. The aqueous solution was adjusted to pH 9.0 with sodium carbonate and extracted with ether (3 × 50 ml.). The combined extracts were dried and evaporated in vacuo to give the title compound as a pale yellow oil (1.8 g., 10%) I.R. Spectrum νmaxfilm 1748, 1570, 1460, 1160, 1030 cm-1. GLC: RT =3.1/2 min. (F11, 2% OV17, T = 150°).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[C:17]([C:18](OCC)=[O:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.C(OC(=O)C)C.O>O1CCCC1>[Cl:7][C:8]1[C:17]([CH2:18][OH:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: CCOC(=O)c1ccc2ncccc2c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2ncccc2c1Cl
Reaction time: 1 h
Yield: 95.1 %

Procedure:
Lithiumaluminiumhydride (1.66 g) was added portionwise to a solution of intermediate 1 (10.11 g) in tetrahydrofuran (325 ml) at 0° C. under N2 and the mixture was stirred for 1 hour. Ethylacetate (70 ml) and water (3 ml) were added to the mixture which was subsequently filtered. The filtrate was dried over MgSO4, filtered and evaporated, yielding 7.9 g (93%) 5-chloro-6-quinolinemethanol (intermediate 2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19]1.C(N(C(C)C)CC)(C)C.CN(C=O)C>CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:23]([C:20]4[CH:21]=[CH:22][S:18][CH:19]=4)(=[O:25])=[O:24])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=12
Reactant: Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Reactant: O=S(=O)(Cl)c1ccsc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ncnc2c1cnn2-c1ccc(NS(=O)(=O)c2ccsc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.6 %

Procedure:
Title compound 11A, 1-(4-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (39 mg, 1.0 eq, 0.17 mmol), 3-thiophenesulphonylchloride (31 mg, 1.0 eq, 0.17 mmol) and diisopropylethylamine (30 μl, 1.0 eq, 0.17 mmol) were added to DMF (1 ml) and the mixture was stirred for 18 hours at room temperature under an inert atmosphere. Methanol was then added (1 ml) and the solvents were removed in vacuo. The resultant residue was absorbed onto silica and purified by column chromatography using DCM/MeOH (96:4) as eluent to yield the title compound as a white solid (13 mg, 0.03 mmol, 20%). LCMS: [M+H]+=373, Rt=1.60 min, 100% purity.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9](Cl)=[O:10])[C:4]([N+:12]([O-:14])=[O:13])=[N:3]1.[CH3:15][NH2:16]>C1(C)C=CC=CC=1>[CH3:15][NH:16][C:9](=[O:10])[CH:8]=[CH:7][C:5]1[C:4]([N+:12]([O-:14])=[O:13])=[N:3][N:2]([CH3:1])[CH:6]=1
Reactant: CN
Reactant: Cn1cc(C=CC(=O)Cl)c([N+](=O)[O-])n1
Solvent: Cc1ccccc1
Product: CNC(=O)C=Cc1cn(C)nc1[N+](=O)[O-]

Procedure:
0.54 g. 3-(1-methyl-3-nitro-4-pyrazolyl)-acrylic acid chloride (preparation see Example 2) is dissolved in 20 ml. anhydrous toluene and, while stirring at 25° C., methylamine gas is passed in for about 10 minutes. The precipitated crystals are filtered off with suction, washed with toluene, triturated with water and dried in a vacuum. There is thus obtained 0.43 g. 3-(1-methyl-3-nitro-4-pyrazolyl)-acrylic acid N-methylamide; m.p. 200°-203° C.
Reaction SMILES: [CH3:1][C:2]1[N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:5]=[N:4][C:3]=1/[CH:26]=[CH:27]/[C:28]([C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1)=[O:29].C1C[O:43]CC1.[C:45]([OH:48])(=[O:47])[CH3:46]>O>[C:28]([OH:43])(=[O:29])/[CH:30]=[CH:46]\[C:45]([OH:48])=[O:47].[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1/[CH:26]=[CH:27]/[C:28]([C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1)=[O:29]
Reactant: Cc1c(/C=C/C(=O)c2cccc3ccccc23)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Reactant: CC(=O)O
Solvent: O
Product: Cc1[nH]cnc1/C=C/C(=O)c1cccc2ccccc12
Product: O=C(O)/C=C\C(=O)O

Procedure:
A solution of (E)-3-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-(1-naphthalenyl)-2-propen-1-one (1.0 g) in a mixture of water (10 ml), THF (10 ml) and acetic acid (10 ml) was heated at reflux under nitrogen for 1 h. The cooled reaction mixture was partitioned between ethyl acetate (100 ml; discarded) and 0.4N hydrochloric acid (2×75 ml). The combined acidic layers were basified with potassium carbonate (to pH8) and extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried and evaporated in vacuo to give the free base of the title compound (0.51 g) as a solid. This was dissolved in hot methanol (15 ml), and a solution of maleic acid (0.23 g) in methanol (2 ml) was added with stirring. Cooling precipitated the title compound (0.62 g), m.p. 170°-173° (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:9]=[CH:8]2.C(OC([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:33][CH2:32]1)=O)(C)(C)C.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC.O>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH2:37][CH:34]1[CH2:35][CH2:36][NH:31][CH2:32][CH2:33]1)[N:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:9]=[CH:8]2
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(O)cc21
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(OCC3CCNCC3)cc21
Temperature: 70 °C
Yield: 39.3 %

Procedure:
To a solution of 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-ol (0.06 g, 0.19 mmol) and 4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (0.08 g, 0.20 mmol) in DMF (3 mL) was added Nal (0.014 g, 0.009 mmol) and K2CO3 (0.08 g, 0.56 mmol). The reaction mixture was heated to 70° C. for 20 hours. The mixture was diluted with ether and water and the layers were separated. The aqueous layer was extracted with ether (2×) and the combined organic layers were washed with water and brine, and dried over Na2SO4. The crude mixture was concentrated under reduced pressure and purified by reverse phase HPLC. The desired fraction was concentrated to 0.037 g that was then treated with HCl (4N in dioxane) for 7 hours. The solvent was removed under reduced pressure and the final product was dried under high vacuum to obtain 0.031 g solid (37% yield). MS (APCI+) m/z 416(M+1) detected.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[Cl-].[NH4+]>C(O)C.O.[Zn]>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][OH:9])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Cl
Product: ONc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 124.2 %

Procedure:
In 21 mL of ethanol, 4.51 g (20 mmol) of 2-chloro-5-nitrobenzotrifluoride was dissolved, and a solution obtained by dissolving 3.8 g of zinc powder and 420 mg of ammonium chloride in 5 mL of water was added thereto, and the mixture solution was stirred at 70° C. for one hour. The reaction solution after removal of insolubles by filtration was concentrated, and the residue was partitioned between water and ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution. The organic layer was dried, and then concentrated under reduced pressure, and to the obtained residue, 30 mL of a 4N hydrogen chloride ethyl acetate solution was added, and the formed white precipitate was collected by filtration, washed with ethyl acetate and vacuum dried to obtain 3.08 g (63%) of N-(4-chloro-3-(trifluoromethyl)phenyl)hydroxylamine hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9]CCN(C)C)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:15]([N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)(N1C=CN=C1)=[O:16].O1CCOC[CH2:28]1>>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[NH:8][C:15](=[O:16])[N:22]([CH2:26][CH2:25][N:24]([CH3:23])[CH3:28])[CH2:9][C:4]=2[CH:3]=1
Reactant: C1COCCO1
Reactant: CN(C)CCCc1cc(Br)cnc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Product: CN(C)CCN1Cc2cc(Br)cnc2NC1=O
Yield: 50 %

Procedure:
A solution of 5-bromo-3-[(2-dimethylamino-ethyl)methyl]pyridin-2-ylamine (490 mg, 1.79 mmol) and 1,1′-carbonyldiimidazole (349 mg, 2.15 mmol) in 1,4-dioxane (15 mL) was heated to 80° C. for 14 h. TLC analysis indicated remaining starting material. After cooling, additional 1,1′-carbonyldiimidazole (349 mg, 2.15 mmol) and 1,4-dioxane (10 mL) were added, and the solution was heated to reflux overnight. The solvent was removed in vacuo. The residue was dissolved in CH2Cl2 (80 mL). The solution was washed with satd NaHCO3, water and brine, dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, CH2Cl2/MeOH/Et3N, 92:7:1) gave the title compound (270 mg, 50%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) 69.83 (s, 1H), 8.16 (d, J=2.1 Hz, 1H), 7.76 (s, 1H), 4.48 (s, 2H), 3.37 (t, J=6.5 Hz, 2H), 2.40 (t, J=6.5 Hz, 2H), 2.16 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1([C:9]([O:11]C)=[O:10])[C:4]([CH3:6])([CH3:5])[C:3]1([Cl:8])[Cl:7].S(=O)(=O)(O)O.O>C(O)=O>[Cl:1][C:2]1([C:9]([OH:11])=[O:10])[C:4]([CH3:6])([CH3:5])[C:3]1([Cl:8])[Cl:7]
Reactant: COC(=O)C1(Cl)C(C)(C)C1(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: O=CO
Solvent: O
Product: CC1(C)C(Cl)(Cl)C1(Cl)C(=O)O
Yield: 36.2 %

Procedure:
Methyl 1,2,2-trichloro-3,3-dimethylcyclopropanecarboxylate (10 g) was dissolved in formic acid (20 ml), and concentrated sulfuric acid (0.1 g) was added. The mixture was gently heated under reflux for 12 hours. After cooling, water (60 ml) was added to the reaction mixture. The precipitated crystals were collected by filtration, and recrystallized from hexane to give the desired 1,2,2-trichloro-3,3-dimethylcyclopropanecarboxylic acid (3.4 g) represented by the following formula. mp. 148°-150° C. ##STR25##
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](=O)[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19].[H-].[Na+].[H][H].[C:25]([O:31][CH2:32]Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>O>[CH3:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([O:20][CH2:32][O:31][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:19]
Reactant: [H][H]
Reactant: Cc1c(CC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1c(CC(=O)OCOC(=O)C(C)(C)C)cccc1Cc1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
A mixture of 3.37 g of the acid of Step A, 25 ml of hexamethylphosphortriamide and 0.57 g of a 50% suspension of sodium hydride in mineral oil stood until evolution of hydrogen ceased and then a solution of 1.78 g of chloromethyl pivalate in 10 ml of hexamethylphosphortriamide was progressively added thereto at room temperature. The mixture was stirred for 2 hours and was then poured into 250 ml of water. The mixture was extracted with isopropyl ether and the extracts were evaporated to dryness under reduced pressure. The residue was purified by chromatography over silica gel with a 95:5 mixture of methylene chloride-ethyl acetate as eluant. The fraction having Rf=0.65 was pivaloyloxymethyl 2-methyl-3-(p-chlorobenzoyl)-phenylacetate melting at 87°C.
Reaction SMILES: [CH2:1]([O:3][CH:4](OCC)[C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([F:17])[CH:8]=1)=O)[CH3:2].[NH2:21][NH:22][C:23]([NH2:25])=[S:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CI>C(O)C>[CH2:1]([O:3][CH:4]1[C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([F:17])[CH:8]=2)=[N:21][NH:22][C:23](=[S:24])[NH:25]1)[CH3:2]
Reactant: CCOC(OCC)C(=O)c1ccc(C(=O)OC)c(F)c1
Reactant: NNC(N)=S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Solvent: CI
Product: CCOC1NC(=S)NN=C1c1ccc(C(=O)OC)c(F)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
A mixture of methyl 4-(diethoxyacetyl)-2-fluorobenzoate (0.63 g, 0.0022 mol), thiosemicarbazide (0.24 g, 0.0026 mol), and p-toluenesulfonic acid monohydrate (20 mg) in ethanol (6 mL) was heated at 90° C. for 1.5 h. After cooling to RT, to the mixture was added methyl iodide (0.7 mL, 0.01 mol). The mixture was stirred at RT for 1 h. The mixture was concentrated. The residue was dissolved in acetic acid (4 mL), and heated at 60° C. for 2 h. After cooling, the reaction mixture was concentrated. The residue was treated with methanol. The formed precipitate was collected by filtration, and dried in-vacuo to afford the desired product (180 mg). Analytical LCMS: (M+H)+=280.0.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=O)[CH2:13][CH:12]1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl.C1(C)C=CC=CC=1.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[N:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:13][CH:12]1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC1CC(=O)c2ccccc2N1C(=O)OCc1ccccc1
Agent: [Ti+4]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1CC(=Nc2ccccc2)c2ccccc2N1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 141.7 %

Procedure:
To a solution of 2-Methyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (9 g), triethylamine (24.65 g), aniline (5.7 g) in dichloromethane (110 ml), cooled at −5° C. in an ice/sodium chloride bath, a solution of titanium chloride in toluene 1 mol/l was dropwise added for 10 minutes. The mixture was stirred over night at room temperature and then washed with dichloromethane and an aqueous solution of potassium carbonate. The organic layer was separated, dried over sodium sulfate and the solvent was removed under reduced pressure to give a brown oil (16 g) which was directly used in the next step.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[C:9]([N:11]3[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12]3)[N:8]=[C:7]([NH:18][C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=3)[CH:6]=2)[CH2:2]1.O1[CH2:34][CH2:33][O:32][CH2:31]C1.C(N(C(C)C)C(C)C)C.O1CC(=O)C1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:16][C:13]1([F:17])[CH2:14][CH2:15][N:11]([C:9]2[N:8]=[C:7]([NH:18][C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[CH:21][N:20]=3)[CH:6]=[C:5]([CH:3]3[CH2:2][N:1]([CH:34]4[CH2:31][O:32][CH2:33]4)[CH2:4]3)[CH:10]=2)[CH2:12]1
Reactant: C1COCCO1
Reactant: FC1(F)CCN(c2cc(C3CNC3)cc(Nc3cc(C(F)(F)F)ccn3)n2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C1COC1
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: FC1(F)CCN(c2cc(C3CN(C4COC4)C3)cc(Nc3cc(C(F)(F)F)ccn3)n2)C1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 3.3 %

Procedure:
To a solution of 4-(azetidin-3-yl)-6-(3,3-difluoropyrrolidin-1-yl)-N-[4-(trifluoromethyl)-2-pyridyl]pyridin-2-amine (1-d, 200 mg, 0.5008 mmol) in 1,4-dioxane (3.0 mL, 35 mmol) and N-ethyldiisopropylamine (0.26 mL, 3.0 equiv., 1.502 mmol) was added 3-oxetanone (219 mg, 6.0 equiv., 3.005 mmol), and the reaction was stirred at 50° C. for 1.5 h. After the reaction was cooled down, sodium triacetoxyborohydride (447 mg, 4.0 equiv., 2.003 mmol) was added in portions. The reaction was stirred at 25° C. overnight. The crude was submitted for HPLC purification to yield 7.5 mg (3.3%) white powder. 1H NMR (400 MHz, DMSO-d6) δ (delta) 9.91 (s, 1H), 8.70 (s, 1H), 8.44 (d, J=5.4 Hz, 1H), 7.14 (d, J=5.3 Hz, 1H), 6.62 (s, 1H), 6.00 (s, 1H), 4.58 (t, J=6.7 Hz, 2H), 4.41 (t, J=5.9 Hz, 2H), 3.85 (t, J=13.2 Hz, 2H), 3.75 (p, J=6.2 Hz, 1H), 3.63 (q, J=6.4, 6.0 Hz, 4H), 3.54 (p, J=7.7, 7.1 Hz, 1H), 3.20 (t, J=6.6 Hz, 2H), 2.58 (td, J=14.5, 7.3 Hz, 2H). LCMS: m/z 456 (M+H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)C=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].[CH:34]1(C(C2CCCCC2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)CCCCC1>>[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([CH2:34][C:8]3[CH:9]=[CH:10][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:4][CH:5]=3)[CH2:25]2)[CH2:21][CH2:20]1)=[O:17]
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccc(C(F)(F)F)cc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 4-(trifluoromethyl)benzaldehyde for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.62 (t, J=7.8, 1H), 7.64 (dd, J=7.0, 11.8, 4H), 7.51 (d, J=8.0, 1H), 7.46 (d, J=7.9, 1H), 7.33 (dd, J=7.4, 12.1, 2H), 7.29-7.24 (m, 1H), 4.40-4.30 (m, 1H), 3.58 (d, J=13.7, 0.5H), 3.48 (t, J=13.8, 1H), 3.35 (d, J=13.7, 0.5H), 3.23 (dd, J=1.4, 10.4, 1H), 2.92 (dd, J=2.7, 9.0, 0.5H), 2.69-2.60 (m, 1H), 2.57 (dd, J=2.7, 9.1, 1H), 2.54-2.47 (m, 0.5H), 2.47-2.39 (m, 1H), 2.39-2.32 (m, 0.5H), 2.31-2.20 (m, 2H), 2.19-2.11 (m, 1H), 1.95-1.82 (m, J=6.4, 37.0, 1H), 1.77 (dt, J=6.4, 13.8, 0.5H), 1.69 (dt, J=6.9, 19.1, 0.5H), 1.50-1.25 (m, J=34.6, 62.0, 1.5H), 1.21 (t, J=6.4, 3H), 0.70 (d, J=5.1, 3H); MS (ESI+) m/z 445 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:29][C:30]1[CH:31]=[C:32]([CH:49]=[CH:50][CH:51]=1)[O:33][C:34]1[CH:35]=[CH:36][C:37]2[N:38]([CH:40]=[C:41]([NH:43][C:44]([CH:46]3[CH2:48][CH2:47]3)=[O:45])[N:42]=2)[N:39]=1>CN(C)C=O.CN1CCCC1=O>[C:1]([C:3]1([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:29][C:30]2[CH:51]=[CH:50][CH:49]=[C:32]([O:33][C:34]3[CH:35]=[CH:36][C:37]4[N:38]([CH:40]=[C:41]([NH:43][C:44]([CH:46]5[CH2:47][CH2:48]5)=[O:45])[N:42]=4)[N:39]=3)[CH:31]=2)=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1)#[N:2]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: N#CC1(c2cccc(C(=O)O)c2)CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C6CC6)cn5n4)c3)c2)CCCCC1
Yield: 77.9 %

Procedure:
Using 3-(1-cyanocyclohexyl)benzoic acid (100 mg, 0.45 mmol), oxalyl chloride (48 μL, 0.56 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (120 mg, 0.37 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (150 mg, 78%) was obtained as a white powder.