Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:35]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A150) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([N:3]([CH:15]1[CH2:20][CH2:19][C:18]([OH:22])([CH3:21])[CH2:17][CH2:16]1)[C:4]1[C:5]([CH3:14])=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7](OC)=[O:8])[CH3:2].[OH-].[Na+].[NH2:25][CH2:26][C:27]1[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=1[CH3:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(O)C.O.CS(C)=O>[CH3:33][C:32]1[CH:31]=[C:30]([CH3:34])[NH:29][C:28](=[O:35])[C:27]=1[CH2:26][NH:25][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][CH:13]=[C:4]([N:3]([CH2:1][CH3:2])[CH:15]2[CH2:16][CH2:17][C:18]([OH:22])([CH3:21])[CH2:19][CH2:20]2)[C:5]=1[CH3:14]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCN(c1cccc(C(=O)OC)c1C)C1CCC(C)(O)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCN(c1cccc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCC(C)(O)CC1
Temperature: 70 °C

Procedure:
A mixture of methyl 3-(ethyl(4-hydroxy-4-methylcyclohexyl)amino)-2-methylbenzoate (300 mg, 0.98 mmol) and NaOH (58 mg, 1.47 mmol) in 5 ml of ethanol and water (3:2) was heated at 70° C. for 2 h. The reaction mixture was concentrated to dryness and the residue was partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford 270 mg of the crude acid. The crude acid (270 g, 0.92 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (282 mg, 1.85 mmol), PyBOP (717 mg, 1.38 mmol) and triethylamine (0.12 ml, 0.92 mmol) were stirred in 3 ml of DMSO at room temperature overnight. The reaction mixture was diluted with water and extracted with 10% MeOH in DCM. The combined organic phases were dried over Na2SO4, concentrated and the residue purified by silica gel column chromatography to give the title compound N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(4-hydroxy-4-methylcyclohexyl)amino)-2-methylbenzamide as a mixture of isomers (120 mg, 30%). LCMS: 426.45 (M+1)+; HPLC: 62.09 & 33.24% (@ 210-370 nm) (Rt; 3.982 & 4.164; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.44 (s, 1H), 8.04 (m, 1H), 7.12 (s, 2H), 6.91 (m, 1H), 5.85 (s, 1H), 4.25 (d, 2H, J=4 Hz), 4.15 (m, 1H), 3.00 (m, 2H), 2.84 (m, 1H), 2.18 (s, 6H), 2.10 (s, 3H), 1.75-1.60 (m, 2H), 1.55-1.35 (m, 4H), 1.35-1.15 (m, 4H), 1.08 & 1.03 (s, 3H), 0.87 & 0.77 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][CH2:20][C:21]([O:23]CC)=[O:22]>[OH-].[Na+]>[C:21]([CH2:20][NH:19][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([C:8]([OH:17])([C:13]([F:15])([F:14])[F:16])[C:9]([F:10])([F:11])[F:12])=[CH:5][C:4]=1[CH3:18])([OH:23])=[O:22]
Reactant: CCOC(=O)CNc1c(C)cc(C(O)(C(F)(F)F)C(F)(F)F)cc1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NCC(=O)O
Reaction time: 1 h

Procedure:
Dissolve ethyl N-[2,6-dimethyl-4-(hexafluoro-2-hydroxy-2-propyl)phenyl]glycinate (3.1 g, 8.3 mmol) in 25 ml 1.0 N NaOH. After 1 hour, add 25 ml 1.0 N NCl and extract with ethyl acetate. Dry and concentrate. Recrstyallize from chloroform-benzene to give the title compound as beige solid, m.p. 153°-155° C. dec.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:15]2[CH:19]=[CH:18][CH:17]=[CH:16]2)=[C:6]([CH:14]=1)[C:7](N1CCCC1)=[O:8]>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:15]3[CH:16]=[CH:17][CH:18]=[C:19]3[C:7](=[O:8])[C:6]=2[CH:14]=1
Reactant: O=C(c1cc(Cl)ccc1-n1cccc1)N1CCCC1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1c2cc(Cl)ccc2-n2cccc21
Yield: 28 %

Procedure:
A solution of 8.5 g (30.9 mmol) of N-[5-chloro-2-(pyrrol-1-yl)benzoyl]pyrrolidine (Preparation 23) in 70 ml of phosphorus oxychloride is heated at 100° C. for 35 minutes. After cooling, the precipitate formed is isolated by filtration, washed with petroleum ether to remove excess phosphorus oxychloride, and then redissolved in 30 ml of water. The aqueous solution is rendered alkaline by the dropwise addition of 10% sodium hydroxide solution and the precipitate formed is filtered and extracted with 100 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, rendered colourless with animal charcoal and concentrated under reduced pressure to yield 1.76 g of the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].C[O:15][P:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[O:17]1.CCl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([P:16]1(=[O:15])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[O:17]1)=[O:6]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: COP1Oc2ccccc2-c2ccccc21
Agent: CCl
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)P2(=O)Oc3ccccc3-c3ccccc32)c(OC)c1
Temperature: 110 °C

Procedure:
35.1 g (0.175 mol) of 2,4-dimethoxybenzoyl chloride were warmed to 70° C. under a nitrogen atmosphere. 40.3 g (0.175 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]oxaphosphorin were added dropwise in the course of two hours while stirring. The temperature was then slowly increased to 110° C. It was kept at this temperature until evolution of methyl chloride could no longer be detected. After cooling to 60° C., 70 ml of toluene were added. After crystallization, 50 g (75% of theory) of the abovementioned compound of melting point 112° to 115° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:21]([C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[C:18]([CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:19]=1)=[N:1]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: COc1ccc(C=O)cc1CN1CCOCC1
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OC)c(CN4CCOCC4)c3)nc2c1
Yield: 28 %

Procedure:
5,7-Dimethoxy-2-(4-methoxy-3-(morpholinomethyl)phenyl)quinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-methoxy-3-morpholin-4-ylmethyl-benzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 5,7-Dimethoxy-2-(4-methoxy-3-(morpholinomethyl)phenyl) quinazolin-4(3H)-one (65 mg, 28%) was isolated as a light yellow solid. Selected data: MS (m/z): 412.07; MP 282.7-284.5° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15](=[O:21])[O:14][CH:13]2[PH2](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[N:41]1[CH:46]=[CH:45][C:44]([CH:47]=O)=[CH:43][CH:42]=1>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15](=[O:21])[O:14][C:13]2=[CH:47][C:44]1[CH:45]=[CH:46][N:41]=[CH:42][CH:43]=1
Reactant: COc1cc2c(cc1OC)C([PH2](c1ccccc1)(c1ccccc1)c1ccccc1)OC2=O
Reactant: O=Cc1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C(=Cc1ccncc1)OC2=O
Yield: 60.9 %

Procedure:
Triethylamine (20 ml, 145 mmoles) was dropwise added to a suspension of 5,6-dimethoxy-3-(triphenyl-λ6-phosphanyl)-3H-isobenzofuran-1-one (78 g, 145 mmoles), obtained as described in example 3, and 4-pyridincarboxaldehyde (13 ml, 145 mmoles) in CH2Cl2 (1 l), at room temperature under stirring. After 1.5 hours the mixture was filtered and evaporated and the residue was treated with ethanol under reflux, cooled and filtered. The mother liquors were chromatographed (eluent: 100% CH2Cl2, then with 1% CH3OH) and the residue was brought to dryness and joined to the above filtrate to give 25 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14](O)=[O:15])=[CH:13][C:8]=3[O:7][C:6]=2[CH:17]=1.B>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH2:14][OH:15])=[CH:13][C:8]=3[O:7][C:6]=2[CH:17]=1
Reactant: O=C(O)c1ccc2c(c1)oc1cc(Br)ccc12
Agent: B
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)oc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.7 %

Procedure:
A cloudy solution of 3-bromo-dibenzofuran-7-carboxylic acid (3.2 g, 10.9 mmol) in 80 ml THF was cooled to 0° C. and a solution of borane in THF. (1.0M, 13.0 ml, 13.0 mmol) was added dropwise. The cooling bath was removed and the reaction was stirred at room temperature for 20 hours and was then quenched by the cautious addition of methanol (10 ml). The solution was evaporated to dryness in vacuo and the residue was dissolved in mthanol--CH2Cl2 (1:1) and again evaporated. After one repetition of this dissolution-evaporation process, 2.74 g (90%) of the title compound was obtained as a brown solid and used in the next reaction without purification.
Reaction SMILES: [C:1]([C@@:18]1(C(O)=O)[CH2:22][C@@H:21]([NH2:23])[CH2:20][N:19]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([O:3]CC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:2]>C(#N)C.N1CCCC1>[NH2:23][CH:21]1[CH2:20][N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH:18]([C:1]([OH:3])=[O:2])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)C[C@]1(C(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CC#N
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CC(N)CC1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a solution of (2S,4R) Fmoc-4-amino-1-boc-pyrrolidine-2-carboxylic acid (400 mg, 0.884 mmol) in acetonitrile (15 mL), five drops of pyrrolidine was added. The reaction mixture was stirred at rt for 3 hr. Then it was concentrated and put on high vacuum to give crude 4-amino-1-boc-pyrrolidine-2-carboxylic acid. In another round-bottomed flask, a solution of Pd2dba3 (40 mg, 5% mol) and racemic-BINAP (56 mg, 10% mol) was stirred under nitrogen in degassed toluene (8 mL) at rt for 1 h. Then 1-chloroisoquinoline (216 mg, 1.326 mmol) and sodium t-butoxide (340 mg, 3.536 mmol) were added and the reaction mixture was stirred for 30 min. Then 4-amino-1-boc-pyrrolidine-2-carboxylic acid was added and the reaction mixture was heated under reflux for 1 h. Water was added to quench the reaction and the aqueous layer was separated and filtered through filter paper. It was then concentrated and purified by Prep. HPLC to give coupled product as TFA salt. (165 mg, 40% yield) 1H NMR (CD3OD, 400 MHz) δ 1.44 (m, 9H), 2.51-2.74 (m, 2H), 3.64 (m, 1H), 4.01 (m, 1H), 4.49 (m, 1H), 4.64 (m, 1H), 7.30 (d, J=6.85 Hz, 1H), 7.58 (d, J=6.85 Hz, 1H), 7.79 (m, 1H), 7.91-7.99 (m, 2H), 8.56 (d, J=8.56 Hz, 1H). MS m/z 358 (MH+).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[OH:13])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(N(CC)CC)C>[Pd].O1CCCC1>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:4]2[C:5]([NH:10][CH2:11][CH:12]([OH:13])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:6][CH:7]=[CH:8][CH:9]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cccnc1NCC(O)c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccnc1NCC(O)c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.1 %

Procedure:
A mixture of α-[(3-nitro-2-pyridinylamino)methyl]benzene methanol (30.8 g, 0.12 mole) and 5% palladium on carbon catalyst in 450 ml of tetrahydrofuran was hydrogenated in a large glass Parr bottle at room temperature. The reaction mixture was dried over magnesium sulfate and filtered through a Celite pad. p-Chlorobenzoyl chloride (15.1 ml, 0.12 mole) and triethylamine (16.5 ml, 0.12 mole) were added simultaneously dropwise to the stirred filtrate at 12°-15° C. (ice-water bath) and the mixture was allowed to stir at ambient temperature overnight. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was partitioned between methylene chloride and water. The methylene chloride layer was separated and extracted with water (1×), 5% potassium hydroxide (2×), and water (2×). The methylene chloride layer was separated, dried, and evaporated to dryness. The residue was purified on a silica gel column (400 g) by eluting with 50% ethyl acetate/50% hexanes. Total recovery: 18.2 g (41.6% yield). A 5-g sample was recrystallized from ethyl acetate/hexanes to give 2.71 g of solid, mp. 157°-159° C.
Reaction SMILES: [Br-:1].[C:2]([CH:5]([CH2:29][CH2:30]C)[CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:9]1=[CH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N+:21]([CH3:28])=[CH:20][CH:19]=1)([OH:4])=[O:3].[Br-].C(C(CC)CCC[N+]1C2C=CC=CC=2SC=1C)(O)=O.[Br-].CC1SC2C=CC=CC=2[NH+]=1.[Br-].C[N+]1C2C(=CC=CC=2)C(C=C2N(CCCCC(O)=O)C3C=CC=CC=3S2)=CC=1>>[Br-:1].[C:2]([CH:5]([CH2:29][CH3:30])[CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:9]1=[CH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N+:21]([CH3:28])=[CH:20][CH:19]=1)([OH:4])=[O:3]
Reactant: CCCC(CCN1C(=Cc2cc[n+](C)c3ccccc23)Sc2ccccc21)C(=O)O
Agent: CCC(CCC[n+]1c(C)sc2ccccc21)C(=O)O
Agent: C[n+]1ccc(C=C2Sc3ccccc3N2CCCCC(=O)O)c2ccccc21
Agent: Cc1[nH+]c2ccccc2s1
Product: CCC(CCN1C(=Cc2cc[n+](C)c3ccccc23)Sc2ccccc21)C(=O)O
Yield: 22 %

Procedure:
Furthermore, 4-((3-(3-carboxyhexyl)benzo[d]thiazole-2(3H)-ylidene) methyl)-1-methylquinoliniumbromide with a linker (a polymethylene chain linked to a carboxyl group) having a carbon number n of 6 was synthesized from the mixture of 3-(4-carboxyhexyl)-2-methylbenzothiazolium bromide and 2-methylbenzothiazolium bromide by the same method as that used for Compound 107, which was obtained with a yield of 22%. The instrumental analytical values are indicated below.
Reaction SMILES: CC[N:3]([CH:7]([CH3:9])C)[CH:4](C)C.[CH3:10][C@H:11]([O:15][C:16]1[CH:17]=[C:18]([O:31][C:32]2[N:33]=[CH:34][C:35]([C:38](O)=[O:39])=[N:36][CH:37]=2)[CH:19]=[C:20]([C:22]([NH:24][C:25]2[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=2)=[O:23])[CH:21]=1)[CH2:12][O:13][CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.N1CCC1>CN(C=O)C.C(OCC)(=O)C>[N:3]1([C:38]([C:35]2[N:36]=[CH:37][C:32]([O:31][C:18]3[CH:19]=[C:20]([CH:21]=[C:16]([O:15][C@@H:11]([CH3:10])[CH2:12][O:13][CH3:14])[CH:17]=3)[C:22]([NH:24][C:25]3[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=3)=[O:23])=[N:33][CH:34]=2)=[O:39])[CH2:4][CH2:9][CH2:7]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)O)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 25.7 %

Procedure:
DIPEA (0.28 mL, 1.59 mmol) was added to a suspension of 5-[(3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylic acid (170 mg, 0.4 mmol), HATU (318 mg, 0.84 mmol) and azetidine hydrochloride (75 mg, 0.8 mmol) in DMF (5 mL) and the mixture stirred at RT for 72 hours. Ethyl acetate (40 mL) was added and washed with water (2×30 mL), brine (30 mL), dried (MgSO4), filtered and reduced in vacuo to give a yellow oil which was chromatographed on silica, eluting with 0-100% ethyl acetate in isohexane, to give the desired compound (48 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[O:29][N:28]=1)([CH3:26])[CH3:25].COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:33]([NH:32][C:30]2[O:29][N:28]=[C:27]([C:24]([F:23])([CH3:25])[CH3:26])[CH:31]=2)=[O:34])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)F)no4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 46 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (200 mg, 0.639 mmol) was reacted with phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate from Example 42A (253 mg, 0.959 mmol) according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B, except the reaction mixture was stirred at room temperature for 72 h. Purification via trituration with methanol afforded 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea as a colorless solid (142 mg, 46%). 1H NMR (300 MHz, DMSO-d6) δ 10.43 (brs, 1H), 9.13 (brs, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.57 (m, 1H), 7.46 (m, 1H), 7.30-7.35 (m, 3H), 6.16 (s, 1H), 3.99 (s, 6H), 1.67 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 484 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.N([O-])=O.[Na+].[CH3:18][CH:19](C(C)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].CC([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>O.Cl.CCO>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:12]=[C:11]2[C:9](=[CH:8][CH:7]=1)[NH:10][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18]2
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: CN(C)CCOc1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc2cc(OCCN(C)C)ccc2[nH]1
Temperature: 20 °C
Reaction time: 1 h
Yield: 23.9 %

Procedure:
A stirred solution of 4-[2-(dimethylamino)ethoxy]aniline [R Paul et al, J. Med. Chem. 36, 1993, 2716-2725](3.61 g, 20 mmol) in water (34 mL) and concentrated HCl (10 mL) was diazotized at 0° C. with a solution of NaNO2 (1.52 g, 22 mmol) in water (4 mL). The cold solution was added in one portion to a vigorously stirred ice-cold mixture of ethyl 2-methylacetoacetate (3.03 g, 21 mmol), anhydrous NaOAc (17 g), EtOH (25 mL), and freshly added ice (20 g). After stirring at 20° C. for 1 h, the mixture was cooled to 0° C., basified by the slow addition of solid Na2CO3, and extracted immediately with CH2Cl2 (×2). The combined organic layers were washed with water, dried (Na2SO4), and evaporated. The residue was extracted with hot petroleum ether (bp 60-65° C.) in the presence of decolorizing charcoal, and the clarified solution was evaporated. The remaining oil (4.55 g) was dissolved in absolute EtOH (6 mL) and HCl-saturated EtOH (10 mL) was added. After heating at reflux for 25 min, the solution was concentrated and the residue was partitioned between dilute Na2CO3 and CH2Cl2. The organic layer was washed with water and NaCl solution, dried, and evaporated. The residue was triturated with iPr2O/hexanes and the resulting solid was recrystallized from iPr2O/hexanes to give ethyl 5-[2-(dimethylamino)ethoxy]indole-2-carboxylate (1.32 g, 24% overall yield) as needles, mp 110° C. 1H NMR [(CD3)2SO] δ 11.72 (s, 1 H, NH), 7.34 (d, J=9.0 Hz, 1 H, H-7), 712 (d, J=2.4 Hz, 1 H, H-4), 7.03 (d, J=1.6 Hz, 1 H, H-3), 6.91 (dd, J=9.0, 2.4 Hz, 1 H, H-6), 4.32 (q, J=7.1 Hz, 2 H, CH2CH3), 4.03 (t, J=5.9 Hz, 2 H, OCH2), 2.63 (t, J=5.9 Hz, 2 H, OCH2CH2), 2.22 (s, 6 H, N(CH3)2), 1.33 (t, J=7.1 Hz, 3 H, CH2CH3).
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13](=[O:25])/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[N:10]=[N:9]2)=CC=1>C(O)(C(F)(F)F)=O>[N+:22]([C:19]1[CH:18]=[CH:17][C:16](/[CH:15]=[CH:14]/[C:13]([C:11]2[N:10]=[N:9][NH:8][CH:12]=2)=[O:25])=[CH:21][CH:20]=1)([O-:24])=[O:23]
Reactant: COc1ccc(Cn2cc(C(=O)/C=C/c3ccc([N+](=O)[O-])cc3)nn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(/C=C/c1ccc([N+](=O)[O-])cc1)c1c[nH]nn1
Temperature: 65 °C
Reaction time: 7 h

Procedure:
To a 5 mL round-bottom flask equipped with a magnetic stir bar, was added enone 4n (27 μmol) in TFA (1 mL). The mixture was stirred 7 hours at 65° C. Then, the TFA was removed under reduced pressure and the crude was purified by chromatography (100% AcOEt) to give the pure product, as a white solid in 45% isolated. m.p. 1H NMR (300 MHz, d6-DMSO) δ 8.83 (s, 1H), 8.34 (d, 2H, J=8.9 Hz), 8.17 (d, 2H, J=8.8 Hz), 8.05 (d, 1H, J=16.1 Hz), 7.97 (d, 1H, J=15.9 Hz). 13C NMR (75 MHz, CDCl3) δ. HRMS (FAB) calcd for C18H15N4O3 ([M+H]+). found.
Reaction SMILES: [CH3:1][C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:30]=[CH:29][C:13]2[O:14]C(C3C=CC=CC=3)(C3C=CC=CC=3)[O:16][C:12]=2[C:11]=1[O:31][CH3:32])=[O:9])([CH3:5])[CH2:3][CH3:4]>Cl>[OH:16][C:12]1[C:11]([O:31][CH3:32])=[C:10]([C:8](=[O:9])[CH2:7][NH:6][C:2]([CH3:1])([CH3:5])[CH2:3][CH3:4])[CH:30]=[CH:29][C:13]=1[OH:14]
Reactant: CCC(C)(C)NCC(=O)c1ccc2c(c1OC)OC(c1ccccc1)(c1ccccc1)O2
Agent: Cl
Product: CCC(C)(C)NCC(=O)c1ccc(O)c(O)c1OC

Procedure:
25 g of 2-(1,1-dimethylpropylamino)-1-(4-methoxy-2,2-diphenylbenzo[1,3]dioxol-5-yl) ethanone is refluxed with 50 mL of 15% methanolic hydrochloric acid for 2 hours with stirring. The solvent is distilled off under reduced pressure and the residue is dissolved in acetonitrile and combined with ethyl acetate. The precipitated crystals are suction filtered and washed with acetonitrile and diethyl ether. Yield: 15 g (92%) of the compound as the hydrochloride.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:7])[CH2:6][CH2:5]1.N1C=CC=CC=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>ClCCl>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:1][CH2:2][CH2:3][C:4]2([OH:7])[CH2:6][CH2:5]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1(O)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2(O)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To an ice-cooled solution of 1-(2-hydroxyethyl)cyclopropanol (1.31 g) and pyridine (4 ml) in dichloromethane (20 ml) was added p-toluenesulphonyl chloride (4.7 g). The mixture was then stirred at room temperature under an atmosphere of nitrogen for 5 hours before being partitioned between ether (100 ml) and water. The organic layer was washed consecutively with 1N hydrochloric acid, water, 5% sodium hydrogen carbonate solution, and brine, and dried. Concentration in vacuo gave a residue which was purified by chromatography (150 g silica gel; 40% ethyl acetate in petroleum ether as eluant) to give the 1-(2-p-toluenesulphonyloxyethyl)cyclopropanol [E; n=1, R1 +R2 =--(CH2)2 --] as an oil.