Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[C:16]([F:19])([F:18])[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([B:25]([OH:30])[OH:26])[CH:12]=[CH:11][C:10]=1[C:16]([F:19])([F:18])[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)c1ccc(I)cc1OCc1ccccc1
Agent: CC(C)[Mg]Cl
Product: OB(O)c1ccc(C(F)(F)F)c(OCc2ccccc2)c1
Yield: 78.9 %

Procedure:
According to the method described in example 4.2, starting from 8 g (21.2 mmol) of 2-(benzyloxy)-4-iodo-1-(trifluoromethyl)benzene, 11.1 mL (22.2 mmol) of iPrMgCl and 5 mL (21.6 mmol) of triisopropyl borate, we obtain 4.95 g of [3-(benzyloxy)-4-(trifluoromethyl)phenyl]boronic acid in the form of oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:28][CH2:29][CH3:30])[C:14]([C:16]1[CH:17]=[C:18]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[C:19]([O:21]CC)=[O:20])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>C1COCC1.C(O)C.O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:28][CH2:29][CH3:30])[C:14]([C:16]1[CH:17]=[C:18]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[C:19]([OH:21])=[O:20])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCN(CCCCOCc1ccccc1)C(=O)c1cc(C)cc(C(=O)OCC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCCN(CCCCOCc1ccccc1)C(=O)c1cc(C)cc(C(=O)O)c1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a mixture of ethyl 3-{[[4-(benzyloxy)butyl](propyl)-amino]carbonyl}-5-methylbenzoate (1.75 g, 4.25 mmol) in THF/ethanol/water (1/2/1, 30 mL) is added lithium hydroxide (0.31 g, 12.76 mmol). The reaction mixture is stirred for 2 h and then acidified to pH=3 with concentrated hydrochloric acid (0.5 mL). The reaction mixture is extracted with ethyl acetate (2×30 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 3-{[[4-(benzyloxy)butyl](propyl)amino]carbonyl}-5-methylbenzoic acid (IX, 1.63 g), ESI-MS (m/z) [M+H]+=384.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:16][C@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:21]1[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:17]([CH3:16])[CH2:22]1
Reactant: O=Cc1ccc(N2CCOCC2)cc1Cl
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2Cl)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
A 100 mL round-bottom flask was charged with 2-chloro-4-(morpholin-4-yl)benzaldehyde (0.800 g, 3.54 mmol, 1.00 equiv), tert-butyl (2S)-2-methylpiperazine-1-carboxylate (0.783 g, 3.91 mmol, 1.10 equiv), 1,2-dichloroethane (20 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.26 g, 10.7 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (30 mL), extracted with dichloromethane (3×30 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (25/75) to provide 1.20 g (74% yield) of tert-butyl (2S)-4-[[2-chloro-4-(morpholin-4-yl)phenyl]methyl]-2-methylpiperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 410 [M+H]+.
Reaction SMILES: [NH:1]([C:30]([CH3:32])=[O:31])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:26]([O:28]C)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-].[Na+]>CO>[NH:1]([C:30]([CH3:32])=[O:31])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:26]([OH:28])=[O:27])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Yield: 94 %

Procedure:
Conversion to the Free Acid. Ac-Leu-Leu-Phe-OMe was dissolved in 150 mL of methanol and 26 mL of 1N sodium hydroxide was added and the rection was stirred 4 hours at which time the methanol was removed under reduced pressure and an additional 7 mL of sodium hydroxide was added. This water fraction was then washed with ethyl acetate (10 mL) and neutralized by the addition of 1N HCL. The resulting mixture was extracted with ethyl acetate 2×100 mL and the extract washed with 1N HCL, brine and dried over MgSO4, filtered and the solvents were removed under reduced pressure to give 7.56 g (94%) of Ac-Leu-Leu-Phe-OH as a white solid. The NMR (100 MHz, CDCl3) of the product acid bears striking resemblance to that of the precursor ester except for the loss of a signal at δ 3.6 and the appearance of a broad singlet at 10.1 (1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23]>FC(F)(F)C(O)=O.[Pt](=O)=O>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23]
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: COCCc1nc2c(N)nc3c(c2n1CCCCN)CCCC3
Reaction time: 600 h
Yield: 45 %

Procedure:
A catalytic amount of platinum (IV) oxide was added to a solution of 1-(4-aminobutyl)-2-methoxyethyl-1H-imidazo[4,5-c]quinolin-4-amine (7.7 g, 24.5 mmol) in trifluoroacetic acid (250 mL). The reaction mixture was hydrogenated at 50 psi (3.44×105 Pa) on a Parr apparatus. The progress of the reaction was monitored by LC/MS. Additional catalyst was added 7, 11, and 17 days after the start of the reaction. After 25 days the reaction was complete. The reaction mixture was filtered through a layer of Celite® filter aid to remove the catalyst and the filtrate was concentrated under vacuum. The residue was combined with 1 N hydrochloric acid (100 mL) and stirred overnight. The mixture was made basic (pH=11) with ammonium hydroxide and then extracted with dichloromethane (3×300 mL). The extracts were combined and concentrated under vacuum to provide 3.5 g of 1-(4-aminobutyl)-6,7,8,9-tetrahydro-2-methoxyethyl-1H-imidazo[4,5-c]quinolin-4-amine as a solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][NH:11][C:10]3=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][CH2:24][NH:25]2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][CH2:24][N:25]2[C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:8]=3)[N:13]=[CH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: O=c1[nH]cnc2ccc(-c3ccccc3)cc12
Reactant: Clc1ccc2c(c1)NCC2
Product: Clc1ccc2c(c1)N(c1ncnc3ccc(-c4ccccc4)cc13)CC2

Procedure:
The title compound was prepared in a manner analogous in the method of Example 4 using 6-Phenyl-3H-quinazolin-4-one (250 mg, 1.124 mmol) and 6-chloroindoline (172 mg, 1.124 mmol)). Three hundred eighty-nine milligrams (88%) of a yellow solid was isolated from the reaction mixture.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21](Br)=[C:20]([F:25])[CH:19]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:39](/B(O)O)=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>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.O>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21](/[CH:39]=[CH:40]/[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[C:20]([F:25])[CH:19]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC/C=C/B(O)O
Reactant: CCCCCCCCOc1ccc(C#Cc2ccc(Br)c(F)c2)cc1
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: O
Solvent: Cc1ccccc1
Product: CCCCCCC/C=C/c1ccc(C#Cc2ccc(OCCCCCCCC)cc2)cc1F
Yield: 72.4 %

Procedure:
In a four necked flask equipped with a thermometer and a stirrer, 1-(4-octyloxylphenyl)-2-(4-bromo-3-fluorophenyl)acetylene (4.8 g, 0.012 mol), tetrakis(triphenylphosphine)palladium (0.23 g, 0.2 mmol), toluene (50 ml), sodium carbonate (10.6 g, 0.1 mol) and water (90 ml) were charged. Then, to the mixture, E-1-nonenyl-dihydroxyborane (2.5 g, 0.015 mol) was added and reacted at a temperature of 80° to 85° C. for 6 hours. After cooling the reaction mixture, the aqueous layer was separated off, and the organic layer was washed with water. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1-(4-octyloxyphenyl)-2-[4-(1-trans-nonenyl)-3-fluorophenyl]acetylene (3.9 g). Yield: 73%.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)(=[O:3])[CH3:2].[C:13]([CH:15]1[CH2:17][NH:16]1)#[N:14].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([N:16]1[CH2:17][CH:15]1[C:13]#[N:14])=[O:12])(=[O:3])[CH3:2]
Reactant: N#CC1CN1
Reactant: CC(=O)NCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(=O)NCCCCCC(=O)N1CC1C#N

Procedure:
3.46 g. 6-Acetylaminohexanoic acid, 1.36 g. 2-cyanoaziridine and 4.3 g. dicyclohexylcarbodiimide are reacted in the usual manner in 35 ml. tetrahydrofuran and the reaction mixture then worked up to give 1.1 g. 1-(6-acetylaminohexanoyl)-2-cyanoaziridine which, after recrystallization from ethyl acetate-ligroin, melts at 74°-77° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:7]([OH:9])=O)=[CH:4][O:3]1.[CH3:10][NH:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH2:16][CH2:15]1>>[CH3:10][N:11]([CH2:12][CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=2)=[O:21])[CH2:18][CH2:19]1)[C:7]([C:5]1[NH:6][C:2](=[O:1])[O:3][CH:4]=1)=[O:9]
Reactant: O=C(O)c1coc(=O)[nH]1
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)c1coc(=O)[nH]1

Procedure:
The title compound was prepared from 2-oxo-2,3-dihydrooxazole-4-carboxylic acid (step 1) and 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3) analogously to Example 15 step 3;
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[BrH:12].CS(C)=O.[OH-].[Na+]>C(O)(=O)C>[Br:12][C:10]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=1
Reactant: Br
Reactant: CC(C)(C)c1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(Br)ccc1N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
25 g (168 mmol) of 2-tert-butylaniline are placed in 300 ml of acetic acid. 450 ml of aqueous HBr at 48% are added and the mixture is then cooled to 0° C. 150 ml of DMSO are added dropwise, the mixture having been brought back to ambient temperature is stirred for 2 hours and it is then poured into ice-cold water and basified to pH 10 with 5N NaOH. It is extracted with diethyl ether and the organic phase is then dried and concentrated to dryness. The residue is column-purified (95/5 heptane/EtOAc). 25.2 g of 4-bromo-2-tert-butylphenylamine are obtained in the form of a yellow oil (yield=65%).
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].[CH:5]1([CH2:11][CH:12]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[C:13]([C:15]2([CH3:21])[CH2:20][O:19][CH2:18][O:17][CH2:16]2)=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[Cl-].[Ca+2].[Cl-].Cl>C(O)C>[CH:5]1([CH2:11][CH:12]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[CH:13]([C:15]2([CH3:21])[CH2:16][O:17][CH2:18][O:19][CH2:20]2)[OH:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CC1(C(=O)C(CC2CCCCC2)n2cncn2)COCOC1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Product: CC1(C(O)C(CC2CCCCC2)n2cncn2)COCOC1
Yield: 101.8 %

Procedure:
A solution of 0.7 g (0.02 mol) of sodium borohydride in 3 ml of 0.1 normal aqueous sodium hydroxide solution is added to a mixture of 6.0 g (0.02 mol) of 3-cyclohexyl-1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-propan-1-one, 2.3 g of powdered calcium chloride and 30 ml of ethanol, while cooling with ice. When the evolution of gas has ended, the precipitate formed is dissolved again by addition of 30 ml of ethanol and 50 ml of dilute hydrochloric acid, the solution is concentrated to 60 ml in vacuo and the concentrate is neutralized with aqueous bicarbonate solution and extracted twice with 100 ml of methylene chloride each time. The combined organic phases are washed with water, dried over sodium sulphate and freed from the solvent in vacuo. 6.3 g (100% of theory) of 3-cyclohexyl-1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-propan-1-ol are obtained as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=2)[CH:3]=[N:2]1.Cl.[CH3:15][C:16]1([CH3:22])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:15][C:16]1([CH3:22])[CH2:21][CH2:20][N:19]([C:11]([C:8]2[CH:7]=[C:6]([C:4]3[CH:5]=[N:1][NH:2][CH:3]=3)[S:10][CH:9]=2)=[O:13])[CH2:18][CH2:17]1
Reactant: O=C(O)c1csc(-c2cn[nH]c2)c1
Reactant: CC1(C)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)CCN(C(=O)c2csc(-c3cn[nH]c3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
5-(1H-Pyrazol-4-yl)-thiophene-3-carboxylic acid (0.075 g, 0.39 mmol) and 4,4-dimethylpiperidine hydrochloride (0.087 g, 0.58 mmol) were dissolved in DMF (3 mL) then DIPEA (0.2 g, 1.55 mmol) and HATU (0.175 g, 1.55 mmol) were added and the reaction mixture was stirred at room temperature overnight. The solvent was removed by evaporation then the residue was dissolved in DCM and washed with aqueous sodium hydrogen carbonate solution. The organics were dried by evaporation. The crude material was purified by HPLC, eluting with 5%-98% acetonitrile in water (0.1% formic acid) over 20 minutes. The fractions containing the desired product were freeze-dried to give the title compound (0.063 g). LCMS m/z 290.18 [M+H]+ R.T.=8.74 min (Analytical Method 2).
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:24])[NH:6][C:7]([NH:10][CH2:11][CH2:12][S:13][CH2:14][C:15]2[CH:19]=[C:18]([CH2:20][N:21]([CH3:23])[CH3:22])[S:17][CH:16]=2)=[N:8][CH:9]=1)([O-])=O.Cl>[Ni].CO>[NH2:1][C:4]1[C:5](=[O:24])[NH:6][C:7]([NH:10][CH2:11][CH2:12][S:13][CH2:14][C:15]2[CH:19]=[C:18]([CH2:20][N:21]([CH3:22])[CH3:23])[S:17][CH:16]=2)=[N:8][CH:9]=1
Reactant: CN(C)Cc1cc(CSCCNc2ncc([N+](=O)[O-])c(=O)[nH]2)cs1
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: CN(C)Cc1cc(CSCCNc2ncc(N)c(=O)[nH]2)cs1
Yield: 34.4 %

Procedure:
A mixture of 5-nitro-2-{2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamino}-4(3H)-pyrimidone (1.3 g; 3.51 mmoles) and a catalytic amount of Raney nickel No. 28 (approximately 1.4 cm3) in 108 ml of methanol was hydrogenated in a Parr apparatus at 50 psi for 2.5 hours. The reaction mixture was filtered, treated with 1.55N methanolic hydrochloric acid (7.0 ml, 10.9 meq.) and then evaporated under reduced pressure. The residue was placed on 85 g of silica gel and chromatographed by flash chromatography using a gradient elution of methanol:CH2Cl2 :H2O from 20:80:1 to 30:70:1. The appropriate fractions were combined and treated with 7.0 ml of 1.55N methanolic HCl, and then evaporated under reduced pressure and dried under high vacuum at 56° C. for 6 hours to give 0.41 g of the title compound as a trihydrochloride salt which had an indeterminate melting point. The NMR spectrum (100 MHz) in d6 dimethyl sulfoxide gave the following resonances δ: 8.88 (m, 6H); 8.18 (m, 1H), 7.82 (s, 1H), 7.56 (s, 1H), 7.40 (s, 1H); 4.50 (s, 2H); 3.82 (s, 2H); 3.50 (m, 2H); 2.73 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[O-:11][CH2:12][CH3:13].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:11][CH2:12][CH3:13])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(Cl)nc(SC)n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a solution of 4,6-dichloro-2-methylsulfanylpyrimidine (500 mg, 2.56 mmol) in anhydrous DMF (6 mL) was added sodium ethoxide (174 mg, 2.56 mmol). The reaction mixture was stirred at 70° C. for overnight. The resulting mixture was poured into 30 mL of water and was extracted with diethyl ether (20 mL×3) three times. The ether layer was separated and dried with anhydrous MgSO4 and concentrated in vacuo to give crude product 4-chloro-6-ethoxy-2-methylsulfanylpyrimidine (525 mg). 1H-NMR (CDCl3): δ 6.39 (s, 1 H), 4.43 (q, J=7.1 Hz, 2 H), 2.54 (s, 3 H), 1.38 (t, J=7.1 H, 3 H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C([O-])([O-])=O.[K+].[K+].[N:17]12CCCNC1CCCC=C2.[H-].[Na+]>C1COCC1.CN(C=O)C.COCCOC.C(N(CC)CC)C>[NH2:17][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1nc2ccccc2o1
Reactant: C1=CN2CCCNC2CCC1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: COCCOC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1nc2ccccc2o1
Temperature: 50 °C

Procedure:
A mixture of an appropriate 2-chlorobenzoxazole, A1 (1 eq), and appropriate amine (2 eq) and optional base (e.g. K2CO3, triethylamine, disopropylamine, 1,8-diazabicyclo[5.4.0]undecene, or sodium hydride) in THF (or DME, DMF) was heated in the range of 20 to 80° C. up to 24 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (typical eluents include 9:1 dichloromethane/methanol, ethyl acetate, hexanes) to afford the desired product 2-aminobenzoxazole. Product structure was confirmed by 1H NMR or by mass analysis.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]([CH:9]=[CH:10][C:11]([O:13]C)=[O:12])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO>[CH3:1][NH:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: CNC(=O)c1ccc(C=CC(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNC(=O)c1ccc(C=CC(=O)O)cc1
Reaction time: 3 h
Yield: 79.8 %

Procedure:
To a solution of methyl 4-(methylcarbamoyl)cinnamate (75 mg) in methanol (3 ml) was added 1 N aqueous sodium hydroxide solution (0.5 ml) at 40° C. The mixture was stirred at same temperature for 3 hours. 1 N-Hydrochloric acid (0.5 ml) was added to the reaction mixture and evaporated in vacuo. Water was added to the residue, the mixture was filtered and the residue was washed with diethyl ether to give 4-(methylcarbamoyl)cinnamic acid (56 mg) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[C:25]([F:26])=[C:24]([F:27])[CH:23]=[C:22](F)[C:3]=1[C:4]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[H-].[Na+]>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[N:13]1[C:22]2[C:3](=[C:2]([CH3:1])[C:25]([F:26])=[C:24]([F:27])[CH:23]=2)[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12]1
Reactant: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)c1c(F)cc(F)c(F)c1C
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2cc(F)c(F)c(C)c2c1=O
Yield: 67 %

Procedure:
Employing ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-(2,4-difluorophenyl)aminoacrylate (1.1 g) and 60% sodium hydride (0.13 g), the procedure of Reference Example 9 is repeated to give ethyl 1-(2,4-difluorophenyl)-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.7 g).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH3:6][N:7]1[C:11]([CH:12]=O)=[CH:10][N:9]=[C:8]1[N+:14]([O-:16])=[O:15]>O.CO>[CH3:6][N:7]1[C:11]([CH:12]=[N:1][NH:2][C:3]([NH2:5])=[S:4])=[CH:10][N:9]=[C:8]1[N+:14]([O-:16])=[O:15]
Reactant: Cn1c(C=O)cnc1[N+](=O)[O-]
Reactant: NNC(N)=S
Solvent: CO
Solvent: O
Product: Cn1c(C=NNC(N)=S)cnc1[N+](=O)[O-]

Procedure:
A solution of 1.42 g. of thiosemicarbazide in water is added to a solution of 1.8 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde in methanol. The solid which precipitates is recovered on the filter. Yield: 2.2 g., m.p. 282°-287° C.
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5]([C:29](F)(F)F)=[CH:4][CH:3]=1.ClC1SC2C(=C(C#N)C=CC=2)[N:38]=1>>[NH2:28][C:12]1[C:11]([C:8]2[S:9][C:10]3[C:6](=[C:5]([C:29]#[N:38])[CH:4]=[CH:3][CH:2]=3)[N:7]=2)=[CH:16][C:15]([C:17]2[CH:18]=[N:19][N:20]([CH:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)[CH:21]=2)=[CH:14][N:13]=1
Reactant: N#Cc1cccc2sc(Cl)nc12
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Product: N#Cc1cccc2sc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)nc12

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 2-chloro-1,3-benzothiazole-4-carbonitrile and conducting the Suzuki coupling at 80° C. for 2 h, the title compound was obtained as a yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ=2.04-2.23 (m, 4H), 3.04 (m, 2H), 3.30 (m, 2H), 4.44 (mc, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.99 (s, 1H), 8.03 (dd, J=7.6, 1.0 Hz, 1H), 8.34 (s, 1H), 8.49 (dd, J=8.1, 1.0 Hz, 1H), 8.51 (d, J=2.3 Hz, 1H), 8.86 (broad s, 1H), 9.03 (broad s, 1H). MS (ES′): m/z=402.15 [MH+]. HPLC: tR=2.28 min (ZQ3, polar—5 min).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH2:6][C:7]1[S:8][CH:9]=[C:10](O)[C:11]=1[C:12]#[N:13].N1C=CC=CC=1>O1CCCC1>[NH2:6][C:7]1[S:8][CH:9]=[C:10]([Cl:3])[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(O)csc1N
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1c(Cl)csc1N
Reaction time: 8 h
Yield: 60 %

Procedure:
15.3 parts of phosphoryl trichloride are added to a mixture of 14 parts of 2-amino-3-cyano-4-hydroxythiophene, 7.9 parts of pyridine and 70 parts of tetrahydrofuran, and the mixture is then heated at the boil for 1 hour. After cooling, the mixture is poured onto water and left to stand overnight, and the precipitate is filtered off under suction, washed with water and dried. 9.4 parts (60% of theory) of 2-amino-4-chloro-3-cyanothiophene are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCc1cccc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCCc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
A solution of 4-(3-benzyloxyphenyl)butyric acid (22.0 g) in tetrahydrofuran (150 ml) was added dropwise to a suspension of lithium aluminum hydride (6.18 g) in tetrahydrofuran (150 ml) at 0° C. and then stirred for one hour at room temperature. The reaction mixture was quenched with H2O, acidified with 1N-hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with 1N-hydrochloric acid, saturated aqueous sodium bicarbonate and water, dried (MgSO4), and concentrated under reduced pressure to give 4-(3-benzyloxyphenyl)butanol (20.5 g, 99%). Oily substance.