Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:20][C:21](=[CH2:23])[CH3:22]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:5]
Reactant: C=C(C)C
Reactant: COC(=O)c1ccc(C(=O)O)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)OC(C)(C)C)c(Cl)c1
Temperature: -78 °C

Procedure:
To 24.9 g of 2-chloro-4-(methoxycarbonyl)benzoic acid and 2 mL of Sulfuric Acid in 350 mL of DCM was added isobutylene gas at −78° C. until the solvent was saturated and capped off securely. Let go several days at room temperature and re-cool to −78° C. before removing cap. Concentrate solvent, extract with Ethyl Acetate and bicarbonate, dry with Magnesium Sulfate, filter and concentrate to give 31.4 g of 1-tert-butyl 4-methyl 2-chloroterephthalate. 3.35 g of 1-tert-butyl 4-methyl 2-chloroterephthalate was hydrolyzed via Procedure M. 2.5 g of 4-(tert-butoxycarbonyl)-3-chlorobenzoic acid was cooled to 0° C. in 25 mL of THF before a solution of 19.5 mL of 1M BH3-THF complex in THF was added dropwise. The ice bath was subsequently removed and the reaction was stirred at room temperature until reaction stalled out at ˜50% complete by TLC. The reaction is re-cooled to 0° C. and another 19.5 mL of BH3-THF is added dropwise before the ice bath is removed. Upon completion, the reaction is re-cooled to 0° C. and quenched with 3N HCl dropwise. The aqueous layer was extracted two times with Ethyl Acetate and the organic layer was then extracted once with bicarbonate solution and brine, dried over Magnesium Sulfate, filtered and concentrated to give tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 564 mg of tert-butyl 2-chloro-4-(hydroxymethyl)benzoate was cooled to 0° C. in 5 mL of DCM before adding 665 mg of Triphenylphosphine and 417 mg of NBS. Reaction was concentrated and directly purified via ISCO Combi-Flash to give pure tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 147 mg of tert-butyl 4-(bromomethyl)-2-chlorobenzoate was reacted with 2,2,2-trifluoroethanamine in DMSO via Procedure P. 141 mg of tert-butyl 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoate was treated with 4N HCl in Dioxane at 45° C. and concentrated to give 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 75 mg of 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to give pure 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2,2,2-trifluoroethylamino)methyl)benzamide. MS (Q1) 454.6 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15]O)=[CH:13][CH:12]=1)[CH3:10].CS(O)(=O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([CH2:9][CH3:10])=[CH:12][CH:13]=2)[CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CCc1ccc(CO)cc1
Agent: CS(=O)(=O)O
Product: CCc1ccc(Cc2cc(Cl)ccc2O)cc1
Temperature: 160 °C
Reaction time: 0.42 h
Yield: 46.2 %

Procedure:
A mixture of 4-chlorophenol (2.0 g, 15.6 mmol), 4-ethylbenzylalcohol (2.12 g, 15.6 mmol) and methanesulfonic acid (80 mg, 0.83 mmol) was heated and stirred at 160° C. for 25 minutes. The reaction mixture was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 4-chloro-2-(4-ethylbenzyl)phenol (1.78 g, 46%) as a light-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[OH-].[K+].[CH3:14][C:15]([CH3:17])=O>>[CH3:17][C:15]1[CH:14]=[CH:8][C:7]2[CH:6]=[N:5][C:4]([S:10][CH3:11])=[N:3][C:2]=2[N:1]=1
Reactant: CC(C)=O
Reactant: CSc1ncc(C=O)c(N)n1
Agent: [K+]
Agent: [OH-]
Product: CSc1ncc2ccc(C)nc2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Treat a solution of 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde (10 g, 59.1 mmol) in acetone (100 mL) with KOH (3.32 g, 59.1 mmol), stir at RT for 10 min, then concentrate to dryness. Treat the residue with EtOAc, wash with saturated. aqueous NaHCO3, then brine, dry over Na2SO4 and concentrate to obtain 7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidine. MS (m/z): 192.1 (M+1). Add a solution of methylamine in ethanol (33%, 80 mL) and heat at 110° C. overnight in a pressure tube. Remove the solvent under reduced pressure and purify the crude product by silica gel chromatography (50-100% EtOAc/Hexanes) to obtain the title compound (6.73 g, 65%, over two steps). MS (m/z): 175.1 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[C:5]([N+:10]([O-])=O)[C:4]=1[CH3:13]>C1COCC1.[H][H].[Ni]>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:14])[CH3:1])=[C:4]([CH3:13])[C:5]=1[NH2:10]
Reactant: Cc1c(N(C)C)ccc(Br)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1c(N(C)C)ccc(Br)c1N
Yield: 90.5 %

Procedure:
15 g of N,N-dimethyl-4-bromo-2-methyl-3-nitroaniline is dissolved in about 200 ml of THF and hydrogenated at 20° C. under 5bars pressure of hydrogen using Raney nickel as catalyst. 12 g of 2-bromo-5-dimethylamino-6-methylaniline is obtained as a brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[C:5]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])=[CH:17][C:16]=2[C:30]#[N:31])=[CH:4][CH:3]=1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:30]([C:16]1[CH:17]=[C:18]([S:21]([NH:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)(=[O:23])=[O:22])[CH:19]=[CH:20][C:15]=1[O:14][C:5]1[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[N:7][C:2]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([F:32])[CH:38]=2)=[CH:3][CH:4]=1)#[N:31]
Reactant: OB(O)c1cccc(F)c1
Reactant: Cn1cc(-c2nc(Cl)ccc2Oc2ccc(S(=O)(=O)Nc3nccs3)cc2C#N)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2nc(-c3cccc(F)c3)ccc2Oc2ccc(S(=O)(=O)Nc3nccs3)cc2C#N)cn1
Reaction time: 0.17 h
Yield: 46.9 %

Procedure:
10 mg (0.02 mmol) of 4-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)-3-cyano-N-(thiazol-2-yl)benzenesulfonamide was dissolved in 3 mL of N,N-dimethylformamide, and 4.4 mg (0.03 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 2.4 mg (10 mol %) of Pd(PPh3)4, 6.7 mg (0.63 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (45% yield) of the title compound.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[CH:15][C:16](=O)[NH:17][N:18]=1>CN(C)C=O>[Cl:3][C:16]1[N:17]=[N:18][C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[OH:6])=[CH:14][CH:15]=1
Reactant: O=c1ccc(-c2ccccc2O)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Oc1ccccc1-c1ccc(Cl)nn1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 96 %

Procedure:
Dimethylformamide (85 ml.) was cooled to 5° and phosphorus oxychloride (115 ml.) was added slowly to maintain a solution temperature below 60°. 6-(2-Hydroxyphenyl)-3(2H)-pyridazinone (30 g., 0.16 m.) was added rapidly in several portions. The reaction mixture was heated to 85° and held at this temperature for 4.5 hours with stirring. The mixture was then cooled to 35° and poured into 1 liter of ice cold water keeping the quenched solution below 35°. The resulting precipitate was filtered off, washed with water and dried to give 30.8 g. (96% yield) of crude 3-chloro-6-(2-hydroxyphenyl)pyridazine.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Si](C)(C)C)[C:3]=1[CH:4]=[O:5].[Br:14]Br.C(=O)([O-])O.[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:14][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=1
Reactant: C[Si](C)(C)c1cccc(O)c1C=O
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1c(O)cccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-hydroxy-6-trimethylsilylbenzaldehyde (8.1 g) in carbon tetrachloride (160 ml) was added bromine (2.15 ml) dropwise at 0° C., and the mixture was stirred at room temperature overnight. To the mixture was added aqueous sodium hydrogencarbonate solution, and the layers were separated. The aqueous layer was extracted with dichloromethane and the organic layers were combined, washed with sodium thiosulfate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane and toluene (4:1) to afford 6-bromo-2-hydroxybenzaldehyde (4.74 g).
Reaction SMILES: [C:1]([C:4]([C:13]1[CH:24]=[CH:23][C:16]2[N:17]([CH3:22])[C:18](=[O:21])[N:19]([CH3:20])[C:15]=2[CH:14]=1)=[CH:5][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)(=O)[CH3:2].C1(C)C=CC(S([NH:34][NH2:35])(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:22][N:17]1[C:16]2[CH:23]=[CH:24][C:13]([C:4]3[C:1]([CH3:2])=[N:34][NH:35][C:5]=3[C:6]3[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=3)=[CH:14][C:15]=2[N:19]([CH3:20])[C:18]1=[O:21]
Reactant: CC(=O)C(=Cc1cccc(C)c1)c1ccc2c(c1)n(C)c(=O)n2C
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cccc(-c2[nH]nc(C)c2-c2ccc3c(c2)n(C)c(=O)n3C)c1
Temperature: 115 °C
Yield: 23.7 %

Procedure:
5-(1-Acetyl-2-m-tolyl-vinyl)-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (1.07 g) in acetic acid (5 mL) was treated with p-toluenesulfonhydrazide (0.685 g). The reaction mixture was heated to 115° C. for 5 hours. Additional p-toluenesulfonhydrazide (0.601 g) was added and the reaction was heated for an additional 4 hours. The mixture was then allowed to cool, was poured onto saturated sodium bicarbonate and extracted into ethyl acetate. Chromatography on silica gel afforded 1,3-Dimethyl-5-(3-methyl-5-m-tolyl-1H-pyrazol-4-yl)-1,3-dihydro-benzoimidazol-2-one (0.263 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[CH2:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:26]2[CH:25]=[C:24]([C:23]3[CH2:22][C:21](=[O:37])[NH:20][C:9]4[CH:10]=[C:11]([C:16]([F:17])([F:18])[F:19])[C:12]([CH:14]=[CH2:15])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)[CH:31]=1
Reactant: C=Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-5-vinyl-phenyl}-carbamic acid tert-butyl ester (Example M194) (273 mg, 0.52 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (127 mg, 60%).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][N:6]=1)=[O:4].[Mg+2].[Cl-].[Cl-].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.Cl>C1COCC1.C(OCC)(=O)C>[Cl:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:3]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:4])[CH:10]=1
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: C1CCNC1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1cc(Cl)ccn1)N1CCCC1
Reaction time: 0.08 h

Procedure:
4-Chloro-pyridine-2-carboxylic acid methylester (200 mg, 1.17 mmol) and MgCl2 (555 mg, 0.58 mmol) are suspended in THF (5 mL) at rt. The mixture is stirred for 5 min and then pyrrolidine (193 μL, 2.33 mmol) is added and the mixture stirred for an additional 15 min. It is worked up by addition of aqueous HCl solution (1M, 1.2 mL) and extraction with ethyl acetate. The combined organic extracts are washed with brine dried over MgSO4. The volatiles are removed under reduced pressure to give the title compound as a yellow oil: C10H11ClN2O: M+=211.3; 1H-NMR (DMSO-d6): 8.55 (d, 1H), 7.82 (s, 1H), 7.59 (d, 1H), 3.62-3.42 (m, 4H), 1.93-1.75 (m, 4H).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>C(Cl)Cl>[CH2:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[C:19](=[O:22])[CH:20]=[CH2:21])[CH:2]=[CH2:3]
Reactant: C=CCNc1ccc(OC)cc1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C=CCN(C(=O)C=C)c1ccc(OC)cc1
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
To a solution of N-allyl-4-methoxyaniline (1.00 g, 6.13 mmol) in methylene chloride (20 mL) was added K2CO3 (2.12 mg, 15.3 mmol) and acryloyl chloride (548 μL, 6.74 mmol) at 0° C. After 15 min., the reaction was quenched with NaHCO3 (5 mL, sat. aq.) and the organic layer was isolated, concentrated and subjected to flash chromatography (Hexanes:EtOAc 4:1) to yield N-allyl-N-(4-methoxyphenyl)acrylamide (1.29 mg, 97%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)([Cl:16])=O>CN(C=O)C.ClC1C=CC=CC=1>[Cl:16][C:9]([C:8]1[CH:12]=[CH:13][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1)=[O:10]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Solvent: Clc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 4-acetoxybenzoic acid (200 mg, 1.11 mmol), thionyl chloride(1.6 mL), 1 drop of DMF, and 7.5 mL of chlorobenzene was heated to 80° C. for 1.5 hrs. The reaction was then cooled to room temperature and the solvent and excess thionyl chloride were removed in vacuo. Theoretical yield of the title compound was assumed and the residue was used as is.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[OH-].[K+].[CH2:12]1[O:14][CH2:13]1>>[C:1]([O:9][CH2:12][CH2:13][OH:14])(=[O:8])[CH2:2][CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: C1CO1
Reactant: CC(C)(C)CCC(=O)O
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)CCC(=O)OCCO
Temperature: 25 °C

Procedure:
To a 1 liter glass flask is added one mole of neoheptanoic acid and 1 gm of potassium hydroxide (solid), to provide the base catalyst for the subsequent ethoxylation reaction. Gaseous nitrogen is introduced to purge oxygen from the flask. A conventional bubbler device provided with NUJOL® oil is provided in the nitrogen gas feed line to the reaction flask. Gases discharged from the reaction flask are passed through a second such bubbler device. With continuous nitrogen flow through the flask, the temperature of the neo-acid/base mixture is raised to 150° C. at a rate of about 10° C./min. by means of a heating mantle. Thereafter, gaseous nitrogen flow is stopped and is replaced with gaseous ethylene oxide which is permitted to bubble through the neo-acid mixture. Periodic withdrawal of samples of the reaction mixture are made which are titrated to determine the level of residual neo-acid. The addition of ethylene oxide is controlled such that substantially all of the ethylene oxide introduced is reacted, thereby avoiding gaseous throughput through the gas withdrawal line of the reaction vessel. The adsorption of the ethylene oxide is also controlled such that there is no substantial rise in temperature of the reaction vessel due to any reaction exotherm. When it is determined that the proper amount of ethylene oxide has been added (via titration, as described above), the flow of ethylene oxide is terminated, and the reaction vessel is again purged with gaseous nitrogen and allowed to cool to room temperature. (An excess of ethylene oxide should be avoided). The crude product is then washed with water until the washwater is determined to be neutral. The monoethyoxylate thereby obtained is distilled at a pressure of 100 mmHg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:40]([O:47][CH2:48][C@@H:49]([NH:66][CH3:67])[C:50]([N:52]([CH3:65])[C@@H:53]([C:61](=[O:64])[NH:62][CH3:63])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:51])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:66]([C@@H:49]([C:50](=[O:51])[N:52]([CH3:65])[C@@H:53]([C:61](=[O:64])[NH:62][CH3:63])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH2:48][O:47][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH3:67])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](COCc1ccccc1)NC
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](COCc1ccccc1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.7 %

Procedure:
(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.12 g; 0.49 mmol) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.07 g; 0.49 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.1 g; 0.51 mmol) were added and the reaction mixture was stirred for 15 min at room temperature. (2R)-3-Benzyloxy-N-methyl-2-(methyl-amino)-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-propionamide (0.17 g; 0.44 mmol) and diisopropylethylamine (0.084 mL; 0.49 mmol) were added and the reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was extracted with an aqueous solution of sodium hydrogen carbonate (saturated; 30 mL) and an aqueous solution of sodium hydrogen sulfate (10%; 30 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (2.5×30 cm) using methylene chloride/ethyl acetate (1:1) as eluent to afford 0.275 g of ((3E)-4-(N-((1R)-2-benzyloxy-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([C:28]([O:30][CH3:31])=[O:29])[C@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[N:11]([C:22](Cl)=[O:23])[C@@H:10]([CH:25]2[CH2:27][CH2:26]2)[CH2:9]1.[F:41][C:42]([F:46])([F:45])[CH2:43][OH:44]>>[F:41][C:42]([F:46])([F:45])[CH2:43][O:44][C:22]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C@H:8]([N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:40])([F:39])[F:1])[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=2)[C:28]([O:30][CH3:31])=[O:29])[CH2:9][C@@H:10]1[CH:25]1[CH2:26][CH2:27]1)=[O:23]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)N(C(=O)Cl)c2ccc(C(F)(F)F)cc21
Reactant: OCC(F)(F)F
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)N(C(=O)OCC(F)(F)F)c2ccc(C(F)(F)F)cc21
Reaction time: 1 h
Yield: 77 %

Procedure:
A solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carbonyl chloride (Example 102B) (20 mg) in 2,2,2-trifluoroethanol (5 mL) was heated to reflux. After 1 h, the reaction was cooled and concentrated, and the residue was chromatographed (5-10% EtOAc/hexane) to afford the title product (22 mg, 77%). MS m/z 685 (M++19); 1H NMR (CDCl3) δ 3.82 (s, 3H), 7.17 (C5, s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]([CH3:37])[C:22]([C:28]1[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=1)([OH:27])[C:23]([F:26])([F:25])[F:24])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1.Cl([O-])=[O:39].[Na+].Cl>C(O)(C)(C)C.CC(=CC)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]([CH3:37])[C:22]([C:28]1[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=1)([OH:27])[C:23]([F:25])([F:26])[F:24])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:39])=[O:11])=[C:8]([C:14]([F:17])([F:15])[F:16])[CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C=O)c(C(F)(F)F)c3)cc2Cl)C(F)(F)F)cn(C)c1=O
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C(=O)O)c(C(F)(F)F)c3)cc2Cl)C(F)(F)F)cn(C)c1=O
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 96.2 %

Procedure:
To a solution of 4-{3-chloro-4-[2-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-2-trifluoromethyl-benzaldehyde (105 mg) in tert.-butanol (1 ml) and 2-methyl-2-butene (0.12 ml) was added a solution of sodium chlorite (28 mg) and sodiumdihydrogenphosphate-dihydrate (34 mg) in water (0.8 ml) at 0° C. The mixture was stirred for 10 minutes at 0° C. and for 4.5 h at room temperature. The mixture was acidified with 1 M aqueous HCl and extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated to give the title compound (104 mg) as a colorless solid. MS (m/e, ISP neg. ion)=562.1 [M−H+].
Reaction SMILES: C(O[C:4]([C:6]1[C:18](=[O:19])[N:14]2[CH2:15][CH2:16][O:17][C:12]3[C:13]2=[C:8]([CH:9]=[CH:10][CH:11]=3)[C:7]=1[OH:20])=[O:5])C.[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[OH:20][C:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:13]=2[N:14]([CH2:15][CH2:16][O:17]3)[C:18](=[O:19])[C:6]=1[C:4](=[O:5])[N:22]([CH3:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1c(O)c2cccc3c2n(c1=O)CCO3
Reactant: CNc1ccccc1
Solvent: c1ccncc1
Product: CN(C(=O)c1c(O)c2cccc3c2n(c1=O)CCO3)c1ccccc1
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 2,3-dihydro-6-ethoxycarbonyl-7-hydroxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (6 g) and N-methylaniline (4 ml) in pyridine (30 ml) was stirred at 125° C. for 4 hours. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (200 g) eluting with a mixture of chloroform and methanol (5:1). The product was recrystallized from a mixture of ethanol and isopropyl ether to give pale brown crystals of 2,3-dihydro-7-hydroxy-6-(N-methyl-N-phenylcarbamoyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (1.7 g).
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[CH:23]=[CH:24]/[C:25](O)=[O:26]>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:25](=[O:26])/[CH:24]=[CH:23]/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([F:28])([F:29])[F:15])=[N:8]1
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Product: CC(F)(F)CCCCn1ccc(NC(=O)/C=C/c2ccccc2C(F)(F)F)n1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and (E)-3-(2-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.15 min; [M+H]+=402.04.