Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[CH3:22][C:23]1[N:24]=[C:25]([CH2:28]O)[S:26][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.O>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:28][C:25]5[S:26][CH:27]=[C:23]([CH3:22])[N:24]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1csc(CO)n1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1csc(COc2ccn(-c3ccc4nc(C5CC5)n(C)c4c3)c(=O)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.2 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (4-methyl-1,3-thiazol-2-yl)methanol (45.9 mg) and triphenylphosphine (140 mg) in THF (5 ml) was added bis(2-methoxyethyl) azodicarboxylate (125 mg), and the mixture was stirred at room temperature for 3 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-water to give the title compound (11.3 mg) as a white solid.
Reaction SMILES: [Cl:1][CH:2]([Cl:7])[C:3](=O)[CH2:4][CH3:5].[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][NH2:19])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[C:20](O)(=O)[CH2:21]C>>[Cl:1][CH:2]([Cl:7])/[C:3](=[N:19]/[NH:18][S:15]([C:12]1[CH:13]=[CH:14][C:9]([CH3:8])=[CH:10][CH:11]=1)(=[O:17])=[O:16])/[CH2:4][CH2:5][CH2:20][CH3:21]
Reactant: CCC(=O)C(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: CCC(=O)O
Product: CCCC/C(=N\NS(=O)(=O)c1ccc(C)cc1)C(Cl)Cl
Temperature: 80 °C

Procedure:
1,1-Dichlorobutan-2-one (CAS Registry Number 2648-56-8) (210 mg, 1.49 mmol) and 4-methylbenzenesulfonohydrazide (268 mg, 1.49 mmol) were added to propionic acid (3 ml), heated to 80° C. for 5 hours and then allowed to cool to room temperature overnight. Hexanes (20 ml) were added and the precipitate was filtered under nitrogen to yield the title compound (100 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:33]([NH:36][CH2:37][CH2:38][NH2:39])(=[O:35])[CH3:34]>O1CCCC1>[OH2:19].[C:33]([NH:36][CH2:37][CH2:38][NH:39][C:18](=[O:20])[CH2:17][N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)NCCN
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(=O)NCCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Product: O
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole), 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for two hours with nitrogen bubbling through it. Solid N-acetylethylenediamine (4.44 g, 0.0435 mole) was added as well as 100 ml of tetrahydrofuran. A solid formed. After stirring overnight under nitrogen, the reaction mixture was evaporated to a white solid which was triturated in water (200 ml) overnight. The solid was collected by filtration, rinsed with water, dissolved in hot isopropyl alcohol and filtered hot. Water was added and the entire mixture was evaporated to a solid which was rinsed several times with light petroleum ether. The solid was dissolved in hot isopropyl alcohol and water was added to the cloud point. Upon cooling, solid precipitated, which was collected by filtration, and recrystallized again from isopropyl alcohol. Upon addition of water, the solid dissolved. All of the solvents were again evaporated under reduced pressure, and the resulting solid was again recrystallized from isopropyl alcohol to give 1.20 g (18%) of title compound, mp 247°-249° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].O[CH:36]1[CH2:41][CH2:40][CH:39]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:38][CH2:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O.C(OCC)(=O)C>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:6]2[C:5](=[O:27])[N:4]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH:36]4[CH2:41][CH2:40][CH:39]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:38][CH2:37]4)=[CH:30][CH:29]=3)[C:3]([CH2:1][CH3:2])=[N:8][C:7]=2[CH2:9][CH2:10][CH3:11])=[CH:14][CH:15]=1)#[N:26]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OC3CCC(C(=O)OCC)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a solution of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.50 g), ethyl 4-hydroxycyclohexanecarboxylate (1.7 g) and triphenylphosphine (2.6 g) in tetrahydrofuran (15 mL) was added diisopropyl azodicarboxylate (5.3 mL, 1.9 M toluene solution), and the mixture was stirred for 1 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.78 g, 88%).
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=O)[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH:40]1[CH2:58][CH2:57][CH2:56][C@H:41]1[C:42]([NH:44][C@H:45]([C:53]([NH2:55])=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:43]>C(OCC)(=O)C.CC(N(C)C)=O>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([N:40]1[CH2:58][CH2:57][CH2:56][C@H:41]1[C:42]([NH:44][C@H:45]([C:53]([NH2:55])=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:43])=[O:16])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Reaction time: 2 h

Procedure:
The mixed anhydride prepared by reacting Boc-Asp(OBzl) (5.82 g, 18 mmoles), N-methylmorpholine (1.98 mL, 18 mmoles) and isobutyl chloroformate (2.34 mL, 18 mmoles) in ethyl acetate (200 mL) at -15° C., was treated with the solution of HCl.Pro-Phe-NH2 (obtained above) and N-methylmorpholine (1.98 mL, 18 mmoles) in dimethylacetamide (40 mL). The reaction was allowed to proceed for 30 minutes at -15° C. and 2 hours at room temperature. The product was worked up as described earlier and reprecipitated from ethyl acetate-hexane.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:37]=[CH:36][C:22]([CH2:23][O:24][C:25](SC2N=C(C)C=C(C)N=2)=[O:26])=[CH:21][CH:20]=1>O.CN(C)C=O>[CH3:17][O:18][C:19]1[CH:37]=[CH:36][C:22]([CH2:23][O:24][C:25]([N:5]2[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]2[C:7]([OH:9])=[O:8])=[O:26])=[CH:21][CH:20]=1
Reactant: COc1ccc(COC(=O)Sc2nc(C)cc(C)n2)cc1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
trans-4-Hydroxy-L-proline (13.1 g) and triethylamine (21 ml) were dissolved in 55 ml of water, and a solution of 33.44 g of S-p-methoxybenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine in 55 ml of dimethylformamide was added thereto. The resulting mixture was stirred at room temperature for 12 hours, diluted with water and washed with ethyl acetate. The aqueous layer was acidified with 5N hydrochloric acid (pH 2) under ice-cooling and extracted with ethyl acetate. The extract was washed successively with dilute hydrochloric acid and brine, dried over anhydrous sodium sulfate and distilled to obtain trans-1-(p-methoxybenzyloxycarbonyl)-4-hydroxy-L-proline. IR maxneat cm-1 : 1670, 1435, 1350, 1240, 1168.
Reaction SMILES: C(O)(=O)C.[C:5]([OH:16])(=[O:15])[C:6]1[CH:14]=[CH:13][C:11]([OH:12])=[C:8]([O:9][CH3:10])[CH:7]=1.[N+:17]([O-])([OH:19])=[O:18]>O>[OH:12][C:11]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:5]([OH:16])=[O:15])=[CH:14][C:13]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)O)ccc1O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Reaction time: 4 h

Procedure:
A reactor was charged with 525 kg of glacial acetic acid and 50 kg vanillic acid. The mixture was heated with warm water gradually to 50° C. in around 75 minutes. Temperature was set to 16° C. Nitric acid, 31.4 kg was then added gradually over a period of 3 hrs. When the administration was complete the mixture was allowed to stir for additional 3.5-4.5 hours.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH2:16][C:17]([OH:19])=O)=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:34]([S:41][C:42](=[O:45])[CH2:43][NH2:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1.CN(C=O)C>[CH2:34]([S:41][C:42]([CH2:43][NH:44][C:17]([CH2:16][C:9]1[C:8]2[C:13](=[CH:14][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[O:12][C:11](=[O:15])[CH:10]=1)=[O:19])=[O:45])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(=O)Oc1ccc2c(CC(=O)O)cc(=O)oc2c1
Reactant: NCC(=O)SCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2c(CC(=O)NCC(=O)SCc3ccccc3)cc(=O)oc2c1
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
To a solution of 10 (0.162 g, 0.62 mmol) in dry THF was added EDC (0.13 g, 0.68 mmol) and HOBt (0.104 g, 0.68 mmol). The reaction was stirred for 30 minutes under ice-cold conditions, followed by addition of 8 (0.135 g, 0.62 mmol) dissolved in minimal amount of DMF. The resulting solution was stirred further for 6 hours at RT. Upon removal of the solvent in vacuo, the resulting mixture was taken into ethyl acetate and washed with 1 N HCl (2×30 ml), water (2×30 ml) and brine (2×30 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to afford a white solid, which was further purified by flash chromatography (silica gel, dichloromethane/ethanol=9:1) to afford 1 (0.15 g, 56%). 1H NMR (300 MHz, CDCl3) δ 7.67 (d, J=9.0 Hz, 1H), 7.27-7.23 (m, 7H), 6.38 (s, 1H), 4.1 (s, 2H), 3.73 (s, 2H), 2.91 (s, 2H), 2.32 (s, 3H). MS (ESI): m/z 448.0 [(M+Na)]+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].CC(C)=O.[F:10][C:11]([F:20])([F:19])[C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>C(N(CC)CC)C>[F:10][C:11]([F:19])([F:20])[C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:1](=[O:4])[CH2:2][CH3:3]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCC(=O)Nc1ccccc1C(F)(F)F
Reaction time: 12 h
Yield: 66 %

Procedure:
33.3 g of propionyl chloride were added over 30 minutes at 20°-30° C to a mixture of 480 ml of acetone, 48.3 g of o-trifluoromethyl aniline and 36.42 g of triethylamine and after standing for 12 hours, the mixture was filtered. The acetone was evaporated from the filtrate and the residue was taken up in 500 ml of ethyl acetate. The solution was washed with 10% potassium carbonate solution, then with water until the pH of the wash waters was 6, then with N hydrochloric acid and then with water until the wash water pH was 6. The solution was dried over magnesium sulfate, treated with activated carbon and then evaporated to dryness to obtain 65 g of raw product which was washed with iced essence G to obtain 43 g of N-(2-trifluoromethylphenyl)-propanamide melting at 86° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:11]([O:13][C:14](=[O:21])[CH2:15][C:16]([CH2:18][O:19][CH3:20])=O)[CH3:12].[NH3:22]>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:7]([C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[C:15]([C:14]([O:13][CH2:11][CH3:12])=[O:21])=[C:16]([CH2:18][O:19][CH3:20])[NH:22][C:16]=1[CH2:18][O:19][CH3:20])=[O:21])[CH3:12]
Reactant: CSc1ccc(C=O)cc1
Reactant: CCOC(=O)CC(=O)COC
Reactant: N
Solvent: CCO
Product: CCOC(=O)C1=C(COC)NC(COC)=C(C(=O)OCC)C1c1ccc(SC)cc1
Yield: 50 %

Procedure:
7.6 g of 4-methylmercaptobenzaldehyde, 16 g of γ-methoxyacetoacetic acid ethyl ester and 6 ml of aqueous concentrated ammonia in 30 ml of ethanol are heated to the boil for 6-8 hours, and 2,6-dimethoxymethyl-4-(4'-methylmercaptophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is obtained in the form of beige crystals of melting point 136°-138°C.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([CH:21]2[CH2:26][CH2:25]N(CC(O)=O)[CH2:23][CH2:22]2)[C:3]=1[Br:31].C[Si](C)(C)CCOC[N:38](COCC[Si](C)(C)C)[C:39]1N2N=CC(C3C=NC4C(C=3)=CC=CC=4)=C2N=C(C2CCC(CC#N)C2)[CH:40]=1.NC1N2N=CC(C3C=NC4C(C=3)=CC=CC=4)=C2N=C(C2CCN(CC(OC(C)(C)C)=O)CC2)C=1>>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([CH:21]2[CH2:26][CH2:25][CH:23]([CH2:40][C:39]#[N:38])[CH2:22]2)[C:3]=1[Br:31]
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(CC#N)C2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: Nc1c(Br)c(C2CCN(CC(=O)O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Agent: CC(C)(C)OC(=O)CN1CCC(c2cc(N)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Product: N#CCC1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)C1

Procedure:
2-(3-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclopentyl)acetonitrile was synthesized in a manner similar to the synthesis of 2-(4-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-1-yl)acetic acid, but with 2-(3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclopentyl)acetonitrile substituted for tert-butyl 2-(4-(7-amino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-1-yl)acetate. The reaction was concentrated in vacuo and purified via reverse-phase preparatory HPLC to yield 2-(3-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclopentyl)acetonitrile as a yellow solid. (m+H=447.22, retention time=3.99 min).
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:18]=[C:17]([C:19]4[N:23]([CH:24]([CH3:26])[CH3:25])[C:22]([CH3:27])=[N:21][CH:20]=4)[C:16]([F:28])=[CH:15][N:14]=3)=[CH:8][CH:7]=2)[CH2:3]1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl.CO>[F:28][C:16]1[C:17]([C:19]2[N:23]([CH:24]([CH3:25])[CH3:26])[C:22]([CH3:27])=[N:21][CH:20]=2)=[N:18][C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([N:4]3[CH2:3][CH:2]([NH:1][C:36](=[O:38])[CH3:37])[CH2:5]3)=[CH:11][CH:10]=2)=[N:14][CH:15]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC(N)C4)cc3)ncc2F)n1C(C)C
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)NC1CN(c2ccc(Nc3ncc(F)c(-c4cnc(C)n4C(C)C)n3)cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81 %

Procedure:
To a stirred solution of N-[4-(3-aminoazetidin-1-yl)phenyl]-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-amine (Example 140; 110 mg, 0.29 mM) and triethylamine (44 μl, 0.317 mM) in dry DCM (4.0 ml), acetic anhydride (30 μl, 0.317 mM) was added. The reaction was stirred at room temperature under nitrogen for 2.5 hours. A few drops of MeOH were added and the solution stirred for 10 minutes. The reaction mixture was then diluted with more DCM and the solution extracted in turn with water (twice) and saturated sodium chloride. The organic layer was then dried with anhydrous sodium sulphate, filtered and evaporated. The crude product was triturated with ether, filtered washed with ether and dried to give the title compound as a yellow solid (99 mg, 81%). NMR 1.4 (d, 6H), 1.8 (s, 3H), 2.5 (s, 3H+DMSO), 3.5 (t, 2H), 4.05 (t, 2H), 4.53 (m, 1H), 5.43 (m, 1H), 6.4 (d, 2H), 7.33 (m, 3H), 8.42 (m, 2H), 9.08 (s, 1H); m/z 424.
Reaction SMILES: C[Mg]Cl.[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH2:16][CH3:17])[O:11][C:10]([CH3:19])([CH3:18])[CH2:9][C:8]2=O.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH2:16][CH3:17])[O:11][C:10]([CH3:19])([CH3:18])[CH:9]=[C:8]2[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1Br)C(C)=CC(C)(C)O2

Procedure:
Following General Procedure C, methylmagnesium chloride (3 M in THF, 1.38 mL, 4.14 mmol) was added to a solution of 6-bromo-7-ethoxy-2,2-dimethyl-chroman-4-one (Compound 5, 588 mg, 2.07 mmol) in THF. The crude alcohol was treated with p-toluenesulfonic acid to afford the title compound as a colorless oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH:9]([OH:16])([OH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(N([CH2:22][CH3:23])CC)C>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:15][CH:9]([O:16][C:6]([C:2]1[O:1][CH:5]=[CH:22][CH:23]=1)=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:7]
Reactant: CCN(CC)CC
Reactant: CCCCCC(O)O
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Product: CCCCCC(OC(=O)c1ccco1)OC(=O)c1ccco1

Procedure:
Furoyl chloride 121 g (0.93 m) added to 52 g (0.44 m) hexanediol, 133 g (1.3 m) triethylamine and 485 g methylene chloride at 5°-10°. Yield of 92 g recrystallized from isopropyl alchol, 69°-71° m.p.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[CH:8][CH:9]=1)[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20]>CC(=O)CC>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][C:4]=1[O:10][CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[O:7]
Reactant: Cc1ccc(C=O)c(O)c1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C(C)Oc1cc(C)ccc1C=O
Temperature: 70 °C

Procedure:
A mixture of 6.0 g (0.0441 mole) of 4-methylsalicylaldehyde, 7.31 g (0.0529 mole) of potassium carbonate, and 8.62 g (0.0529 mole) of methyl 2-bromopropionate in 50 mL of 2-butanone was heated at 70° C. for approximately seventeen hours. The mixture was then filtered, and the filtrate was evaporated under reduced pressure, leaving a light yellow oil as a residue. This oil was placed on a silica gel column and eluted first with diethyl ether/petroleum ether (25/75) and then with diethyl ether. After the product-containing fractions were combined and the solvents evaporated under reduced pressure, 8.2 g of methyl 2-(2-formyl-5-methylphenoxy)propionate was recovered as a white solid, m.p. 65°-68° C. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[CH2:3][N:4]1[C:11](=[O:12])[CH2:10][CH2:9][C@H:5]1[C:6]([OH:8])=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl:37][C:38]1[C:43]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:48][NH2:49]>ClCCl>[Cl:37][C:38]1[C:43]([C:44]([F:46])([F:47])[F:45])=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:48][NH:49][C:6](=[O:8])[C@@H:5]1[CH2:9][CH2:10][C:11](=[O:12])[N:4]1[CH2:3][C:2]([CH3:1])([CH3:14])[CH3:13]
Reactant: CC(C)(C)CN1C(=O)CC[C@H]1C(=O)O
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)CN1C(=O)CC[C@H]1C(=O)NCc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(2,2-dimethylpropyl)-5-oxoproline (0.100 g, 0.5 mmol, prepared as described below) was dissolved in dichloromethane (5 ml) and to this was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.191 g, 1 mmol), and 1-hydroxybenzotriazole (0.135 g, 1 mmol). The mixture was stirred for 30 minutes at room temperature and then {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine (0.209 g, 1 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was then washed sequentially with water, 3N aqueous citric acid, and three more times with water then dried by filtering through a hydromatrix cartridge (Varian 5 g). The solvent was then evaporated and the residue was purified by mass-directed automated HPLC to give pure N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-1-(2,2-dimethylpropyl)-5-oxoprolinamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](O)=[N:16]2)=[CH:11][CH:10]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[N:27]=[C:26]([CH2:28][OH:29])[NH:25][C:24]=2[CH:30]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[N:27]=[C:26]([CH2:28][OH:29])[NH:25][C:24]=4[CH:30]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: Nc1ccc2nc(CO)[nH]c2c1
Reactant: COc1ccccc1-c1ccc2cnc(O)nn12
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4nc(CO)[nH]c4c3)nn12

Procedure:
{6-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-1H-benzoimidazol-2-yl}-methanol was prepared from 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol and (6-amino-1H-benzoimidazol-2-yl)-methanol; dihydrochloride in an analogous manner to Example 1052a. Product isolated as a yellow solid (55 mg, 46%). m.p.=239-243° C.; LCMS (m/e) 387 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 12.05 (bs, 1H), 9.23 (s, 1H), 8.93 (s, 1H), 8.15-7.42 (m, 2H), 7.87 (d, 1H, J=7.2 Hz), 7.50-7.40 (m, 1H), 7.40-7.22 (m, 1H), 7.22 (d, 1H, J=8.3 Hz), 7.19-7.07 (m, 1H), 6.99-6.85 (m, 2H), 5.60 (bs, 1H), 4.64 (s, 2H), 3.83 (s, 3H).
Reaction SMILES: [CH3:1][S+:2]([CH3:4])[CH3:3].P(CNC[C:12]([OH:14])=[O:13])(O)(O)=[O:6].[I-:15].C[S+](C)C.OO.C(=O)=O>>[OH-:6].[CH3:1][S+:2]([CH3:4])[CH3:3].[I+2:15].[C:12](=[O:14])=[O:13]
Reactant: O=C(O)CNCP(=O)(O)O
Reactant: [I-]
Agent: C[S+](C)C
Agent: O=C=O
Agent: OO
Product: [I+2]
Product: [OH-]

Procedure:
A process for the manufacture of the trimethylsulfonium salt of N-phosphonomethylglycine which comprises (i) reacting trimethylsulfonium iodide, hydrogen peroxide and carbon dioxide to form trimethylsulfonium hydroxide and free iodine (ii) reacting the resultant solution with gaseous carbon dioxide to form trimethylsulfonium carbonate or bicarbonate or a mixture thereof (iii) optionally obtaining the trimethylsulfonium bicarbonate or carbonate or the mixture thereof as a transportable solid or a concentrated aqueous solution, and (v) reacting N-phosphonomethylglycine with an aqueous solution of trimethylsulfonium bicarbonate or carbonate or the mixture thereof.