Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1)=[O:7])#[N:4].[H-].[CH3:15][N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21](Cl)=[O:22].Cl>COCCOC.O.CN(C)C=O>[O:22]=[C:21]([C:17]1[N:16]([CH3:15])[CH:20]=[CH:19][CH:18]=1)[CH:5]([C:6](=[O:7])[NH:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1)[C:3]#[N:4]
Reactant: N#CCC(=O)Nc1nccs1
Reactant: Cn1cccc1C(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1nccs1
Reaction time: 8 h

Procedure:
To the suspension of 2.1 g of 50% NaH mineral oil (washed with petroleum ether) in 25 ml of 1,2-dimethoxyethane and 15 ml of dimethylformamide was added 6.7 g of 2-(cyanoacetylamino)thiazole. After the moderately exothermic, effervescent reaction of the hydride, there was added (swirling) a solution of N-methyl-2-pyrroloyl chloride (prepared from 2.5 g of the acid) in 20 ml of 1,2-dimethoxyethane. The dark suspension resulting from the exothermic reaction was let stand overnight. After treatment with ca. 300 ml water, the filtered aqueous solution was acidified with 6 ml of 6 N HCl. The crude product was collected, redissolved in NaHCO3 solution, and the filtered solution carefully acidified with 6 N HCl. The product was collected, washed with water, dried, and triturated with methanol to give crystals, m.p. 201°-2° dec. Recrystallization from dimethylformamide-methanol gave β-oxo-α-(2-thiazolylcarbamoyl)-β-(1-methyl-2-pyrrolyl)propionitrile, m.p. 208°-9° dec.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([CH3:14])[N:11](CCC(=O)C)[C@H:10]([CH3:20])[CH2:9]1)=O)(C)(C)C.[Cl:21]C1C=CC=C(C(OO)=[O:29])C=1>C(Cl)(Cl)Cl>[ClH:21].[CH3:14][C@H:12]1[CH2:13][NH:8][CH2:9][C@@H:10]([CH3:20])[N:11]1[OH:29]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)CCN1[C@H](C)CN(C(=O)OC(C)(C)C)C[C@@H]1C
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CNC[C@H](C)N1O
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.5 %

Procedure:
Cis-3,5-Dimethyl-4-(3-oxo-butyl)-piperazine-1-carboxylic acid tert-butyl ester (1.00 g) in chloroform (40 mL) was treated with m-chloroperbenzoic acid (77%, 0.97 g) at 0° C. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was then cooled to 0° C., filtered to remove precipitates, washed with saturated aqueous sodium bicarbonate, filtered through a plug of silica gel and concentrated. The residue was taken up in a 1:1 mixture of DCM and MeOH and treated with an excess of 4.0 M HCl/dioxane. The reaction mixture was stirred overnight and then purified by column chromatography (0 to 10% MeOH:DCM) to yield 50 mg of the title compound. ESMS (0.41 minutes, (M+1) 131.13, Method E).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[N:13]=[C:12]([CH2:18][C:19](=O)[CH3:20])[N:11]=1.Cl.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30]N)=[CH:26][CH:25]=1.C(OCC)(=O)C>[Cl-].[Zn+2].[Cl-].O>[Cl:23][C:24]1[CH:29]=[C:28]2[C:27](=[CH:26][CH:25]=1)[NH:30][C:19]([CH3:20])=[C:18]2[C:12]1[N:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:10]([O:9][CH3:8])[N:11]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: COc1cc(OC)nc(CC(C)=O)n1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(OC)nc(-c2c(C)[nH]c3ccc(Cl)cc23)n1
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To 80 ml of toluene were added 8.0 g (40 m moles) of 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone and 7.9 g (44 m moles) of 4-chlorophenylhydrazine hydrochloride. Thereto was added 6.54 g (48 m moles) of zinc chloride. Refluxing was made for 2 hours with heating. The reaction mixture was allowed to cool. Then, ethyl acetate and water were added to dissolve the whole reaction mixture. The organic layer was washed with water, separated, and dried over Glauber's salt. The resulting organic layer was concentrated under reduced pressure using a rotary evaporator to obtain an orange solid. The solid was washed with isopropyl ether to obtain 10.2 g (33.7 m moles) of 5-chloro-3-(4,6-dimethoxypyrimidine-2-yl)-2-methylindole. Yield: 84% Melting point: 179 to 181° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br)[CH3:2].C[C:14]1([C:20]([O-:22])=[O:21])[CH2:18][CH2:17][CH2:16][C:15]1=[O:19].[C:23](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:14]1([C:20]([O:22][CH3:23])=[O:21])[C:15](=[O:19])[CH2:16][CH2:17][CH2:18]1)[CH3:2]
Reactant: CC1(C(=O)[O-])CCCC1=O
Reactant: CCOC(=O)CCCCCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCCCCC1(C(=O)OC)CCCC1=O
Yield: 12 %

Procedure:
A mixture of 10 g. of ethyl-7-bromoheptanoate and 5.9 g. of methyl-2-oxocyclopentylcarboxylate was refluxed for 20 hours in 100 ml. of dry acetone over 13 g. of anhydrous potassium carbonate in a nitrogen atmosphere. After cooling, the reaction mixture was filtered and the solvent removed at the rotovap. The residual oil was distilled on the Kugelrohr apparatus, with some unreacted bromoheptanoate first collected at 80° C., followed by distillation of product at 140° C. A total of 10.9 g. of product was obtained, with about 12-15% O-alkylated material.
Reaction SMILES: [I:1]I.[CH3:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14]>S(=O)(=O)(O)O>[I:1][C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[C:4]=1[CH3:3])[C:8]([OH:10])=[O:9]
Reactant: II
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: Cc1c(I)cc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 85 °C
Yield: 94.8 %

Procedure:
To a mixture of iodine (19.6 g, 77.3 mmol) in fuming sulfuric acid (35 mL) was added 4-methyl-3-nitro-benzoic acid (10.0 g, 55.2 mmol). The mixture was stirred at 85° C. over night, then cooled to room temperature and poured over ice. The mixture was partitioned between ethyl acetate and aqueous sodium bisulfite, and the organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to give 16.06 g (95%) of 3-iodo-4-methyl-5-nitro-benzoic acid.
Reaction SMILES: [CH:1]1([C:7]([N:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=3[O:27][CH3:28])[CH2:14][CH2:13]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.O.NN>[Ni+2].CO>[CH:1]1([C:7]([N:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[O:27][CH3:28])[CH2:14][CH2:13]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc([N+](=O)[O-])ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccn2)CC1
Agent: [Ni+2]
Agent: NN
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N)ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A mixture consisting of 1.70 g of compound of Example 5, 18 mL of tetrahydrofurane, 18 mL of methanol, 50 mg of Nichel-Raney and 1 mL of hydrazine hydrate was stirred for 2 h, at room temperature, followed by the addition of 1 mL of hydrazine hydrate, and stirred for 1 h, at a temperature of 50° C. The catalyst was then filtered out, and the recovered solution was evaporated to dryness, affording the crude product, which was then purified by flash chromatography (ethyl acetate—3 N solution of ammonia, in methanol; 95:5). Subsequent evaporation of the solvents afforded 1.33 g of the title compound (yield 84%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[O:14][CH3:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].CN(C)C=O.[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>O.C(OCC)(=O)C>[Cl:27][CH2:26][CH2:25][CH2:24][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]([O:14][CH3:15])=[C:5]1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1[nH]c2ccccc2c1OC
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(OC)c2ccccc2n1CCCCl
Temperature: 0 °C

Procedure:
20.5 g. of 2-methoxy carbonyl-3-methoxy indole are dissolved in 100 ml. of dimethyl formamide. 3 g. of 80% sodium hydride are added portion by portion thereto at 0° C., while stirring. After heating the mixture to room temperature, 20 g. of 1-bromo-3-chloro propane are added thereto. The reaction mixture is heated to 80° C. for 12 hours whereupon the solvent is drawn off. The reaction mixture is worked up in the usual manner by means of ethyl acetate and water. The resulting crude reaction product is subjected to a distillation in a tubular distillation apparatus with bulbar enlargements. 24.7 g. of 1-(γ-chloro propyl)-2-methoxy carbonyl-3-methoxy indole are obtained in the form of an oil. Said compound is dissolved in 100 ml. of dimethyl formamide. The solution is then heated with 20 g. of diethylamine to 60° C. for 5 hours. After drawing off the solvent and adding 10% hydrochloric acid to the residue, the mixture is extracted with ethyl acetate. Thereupon the aqueous phase is rendered alkaline by the addition of a sodium carbonate solution and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered, and the filtrate is evaporated to dryness under reduced pressure. 25.8 g. of 1-(γ-diethyl amino propyl)-2-methoxy carbonyl-3-methoxy indole are obtained as an oily residue. The yield is 81% of the theoretical yield. Said compound can be converted into its crystalline maleinate with a melting point of 110°-112° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C@@:6]1([C:26]([OH:28])=[O:27])[C@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:25])[C:22]([OH:24])=[O:23].[CH3:29]O>>[ClH:3].[CH3:29][O:23][C:22]([C@:8]1([F:25])[C@@H:7]2[C@H:9]1[CH2:10][C@@H:11]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[C@@:6]2([NH2:5])[C:26]([OH:28])=[O:27])=[O:24]
Reactant: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)O
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)[C@@]1(F)[C@@H]2C[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](N)(C(=O)O)[C@@H]21
Product: Cl
Temperature: 50 °C
Reaction time: 4 h

Procedure:
0.65 mL of thionyl chloride was added to 800 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid suspended in 8 mL of methanol at ice-cooling, and the mixture was stirred for 4 hours at 50° C. The mixture was further stirred for 3 hours at room temperature, and methanol was distilled under reduced pressure. After 20 mL of hexane was added to the residue, the mixture was stirred for 2 hours, and then the solids were filtured. The solids were washed with diisopropyl ether and hexane, thereby yielding 820 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-methyl ester hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](N)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:12].N([O-])=O.[Na+].NC(N)=O>O>[Cl:1][C:2]1[CH:9]=[C:8]([OH:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(N)cc1Cl
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(O)cc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
A mixture of 2-chloro-4-aminobenzonitrile (25 g, 0.187 m) in stirred concentrated sulfuric acid (58 g) and water (570 ml) was heated at between 49° and 61° C. for approximately thirty minutes. The suspension was cooled to approximately 0° C. and a cold solution of sodium nitrite (13.2 g, 0.187 m) in water (125 ml) was added dropwise at a solution temperature of between 0° and 6° C. Stirring continued thereafter for approximately three hours and then urea (1.5 g) was added to the mixture. The resulting insoluble impurity was filtered off. An aqueous solution of 50% sulfuric acid (600 ml) was added while the reaction mixture was heated at a temperature between 74° and 81° C. and stirred until the evolution of nitrogen gas ceased. The reaction product was separated by filtration and then recrystallized from water to yield 2-chloro-4-hydroxybenzonitrile (17.9 g, 62.5%, mp 160° C.).
Reaction SMILES: P(Cl)(Cl)Cl.[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)N=C[N:13]=2)=[CH:8][CH:7]=1.[C:24]([CH2:26][C:27]([OH:29])=O)#[N:25].[C:30](#[N:32])C>C(N(CC)CC)C>[C:24]([CH2:26][C:27]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH:30]=[N:32][N:13]=2)=[CH:10][CH:11]=1)=[O:29])#[N:25]
Reactant: N#CCC(=O)O
Reactant: CC#N
Reactant: Nc1ccc(-c2ncnn2-c2ccc(F)cc2)cc1
Solvent: ClP(Cl)Cl
Solvent: CCN(CC)CC
Product: N#CCC(=O)Nc1ccc(-c2nncn2-c2ccc(F)cc2)cc1
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
A solution of 3.5 ml. of phosphorus trichloride in 25 ml. of acetonitrile is added dropwise to a stirred suspension of 19.0 g. of 5-(p-aminophenyl)-1-(p-fluorophenyl)-1H-1,2,4-triazole in a mixture of 15.6 ml. of triethylamine, 6.35 g. of cyanoacetic acid and 200 ml. of acetonitrile at room temperature over a period of one hour. The mixture is heated to boiling, giving a clear solution and kept at 90° C. for 2.5 hours. The suspension is filtered hot through diatomaceous earth. The filtrate is heated to boiling, 250 ml. of hot water is added and the solution is slowly cooled to 5° C. A 400 ml. portion of water is added and the solid is collected and recrystallized from ethanol giving the desired product as 19.0 g. of cream crystals, mp. 223°-225° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[C:29]4[CH:28]=[CH:27][C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:25][C:24]=4[C:8]4[CH:9]=[C:10]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH:11]=[C:12]([C:13]([CH3:17])([CH3:16])[C:14]=2[CH:15]=1)[C:7]3=4.C([Li])CCC.[B:41]([O:46]C)(OC)[O:42]C>C1COCC1.C1CCCCC1>[CH3:16][C:13]1([CH3:17])[C:12]2[C:7]3=[C:8]([C:24]4[CH:25]=[C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:27]=[CH:28][C:29]=4[N:6]3[C:5]3[CH:4]=[CH:3][C:2]([B:41]([OH:46])[OH:42])=[CH:15][C:14]1=3)[CH:9]=[C:10]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:11]=2
Reactant: CC1(C)c2cc(Br)ccc2-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)cc1c32
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC1(C)c2cc(B(O)O)ccc2-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)cc1c32
Temperature: 25 °C

Procedure:
133 g (259 mmol) of 10-bromo-8,8-dimethyl-3,6-diphenyl-8H-indolo-[3,2,1-de]acridine are dissolved in 1500 ml of dry THF, 135 ml (337 mmol) of a 2.5 M solution of n-butyllithium in cyclohexane are added dropwise at −70° C., after 1 h 37 ml of trimethyl borate (336 mmol) are added dropwise, the mixture is warmed to room temperature over the course of 1 h, the solvent is removed, and the residue, which is uniform according to 1H-NMR, is employed in the subsequent reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH:13]=[CH2:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:15]([Zn]CC)C.FC(F)(F)C(O)=O.C(I)I>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH:13]2[CH2:15][CH2:14]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: C=COc1ccc(Cl)cc1C(=O)OC
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)ccc1OC1CC1
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To a solution of methyl 5-chloro-2-(vinyloxy)benzoate in 100 mL dichloromethane was added diethylzinc (1 M hexanes solution) (200 mL, 0.2 mol) under N2 atmosphere. The solution was cooled in an ice bath and a solution of trifluoroacetic acid (16 mL) in dichloromethane (100 mL) was dropped very slowly into the mixture. After stirring for 20 minutes, a solution of CH2I2 (16.4 mL, 0.2 mol) in dichloromethane (100 mL) was added dropwise. After stirring an additional 20 minutes, a solution of methyl 5-chloro-2-(vinyloxy)benzoate (21.3 g, 0.1 mol) in dichloromethane (100 mL) was added and the ice bath was removed. 8 hours later, the mixture was quenched with saturated NH4Cl solution and extracted twice with dichloromethane. The combined organics were dried over Na2SO4, filtered and evaporated to dryness to afford 21 g (92%) of methyl 5-chloro-2-cyclopropoxybenzoate. 1H NMR (400 MHz, CDCl3) δ: 7.75 (d, 1H), 7.43 (q, 1H), 3.86 (s, 3H), 3.80 (m, 1H), 0.85 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.CCN(C(C)C)C(C)C.[CH3:25][CH:26]([CH3:37])[CH2:27][CH:28](C1C=NC=CC=1)[CH2:29][NH2:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[Cl:1][C:2]1[C:6]([C:7]([NH:30][CH2:29][CH2:28][CH2:27][C:26](=[CH2:25])[CH3:37])=[O:9])=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: CC(C)CC(CN)c1cccnc1
Reactant: O=C(O)c1cn(-c2ncccn2)nc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)CCCNC(=O)c1cn(-c2ncccn2)nc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 3-chloro-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylic acid (75 mg, 0.33 mmol) in 1.0 mL of DMF is added sequentially DIEA (0.11 mL, 0.66 mmol), 4-methyl-2-pyridin-3-yl-pentan-1-amine (59 mg, 0.33 mmol), and BOP (177 mg, 0.40 mmol). The resulting mixture is stirred at RT for 20 h. Water (3 mL) is added, and the mixture is extracted with EtOAc (5 mL). The EtOAc layer is dried (Na2SO4), filtered, and evaporated in vacuo. The residue is purified by preparative chromatography (2% MeOH/CH2Cl2) to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.13 (1H, s), 8.89 (2H, d, J 4.8), 8.39 (3H, m), 7.67 (1H, d, J 7.6), 7.55 (1H, t, J 4.4), 7.32 (1H, m), 3.43 (1H, m), 3.32 (1H, m), 2.99 (1H, bs), 1.58 (1H, m), 1.50 (1H, m), 1.25 (1H, m), 0.81 (6H, d, J 6). MS (M+1)=385.09; RT=1.25 min.
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[CH2:16]([O:18][C:19](=[O:31])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)[CH3:17].[Cl:32][C:33]1[N:38]=[C:37]([Cl:39])[C:36]([CH2:40]I)=[CH:35][N:34]=1>O1CCCC1.C(OCC)(=O)C>[CH2:16]([O:18][C:19](=[O:31])[CH:20]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)[CH2:40][C:36]1[C:37]([Cl:39])=[N:38][C:33]([Cl:32])=[N:34][CH:35]=1)[CH3:17]
Reactant: Clc1ncc(CI)c(Cl)n1
Reactant: CCOC(=O)Cc1ccc(OC)c(OC)c1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1cnc(Cl)nc1Cl)c1ccc(OC)c(OC)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-isopropylcyclohexylamine (720 mg, 5.0 mmol) (Aldrich) in dry tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M in hexanes, 2.0 mL, 5.0 mmol) (Aldrich) at −78° C. under argon. After 30 minutes, a solution of 3,4-dimethoxyphenylacetic acid ethyl ester (1.12 g, 5.0 mmol) (Lancaster) in tetrahydrofuran (3 mL) was added by injection via a syringe and the reaction mixture was stirred at −78° C. for another 30 minutes. To the reaction mixture was added a solution of 2,4-dichloro-5-iodomethyl-pyrimidine (722.5 mg, 2.5 mmol) (from Example 1c supra) in tetrahydrofuran (3 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 1 hour then slowly allowed to warm up to −30° C. and stirred for 10 minutes. After cooling the reaction mixture was diluted with ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (50 mL), water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was then purified by flash column chromatography to give 3-(2,4-dichloro-pyrimidin-5-yl)-2-(3,4-dimethoxy-phenyl)-propionic acid ethyl ester. (Yield 440 mg, 46.0%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][CH:4]=1.C([Li])CCC.CN(C)[CH:25]=[O:26].Cl>>[CH:25]([C:5]1[CH:4]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:8]=[CH:7][C:6]=1[NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:13])[CH3:14])=[O:26]
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li]CCCC
Product: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1C=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
A 1 liter three neck round bottom flask equipped with equalizing addition funnel, magnetic stirer and temperature monitoring device was charged with N-(4-trifluromethylphenyl)-2,2-dimethyl propanamide (10.13 g, 41.4 mmol) and anhydrous tetrahydrafuran (150 mL). The reaction was chilled to −78° C. under nitrogen followed by slow addition of n-butyllithium (50 ml, 2.5 M in hexanes, 124 mmol) over 0.5 hours, such that the temperature of the reaction did not rise above −65° C. The contents were held at −78° C. for one hour, 0° C. for two hours, then chilled back to −78° C. Excess N,N-dimethylformamide (100 mL, 1.37 mol) was added. The contents were warmed to room temperature and stirred for two hours. Aqueous 1 N HCl was added to the reaction until the pH reached 1. The reaction was washed with water (2×200 mL), saturated ammonium chloride solution (2×200 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford a yellow solid. The product was purified by flash chromatography (silica gel, 10% ethyl acetate, 90% hexanes) to yield, upon concentration of the appropriate fractions, N-(2-formyl-4-trifluoromethylphenyl)-2,2-dimethylpropanamide as a solid (7.36 g, 65%): mp 69–73° C. 1H NMR (CDCl3/300 MHz) 11.5 (br s, 1H), 9.99 (s, 1H), 8.67 (d, 1H, J=8.8 Hz), 7.94 (d, 1H, J=1.6 Hz), 7.83 (m, 1H,), 1.37 (s, 9H). ESHRMS m/z 274.1060 (M+H+, Calc'd 274.1055). Anal. Calc'd for C13H14F3NO2: C, 57.14; H, 5.16; N, 5.13. Found: C, 57.15; H, 5.43; N, 5.01.
Reaction SMILES: [CH3:1][Mg+].[Br-].CON(C)[C:7]([C:9]1[C:14](=[O:15])[C:13]([CH2:16][O:17][CH3:18])=[CH:12][N:11]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:10]=1)=[O:8]>C1COCC1>[C:7]([C:9]1[C:14](=[O:15])[C:13]([CH2:16][O:17][CH3:18])=[CH:12][N:11]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=2)[N:10]=1)(=[O:8])[CH3:1]
Reactant: COCc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)N(C)OC)c1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COCc1cn(-c2cccc(C(F)(F)F)c2)nc(C(C)=O)c1=O
Reaction time: 1 h
Yield: 82.9 %

Procedure:
MeMgBr (1 M solution in THF, 16 mL, 16 mmol) was added dropwise at −78° C. to a solution of N-methoxy-5-(methoxymethyl)-N-methyl-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide (1.95 g, 5.25 mmol) in THF (50 mL). After stirring for 1 h, the reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and recrystallized from hexane/AcOEt to give the title compound (1.42 g, 83% yield) as a pale yellow solid: mp 141-143° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.68 (3H, s), 3.54 (3H, s), 4.50 (2H, d, J=1.5 Hz), 7.66-7.74 (2H, m), 7.81-7.87 (1H, m), 7.89 (1H, s), 8.38 (1H, t, J=1.5 Hz). Anal. Calcd for C15H13F3N2O3: C, 55.22; H, 4.02; N, 8.59. Found: C, 55.26; H, 3.95; N, 8.58.