Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]([C:18]([NH2:20])=[O:19])[CH2:12]2.[C:21](Cl)(=[O:23])[CH3:22]>ClC(Cl)Cl>[C:21]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([Cl:8])=[CH:17][CH:16]=2)[CH2:12][CH:13]1[C:18]([NH2:20])=[O:19])(=[O:23])[CH3:22]
Reactant: NC(=O)C1Cc2cc(Cl)ccc2N1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1c2ccc(Cl)cc2CC1C(N)=O
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 85.7 %

Procedure:
Triethylamine (0.02080 mole) was added to intermediate (7) (0.09632 mole) dissolved in trichloromethane (700 ml). The mixture was cooled to 5° C. Acetyl chloride (0.2480 mole) was added over 2 minutes with stiffing. After 5 minutes, a precipitate formed. The ice bath was removed, and the container allowed to sit for 15 minutes. Ice water (250 ml) was added, and the mixture was stirred for 10 minutes. The sample was filtered, rinsed with water and trichloromethane. The solid was suspended in water (200 ml), and swirled for 10 minutes. Trichloromethane (200 ml) was added and the mixture was stirred, then filtered and rinsed with water and trichloromethane, and then dried to the air overnight, yielding 19.71 g of 1-acetyl-5-chloro-2,3-dihydro-1H-indole-2-carboxamide (intermediate 8).
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]([OH:9])=[O:8])[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]1.[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O>[CH2:13]([O:8][C:7]([CH:5]1[CH:4]([C:10]([OH:12])=[O:11])[CH2:3][C:2](=[O:1])[O:6]1)=[O:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CC(C(=O)O)C(C(=O)O)O1
Reactant: OCc1ccccc1
Solvent: CC(C)=O
Product: O=C1CC(C(=O)O)C(C(=O)OCc2ccccc2)O1
Reaction time: 12 h

Procedure:
5.2 g of (2RS,3SR)-5-oxotetrahydrofuran-2,3-dicarboxylic acid in 88 ml of acetone was stirred together with 6.5 g of 1,1'-dicyclohexylcarbodiimide at room temperature for 2 hours. After addition of 3.26 ml of benzyl alcohol, the reaction solution was stirred at the same temperature for 12 hours. The insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=4/1→chloroform/methanol=50/1] to give 7.93 g of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[S:13]([Cl:12])(=[O:15])=[O:14]
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: O=S(=O)(O)Cl
Product: O=C1Cc2cc(S(=O)(=O)Cl)c(Br)cc2N1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Chlorosulphonic acid (30 mL) is taken, cooled to 0° C. cooled and combined with 8 g of 6-bromoindolinone with vigorous stirring. The ice bath is removed and the mixture is stirred for a further 16 h at RT. The reaction mixture is slowly poured onto ice with vigorous stirring, the precipitate formed is filtered off and dried in the vacuum dryer. 6-Bromindolinone-5-sulphonyl chloride is obtained as crude product, which is further used directly.
Reaction SMILES: [CH2:1]([O:3][CH:4]([P:8]([O-:12])[O:9][CH2:10][CH3:11])[O:5][CH2:6][CH3:7])[CH3:2].[C:13](#[N:17])[C:14]([CH3:16])=[CH2:15].[H-].[Na+].C(O)(=O)C>C(O)C>[CH2:10]([O:9][P:8]([CH2:15][CH:14]([C:13]#[N:17])[CH3:16])([CH:4]([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[O:12])[CH3:11]
Reactant: C=C(C)C#N
Reactant: CCOC(OCC)P([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(OCC)P(=O)(CC(C)C#N)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 23.5 g of ethyl (diethoxymethyl)phosphonite and 6.7 g of methacrylonitrile in 30 ml of ethanol is added dropwise to a stirred mixture of 1.2 g of sodium hydride (50% dispersion in oil) in 30 ml of ethanol at 0° C. under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture is concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 25 ml of water, and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled under reduced pressure to give ethyl-2-cyanopropyl(diethoxymethyl)phosphinate, b.p. 116° C./0.01 mbar, 31P=+40.4 and +40.3 ppm (CDCl3).
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:9]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=O)=[C:8]([N:19]2[C:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:22][N:21]=[C:20]2[CH2:31][N:32]2C(=O)C3=CC=CC=C3C2=O)[CH:7]=[CH:6][CH:5]=1)=[O:2].O.NN>C(O)C>[CH2:24]([C:23]1[N:19]2[C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([NH:3][CH:1]=[O:2])[C:9]=3[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:32][CH2:31][C:20]2=[N:21][N:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=CNc1cccc(-n2c(Cc3ccccc3)nnc2CN2C(=O)c3ccccc3C2=O)c1C(=O)c1ccccc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: O=CNc1cccc2c1C(c1ccccc1Cl)=NCc1nnc(Cc3ccccc3)n1-2

Procedure:
In the manner given in Example 5, 6-formamido-2'-chloro-2-[3-(phthalimidomethyl)-5-benzyl-4H-1,2,4-triazol-4-yl]benzophenone was heated in ethanol with hydrazine hydrate to give 1-benzyl-7-formamido-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]#[N:14])([O-:3])=[O:2].O[CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:13]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:9]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:8]=1)#[N:14]
Reactant: N#Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C#N)c3cc([N+](=O)[O-])ccc32)CC1
Temperature: 25 °C
Reaction time: 32 h
Yield: 32.8 %

Procedure:
To a solution of 5-nitro-1H-indole-3-carbonitrile (2.0 g, 10.69 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (4.30 g, 21.37 mmol) and triphenylphosphine (5.61 g, 21.37 mmol) in 90 ml THF was slowly added DEAD (3.38 mL, 21.37 mmol) in 50 ml of THF over 3 hrs. The mixture was stirred 32 hrs at 25° C. The mixture was concentrated and purified on silica: 100% DCM 500 ml, then (5-60% EtOAc in Hexanes) to give tert-butyl 4-(3-cyano-5-nitro-1H-indol-1-yl)piperidine-1-carboxylate (1.3 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:10][CH2:9][CH2:8][N:7]1[CH2:6][CH2:5][CH2:4]2.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.ClC(Cl)(Cl)N[C:23](=O)[O-:24]>C1(C)C=CC=CC=1>[CH2:4]1[C:3]2([CH2:2][NH:1][C:23]([N:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)=[O:24])[N:7]([CH2:8][CH2:9][CH2:10]2)[CH2:6][CH2:5]1
Reactant: O=C([O-])NC(Cl)(Cl)Cl
Reactant: NCC12CCCN1CCC2
Reactant: c1ccc2c(c1)CCN2
Solvent: Cc1ccccc1
Product: O=C(NCC12CCCN1CCC2)N1CCc2ccccc21

Procedure:
7a-Aminomethylhexahydro-1H-pyrrolizine is reacted with indoline-N-trichloromethylcarbamate [J. Medicinal Chemistry (1990) 33: 1929] in toluene at reflux to afford the title compound after extractive workup and column chromatography.
Reaction SMILES: [CH:1]([N:5]([C:7]#[N:8])[NH2:6])([CH2:3][CH3:4])[CH3:2].C(Cl)([Cl:11])=O.C.[C:14](=[O:17])(O)[O-].[Na+]>O1CCOCC1>[CH:1]([N:5]1[C:7]([Cl:11])=[N:8][C:14]([OH:17])=[N:6]1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)N(N)C#N
Reactant: O=C([O-])O
Reactant: O=C(Cl)Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CCC(C)n1nc(O)nc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 110 %

Procedure:
A solution of 22.6 g of 1-sec.butyl-1-cyanohydrazine in 30 ml of dioxane isadded dropwise at room temperature, during 15 to 20 minutes, to a solution of 25 g of phosgene in 120 ml of dioxane. After completion of the addition, there is added 1 g of active charcoal and the reaction mixture is refluxed for 3 hours. After cooling to room temperature, 10 g of sodiumbicarbonate is added. After 15 hours, the mixture obtained is filtered through Hyflo for removal of the salts. The filtrate is concentrated at 70° C in vacuo, with 31.5 g of a brown oil remaining. After the addition of a solution of 8 g of sodium hydroxide in 50 ml of water, the whole is heated for 15 minutes at 90° C. After cooling to room temperature, the mixture is extracted with 75 ml of ether. After separation of the ether, the aqueous phase is neutralised with 100 ml of 2N hydrochloric acid, whereupon 1-sec.butyl-3-hydroxy-5-chloro-1,2,4-triazole precipitates firstly as oil,which coon crystallises. There is obtained 23 g (65.5% of theory) of 1-sec.butyl-3-hydroxy-5-chloro-1,2,4-triazole, m.p. 77°-79° C.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:10]=[C:11]2[C:19](=[C:20]([N+:23]([O-:25])=[O:24])[C:21]=1F)[NH:18][C:17]1[CH:16]=[N:15][CH:14]=[CH:13][C:12]2=1.O>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[C:11]2[C:19](=[C:20]([N+:23]([O-:25])=[O:24])[C:21]=1[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)[NH:18][C:17]1[CH:16]=[N:15][CH:14]=[CH:13][C:12]2=1
Reactant: OCC1CC1
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(OCC2CC2)c(Cl)cc2c1[nH]c1cnccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.5 %

Procedure:
Cyclopropylmethyl alcohol (0.921 ml, 11.4 mmol) was added to a stirring suspension of NaH (455 mg, 11.4 mmol) in DMF (20 ml) under an argon atmosphere. The resulting solution was allowed to stir at RT for 20 min. 6-chloro-7-fluoro-8-nitro-9H-β-carboline (500 mg, 1.9 mmol) was added to the stirring solution and the resulting mixture was allowed to stir at RT. Upon addition of H2O, a brown solid precipitated out which was filtered to give the desired 6-chloro-7-cyclopropylmethyoxy-8-nitro-9H-β-carboline (510 mg, 85%). 1H-NMR (300 MHz, DMSO-d6): δ 0.35 (m, 2H), 0.59 (m, 2H), 1.32 (m, 1H), 4.04 (d, 2H), 8.21 (d, 1H), 8.46 (d, 1H), 8.90 (s, 1H), 9.02 (s, 1H), 12.32 (b, 1H). Retention Time (LC, method: ammonium acetate standard): 2.63 min. MS (M+H+): 318.
Reaction SMILES: N.[CH3:2][CH2:3][CH2:4][CH2:5][O:6]CCO.[CH2:10]([OH:14])[CH:11](O)[CH3:12].[C:15]1(C=C[CH:21]=[C:19]([OH:20])[C:17]=1[OH:18])[OH:16]>[O-2].[O-2].[Ti+4].O>[CH:21]1[C:3]2[CH:2]=[CH:12][CH:11]=[C:10]([OH:14])[C:5](=[O:6])[C:4]=2[C:15]([OH:16])=[C:17]([OH:18])[C:19]=1[OH:20]
Reactant: Oc1cccc(O)c1O
Reactant: CC(O)CO
Reactant: CCCCOCCO
Agent: [Ti+4]
Agent: N
Agent: [O-2]
Solvent: O
Product: O=c1c(O)cccc2cc(O)c(O)c(O)c12

Procedure:
TiO2 grind [16.4 g Ti Pure® titanium dioxide supplied by DuPont Company, Wilmington, Del., 0.7 g dispersing, 0.1 g ammonia (28% strength), 0.2 g surfactant, 0.1 g defoamer, and 1.6 g water] mixed with 54 g of the oxidative polymer and 8 grams of Butyl Cellosolve cosolvent, 1.5 grams of propylene glycol was added to 12.6 grams of water to form a paint. To the paint, 0.6 ml of P-6140 horseradish peroxidase P-6140 (EC 1.11.1.7) supplied by Sigma Chemical, PO Box 14508, St. Louis, Mo. 63178 (1 ml contains 21 mg enzyme which has an activity of 250 units/mg. One unit will form 1 mg of purpurogallin from pyrogallol in 20 sec. at pH 6 and 20 C.) was added (0.15 ml is equivalent to 3.15 mg enzyme having 250 units activity per mg). The pot mix was then conventionally applied to a plastic sheet as a clear layer having a dry film thickness of 50 microns. The layer was air dried for 4 days to form a film. Thereafter, specimens of the film were removed and measured for the degree of crosslinking achieved by the oxidizing enzyme. The film was found to have a swell ratio of 5.7 indicating significant crosslinking of the oxidative polymer by the oxidizing enzyme.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=1.Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.O>CN(C=O)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: O=c1cc(O)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of potassium carbonate (12.44 g, 90 mmol), 4-hydroxypyridin-2(1H)-one (10 g, 90 mmol) in DMF (500 mL) was stirred at 140° C. for 60 min prior to addition of a solution of 1-(chloromethyl)-4-fluorobenzene (13.01 g, 90 mmol) in DMF (5.0 mL). After stirring at 140° C. for 60 min, the reaction was cooled to RT prior to dilution with water (1.0 L). The resulting suspension was stirred at RT for 60 min prior to collection of precipitate by filtration. The filter cake was washed with water (250 mL), suspended with stirring in ethyl ether (500 mL) for 15 min and collected by filtration. After air-drying, 4-(4-fluorobenzyloxy)pyridin-2(1H)-one 17A was obtained as a white solid (6.67 g, 28.9 mmol, 32.1% yield). 1H NMR (400 MHz, MeOD) δ ppm 7.42-7.56 (2H, m), 7.34 (1H, d, J=7.26 Hz), 7.03-7.25 (2H, m), 6.12-6.24 (1H, m), 6.01 (1H, br. s.), 5.10 (2H, s).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][O:4][N:3]=1.NC1CCON=1.C([O:15][C:16](=[O:20])[CH2:17][NH:18][CH3:19])C>>[O:4]1[CH2:5][CH2:6][C:2]([N:18]([CH3:19])[CH2:17][C:16]([OH:20])=[O:15])=[N:3]1
Reactant: CCOC(=O)CNC
Reactant: BrC1=NOCC1
Agent: NC1=NOCC1
Product: CN(CC(=O)O)C1=NOCC1

Procedure:
2-((4,5-dihydroisoxazol-3-yl)(methyl)amino)acetic acid I-244a and I-244b were prepared in 2 steps according to the following procedure: racemic 3-bromo-4,5-dihydroisoxazole I-10 was converted to the corresponding 3-amino-4,5-dihydroisoxazole by reacting it with sarcosine ethyl ester under the same conditions as in Example 238. The ethyl ester was then hydrolyzed using the analogous conditions as in Example 119 to provide a mixture of racemic I-244. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M−H]−=327.5 m/z. Activity: B
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:8][CH3:9])[CH2:6][CH3:7])=[O:4].[OH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][N:15]=[C:14]2[NH:23][C:24]1[CH:29]=[C:28]([NH:30][C:31]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[CH:34]=2)=[O:32])[CH:27]=[CH:26][C:25]=1[CH3:45].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[CH2:6]([N:5]([CH2:8][CH3:9])[C:3]([CH2:2][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][N:15]=[C:14]2[NH:23][C:24]1[CH:29]=[C:28]([NH:30][C:31]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)[CH:34]=2)=[O:32])[CH:27]=[CH:26][C:25]=1[CH3:45])=[O:4])[CH3:7]
Reactant: CCN(CC)C(=O)CCl
Reactant: COc1cc2ncnc(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)c2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCN(CC)C(=O)COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1OC
Temperature: 100 °C
Yield: 21.6 %

Procedure:
2-Chloro-N,N-diethylacetamide (0.05 g) was added to a mixture of 6-hydroxy-7-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline (0.15 g), cesium carbonate (0.3 g) and dimethylacetamide (2 ml) and the reaction mixture was stirred and heated to 100° C. for 18 hours. After cooling to ambient temperature the reaction mixture was partitioned between methylene chloride and water. The organic layer was dried with brine and sodium sulphate, filtered and evaporated. The residual gum was triturated under diethyl ether. There was thus obtained the title compound as a solid (0.04 g, 20%); NMR: 1.05 (t, 3H), 1.4 (t, 3H), 2.13 (s, 3H), 3.35 (m, 4H), 3.51 (m, 4H), 3.7 (m, 4H), 3.95 (s, 3H), 4.91 (s, 2H), 7.11 (m, 1H), 7.18 (s, 1H),7.24 (s, 1H), 7.29 (m, 1H), 7.6 (m, 1H), 7.77 (m, 2H), 8.26 (m, 2H), 9.3 (broad s, 1H), 10.32 (broad s, 1H); m/s: M+H+ 600.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH:26]([CH3:28])[O:25][CH:24]([CH3:29])[CH2:23]3)[CH:17]=1)[C:10]([CH3:31])([CH3:30])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:28][CH:26]1[O:25][CH:24]([CH3:29])[CH2:23][N:22]([C:18]2[CH:17]=[C:16]([CH:11]3[C:10]([CH3:30])([CH3:31])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:21]=[CH:20][CH:19]=2)[CH2:27]1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CC(C)OC(C)C3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1CN(c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)CC(C)O1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.9 %

Procedure:
To a stirred mixture solution of 2-[3-(2,6-dimethyl-morpholin-4-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.9 g, 2.1 mmol) in methanol (5.0 mL) and tetrahydrofuran (6.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(2,6-dimethyl-morpholin-4-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (745 mg, 90%) as a white solid: LC/MS m/e calcd for C24H30N2O3 (M+H)+: 395.52, observed: 395.0.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[N:4][C:5]([C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][O:11][CH2:10]1.Cl[CH2:28][CH:29]1[CH2:31][O:30]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][C:2]1[C:7]([NH:8][C@@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)=[N:6][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:28][CH:29]3[CH2:31][O:30]3)[CH:15]=2)=[N:4][C:3]=1[N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: ClCC1CO1
Reactant: Cc1c(N[C@@H]2CCOC2)nc(-c2cccc(O)c2)nc1N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(N[C@@H]2CCOC2)nc(-c2cccc(OCC3CO3)c2)nc1N1CCOCC1
Yield: 34.6 %

Procedure:
A mixture of (R)-3-(5-methyl-4-morpholino-6-(tetrahydrofuran-3-ylamino)pyrimidin-2-yl)phenol (50 mg, 0.14 mmol); 2-(chloromethyl)oxirane (16 mg, 0.17 mmol) and K2CO3 (39 mg, 0.28 mmol) in MeCN (10 mL) was heated at 80° C. in a sealed vial for 14 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by chromatographic column on silica gel (EtOAc/petroleum ether, gradient elution, from 1/5 to 4:1) to give the 5-methyl-6-morpholino-2-(3-(oxiran-2-ylmethoxy)phenyl)-N—((R)-tetrahydrofuran-3-yl)pyrimidin-4-amine (20 mg, 34% yield) as a light yellow solid. ESI-LCMS (m/z): 413.2 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:21])[NH:8][CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]=2)=[C:5]([C:22](O)=[O:23])[N:4]=[C:3]1[CH3:25].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:16][N:15]1[C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[N:12]=[C:11]1[CH2:10][CH2:9][NH:8][C:7]([C:6]1[N:2]([CH3:1])[C:3]([CH3:25])=[N:4][C:5]=1[C:22]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:23])=[O:21]
Reactant: Cc1nc(C(=O)O)c(C(=O)NCCc2nc3ccccc3n2C)n1C
Reactant: C1COCCN1
Product: Cc1nc(C(=O)N2CCOCC2)c(C(=O)NCCc2nc3ccccc3n2C)n1C

Procedure:
The product was obtained starting from 1,2-dimethyl-5-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethylcarbamoyl)-1H-imidazole-4-carboxylic acid (51 mg, 149 μmol) and morpholine (39.0 μL, 448 μmol) according to the method described in example 8, step 3 as light brown waxy solid (17.3 mg, 42.1 μmol, 28.2%). MS: M=411.3 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[S:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nc3ccc(Br)cc3s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc2nc(OC3CCNCC3)sc2c1
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of tert-butyl 4-(6-bromobenzo[d]thiazol-2-yloxy)piperidine-1-carboxylate (257 mg, 0.622 mmol) in CH2Cl2 (5 mL) was added TFA (0.719 mL, 9.33 mmol). After 2 h, the reaction mixture was diluted with DCM and washed with 1N NaOH and then brine, dried over Na2SO4, filtered and then concentrated under reduced pressure to obtain Compound 1B as a light yellow solid (190 mg, 0.607 mmol, 98% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 7.75 (1H, d, J=1.9 Hz), 7.48-7.52 (1H, m), 7.43-7.47 (1H, m), 5.21-5.29 (1H, m), 3.15 (2H, dt, J=12.9, 4.7 Hz), 2.80 (2H, ddd, J=12.7, 9.5, 3.2 Hz), 2.10-2.22 (2H, m), 1.71-1.84 (2H, m), 1.47 (1H, br. s.).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([F:28])[C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:38])[CH2:40][OH:41])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f42) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[CH3:14])([CH3:3])[CH3:2].S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:17])=[O:10])=[CH:7][C:6]=1[CH3:14])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(=O)Cl)ccc1OC(C)C

Procedure:
To a solution of 4-isopropoxy-3-methyl-benzoic acid (1.35 g, 6.95 mmol) in chloroform (20 mL), thionylchloride (2.48 g, 20.9 mmol) is added. The mixture is refluxed for 2 h before the solvents are removed in vacuo to give crude 4-isopropoxy-3-methyl-benzoic acid chloride; LC-MS: tR=1.00 min.