Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:23]=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[C:13]([F:24])[C:12]=3[Cl:25])=[CH:6][C:5]=12.FC(F)(F)C(O)=O>ClCCl>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:23]=[CH:22][C:14]([C:15]([OH:17])=[O:16])=[C:13]([F:24])[C:12]=3[Cl:25])=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccn3ncnc3c2)c(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(Oc2ccn3ncnc3c2)c(Cl)c1F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A 25 ml flask was charged with tert-butyl 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chloro-2-fluorobenzoate (0.060 g, 0.16 mmol) and dichloromethane (1.6 ml). The reaction was cooled to 0° C., and 2,2,2-trifluoroacetic acid (0.50 ml, 0.16 mmol) was added. The reaction was stirred for 20 minutes, then warmed to ambient temperature, stirred an additional 3 hours, and then concentrated to provide the desired product as a colorless oily residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=1[O:11]C)[C:6]#[N:7].[Cl-].[NH4+].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[NH:20][N:19]=[N:18][N:7]=2)[CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=1[OH:11]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(C#N)cc([N+](=O)[O-])c1OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nnn[nH]2)cc([N+](=O)[O-])c1O
Reaction time: 31 h

Procedure:
4.0 g of 3,4-dimethoxy-5-nitro-benzonitrile are dissolved in 50 ml of dimethylformamide, whereupon the solution is treated with 1.66 g of ammonium chloride and 2.02 g of sodium azide and stirred at 125° for 31 hours. After in each case 8 and 15 hours the same amounts of ammonium chloride and sodium azide are added thereto. After cooling the mixture is poured on to ice. The separated precipitate is filtered under suction, washed with water and dried. There is obtained 2-methoxy-6-nitro-4-(1H-tetrazol-5-yl)phenol in the form of orange crystals of m.p. >240° (dec.).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH:5]([O:7][CH3:8])[O:4][C:3]1([CH3:11])[CH2:9][OH:10].CO>C(N(CC)CC)C>[NH2:1][C@@H:2]1[C@@H:9]([OH:10])[C@H:3]([CH3:11])[O:4][CH:5]([O:7][CH3:8])[CH2:6]1
Reactant: COC1CC(N)C(C)(CO)O1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC1C[C@H](N)[C@@H](O)[C@H](C)O1
Reaction time: 1 h

Procedure:
A mixture of 4.524 g (0.028 mole) [2β,2S*,3β)]-3-aminotetrahydro-5-methoxy-methyl-2-furanmethanol, 250 ml methanol, 2.57 g Amberlite CG 120 200-400 mesh (H+ form) and 1.5 g 3A molecular sieves was stirred for 20 hr. then 10 ml triethylamine was added. After 1 hour, the mixture was filtered through diatomaceous earth and filtrate evaporated in vacuo. The reaction was not complete (nmr) so the crude material was stirred with 250 ml methanol and 5.14 g Amberlite CG 120 200-400 mesh (H+ form) for 65 hr., then 15 ml triethylamine added. After stirring for 11/2 hr, the mixture was filtered through diatomaceous earth. The filtercake was stirred 1 hour with 200 ml methanol, 5 ml triethylamine then filtered. The combined filtrates were concentrated in vacuo to give 4.056 g crude product from which 2.189 g methyl 3-amino- 2,3,6-trideoxy-L-arabinohexopyranoside was crystallized from ether as a 2:1 parts by weight mixture (α:β) of anomers as determined by nmr.
Reaction SMILES: C(OC([NH:11][C:12]1[C:13]([C:24]([OH:26])=[O:25])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([CH:22]=[CH2:23])[CH:16]=2)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][C:12]1[C:13]([C:24]([OH:26])=[O:25])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([CH2:22][CH3:23])[CH:16]=2
Reactant: C=Cc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)O)nc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1ccc2cc(N)c(C(=O)O)nc2c1

Procedure:
To a solution of 3-{[(benzyloxy)carbonyl]amino}-7-vinylquinoline-2-carboxylic acid (673.9 mg, 1.934 mmol) in MeOH (25.0 mL) was added 10 wt % Pd on carbon (100.1 mg, 0.09406 mmol). The mixture was stirred at room temperature hydrogen (1 atm) for 15 h. The reaction mixture was filtered through a pad of diatomaceous earth (eluted with MeOH) and then concentrated under reduced pressure. The resulting crude sub-title compound was used directly in the next step residue without further purification (380.6 mg, 91%). LCMS calc. for C12H13N2O2 (M+H)+: m/z=217.1. found 217.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([F:21])[CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1>[NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=2[F:21])=[CH:6][N:7]=1
Reactant: N#Cc1nc(Br)cnc1N
Reactant: OB(O)c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1nc(-c2ccc(Cl)cc2F)cnc1N
Temperature: 80 °C
Yield: 83.8 %

Procedure:
To a solution of 3-amino-6-bromopyrazine-2-carbonitrile (2.00 g, 9.55 mmol) in 1,4-dioxane (48 mL), were added (4-chloro-2-fluorophenyl)boronic acid (1.66 g, 9.55 mmol) and aqueous Na2CO3 (2 M, 24 mL, 48 mmol) and the reaction mixture sparged with N2 gas for 10 min. Pd(dppf)Cl2.CH2Cl2 (0.349 g, 0.477 mmol) was then added and the reaction mixture sparged for an additional 10 min with N2 gas. The reaction vessel was sealed and heated for 3 hours at 80° Celsius. The mixture was cooled to rt, filtered through celite, and the filter cake washed with EtOAc (300 mL). The filtrate was washed with a 1:1 mixture of brine/H2O (2×100 mL). The organic phase was concentrated to dryness and subjected to FCC to give the title compound (1.99 g, 84%). MS (ESI): mass calcd. for C11H6ClFN4, 248.03; m/z found 249.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J=2.0, 1H), 7.83 (m, 1H), 7.25-7.08 (m, 2H), 5.36 (s, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Na+].[OH2:17]>ClCCl>[C:3]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][S:11]([CH3:14])(=[O:12])=[O:13])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)(=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)CCN2
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)CCN2C(=O)c1ccccc1
Reaction time: 1 h
Yield: 50 %

Procedure:
N-(2,3-dihydro-1H-indole-5-yl)-methanesulfonamide (20 mg, 0.095 mmol) was dissolved in anhydrous dichloromethane (3 ml), sodium hydride (0.010 g, 50% in oil) was added and then, benzolychloride (0.011 ml, 0.095 mmol) was added at a temperature under −20° C. The resulting solution was stirred at the same temperature for 1 hour, stirred again at room temperature for 24 hours to complete the reaction. After pouring water (3 ml), dichloromethane layer was separated, washed with brine, dried over anhydrous magnesium sulfate and then, concentrated under reduced pressure. Afterward, the residue was purified through flash column chromatography (an eluent: ethyl acetate/n-hexane=1/1, v/v) and triturated with isooctane. As a result, the present compound (15 mg, productive yield 50%) was obtained as a solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH:19]1[CH2:23][CH2:22][O:21][CH2:20]1>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:18][CH:19]2[CH2:23][CH2:22][O:21][CH2:20]2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: BrCC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC2CCOC2)cc(C)c1Br
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (1.5 g) and K2CO3 (3.2 g) in N,N-dimethylformamide (12 mL) is added 3-(bromomethyl)tetrahydrofuran (3.6 g). The mixture is stirred for 16 hours at 80° C. and then partitioned between water and ethyl acetate. The organic phase is washed with brine and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. Yield: 1.72 g; LC (method 1): tR=1.37 min; Mass spectrum (ESI+): m/z=285 [M+H]+.
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[CH:33])=[N:30][CH:31]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:2]3[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=3)=[N:30][CH:31]=2)=[CH:24][CH:25]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: O=[N+]([O-])c1cc(I)ccc1OCCN1CCCC1
Product: O=[N+]([O-])c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
Prepared according to general working method I from 1-[2-(4-iodo-2-nitro-phenoxy)-ethyl]-pyrrolidine (600 mg, 1.66 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (363 mg, 1.70 mmol).
Reaction SMILES: [F:1][CH:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][O:16][C:15]2=[O:19])=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].[N+:20]([O-])([OH:22])=[O:21]>S(=O)(=O)(O)O>[N+:20]([C:12]1[CH:13]=[C:8]([O:7][CH:2]([F:1])[C:3]([F:5])([F:4])[F:6])[CH:9]=[CH:10][C:11]=1[N:14]1[CH2:18][CH2:17][O:16][C:15]1=[O:19])([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: O=C1OCCN1c1ccc(OC(F)C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Product: O=C1OCCN1c1ccc(OC(F)C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
2.79 g (10 mmoles) of the oxazolidinon of Step 2 are dissolved in 7 ml concentrated sulfuric acid and nitrated at 0° C. with a mixture of 0.43 ml (10 mmoles) fuming nitric acid and 3.6 ml concentrated sulfuric acid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=3)[CH:14]=2)=[C:5]([C:25]([O:27]CC)=[O:26])[CH:4]=[N:3]1.O.[OH-].[Li+].Cl>CO.O>[CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=3)[CH:14]=2)=[C:5]([C:25]([OH:27])=[O:26])[CH:4]=[N:3]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 1-methyl-5-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylate (810 mg, 2.07 mmol) and lithium hydroxide hydrate (434 mg, 10.3 mmol) in methanol (30 ml) and water (5 ml) was stirred for 18 hours at 25° C. The mixture was adjusted to pH=7 using hydrochloric acid (2molar, 5.15 ml) and then evaporated to dryness under reduced pressure. 1-Methyl-5-(2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (1.38 g) as light brown solid was used without further purification. MS: m/z=364.1 (M+H+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].CCN(C(C)C)C(C)C.Cl.[CH3:25][NH:26][O:27][CH3:28]>C(Cl)Cl>[CH3:28][O:27][N:26]([CH3:25])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[C:2]1[O:1][CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccccc1-c1ncco1
Reactant: CNOC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1ccccc1-c1ncco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a mixture of 2-Oxazol-2-yl-benzoyl chloride (104 mg, 0.5 mmol), DIEA (0.26 mL, 1.5 mmol) in 2 ml of DCM was added N,O-dimethylhydroxylaminehydrochloride (59 mg, 0.6 mmol). The mixture was stirred at room temperature for 2 hours, washed with dilute HCl solution followed by brine. Concentration of the organic layer afforded 100 mg of N-Methoxy-N-methyl-2-oxazol-2-yl-benzamide as a sticky light yellow liquid. MS: (M+H)/z=233.1.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.C(OCC)(=O)C.ClCCl.[OH-].[Na+]>Cl>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Nc1ccc(S(=O)(=O)N2CCCCC2)cc1
Yield: 70.62 %

Procedure:
N-[4-(Acetylamino)phenylsulfonyl]piperidine (Example 5) was heated at 100° C. in 20% hydrochloric acid (5 mL) for one hour (TLC ethyl acetate/dichloromethane 8:2). The solution is neutralized at 0° C. with NaOH. The precipitate that forms is filtered and recrystallized from methanol/diethyl ether to afford the desired N-[4-(amino)phenylsulfonyl]piperidine. 70.62% yield; white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)[CH3:3].CC([O:21][C@@H:22]1[C@@H:27]([O:28]C(C)=O)[C@@H:26](Br)[O:25][C@H:24]([C:33]([O:35]C)=[O:34])[C@H:23]1[O:37]C(C)=O)=O.[OH-].[Li+]>CO.O>[CH3:3][N:2]([CH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[O:17][CH:26]1[O:25][CH:24]([C:33]([OH:35])=[O:34])[CH:23]([OH:37])[CH:22]([OH:21])[CH:27]1[OH:28])[CH3:1]
Reactant: COC(=O)[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CN(C)C[C@@H]1CCCC[C@H]1c1cccc(O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)C[C@@H]1CCCC[C@H]1c1cccc(OC2OC(C(=O)O)C(O)C(O)C2O)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2.33 g (10 mmol) (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol, 3.58 g (9 mmol) acetobromo-α-D-glucuronic acid methyl ester and 0.23 g (9.5 mmol) lithium hydroxide in 23 ml dry methanol was first stirred at 20° C. for 30 minutes, a solution of 0.65 g lithium hydroxide in 25 ml water was then added and the mixture was stirred again for 30 minutes. It was extracted with ethyl acetate and the aqueous phase was adjusted to a pH of 3.5 by addition of acetic acid and extracted again with ethyl acetate. The aqueous phase was evaporated in vacuo and the residue was purified by HPLC. 0.85 g (23% of theory) of the title compound was obtained in this manner in the form of a white powder.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][NH:13]2)=[C:9]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[N:8]=1.I[CH2:24][CH:25]([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Cl:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH2:24][CH:25]([CH3:27])[CH3:26])=[C:9]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[N:8]=1
Reactant: CC(C)CI
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Cn1cnc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Temperature: 50 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
An N,N-dimethylformamide (5 ml) suspension of 2-chloro-6-((S)-3-methylmorpholin-4-yl)-9H-purine (839 mg, 3.31 mmol), 1-iodo-2-methylpropane (730 mg, 3.97 mmol), and potassium carbonate (594 mg, 4.30 mmol) was stirred at 50° C. for 4 hours. The reaction mixture was returned to room temperature. Ethyl acetate was added to the reaction mixture and the resulting mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and, after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (hexane:ethyl acetate=7:3) to give the title compound (868 mg, 85%) as an amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:22][C:23]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[CH:26][C:24]=1[NH2:25].Cl>C(O)(C)C>[ClH:1].[F:22][C:23]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[CH:26][C:24]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccncc1
Reactant: Cc1cc(F)c(N)cc1O
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCc1ccncc1
Yield: 51.9 %

Procedure:
A stirred solution of 4-chloro-6-methoxy-7-(4-pyridylmethoxy)quinazoline (35 mg, 0.1 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (15 mg, 0.1 mmol) in a mixture of ethereal hydrogen chloride (2 ml) and isopropanol (5 ml) was heated at reflux for 4 hours. The precipitated product was collected by filtration, washed with acetone and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylmethoxy)quinazoline hydrochloride (23 mg, 47%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]([CH3:32])([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=[CH:23][C:16]=23)[CH:12]=[N:11]1)[CH3:9])(=O)=O.[C-:33]#[N:34].[K+]>CN(C=O)C.O>[CH3:32][C:8]([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:22]=[CH:23][C:16]=23)[CH:12]=[N:11]1)([CH3:9])[CH2:7][CH2:6][C:33]#[N:34]
Reactant: [C-]#N
Reactant: CC(C)(CCOS(C)(=O)=O)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CCC#N)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 125 °C
Reaction time: 0.5 h
Yield: 169.2 %

Procedure:
A mixture of 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butyl methanesulfonate (42 mg, 0.000088 mol) and potassium cyanide (46 mg, 0.000702 mol) in DMF (1 mL) was heated in the microwave reactor for 30 min at 125° C. followed by additional 30 min at 135° C. The mixture was then diluted with water, and the product was extracted with three portions of MTBE. The combined extracts were dried over sodium sulfate, filtered and concentrated to give 61 mg of crude 4-methyl-4-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo-[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]pentanenitrile, which was used without further purification. MS(ES): 410 (M+1).
Reaction SMILES: COC[O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([I:16])=[C:10]2[C:6]=1[CH:7](O)[N:8](C(C)(C1C=CC=CC=1)C)[C:9]2=[O:17].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[N+](C)([O-])=O>[OH:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([I:16])=[C:10]2[C:6]=1[CH2:7][NH:8][C:9]2=[O:17]
Reactant: COCOc1c(OC)cc(I)c2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Product: COc1cc(I)c2c(c1O)CNC2=O
Yield: 70.7 %

Procedure:
In a similar manner to Step 4 of Example 16, 4-methoxymethoxy-5-methoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (763 mg, 1.58 mmol) was dissolved in nitromethane (12 mL), and the solution was treated with trifluoroacetic acid (1.22 mL, 15.8 mmol) and triethylsilane (2.55 mL, 15.8 mmol), followed by purification by slurry using chloroform to obtain 4-hydroxy-5-methoxy-7-iodoisoindolinone (341 mg, yield 71%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1.P([O-])(OCC)(SCC)=[S:14]>O>[NH2:11][C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:12])=[CH:5][CH:6]=1)=[S:14]
Reactant: CCOP([O-])(=S)SCC
Reactant: COC(=O)c1ccc(C#N)cc1
Solvent: O
Product: COC(=O)c1ccc(C(N)=S)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
A mixture of methyl-4-cyanobenzoate (5.0 g, 0.031 mol) and diethyl dithiophosphate (11.5 g, 0.062 mol) in water (100 mL) was stirred overnight at 80° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to ambient temperatures and the solid was filtered and washed with water (100 mL). The solid was then dried in vacuo at 40° C. to give the crude product (4.74 g, 78%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[S:18][C:17]([C:19]([O:21][CH3:22])=[O:20])=[C:16]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:15]=3)=[C:9]([N+:31]([O-])=O)[CH:8]=2)[CH:4]=[N:3]1.[CH3:34]OC(OC)OC.C(O)=O>CO.[Zn]>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]3[N:13]([C:14]4[S:18][C:17]([C:19]([O:21][CH3:22])=[O:20])=[C:16]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH:15]=4)[CH:34]=[N:31][C:9]=3[CH:8]=2)[CH:4]=[N:3]1
Reactant: COC(=O)c1sc(Nc2ccc(-c3cnn(C)c3)cc2[N+](=O)[O-])cc1OCc1ccccc1
Reactant: COC(OC)OC
Agent: [Zn]
Solvent: CO
Solvent: O=CO
Product: COC(=O)c1sc(-n2cnc3cc(-c4cnn(C)c4)ccc32)cc1OCc1ccccc1
Temperature: 70 °C
Yield: 86.9 %

Procedure:
Methyl 5-{[4-(1-methyl-1H-pyrazol-4-yl)-2-nitrophenyl]amino}-3-[(phenylmethyl)oxy]-2-thiophenecarboxylate (1.0 g, 2.2 mmol) from a different batch than that made in Step A3, was dissolved In MeOH (30 mL). Trimethylorthoformate (6.0 mL, 54 mmol) was added followed by formic acid (0.81 ml, 21.5 mmol). Zinc dust (0.70 g, 11 mmol) was added and the reaction mixture was heated to 70° C. for 2 h and then cooled to rt. The reaction mixture was filtered through a pad of celite which was then washed with 20% MeOH/DCM. The crude reaction mixture was concentrated to remove the MeOH and the remaining mixture was poured into half-saturated aqueous NaHCO3 solution and then extracted with a mixture of 4:1 DCM:i-PrOH. The combined organics were dried over anhydrous MgSO4 and purified by flash chromatography to give 850 mg (89%) of the title compound, methyl 5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-[(phenylmethyl)oxy]-2-thiophenecarboxylate. MS (ESI): 445 [M+H]+
Reaction SMILES: [CH2:1]([N:8]([C:10]1([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:8]([C:10]1([C:13]2[CH:18]=[CH:17][C:16]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)C1(c2ccc(Br)cc2)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CN(Cc1ccccc1)C1(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Temperature: 70 °C
Yield: 85.7 %

Procedure:
Using General Procedure D; benzyl-[1-(4-bromophenyl)-cyclopropyl]-methylamine (Intermediate 130, 90.0 mg, 0.28 mmol) in triethylamine (8 mL) was treated ,with copper(I)iodide (6.0 mg, 0.03 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (20.0 mg, 0.03 mmol). The resulting reaction mixture was heated to 70° C. for 5 days. The title compound 80 mg (84%) was isolated by chromatography (0-2% EtOAc-hexanes).
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]1[CH:5]=[C:6]([C:21]2[CH:22]=[N:23][N:24]([CH:26]([CH3:31])[C:27]([O:29]C)=[O:28])[CH:25]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=2)[CH:9]=1>CO.O>[CH3:3][C:4]1[CH:5]=[C:6]([C:21]2[CH:22]=[N:23][N:24]([CH:26]([CH3:31])[C:27]([OH:29])=[O:28])[CH:25]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][N:12]=2)[CH:9]=1
Reactant: COC(=O)C(C)n1cc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C(C)C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
LiOH (10.6 mg, 0.44 mmol) was added to a solution of methyl 2-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanoate (18 mg, 0.04 mmol) in methanol (870 μL) and water (87 μL). The reaction mixture was allowed to stir at room temperature for 3 hours then concentrated using under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA modifier) to afford 2-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanoic acid. MS ESI calcd. for C18H17F3N5O2[M+H]+ 392. found, 392. 1H NMR (500 MHz, DMOS-d6) δ 13.04 (s, 1H), 10.11 (s, 1H), 8.80 (d, J=4.9, 1H), 8.12 (s, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.32 (s, 1H), 7.24 (d, J=4.9, 1H), 7.09 (s, 1H), 5.11 (q, J=7.3, 1H), 2.29 (s, 3H), 1.67 (d, J=7.3, 3H).