Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]1([NH:13][NH:14][C:15](=O)[C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(O)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:7]1([NH:13][N:14]=[C:15]([Cl:2])[C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CSc1ccc(C(=O)NNc2ccccc2)cc1
Solvent: Oc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ccc(C(Cl)=NNc2ccccc2)cc1
Yield: 44.9 %

Procedure:
A mixture consisting of 14.2 g. (0.068 mole) phosphorus pentachloride, 100 ml. carbon tetrachloride, and 16.78 g. (0.065 mole) p-(methylthio)benzoic acid 2-phenylhydrazide (prepared in Part A above) was reacted at 25° C. until evolution of gas ceased. The reaction mixture was then heated to the reflux temperature and a clear solution resulted. The solution was chilled in ice and a suspension of 20.7 g. (0.22 mole) phenol in 50 ml. carbon tetrachloride was added. After removing the carbon tetrachloride by evaporation on a rotary evaporator at 31° C. the resulting suspension of product in triphenylphosphate was filtered. The filter cake was washed with technical hexane (Skellysolve B, a mixture of isomeric hexanes having a boiling range between 146° and 156° Fahrenheit), and then was washed with diethyl ether. Crystallization from 75 ml. ethyl acetate gave 8.10 g. (44.9% yield) of p-(methylthio)benzoyl chloride phenylhydrazone having a melting point of 138.5° to 142.5° C. Recrystallization from a mixture of ethyl acetate and the Skellysolve B gave the compound with the same melting point.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.B(Cl)(Cl)Cl.O.C([O-])(O)=O.[Na+]>C(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)CC(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Product: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 63.5 %

Procedure:
To a solution of N-(4-chloro-benzyl)-N-isobutyl-4-methoxy-benzenesulfonamide (1.03 g, 2.8 mmol) in DCM (25 mL) was added tetrabutylammonium iodide (1.14 g, 3.1 mmol) and the reaction was cool to −78° C. To the solution was added boron trichloride (4.2 mL, 4.2 mmol of 1 M solution in DCM) over 2 minutes then stirred for a further 5 minutes. The reaction was left to warm to 0° C. and stirred for further 2 hours. Water and saturated aqueous NaHCO3 were added, extracted with DCM, filtered through a phase separator, concentrated then purified by silica gel column chromatography (0-30% EtOAc in cyclohexane) to give N-(4-chloro-benzyl)-4-hydroxy-N-isobutyl-benzenesulfonamide (629 mg, 64%). LCMS (m/z, Method A) ES− 352 [M−1]−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[C:12]([CH2:17][NH2:18])(=[O:16])[CH:13]([CH3:15])[CH3:14].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][CH2:17][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CN
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C(=O)CNC(=O)c1ccc(Cl)cc1
Yield: 99 %

Procedure:
4.5 g of 4-chlorobenzoyl chloride are added dropwise to a mixture of 4 g of isobutyrylmethylamine hydrochloride, 9.8 g of sodium bicarbonate, 200 ml of ethyl acetate and 100 ml of water at 5° C. to 10° C. under stirring. The mixture is further stirred at room temperature for 3 hours. The ethyl acetate layer is collected, and said layer is washed with water, dried and then condensed under reduced pressure to remove solvent. 6.1 g of N-(4-chlorobenzoyl)isobutyrylmethylamine are obtained. Yield: 87.5%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]([F:24])([F:23])[C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[CH2:14][NH2:15].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:9][C:10]([F:23])([F:24])[C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=1)[CH2:14][NH:15][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: Brc1ccc(Br)nc1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(CNc2ccc(Br)cn2)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 26 %

Procedure:
2,5-Dibromopyridine (4.74 g) is dissolved in toluene (100 ml) and thereto are added 3,5-bis-trifluoromethyl-benzylamine (5.84 g) and palladium acetate (449.0 mg), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.25 g) and sodium tert-butoxide (4.23 g) and the mixture is stirred under nitrogen atmosphere at 80° C. for 12 hours. The reaction solution is cooled to room temperature, and thereto is added a saturated aqueous sodium bicarbonate solution and the mixture is extracted with ethyl acetate twice, and the organic layer is washed successively with water and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromopyridin-2-yl)-amine (2.08 g). MS (m/z): 399/401 [M+H]+
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([NH2:17])=O)[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.C(OC(=O)C)(=O)C>ClCCl>[C:1]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]#[N:17])[N:14]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCc1nc(C(N)=O)cs1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1nc(C#N)cs1
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a cooled (0° C.) solution of 2-(N-Boc-aminomethyl)thiazole-4-carboxamide (200 mg, 0.78 mmol, see Angew. Chem. Int. Ed. Engl. 1996, 35, 1503) in dichloromethane (7 mL) was added triethylamine (0.32 mL, 2.34 mmol) and acetic anhydride (0.22 mL, 1.56 mmol) and the mixture stirred for 1 h. After the solvent was removed, the residue was purified by column chromatography (EtOAc: n-hexane, 3:7). 2-(N-Boc-aminomethyl)thiazole-4-carbonitrile (150 mg, 0.627 mmol) thus obtained was dissolved in methanol (10 mL) and cooled to 0° C. To this was added dropwise acetylchloride (30 equivalent) and the mixture stirred for 1 h at rt. The solvent was removed in vacuo to give the title compound (90 mg, 81%).
Reaction SMILES: C(O[CH2:4][CH2:5][C:6]#[N:7])C.C(O)C.[NH:11]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[NH2:12].OCC[N+](C)(C)C>CO>[NH2:7][C:6]1[CH2:5][CH2:4][N:11]([C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[N:12]=1
Reactant: CCOCCC#N
Reactant: NNc1nc2ccccc2s1
Agent: C[N+](C)(C)CCO
Solvent: CCO
Solvent: CO
Product: NC1=NN(c2nc3ccccc3s2)CC1

Procedure:
A mixture of 5.0 g. of β-ethoxypropionitrile, 100 ml. of absolute ethanol, 8.25 g. of 2-hydrazinobenzothiazole and 2.5 g. of 50% w/v choline in methanol is refluxed on a steam bath for 16 hours, then the solvent is removed in vacuo. Water is added and the solid is collected by filtration. The solid is recrystalized twice from ethanol to give 5.75 g. of the product of the Example as grey prisms, m.p. 231.5°-235° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.[N:43]1[CH:48]=[CH:47][C:46]([NH:49][CH2:50][CH2:51][NH2:52])=[CH:45][CH:44]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([NH:52][CH2:51][CH2:50][NH:49][C:46]1[CH:47]=[CH:48][N:43]=[CH:44][CH:45]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Reactant: NCCNc1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)NCCNc1ccncc1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and 2-(pyridin-4-yl-amino)-ethylamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: CCOC(=O)CCC(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCC(Oc1cccc(OCc2ccccc2)c1)c1ccccc1
Yield: 17.1 %

Procedure:
A mixture of 3-benzyloxyphenol (3 g), ethyl (RS)-4-chloro-4-phenylbutanoate (4.53 g), potassium carbonate (4.14 g), potassium iodide (100 mg) and methyl ethyl ketone (100 mL) is heated at reflux for 40 hours. The mixture is evaporated to dryness and the residue is partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer is dried over magnesium sulphate, filtered, and concentrated in vacuo. Flash chromatography of the resulting oil, eluting with a mixture of ethyl acetate and cyclohexane (1:19 v/v), gives ethyl (RS)-4-(3-benzyloxyphenoxy)-4-phenylbutanoate (1 g), in the form of a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1.C(N(CC)C(C)C)(C)C.[Cl:40][C:41]1[CH:42]=[C:43]([CH2:47][S:48](Cl)(=[O:50])=[O:49])[CH:44]=[CH:45][CH:46]=1>C(Cl)Cl.O>[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:24][CH2:25][N:26]([S:48]([CH2:47][C:43]3[CH:44]=[CH:45][CH:46]=[C:41]([Cl:40])[CH:42]=3)(=[O:49])=[O:50])[CH2:27][CH2:28]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Reactant: O=S(=O)(Cl)Cc1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)Cc3cccc(Cl)c3)CC2)c1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
To a 0° C. solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 102 mg, 0.237 mmol) and N,N-diisopropylethylamine (124 μL, 0.711 mmol) in methylene chloride (6.0 mL) was added (3-chloro-phenyl)-methanesulfonyl chloride (106.7 mg, 0.474 mmol). The reaction mixture was stirred at 0° C. for 10 minutes, then it was warmed to room temperature and stirred at room temperature overnight. The reaction mixture was diluted with water. The resulting mixture was extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered, and concentrated. Silica gel chromatography (20-25% ethyl acetate in hexanes) provided {4-[1-(3-chloro-phenylmethanesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (52.4 mg, 44%) as a colorless film. MS cald. For C26H28ClFNO4S [(M+H)+]: 504, obsd. 504.1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=O)[C:6]=2[N:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([NH2:24])=[N:20][C:21]=1[O:22][CH3:23].C(N(CC)C(C)C)(C)C.C1CN(C(ON2N=NC3C2=CC=CC=3)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl.O.CN(C)C=O>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:24][C:11]([C:8]2[C:6]3[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=3[S:10][CH:9]=2)=[O:13])=[N:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(N)nc1OC
Reactant: O=C(O)c1csc2cnc(Cl)nc12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2OC(N1CCCC1)=[N+]1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2csc3cnc(Cl)nc23)nc1OC
Temperature: 25 °C

Procedure:
To a solution of 0.050 g (0.233 mmole) 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid, 0.0718 g (0.466 mmole) of 5,6-dimethoxypyridin-2-amine, 0.122 mL (0.699 mmole) of N,N-diisopropylethylamine and 1.55 ml of dimethylformamide was added 0.111 g (0.256 mmole) of O-(benzotriazol-1-yl)-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate. The mixture was stirred at room temperature for over night. Water and dichloromethane were added. The aqueous layer was washed three times with dichloromethane. The combined organic layer was washed with aqueous sodium carbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried in high vacuum to give 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid (5,6-dimethoxy-pyridin-2-yl)-amide as a black solid.
Reaction SMILES: [Cl-].[CH2:2]1[N+:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[F:10][C:11]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([OH:33])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([CH3:34])[NH:15]2.CN1CCCC1=O.C(=O)([O-])[O-].[K+].[K+]>O.C(OC)(C)(C)C>[F:10][C:11]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH2:4][CH2:3][CH2:2][N:5]4[CH2:9][CH2:8][CH2:7][CH2:6]4)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([CH3:34])[NH:15]2
Reactant: C1CC[N+]2(C1)CCC2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: COC(C)(C)C
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCCC1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
4-Azoniaspiro[3,4]octane chloride (1.14 g) was added to a mixture of 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-ol (2.5 g), 1-methyl-2-pyrrolidinone (25 ml), methyl tert-butyl ether (1.8 ml) and potassium carbonate (815 mg) at 80° C. After stirring at 80° C. for 3 hours water (27 ml) was added over 40 minutes. The mixture was allowed to cool to 20° C. and left overnight. The mixture was reheated to 60° C. and filtered. The filter cake was washed with 1:1 v/v 1-methyl-2-pyrrolidinone/water (5 ml) and then with water (4×5 ml). The solid was dried in a vacuum oven to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].C(N(CCCC)CCCC)CCC.[C:26]([O-:29])(=[O:28])C.[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C=O)C>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:2]([CH:3]=1)[C:26]([OH:29])=[O:28])=[O:6]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1ccc(C)c(Br)c1
Agent: [Pd+2]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: COC(=O)c1ccc(C)c(C(=O)O)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A pressure vessel was charged with methyl 3-bromo-4-methylbenzoate (5.0 g, 22 mmol), DMF (20 ml), water (1.25 ml) and tributylamine (8 ml, 34 mmol). Cesium acetate (2.1 g, 11 mmol) was then added and the flask was purged with N2. Palladium acetate (0.25 g, 1.0 mmol) and triphenylphosphine (2.9 g, 11 mmol) were added and the flask was purged with CO gas. The reaction mixture was then heated at 90° C. under 20 psi of CO gas with vigorous stirring overnight. The reaction mixture was diluted with 50 mL of toluene and extracted with saturated NaHCO3 (3×50 ml). The combined aqueous layer was washed with EtOAc (10 mL), then acidified using 2 N HCl to pH 5. The volume was reduced to about 50 mL and the resulting precipitate was collected by filtration, washed with water and dried to give 5-(methoxycarbonyl)-2-methylbenzoic acid as a white solid. MS (ESI, pos. ion) m/z: 193.1 (M−1).
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[N:13]1[N:17]=[C:16]([C:18](O)=[O:19])[C:15]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:14]1.[NH2:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([O:35][CH3:36])=[O:34].ON1C2C=CC=CC=2N=N1>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[CH3:36][O:35][C:33](=[O:34])[C:32]1[CH:37]=[CH:38][CH:39]=[C:30]([NH:29][C:18]([C:16]2[C:15]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:14][N:13]([C:7]3[C:6]([Cl:5])=[CH:11][CH:10]=[CH:9][C:8]=3[Cl:12])[N:17]=2)=[O:19])[CH:31]=1
Reactant: O=C(O)c1nn(-c2c(Cl)cccc2Cl)nc1COc1ccccc1
Reactant: COC(=O)c1cccc(N)c1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(NC(=O)c2nn(-c3c(Cl)cccc3Cl)nc2COc2ccccc2)c1
Reaction time: 72 h
Yield: 62.3 %

Procedure:
EDC (869 mg, 4.53 mmol) was added to a stirred solution of the product from step c (1.10 g, 3.02 mmol), methyl 3-aminobenzoate (685 mg, 4.53 mmol), N-hydoxybenzotriazole (612 mg, 4.53 mmol) and 4-DMAP (cat) in DMF (10 ml). The solution was stirred for 72 h and then diluted with ethyl acetate (40 mL). The solution was washed sequentially with water (40 mL) and twice with brine (40 mL). The organic phase was dried (MgSO4) and the filtrate was evaporated at reduced pressure. The residue was purified by flash column chromatography (100% DCM) to yield the title compound (935 mg, 62%). 1H NMR (CDCl3) 8.71 (1H, br s), 8.21-8.20 (1H, t, J=1.8 Hz), 8.05-8.02 (1H, m), 7.86-7.83 (1H, m), 7.54-7.43 (4H, m), 7.31-7.26 (2H, m), 7.11-7.07 (2H, m), 7.00-6.97 (1H, m), 5.65 (2H, s), 3.92 (3H, s).
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:10]1[CH2:13][CH:12]([OH:14])[CH2:11]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[NH:10]1[CH2:13][CH:12]([O:14][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])[CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CNC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
A solution of tert-butylchlorodimethylsilane (12.01 g, 79.69 mmol) in DCM (20 mL) was added dropwise to a stirred solution of azetidin-3-ol hydrochloride (CAS no. 18621-18-6) (8.73 g, 79.69 mmol) and anhydrous N-ethyl-N-isopropylpropan-2-amine (34.1 mL, 199.22 mmol) in DCM (20 mL) cooled to 10° C., over a period of 2 minutes under nitrogen. The resulting solution was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated, diluted with EtOAc (75 mL), and washed sequentially with saturated NaHCO3 (25 mL), water (20 mL), and saturated brine (20 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford the product (11.1 g, 74%). 1H NMR (400 MHz, CDCl3) δ 0.04 (6H, s), 0.87 (9H, m), 2.80 (1H, s), 3.57-3.61 (2H, m), 3.67-3.71 (2H, m), 4.57-4.64 (1H, m).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([NH2:19])=[O:18])[C:5]([CH3:20])=[CH:4][N:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:69][C:70]1[CH:75]=[CH:74][C:73]([C:76]2([NH:80][C:81](=[O:84])[O:82][CH3:83])[CH2:79][CH2:78][CH2:77]2)=[CH:72][CH:71]=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:19][C:17](=[O:18])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8][C:6]1[C:5]([CH3:20])=[CH:4][N:3]=[C:2]([NH:69][C:70]2[CH:71]=[CH:72][C:73]([C:76]3([NH:80][C:81](=[O:84])[O:82][CH3:83])[CH2:77][CH2:78][CH2:79]3)=[CH:74][CH:75]=2)[N:7]=1
Reactant: Cc1cnc(Cl)nc1CCc1ccccc1CC(N)=O
Reactant: COC(=O)NC1(c2ccc(N)cc2)CCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COC(=O)NC1(c2ccc(Nc3ncc(C)c(CCc4ccccc4CC(N)=O)n3)cc2)CCC1
Temperature: 150 °C
Yield: 35.1 %

Procedure:
A suspension of 2-(2-(2-(2-chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide (K6) (150 mg, 0.518 mmol), Pd(OAc)2 (11.6 mg, 0.052 mmol), Xantphos (45.0 mg, 0.078 mmol), Cs2CO3 (486 mg, 1.49 mmol) and methyl 1-(4-aminophenyl)cyclobutylcarbamate (A119) (125 mg, 0.569 mmol) in 1,4-dioxane (4.0 mL) was heated under microwave irradiation for 10 minutes at 150° C. The resulting mixture was filtered through Celite, and washed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by semi preparative HPLC to give the title compound 29 (86 mg, 35%); 1H NMR (300 MHz, CDCl3): δ 8.17 (br s, 1H), 7.56 (m, 2H), 7.42 (m, 2H), 7.28 (4H, obscured by solvent peak), 5.65 (br s, 1H), 5.42 (br s, 1H), 5.30 (br s, 1H), 3.70 (s, 2H), 3.61 (s, 3H), 3.13 (m, 2H), 2.99 (m, 2H), 2.57 (s, 3H), 2.12-1.62 (m, 6H). LCMS-B: rt 6.28 min; m/z 474.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1=[N:6][N:7]([CH3:19])[C:8](=[O:18])/[C:9]/1=[C:10](\OCC)/[CH2:11][CH2:12][CH2:13][CH3:14].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH2:28]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1=[N:6][N:7]([CH3:19])[C:8](=[O:18])/[C:9]/1=[C:10](\[NH:28][CH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=1)/[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCC/C(OCC)=C1/C(=O)N(C)N=C1CC(=O)OC
Reactant: NCc1ccccn1
Solvent: Cc1ccccc1
Product: CCCC/C(NCc1ccccn1)=C1/C(=O)N(C)N=C1CC(=O)OC
Yield: 92 %

Procedure:
The mixture of the above obtained methyl[(4Z)-4-(1-ethoxypentylidene)-1-methyl-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of Formula (VII), 1.05 g) and 1-pyridin-2-ylmethanamine (0.262 mL) was stirred at room temperature in toluene (25 mL) for 0.5 h. The solvent was removed in vacuo. The resulting residue was dissolved in a minimum of CH2Cl2 and added dropwise to a stirred solution of 200 mL of cyclohexane resulting in the formation of a brown precipitate that was filtered off. This precipitate was proved to be the pure methyl[(4Z)-1-methyl-5-oxo-4-{1-[(pyridin-2-ylmethyl)amino]pentylidene}-4,5-dihydro-1H-pyrazol-3-yl]acetate (1.20 g). Yield 92%. MS (ESI+): 345.4; MS (ESI−): 342.5.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([C:25](=[O:38])[NH:26][C@H:27]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[CH:30]=4)[CH3:28])=[CH:22][CH:23]=3)[C:18]([CH3:39])=[C:17]2[CH3:40])=[CH:11][C:3]=1[O:4][C@@H:5]([CH3:10])[C:6]([O:8]C)=[O:7].CS(C)=O.O.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([C:25](=[O:38])[NH:26][C@H:27]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:36])[CH3:37])[CH:30]=4)[CH3:28])=[CH:22][CH:23]=3)[C:18]([CH3:39])=[C:17]2[CH3:40])=[CH:11][C:3]=1[O:4][C@@H:5]([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)[C@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CO
Product: Cc1c(C)n(Cc2ccc(Cl)c(O[C@@H](C)C(=O)O)c2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12

Procedure:
The (S)-methyl 2-(2-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate was dissolved in methanol (1.5 mL), DMSO (˜1.5 mL) and water (0.1 mL) then NaOH (2 N, 0.1 mL) was added dropwise. The reaction was monitored by LC/MS. It was stirred until all the starting material was consumed (˜3 h). It was acidified with trifluoroacetic acid, filtered and purified by preparative HPLC to yield the title compound. ESI-MS (m/z): 547.1 [M+H]+.