Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][C:9]=2[CH:10]=1)=[O:5])C.[CH3:23][CH2:24][Mg+].[Br-].[CH2:27]1COC[CH2:28]1>>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:8]2[O:7][C:6]([C:4]([OH:5])([CH2:23][CH3:24])[CH2:27][CH3:28])=[CH:10][C:9]=2[CH:11]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC[Mg+]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2o1
Agent: [Br-]
Product: CCC(O)(CC)c1cc2cc(OCc3ccccc3)ccc2o1
Yield: 97 %

Procedure:
5-Benzyloxy-benzofuran-2-carboxylic acid ethyl ester (6.02 g, 20.3 mmol) and EtMgBr (20.3 mL, 3.0 M) in THF (100 mL) are reacted analogous to Example 18-B to give the title compound (6.10 g, 97%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[CH2:8]([O:10][C:11]([C:13]1[C:14]([CH2:38]Cl)=[N+:15]([O-:37])[C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)=[CH:20][C:19]([O:33][CH3:34])=[C:18]([O:35][CH3:36])[CH:17]=2)=[O:12])[CH3:9].O>CN(C)C=O>[CH2:8]([O:10][C:11]([C:13]1[C:14]([CH2:38][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[N+:15]([O-:37])[C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)=[CH:20][C:19]([O:33][CH3:34])=[C:18]([O:35][CH3:36])[CH:17]=2)=[O:12])[CH3:9]
Reactant: c1nc[nH]n1
Reactant: CCOC(=O)c1c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2[n+]([O-])c1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2[n+]([O-])c1Cn1cncn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.8 %

Procedure:
Oily sodium hydride (60%, 0.156 g) was added to a solution of 1H-1,2,4-triazole (0.27 g) in N,N-dimethylformamide (DMF) (20 ml), followed by stirring at room temperature for 15 minutes. Then 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylic acid ethyl ester 1-oxide (1.5 g) was added, followed by stirring at 80° C. for 45 minutes. The reaction mixture was poured over water and extracted with dichloromethane. The dichloromethane layer was washed with water and then dried (MgSO4), after which the solvent was distilled off. The residual oily substance was subjected to silica gel column chromatography and eluted with chloroform-methanol (30:1, v/v) to yield 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester 1-oxide (0.8 g, 50%), which was then recrystallized from dichloromethane-hexane to yield a colorless prismatic crystal having a melting point of 221° to 222° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][S:6]1(=[O:16])=[O:15].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:5]([CH2:4][CH2:3][CH2:2][Cl:1])[S:6]2(=[O:16])=[O:15])=[CH:20][CH:19]=1
Reactant: O=S1(=O)Nc2ccccc2CN1CCCCl
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1ccc(Cl)cc1

Procedure:
In an analogous manner to Example 1 step 7, 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (468 mg) was coupled to p-chloro phenylboronic acid to provide 1-(4-chlorophenyl)-3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (50 mg):
Reaction SMILES: [CH2:1]([O:3][CH:4]=[C:5]([C:9]([O-:11])=O)[C:6]([O-])=O)[CH3:2].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1([O:25]C2C=CC=CC=2)C=CC=CC=1>>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[N:12][C:13]2[C:18]([C:9]=1[OH:11])=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:25])[CH3:2]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: Nc1ccccc1
Reactant: CCOC=C(C(=O)[O-])C(=O)[O-]
Product: CCOC(=O)c1cnc2ccccc2c1O

Procedure:
The intermediates (1) are prepared according to the procedures described in J. Amer Chem. Soc. 68, 1204 (1946). Ethoxymethylenemalonate is warmed with an appropriate aniline to give an anil which cyclizes upon heating in boiling diphenylether to give the ethyl-4-hydroxyquinoline-3-carboxylate. Reaction of this intermediate with phosphorus oxychloride gives the intermediate (1). The intermediates (2) are either commercially available or can be prepared from the corresponding ester by hydrolysis. The intermediate (3) can be prepared from (6) by ##STR11## treatment with hydroxylamine hydrochloride followed by reduction of the oxime with nickle/aluminum alloy as described in U.S. Pat. No. 3,875,163, or, when a weaker reducing agent is required, by treatment with ammonium acetate followed by reduction with sodium cyanoborohydride as described in J. Amer. Chem. Soc., 68, 7032 (1979). The intermediate (6) can be prepared. as described in U.S. Pat. No. 4,816,464. The intermediate R8NHR17 where R17 is ##STR12## and R8 is not H can be prepared from (3) by acylation with R15COCl or (R15CO)2O or formylation with formic acetic anhydride followed by reduction with lithium aluminum hydride.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[CH3:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[NH:18][CH:19]1[CH2:24][O:23][C:21](=[O:22])[CH2:20]1.N1C=CC=CC=1>ClCCl>[CH3:1][O:2][CH2:3][C:4]([N:18]([CH:19]1[CH2:24][O:23][C:21](=[O:22])[CH2:20]1)[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[CH3:7])=[O:5]
Reactant: COCC(=O)Cl
Reactant: Cc1ccc2ccccc2c1NC1COC(=O)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC(=O)N(c1c(C)ccc2ccccc12)C1COC(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2.4 g (0.022 mol) sample of methoxyacetyl chloride was added dropwise to a solution of 5.5 g (0.022 mol) 3-(N-2-methylnaphth-1-ylamino)-gamma-butyrolactone and 1.7 g (0.022 mol) pyridine in 100 ml dichloromethane. The reaction mixture was stirred one hour at about 25° C. and then heated under reflux for 6 hours. After cooling overnight, the reaction mixture was washed successively with water, saturated sodium bicarbonate solution, water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed through a silica gel column. Elution with 25% acetone/75% petroleum ether gave 4.3 g of the product, m.p. 42°-46° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12](=O)[CH2:13]Cl)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH2:16][C:17]([NH2:19])=[S:18].O.O.O.C([O-])(=O)C.[Na+].C(O)C>O>[NH2:19][C:17]1[S:18][CH:13]=[C:12]([C:6](=[N:5][O:4][CH2:3][CH2:2][Cl:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:16]=1
Reactant: CCOC(=O)C(=NOCCCl)C(=O)CCl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NOCCCl)c1csc(N)n1
Yield: 45.7 %

Procedure:
Ethyl 2-(2-chloroethoxyimino)-3-oxo-4-chlorobutyrate (syn isomer, 68 g.), thiourea (20.2 g.), sodium acetate trihydrate (36.2 g.), ethanol (270 ml.) and water (170 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-(2-chloroethoxyimino)acetate (syn isomer, 33.7 g.), mp 126° to 128° C.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25]=[CH:26][O:27][S:28]([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:20]([NH:38][C:39](=[O:69])[C:40](=[N:66][O:67][CH3:68])[C:41]1[N:42]=[C:43]([NH:46]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:44][CH:45]=1)[C:19]2=[O:70])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[NH2:46][C:43]1[S:44][CH:45]=[C:41]([C:40](=[N:66][O:67][CH3:68])[C:39]([NH:38][CH:20]2[C:19](=[O:70])[N:18]3[CH:21]2[S:22][CH2:23][C:24]([CH:25]=[CH:26][O:27][S:28]([C:31]2[CH:32]=[CH:33][C:34]([CH3:35])=[CH:36][CH:37]=2)(=[O:29])=[O:30])=[C:17]3[C:15]([O:14][CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:16])=[O:69])[N:42]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=COS(=O)(=O)c3ccc(C)cc3)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=COS(=O)(=O)c3ccc(C)cc3)CSC12)c1csc(N)n1
Yield: 40.2 %

Procedure:
A mixture of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(tritylamino-thiazol-4-yl)-acetamido]-8-oxo-3-(2-tosyloxy-vinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, E-form) (0.494 g), acetone (20 cc) and p-toluenesulphonic acid hydrate (10 mg) is heated under reflux for 20 hours. It is then concentrated to dryness under 20 mm Hg at 20° C., the residue is taken up in ethyl acetate (30 cc) and a 5% strength sodium bicarbonate solution (20 cc), and the organic phase is decanted, dried over sodium sulphate, filtered and concentrated to dryness under 20 mm Hg at 20° C. The residue is chromatographed on a column (column diameter: 3 cm, height: 27 cm) of Merck silica gel (0.06-0.2 mm) (50 g). Elution is carried out with ethyl acetate (0.4 liter), 20 cc fractions being collected. Fractions 8 to 10 are a mixture of the starting material and of the expected product; fractions 11 to 17 are concentrated to dryness under 20 mm Hg at 20° C. 7-[2-(2-amino-thiazol-4-yl)-2-methoxyimino-acetamido]-2-benzhydryloxycarbonyl-8-oxo-3-(2-tosyloxy-vinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, E-form) (0.15 g) is obtained in the form of a cream-coloured solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].C(N(CC)CC)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:17](=[O:20])[CH:18]=[CH2:19])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 3,4-dichloroaniline (3.6 g, 22.3 mmol) and 4.2 mL (30.2 mmol) of triethylamine in 20 mL of anhydrous methylene chloride was cooled to 0° C. under a nitrogen atmosphere and treated with acryloyl chloride (2.1 g, 23.2 mmol). The ice bath was removed and the mixture was stirred at room temperature for 1 hour after which time it was diluted with 120 mL of methylene chloride and washed with water and saturated aqueous sodium chloride (NaCl). After drying with calcium sulfate (CaSO4), the solvent was removed in vacuo to give a yellow solid, 4.84 g.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[Cl:25])[C:21]([O:26]CC2C=CC=CC=2)=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C>CO>[ClH:25].[Cl:25][C:24]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][NH:20][C:21]2=[O:26])=[CH:16][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CC1
Solvent: CO
Product: Cl
Product: O=c1[nH]ccc2cc(OC3CCNCC3)c(Cl)cc12
Yield: 69.6 %

Procedure:
254 mg (0.52 mmol) of 4-(1-Benzyloxy-7-chloro-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl-ester (6) were stirred in methanol/2 N HCl (1:1) at room temperature overnight. The solvent was removed i. vac. and the residue was purified by preparative HPLC. The product fractions were evaporated and dissolved in 2 N HCl. Lyophilization results in 57 mg of the desired compound. Rt=0.95 min (Method B). Detected mass: 279.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[C:4]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1.Cl[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[CH3:29])[O:22][CH2:21][CH2:20]1>>[CH3:17][N:15]([CH3:16])[C:13]([C:4]1[CH:3]=[C:2]([O:1][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[CH3:29])[O:22][CH2:21][CH2:20]2)[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=1)=[O:14]
Reactant: Cc1cccc2c1C(Cl)CCO2
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cc2n1C
Product: Cc1cccc2c1C(Oc1cc(C(=O)N(C)C)cc3c1nc(C)n3C)CCO2
Yield: 50 %

Procedure:
The title compound was prepared as a white solid in 50% yield (116 mg) from 4-hydroxy-N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide (100 mg, 0.61 mmol, WO 2004054984) and 4-chloro-5-methylchromane (191 mg, 1.0 mmol, STEP 2) by the same manner in STEP 1 of Example 1:
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[Li]CCCC.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:16]=[O:17]>C1COCC1>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]([OH:17])[C:5]#[C:4][C:2]([CH3:3])([OH:6])[CH3:1])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: C#CC(C)(C)O
Reactant: COc1ccc(C=O)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)C#CC(C)(C)O)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
To a −78° C. stirred solution of 2-methylbut-3-yn-2-ol (0.89 g, 10.710 mmol) in dry THF (50 mL), n-BuLi (16.0 mL, 27.001 mmol, 1.6 M hexane) was added dropwise over 5 minutes under an inert atmosphere. The reaction mixture was stirred for 30 min at −78° C., and then a solution of 3-chloro-4-methoxybenzaldehyde (1.8 g, 10.710 mmol) in dry THF (10 mL) was added and stirring was continued for an additional 3 h at RT. The reaction mixture was then quenched with a saturated NH4Cl solution and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 2-4% EtOAc hexanes to afford 1-(3-chloro-4-methoxyphenyl)-4-methylpent-2-yne-1,4-diol (0.69 g, 26%) as a yellow syrup.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].C(O)C.[NH2:14][OH:15]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5](=[N:14][OH:15])[NH2:6]
Reactant: NO
Reactant: Cc1ccc(C#N)cc1F
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(N)=NO)cc1F
Temperature: 25 °C
Yield: 91.6 %

Procedure:
To a suitable vessel equipped with mechanical stirrer under N2 atmosphere was charged 202.0 g of 3-fluoro-4-methylbenzonitrile followed by 1.0 L of ethanol. Hydroxylamine (144 mL of 50% solution in water) was added via addition fKieel over 20 minutes. The mixture was stirred at ambient temperature until HPLC analysis showed that reaction was complete (no starting material remained). Water (3.0 L) was added dropwise to the pale yellow solution over 1 hour to give a thick slurry. The slurry was cooled in an ice water bath to 2° C. for 1.5 hours, filtered and dried under vacuum at 35° C. for 22 hours to give the title compound (230.3 g, 91.6%) as a white solid. 1H-NMR (CDCl3, 500 MHz) δ7.30 (m, 2H), 7.19 (m, 1H), 4.87 (s, 2H), 2.28 (s, 3H); 13C-NMR (CDCl3, 500 MHz) δ162.15, 160.19, 151.58, 131.82, 131.76, 131.66, 131.62, 127.01, 126.87, 121.06, 112.69, 112.51, 14.48; 19F-NMR (CDCl3, 500 MHz) δ−116.35, −116.37, −116.39. LC-MS M+H169.19.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([CH3:22])[C:12]([C:14]1[CH:15]=[CH:16][C:17](=[O:21])[N:18]([CH3:20])[CH:19]=1)=[O:13].[F:23][C:24]([Si](C)(C)C)([F:26])[F:25].[F-].C[N+](C)(C)C>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([CH3:22])[C:12]([C:14]1[CH:15]=[CH:16][C:17](=[O:21])[N:18]([CH3:20])[CH:19]=1)([OH:13])[C:24]([F:26])([F:25])[F:23]
Reactant: COc1ccc(C(C)C(=O)c2ccc(=O)n(C)c2)c(Cl)c1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [F-]
Product: COc1ccc(C(C)C(O)(c2ccc(=O)n(C)c2)C(F)(F)F)c(Cl)c1Cl

Procedure:
In analogy to Example 165, step 3, 5-[2-(2,3-dichloro-4-methoxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one was reacted with (trifluoromethyl)trimethylsilane and tetramethylammonium fluoride to give the title compound as a colorless solid. MS (m/e, ISP neg. ion.)=408.2 [M−H+].
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.C(N(CC)CC)C.Cl.[NH2:19][CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CCO.O>[I:8][C:7]1[C:2]([NH:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:3][C:4]([NH2:10])=[N:5][C:6]=1[CH3:9]
Reactant: Cc1nc(N)nc(Cl)c1I
Reactant: NC1CCOCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc(N)nc(NC2CCOCC2)c1I
Temperature: 25 °C
Reaction time: 72 h
Yield: 51.6 %

Procedure:
To a suspension of 4-chloro-5-iodo-6-methylpyrimidin-2-amine (16.0 g, 59.3 mmol) in EtOH (200 mL) and H2O (250 mL) was added triethylamine (30.0 mL, 207.5 mmol) and 4-aminotetrahydropyran HCl salt (9.75 g, 71.2 mmol) successively. The reaction was heated to reflux, stirred for 72 h, and then cooled to RT. About 80% of the solvent was evaporated under reduced pressure. The mixture was partitioned between ethyl acetate and H2O. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude product. The product was purified by a flash chromatography (50% ethyl acetate/hexanes to 100% ethyl acetate) to afford 5-iodo-6-methyl-N4-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4-diamine as a light yellow crystal (yield: 10.23 g, 51.7%). LC/MS: calculated for C10H15IN4O (334.03). found: 335.08 (MH+). HPLC analytical purity: >99.0%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=1.[CH2:21]=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][N:14]([CH3:21])[CH2:13][CH2:12]3)=[CH:4][CH:3]=1
Reactant: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Reactant: C=O
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCN(C)CC2

Procedure:
The title compound (113 mg) was prepared from 3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 190) and paraformaldehyde as in Example 35. MS (ESI): exact mass calculated for C17H22FN3, 287.18. found, m/z 288.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.42-7.40 (m, 2H), 7.34-7.30 (m, 2H), 4.42 (m, 1H), 3.77-3.74 (m, 1H), 3.67-3.62 (m, 2H), 3.36-3.34 (m, 1H), 3.27-3.21 (m, 3H), 3.03 (s, 3H), 2.92-2.89 (m, 1H), 2.80-2.76 (m, 1H), 1.49-1.29 (m, 6H).
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][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24]([O:26]CC)=[O:25])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Li+]>O1CCOCC1.O>[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][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24]([OH:26])=[O:25])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)C1CC(c2ccc(CC)cc2)CN(C(=O)N2CCC(O)CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
880 mg (2.24 mmol) of ethyl 5-(4-ethylphenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine-3-carboxylate were dissolved in a mixture of 15.5 ml of dioxane and 7.7 ml of water, 215 mg (8.97 mmol) of lithium hydroxide were added and the mixture was stirred at RT overnight. For work-up, the reaction solution was concentrated under reduced pressure, water was then added and the mixture was acidified with 1N hydrochloric acid. The precipitate formed was filtered off and dried under reduced pressure. The filtrate was extracted with ethyl acetate. The combined organic phases were dried with sodium sulphate and concentrated under reduced pressure. The two solids gave a total yield of 764 mg (95% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:21][C:22]([C:24]2[CH:33]=[C:32](Cl)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH:35][C@@H:36]1[CH2:41][CH2:40]C[NH:38][CH2:37]1.CCN(C(C)C)C(C)C.[OH-].[Li+]>CS(C)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:21][C:22]([C:24]2[CH:33]=[C:32]([N:38]3[CH2:40][CH2:41][CH:36]([OH:35])[CH2:37]3)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC)NC(=O)c2cc(Cl)c3ccccc3n2)CC1
Reactant: O[C@@H]1CCCNC1
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)O)NC(=O)c2cc(N3CCC(O)C3)c3ccccc3n2)CC1
Temperature: 110 °C
Yield: 24.7 %

Procedure:
To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(methoxycarbonyl)propyl]aminocarbonyl-4-chloroquinoline (150 mg, 0.315 mmol) in DMSO (3.0 mL) was added (R)-3-hydroxypiperidine (68 mg, 0.5 mmol) and DIEA (65 mg, 0.5 mL). The mixture was heated at 110° C. for 18 hours. The crude reaction mixture was treated with lithium hydroxide (3.0 mL 0.25 M) for 4 hours. The reaction was purified by preparative HPLC to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-hydroxypyrrolidin-1-yl)quinoline (41.0 mg); NMR (DMSO-d6) 1.2 (t, 3), 2.00–2.20 (m, 4), 2.45 (m, 2), 3.30–3.75 (m, 8), 4.05 (q, 2), 4.60 (s, 1), 5.11 (m, 1), 7.39 (s, 1), 7.65 (m, 1), 7.95 (m, 1), 8.28 (m, 1), 8.58 (br s, 1), 9.75 (m, 1) ppm.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.[NH2:8][CH2:9][CH:10]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1.[S-:21][C:22]#[N:23].[K+].II>C(#N)C>[C:2]([C:3]1[S:21][C:22](=[NH:23])[N:8]([CH2:9][CH:10]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]2)[CH:4]=1)([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Reactant: N#C[S-]
Reactant: CC(C)(C)CC=O
Agent: II
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(Cn2cc(C(C)(C)C)sc2=N)C1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
3,3-Dimethylbutanal (0.7 mL, 5.4 mmol), tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (Astatech™, 1.0 g, 5.4 mmol) were mixed with 2 g of 4 Å molecular sieves in 5 mL of dry acetonitrile at room temperature for 20 hours. The reaction was filtered through Celite, washed with 5 mL of acetonitrile and the filtrate used without further purification. Potassium thiocyanate (0.7 g, 7.1 mmol) was added and the mixture heated to 50° C. for 10 minutes. Iodine (1.4 g, 5.4 mmol) was added and the reaction mixture was continued to stir at 50° C. for 6 hours. The reaction mixture was cooled to room temperature, 10 mL of acetonitrile was added, followed byt 10 mL of 20% Na2S2O5. The phases were separated and the organic phase was dried with Na2SO4, filtered, and the solvent removed to provide the title compound. LC/MS m/z 326.3 (M+H)+. The product was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:4]=[N:3][CH:2]=1.O=S(Cl)Cl.[Cl:20][C:21]([F:31])([F:30])[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>C(Cl)Cl>[Cl:20][C:21]([F:30])([F:31])[O:22][C:23]1[CH:24]=[CH:25][C:26]([NH:27][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][CH:15]=[C:7]([C:5]3[CH:4]=[N:3][CH:2]=[N:1][CH:6]=3)[CH:8]=2)=[CH:28][CH:29]=1
Reactant: Nc1ccc(OC(F)(F)Cl)cc1
Reactant: O=C(O)c1cccc(-c2cncnc2)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cccc(-c2cncnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-pyrimidin-5-yl-benzoic acid (100 mg, 0.50 mmol) and SOCl2 (73 μL, 1.0 mmol) was heated under reflux for 4 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in DCM (5 mL) and slowly added to a mixture of 4-(chlorodifluoromethoxy)aniline (106 mg, 0.55 mmol) and TEA (140 μL, 1.0 mmol) in DCM (5 mL). The mixture was stirred at RT overnight. The solvent was evaporated off under reduced pressure and the residue was suspended in EtOAc (10 mL), filtered through a 10 μm Isolute® fritted cartridge and the filtrate was evaporated to dryness under reduced pressure to give the crude product which was purified by preparative HPLC to afford the title compound. LC-MS (Condition 4) tR=1.15 min, m/z=375.8 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.40 (d, J=9.05 Hz, 2H) 7.73 (t, J=7.82 Hz, 1H) 7.92 (m, 2H) 8.06 (t, J=6.97 Hz, 2H) 8.37 (t, J=1.96 Hz, 1H) 9.24-9.29 (m, 3H) 10.52 (s, 1H).