Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]12.Cl[C:12]1[N:13]=[CH:14][C:15]([C:18]([NH:20][C:21]2[NH:22][N:23]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=3)[CH:25]=2)=[O:19])=[N:16][CH:17]=1>CS(C)=O>[CH2:1]1[CH:2]2[CH2:10][CH2:9][CH2:8][CH2:7][N:3]2[CH2:4][CH2:5][N:6]1[C:12]1[N:13]=[CH:14][C:15]([C:18]([NH:20][C:21]2[NH:22][N:23]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=3)[CH:25]=2)=[O:19])=[N:16][CH:17]=1
Reactant: C1CCN2CCNCC2C1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Solvent: CS(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN5CCCCC5C4)cn3)[nH]n2)cc(OC)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
2,3,4,6,7,8,9,9a-Octahydro-1H-pyrido[1,2-a]pyrazine (477 mg, 3.40 mmol) was added in one portion to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (659 mg, 1.70 mmol) in anhydrous dimethylsulfoxide (1.70 ml) at 25° C. The resulting solution was stirred at 100° C. for 18 h. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluant was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% formic acid) and MeCN as eluents. The sample was then put through a basic HPLC system to obtain the free base. Fractions containing the desired compound were evaporated to dryness to afford the title compound (395 mg, 47%) as a cream solid.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[C:17]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([NH:16][S:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[O:40])=[O:39])=[CH:15][C:9]=3[O:8]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 6 %

Procedure:
2,2-Diphenyl-1,3-benzodioxol-5-amine was dissolved in dichloromethane (5 ml). N-ethyldiisopropyl amine (0.1 ml. 0.6 mmol) and benzenesulfonyl chloride (88 mg, 0.5 mmol) were added. The reaction was stirred for 5 hours at room temperature. The reaction was washed with cold 1N aqueous HCl, with 1N aqueous NaOH and with saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated in vacuo. The residue was purified by column chromatography using dichloromethane as the eluant. The product was crystallized from hexane to yield the product as white crystals (12 mg, 6%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:36])([F:35])[C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:36])([F:19])[F:35])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1cccc(C(F)(F)F)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(C(F)(F)F)c3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=0.98 min; [M+H]+=445.13.
Reaction SMILES: [C:1]([O:7][CH2:8][O:9][C:10]([C:12]1[N:17]2[C:18](=[O:39])[C@@H:19]([NH:20][C:21](=[O:38])/[C:22](/[C:25]3[N:26]=[C:27]([NH:30]C(OC(C)(C)C)=O)[S:28][CH:29]=3)=[CH:23]\[CH3:24])[C@H:16]2[S:15][CH2:14][C:13]=1[CH2:40][O:41][C:42](=[O:44])[NH2:43])=[O:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>FC(F)(F)C(O)=O>[C:1]([O:7][CH2:8][O:9][C:10]([C:12]1[N:17]2[C:18](=[O:39])[C@@H:19]([NH:20][C:21](=[O:38])/[C:22](/[C:25]3[N:26]=[C:27]([NH2:30])[S:28][CH:29]=3)=[CH:23]\[CH3:24])[C@H:16]2[S:15][CH2:14][C:13]=1[CH2:40][O:41][C:42](=[O:44])[NH2:43])=[O:11])(=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4]
Reactant: C/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(COC(N)=O)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Product: C/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(COC(N)=O)CS[C@H]12)c1csc(N)n1
Yield: 55.4 %

Procedure:
A solution of 7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-butenoyl]amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (160 mg) in trifluoroacetic acid (2 ml) is stirred at room temperature for 120 minutes and concentrated. To the resulting residue is added aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract solution is purified by silica gel chromatography to give 7beta-[(Z)-2-(2-aminothiazol-4-yl)-2-butenoyl]amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (75 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:27])([F:26])[F:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)=[CH:10][N:4]2[N:3]=1.[Cu](C#N)[C:29]#[N:30].CN1CCOCC1>CCOCC.C([O-])(O)=O.[Na+]>[C:29]([C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:27])([F:26])[F:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)=[CH:10][N:4]2[N:3]=1)#[N:30]
Reactant: N#C[Cu]C#N
Reactant: CC(C)(C)C(=O)Nc1cc(-c2cn3nc(Cl)ccc3n2)ccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: CC(C)(C)C(=O)Nc1cc(-c2cn3nc(C#N)ccc3n2)ccc1C(F)(F)F
Temperature: 215 °C
Reaction time: 4 h
Yield: 25.8 %

Procedure:
An 8 mL vial is charged with N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-(trifluoromethyl)phenyl]-2,2-dimethyl-propanamide (0.059 g, 0.15 mmol), copper cyanide (0.035 g, 0.3 mmol), and 4-methylmorpholine (0.43 mL). The mixture is stirred at 215° C. for 4 hr in the microwave, then cooled, diluted with Et2O, sat. aqueous NaHCO3 and the biphasic mixture is filtered. Organics are collected and aqueous layer is extracted twice more with Et2O. Organics are combined, dried, concentrated, and purified by prep plate TLC (1:1 Hex:EtOAc) to give the title compound (15 mg, 26% yield). LCMS m/z=388.5 [M+H]+, tR=2.56 min. (compound same as Example 173)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)(=O)C.CCCCCC>[CH3:8][CH:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC=Cc1ccccc1
Reactant: Nc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(Cc1ccccc1)Nc1ccccc1
Yield: 50 %

Procedure:
According to GWM, 0.011 mol (=1.00 ml) of aniline and 0.011 mol (=1.43 ml) of β-methylstyrene are reacted with one another. The product is isolated by column chromatography using ethyl acetate/n-hexane (1:10) as eluent, the product (±)-N-(1-methyl-2-phenylethyl)aniline being obtained as a slightly pink liquid.
Reaction SMILES: C[O:2][C:3](=[O:43])/[C:4](/[CH2:33][C:34]1[CH:39]=[CH:38][C:37]2[O:40][CH2:41][O:42][C:36]=2[CH:35]=1)=[C:5](/[C:23]1[N:27]([CH3:28])[C:26]([CH2:29][CH2:30][CH2:31][CH3:32])=[N:25][CH:24]=1)\[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[O:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17]>[OH-].[Na+].C(O)(C)C>[CH2:29]([C:26]1[N:27]([CH3:28])[C:23](/[C:5](/[C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[O:14][CH2:15][C:16]([OH:18])=[O:17])=[C:4](\[CH2:33][C:34]2[CH:39]=[CH:38][C:37]3[O:40][CH2:41][O:42][C:36]=3[CH:35]=2)/[C:3]([OH:43])=[O:2])=[CH:24][N:25]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCc1ncc(/C(=C(\Cc2ccc3c(c2)OCO3)C(=O)OC)c2ccc(OC)cc2OCC(=O)OC(C)(C)C)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCCc1ncc(/C(=C(\Cc2ccc3c(c2)OCO3)C(=O)O)c2ccc(OC)cc2OCC(=O)O)n1C

Procedure:
Methyl-(E)-3(2-n-Butyl-1-methyl-1H-imidazol-5-yl)-3-(2-t-butoxycarbonylmethoxy-4-methoxyphenyl)-2-(3,4-methylenedioxybenzyl)prop-2-enoate (85 mg, 0.144 mmol) in 2.5N NaOH (1.0 ml) and isopropanol (2.0 ml) was heated under argon at 95° for 18 hours. The solvent (i-PrOH) was removed under reduced pressure and the residue was diluted with H2O and washed with EtOAc. The pH of the aqueous layer was lowered to 3.5 with 1M HCl and the solution was extracted with EtOAc (5x). The combined extracts were dried (Na2SO4 anhydrous) and evaporated. (48 mg, 64%). The crude title compound was recrystallized from CHCl3 /CH3CN to afford a white solid. (26 mg, 36%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[C:11]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:12]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=S(=O)(O)Cl
Product: COc1ccc(Br)cc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To chlorosulphonic acid (140 mL, 2 mol), cooled to 0-5° C., there added dropwise 35 ml (0.279 mol) of 4-bromoanisole. The solution is stirred for 30 minutes at 0° C. and then for about 16 hours at ambient temperature; it is poured slowly onto ice and is then stirred for a few more minutes. The white precipitate formed is filtered off and then washed with copious amounts of water.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:11])[CH:7]=[CH:8][C:9]=1[Br:10])([O-])=O.Cl.[OH-].[K+]>O.C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH3:11])[CH:7]=[CH:8][C:9]=1[Br:10]
Reactant: Cc1ccc(Br)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(Br)c(N)c1
Yield: 93.8 %

Procedure:
3-Nitro-4-bromotoluene (54 g) (ex Lancaster) in a water, ethanol solution (100 ml. 1:1) was rapidly stirred and iron powder (84 g) (ex BDH) was added at 25°. This mixture was heated to reflux and concentrated hydrochloric acid (2.19 g) in water, ethanol (50 ml, 1:1) was added dropwise over 30 minutes. After 4 hours at reflux, the mixture was cooled, made alkaline with 15% potassium hydroxide solution and filtered through celite washing with ethanol (2×50 ml). The resulting mixture was diluted with water (1000 ml) and worked up in the usual manner, to give 3-amino-4-bromotoluene (43.6 g). NMR 1H : 7.25(1H,d), 6.40(2H,m), 3.96(2H,bs), 2.2(3H,s).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH2:26]([O:28][CH2:29][CH2:30][C:31](=[NH:34])[NH:32]O)[CH3:27]>>[CH2:26]([O:28][CH2:29][CH2:30][C:31]1[N:34]=[C:23]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:25][N:32]=1)[CH3:27]
Reactant: CCOCCC(=N)NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1
Product: CCOCCc1noc(C2CC(c3ccc(CC)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 600 mg (1.655 mmol) of the compound from Example 7A and 355 mg (approx. 2.152 mmol) of 3-Ethoxy-N-hydroxypropanimidamide were reacted Yield: 389 mg (49% of theory)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Cl:19][C:20]1[CH:21]=[CH:22][C:23](/[C:28](/[C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH3:43])[CH:37]=2)=[CH:29]/[C@@H:30]2[NH:34][C:33](=[O:35])[CH2:32][CH2:31]2)=[N:24][C:25]=1[O:26][CH3:27].O>CN(C)C=O>[Si:12]([O:11][CH2:10][CH2:9][CH2:8][O:42][C:39]1[CH:40]=[CH:41][C:36](/[C:28](/[C:23]2[CH:22]=[CH:21][C:20]([Cl:19])=[C:25]([O:26][CH3:27])[N:24]=2)=[CH:29]\[C@@H:30]2[NH:34][C:33](=[O:35])[CH2:32][CH2:31]2)=[CH:37][C:38]=1[CH3:43])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(O)c(C)c2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(C)c2)ccc1Cl
Temperature: 65 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (470 mg) and (3-bromopropoxy)-tert-butyldimethylsilane (600 μL) were sequentially added to a solution of (5R)-5-[(E)-2-(5-chloro-6-methoxypyridin-2-yl)-2-(4-hydroxy-3-methylphenyl)ethenyl]pyrrolidin-2-one obtained in Example 4-50(2) (610 mg) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 15 hours and at 65° C. for three hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:4→2:8) to give (5R)-5-[(E)-2-[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-3-methylphenyl]-2-(5-chloro-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one as a colorless amorphous (879 mg, 97%).
Reaction SMILES: FC1C=C(Cl)C(OC2CCCC2)=CC=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].COC1C=C(CC[NH2:38])C=CC=1OC.C(N(CC)CC)C>C1C=CC=CC=1>[C:16]([NH2:38])(=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH2:15])=[O:20]
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: NC(=O)C1=C(C(N)=O)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 250.8 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), 2-(3,4-dimethoxyphenyl)ethylamine (0.600 g, 3.31 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (20. ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-{2-3,4-dimethoxyphenyl)ethyl)-3,4,5,6-tetrahydrophthalamide as white crystals (1.16 g, 77.5% yield).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[CH:8]>>[C:9]1([C:7]#[C:8][C:2]2[N:3]=[CH:4][NH:5][CH:6]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1c[nH]cn1
Product: C(#Cc1c[nH]cn1)c1ccccc1

Procedure:
The title compound, MS: m/e=169.2 (M+H+) was prepared in accordance with the general method of example 1b from 4-bromoimidazole and ethynylbenzene.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([CH:16]=[O:17])=[CH:15][C:4]=2[N:3]=1.[Li][CH3:19]>C1COCC1>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([CH:16]([OH:17])[CH3:19])=[CH:15][C:4]=2[N:3]=1
Reactant: Nc1nc2cc(C=O)ccc2c2cccnc12
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(c1)nc(N)c1ncccc12
Temperature: 25 °C

Procedure:
To a solution of 5-aminobenzo[f][1,7]naphthyridine-8-carbaldehyde (from Example 87) (1.0 eq.) in THF (0.02M) was added MeLi (2.5 eq.) at −78° C. The reaction was allowed to warm to ambient temperature overnight. The reaction was quenched by saturated NH4Cl and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated en vacuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give 145-aminobenzo[f][1,7]naphthyridin-8-yl)ethanol as a yellow solid: 1H NMR (methanol-d4): δ 8.94 (dd, 1H), 8.88 (dd, 1H), 8.38 (d, 1H), 7.81 (dd, 1H), 7.62 (d, 1H), 7.41 (dd, 1H), 4.97 (q, 1H), 1.53 (d, 3H). LRMS [M+H]=240.1.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:8]([F:10])([F:9])[C:7]([F:12])([F:11])[C:6]=1Cl)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>O.[C].[Pd]>[CH:1]([O:4][CH:5]1[CH2:6][C:7]([F:11])([F:12])[C:8]1([F:9])[F:10])([CH3:3])[CH3:2]
Reactant: CC(C)OC1=C(Cl)C(F)(F)C1(F)F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)OC1CC(F)(F)C1(F)F
Yield: 55 %

Procedure:
30 g (0.132 mol) of 2-chloro-3,3,4,4-tetrafluorocyclobutenyl isopropyl ether and 20 g (0.145 mol) of potassium carbonate are hydrogenated over 10 g of palladium-carbon in 100 ml of water at 120° C. for 5 hours. The catalyst is filtered off and the filtrate is extracted with dichloromethane. After drying, 2,2,3,3-tetrafluorocyclobutyl isopropyl ether is obtained with a yield of 55%.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:26]=[CH:25][C:9]([O:10][CH2:11][CH2:12][CH:13]2[CH2:16][N:15]([CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[CH2:14]2)=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH:13]2[CH2:14][N:15]([CH:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:18])[CH2:16]2)=[CH:25][CH:26]=1)=[O:4]
Reactant: CN=C=O
Reactant: CC(c1ccccc1)N1CC(CCOc2ccc(N)cc2)C1
Solvent: ClC(Cl)Cl
Product: CNC(=O)Nc1ccc(OCCC2CN(C(C)c3ccccc3)C2)cc1
Reaction time: 3 h

Procedure:
Under anhydous conditions, methyl isocyanate (10 mmol) is added dropwise to a stirred solution of 3-[2-(4-aminophenoxy)ethyl]-1-(1-phenylethyl)azetidine (10 mmol) in chloroform (100 ml). After stirring for 3 hr the solvent is removed and the residue purified by standard laboratory procedures.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:11][C:10]2[C:5](=[N:6][CH:7]=[C:8]([OH:12])[CH:9]=2)[CH:4]=1.Cl.Cl[C:15]1[S:16][C:17]2[C:18]([N:23]=1)=[N:19][CH:20]=[CH:21][CH:22]=2.C([O-])([O-])=O.[Cs+].[Cs+].[NH4+].[Cl-]>CN(C=O)C>[S:16]1[C:17]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:23]=[C:15]1[O:12][C:8]1[CH:9]=[C:10]2[O:11][C:3]([CH2:2][OH:1])=[CH:4][C:5]2=[N:6][CH:7]=1
Reactant: Clc1nc2ncccc2s1
Reactant: OCc1cc2ncc(O)cc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: OCc1cc2ncc(Oc3nc4ncccc4s3)cc2o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a mixture of 2-(hydroxymethyl)furo[3,2-b]pyridin-6-ol (200 mg, 1.21 mmol), 2-chloro-thiazolo-[4,5-b]pyridine hydrochloride (300 mg, 1.45 mmol) and Cs2CO3 (800 mg, 2.46 mmol) was added DMF (12 mL). The suspension was stirred (rt, 16 h) and then poured into ice-cold sat'd. aq. NH4Cl. The resultant precipitate was filtered, rinsed with water and dried to provide the product as a beige solid (326 mg, 90%). MS (ESI): mass calcd. for C14H9N3O3S, 299.04; m/z found, 300.0 [M+H]+. 1H NMR (600 MHz, CD3OD): 8.63 (d, J=2.3, 1H), 8.49 (dd, J=4.9, 1.6, 1H), 8.36 (dd, J=8.0, 1.6, 1H), 8.23 (dd, J=2.3, 0.9, 1H), 7.37 (dd, J=8.0, 4.9, 1H), 6.95 (s, 1H), 4.76 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([CH:7]=[CH:8][CH2:9][CH:10]=1)[C:4]([OH:6])=[O:5].[Al]>C1C2C(CCCC2)CCC1.CCCCCC.[Rh]>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC1=CCC=CC1C(=O)O
Agent: [Rh]
Agent: *O[SiH2]*
Agent: [Al]
Solvent: CCCCCC
Solvent: C1CCC2CCCCC2C1
Product: Cc1ccccc1C(=O)O

Procedure:
To a suspension of 2-methyl-1,4-dihydrobenzoic acid (0.085g, 0.50 mmol; 81% pure, from Aldrich Chemical Company) in decalin (5 mL) under a nitrogen atmosphere is added a polysiloxane matrix material containing a homogenous dispersion of rhodium and aluminum (0.100 g). The solution is heated to reflux for 19 hours. On cooling the reaction mixture is diluted with hexane (25 mL) and extracted with aqueous sodium hydroxide (5%) solution (2×5 mL). The basic aqueous solution is acidified and extracted with chloroform (3×4 mL). The combined organic layer is dried over anhydrous sodium sulfate. The solvent is evaporated using a rotary evaporator to give 2-methylbenzoic acid.
Reaction SMILES: CO.[F:3][C:4]([F:23])([F:22])[C:5]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([O:20]C)=[O:19])[CH:14]=2)[N:9]=1)([CH3:7])[CH3:6].[OH-].[Na+]>C1COCC1>[F:23][C:4]([F:3])([F:22])[C:5]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([OH:20])=[O:19])[CH:14]=2)[N:9]=1)([CH3:7])[CH3:6]
Reactant: COC(=O)c1ccc2nc(C(C)(C)C(F)(F)F)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(c1ccc2cc(C(=O)O)ccc2n1)C(F)(F)F
Yield: 99.8 %

Procedure:
A methanol (6 ml) and THF (6 ml) solution of methyl 2-(2,2,2-trifluoro-1,1-dimethylethyl)quinoline-6-carboxylate (777 mg, 2.6 mmol) and 2M sodium hydroxide aqueous solution (2.6 ml, 5.2 mmol) was treated in the procedure described in Step C-2C to furnish the title compound (735 mg, 99% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.75 (6H, s), 7.74 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=8.8 Hz), 8.29 (1H, d, J=8.8 Hz), 8.35-8.40 (1H, m), 8.69-8.70 (1H, m). MS (ESI): m/z 284 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:25]#[C:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:23][C@@H:22]([OH:24])[CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C1COCC1.CO.[OH-].[Li+]>O>[CH3:29][C:27]([CH3:28])([CH3:30])[C:26]#[C:25][C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C@H:20]2[CH2:21][C@@H:22]([OH:24])[CH2:23]2)[C:11]([CH:13]2[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]2)=[O:12])[CH:8]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1C[C@@H](O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)[C@H]2C[C@@H](O)C2)CC1
Temperature: 60 °C

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(cis-3-hydroxy-cyclobutyl)-(trans-4-methyl-cyclohexancarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (400 mg, 0.93 mmol) in a 3:2:1 mixture of THF:MeOH:water (20 mL) was treated with lithium hydroxide (4.5 mL, 1.0 M aqueous solution) and heated to 60° C. for 2 hours. The organic volatiles were evaporated under reduced pressure and remaining solution was acidified with 10% HCl(aq). A white precipitate was collected by vacuum filtration, washed with water, and dried to afford 290 mg (74% yield) of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(cis-3-hydroxy-cyclobutyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid as a white powder. MS (m/z): 415.8 [M−H]−; HPLC retention time: 4.10 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]([CH2:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)(=[O:18])[NH2:17]>>[C:16]([CH2:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:23][CH:22]=1)(=[O:18])[NH2:17]
Reactant: NC(=O)COc1ccc(N)cc1
Reactant: Cc1cccc(Nc2cc(Cl)ncn2)c1
Product: Cc1cccc(Nc2cc(Nc3ccc(OCC(N)=O)cc3)ncn2)c1
Yield: 30 %

Procedure:
Using an analogous procedure to that described in Example 13, 4-chloro-6-(3'-methylanilino)pyrimidine (0.23 g) was reacted with 4-(carbamoylmethoxy)aniline to give 4-[4'-(carbamoylmethoxy)anilino]6-(3'-methylanilino)pyrimidine in 30% yield, m.p. 212°-215° C.;