Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-:1].[Mg+2].[Br-].CS([CH2:8][CH2:9][CH:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1)(=O)=O>C(OCC)C>[Br:1][CH2:8][CH2:9][CH:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1
Reactant: CC1(C)OCC(CCS(C)(=O)=O)O1
Reactant: [Br-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC1(C)OCC(CCBr)O1
Reaction time: 8 h
Yield: 98.1 %

Procedure:
Magnesium bromide etherate (40 g, 130 mmol) and a stir bar were added to a 2000 mL round bottom flask and flushed with nitrogen. A solution of 4-(2-methanesulfonylethyl)-2,2-dimethyl-1,3-dioxolane (I) (17.5 g, 78 mmol) in anhydrous diethyl ether (900 mL) was added via canulla, and the suspension stirred overnight. The ether was first decanted into a beaker. Water (200 mL) and ether (300 mL) were added to the precipitate and stirred for 5 minutes. The precipitate was dissolved, and the ether phase was then collected and added to the ether solution from the reaction. The organic phase was then washed, concentrated to about 500 mL, washed with water, dried over anhydrous Mg2SO4, filtered, and concentrated to yield a yellow oil (16.0 g). This was purified by flash chromatography to yield 10.6 g of product (50.7 mmol, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[H-].[Na+].Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[CH:16][C:15]=1[C:26]([F:29])([F:28])[F:27].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH:4][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[CH:16][C:15]=1[C:26]([F:27])([F:29])[F:28]
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2c(Cl)cc(Cl)cc2Cl)c(C(F)(F)F)c1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
2,4,6-trichloroaniline (3.9 g.) was dissolved in dimethylformamide (20 ml.) and carefully added to sodium hydride (obtained by washing sodium hydride in mineral oil (2.0 g; 50%) with petrol) suspended in dimethylformamide (10 ml.) at 10° C. When the addition was complete the temperature of the mixture was allowed to rise to the ambient temperature over a period of 30 minutes, before being cooled to 10° C. A solution of 2-chloro-3,5-dinitrobenzotrifluoride (5.4 g.) in dimethylformamide (20 ml.) was slowly added, and the mixture stirred at the ambient temperature for 5 hours, and allowed to stand for further 16 hours. The mixture was poured into iced water and the resultant mixture acidified with concentrated hydrochloric acid. The precipitate was collected by decanting off the supernatant liquid and recrystallised from methylated spirit to yield 2(2,4,6-trichloroanilino)-3,5-dinitrobenzotrifluoride, melting point 105° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:6])[O-:5])[CH3:2].[OH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1.[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br>>[CH2:1]([NH:3][C:4](=[O:5])[O-:6])[CH3:2].[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1
Reactant: Fc1ccccc1CBr
Reactant: CC1c2ccc(O)cc2C2CNCC12
Agent: CCNC(=O)[O-]
Product: CC1c2ccc(OCc3ccccc3F)cc2C2CNCC12

Procedure:
The subtitle compound was prepared by the method of Example 43, Step B utilizing N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 43, Step A) (0.1 mmol) and 2-fluorobenzyl bromide. The crude product was obtained without further purification. MS calculated for C22H24FNO3+H: 370, observed: 370.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][CH:6]=[CH:5][N:4]=1)#[N:2].[CH3:11][C:12](=[CH2:14])[CH3:13].S(=O)(=O)(O)[OH:16]>C(O)(C)(C)C>[C:12]([NH:10][C:9]([C:8]1[CH:3]=[N:4][CH:5]=[CH:6][N:7]=1)=[O:16])([CH3:13])([CH3:11])[CH3:14].[C:9]([C:8]1[C:3]([C:1]([NH:2][C:12]([CH3:13])([CH3:11])[CH3:14])=[O:16])=[N:4][CH:5]=[CH:6][N:7]=1)#[N:10]
Reactant: O=S(=O)(O)O
Reactant: C=C(C)C
Reactant: N#Cc1nccnc1C#N
Solvent: CC(C)(C)O
Product: CC(C)(C)NC(=O)c1cnccn1
Product: CC(C)(C)NC(=O)c1nccnc1C#N

Procedure:
A compound having the formula (4) can be obtained as follows. The corresponding 2, 3-dicyano-pyrazine is reacted with tert-butyl alcohol or isobutylene in the presence of sulfuric acid to obtain the corresponding N-tert-butyl-2-pyrazinecarboxamide and/or 3-cyano-N-tert-butyl-2-pyrazinecarboxamide. Then, thus obtained corresponding N-tert-butyl-2-pyrazinecarboxamide and/or 3-cyano-N-tert-butyl-2-pyrazinecarboxamide are hydrolyzed under an alkaline condition.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].C1(C)C=CC(S(O[CH2:21][CH:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:23])(=O)=O)=CC=1.Cl>O.C(O)C>[CH2:25]([O:24][CH:22]([CH3:23])[CH2:21][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: Oc1ccc(O)cc1
Reactant: CCCCCOC(C)COS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCOC(C)COc1ccc(O)cc1
Reaction time: 13 h

Procedure:
16.7 g of hydroquinone, 8.6 g of 85% KOH, 14 g of water and 200 ml of ethanol were added into a four-necked flask, and the reaction was carried out for 13 hours. After elevated in temperature to 50° C., the reaction was further carried out for 3 hours and 30 g of (2'-pentyloxypropyl) p-toluenesulfonate was added dropwise to the reaction mixture and at the temperature elevated to 70° C., the reaction was carried out for 1 hour and then for 3 hours by heating under reflux, and the mixture was left standing at room temperature for 22 hours. After 500 ml of water and a small amount of hydrochloric acid were added to the residue after evaporation of ethanol, the mixture was extracted with 500 ml of hexane. The product after washing twice with water was dried over Na2SO4, recrystallization was effected with hexane.
Reaction SMILES: C1([O:4][S:5](=[O:8])(=[O:7])[NH2:6])CC1.[F:9][CH:10]([F:13])[CH2:11][OH:12]>>[F:9][CH:10]([F:13])[CH2:11][NH:6][S:5](=[O:8])(=[O:7])[O-:4].[F:9][CH:10]([F:13])[CH2:11][O:12][S:5](=[O:7])(=[O:4])[NH2:6]
Reactant: OCC(F)F
Reactant: NS(=O)(=O)OC1CC1
Product: NS(=O)(=O)OCC(F)F
Product: O=S(=O)([O-])NCC(F)F

Procedure:
2,2-Difluoroethylsulfamate was synthesized according to the method presented in the synthesis of sulfamic acid cyclopropyl ester in Example 1 with the exception of utilizing 2,2-difluoroethylalcohol to obtain sulfamic acid 2,2-difluoro-ethyl ester.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[OH:23][CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:24]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([CH2:35][OH:36])=[CH:27][CH:26]=2)=[O:23])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(CO)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1ccc(CO)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (300 mg, 0.96 mmol) in acetonitrile (30 ml) were added 4-(hydroxymethyl)-1-naphthalenecarboxylic acid (194 mg, 0.96 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (275 mg, 1.44 mmol) and 1-hydroxy-1H-benzotriazole (147 mg, 0.96 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=2:1). Recrystallization from ethyl acetate-hexane gave the title compound (365 mg, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][O:8][CH2:7][N:6]1[C:10](=[O:15])[C:11]([O:13]C)=O)=[O:4].[CH3:16][C:17]([Mg]Cl)([CH3:20])[CH2:18][CH3:19]>C1COCC1>[CH3:16][C:17]([CH3:20])([CH2:18][CH3:19])[C:11](=[O:13])[C:10]([N:6]1[CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:9][O:8][CH2:7]1)=[O:15]
Reactant: COC(=O)C(=O)N1COCC1C(=O)OC
Reactant: CCC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCC(C)(C)C(=O)C(=O)N1COCC1C(=O)OC
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of methyl 2-[4-(methoxycarbonyl)(1,3-oxazolidin-3-yl)]-2-oxoacetate (2) (0.84 g, 3.87 mM) in THF (50 ml) cooled to −78° C. was added 1,1-dimethylpropylmagnesium chloride (1M in THF, 8 ml, 8 mM). After 3 hrs. at −78° C. the mixture was quenched with saturated NH4Cl (50 ml) and extracted with ethyl acetate (100 ml). The organic layer separated, washed with brine (100 ml), dried with anhydrous magnesium sulfate, filtered and evaporated. The resulting pale yellow oil was flash chromatographed eluting with 20% EtOAc/hexane. A clear oil (3) (0.61 g, 61%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=O)=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:19])[C:6]([CH3:18])=[CH:7]2.[CH3:20][C:21]([NH2:26])([CH2:24][OH:25])[CH2:22][OH:23]>>[ClH:1].[Cl:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][NH:26][C:21]([CH3:20])([CH2:24][OH:25])[CH2:22][OH:23])=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:19])[C:6]([CH3:18])=[CH:7]2
Reactant: CC(N)(CO)CO
Reactant: Cc1cc2c(Cl)c3ccccc3c(C=O)c2cc1C
Product: Cc1cc2c(Cl)c3ccccc3c(CNC(C)(CO)CO)c2cc1C
Product: Cl

Procedure:
Using the reductive amination procedure outlined in 1, 10-chloro-2,3-dimethyl-9-anthracenecarbaldehyde and 2-methyl-2-amino-1,3-propanediol (Aldrich) gave 2-((10-chloro-2,3-dimethyl-9-anthracenylmethyl)amino)-2-methyl-1,3-propanediol hydrochloride mp 251°-252° (dec), (CH3OH/Et2O), (C, H, Cl, N).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19]C1N=C(F)N=C(F)N=1>ClCCl.N1C=CC=CC=1>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([F:19])=[O:18])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a mixture of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (3.00 g, 11.7 mmol) and pyridine (1.132 mL, 14 0 mmol) in dichloromethane (100 mL) at room temperature was added 2,4,6-trifluoro-1,3,5-triazine (cyanuric fluoride) (1.18 mL, 14.0 mmol). The reaction mixture was stirred at room temperature overnight, diluted with dichloromethane (300 mL), washed with an ice-cold solution of 0.5N aqueous hydrochloric acid (2×100 mL), and the organic layer was collected. The aqueous layer was back-extracted with dichloromethane (200 mL), and the combined organic layers were dried anhydrous sodium sulfate and concentrated to afford 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride (2.91 g, 11.2 mmol, 96% yield) as a yellow, viscous oil. The product was found to react readily with methanol and on analysis was characterized as the methyl ester, which had an HPLC ret. time=2.56 min.-Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=272.3 (methyl ester).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O.[Cl-].[NH4+].CCOCC>O1CCCC1>[Br:16][C:10]1[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1cccc2cc(-c3ccco3)nn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Clc1cccc2c(Br)c(-c3ccco3)nn12
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
7-Chloro-2-(2-furyl)-pyrazolo[1,5-a]pyridine (0.23 g, 1.05 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to 0° C. N-Bromosuccinimide (0.19 g, 1.05 mmol) was added. The reaction was stirred for 1 hour. The reaction solution was poured into equal volumes (10 mL) of saturated aqueous ammonium chloride and ether. The ether layer was collected and the solvent removed in vacuo to give the crude product The product was purified by silica gel chromatography (6:1 hexane:ethyl acetate) to give 0.3 g (96%) of 3-bromo-7-chloro-2-(2-furyl)pyrazolo[1,5-a]pyridine as a solid. 1H NMR (CDCl3) δ 7.63 (d, 1H), 7.51 (d, 1H), 7.29 (d, 1H), 7.21 (dd, 1H), 6.98 (d, 1H), 6.58 (dd, 1H); MS m/z 298 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][C:43](Cl)=[O:44]>>[CH3:36][N:34]([CH3:35])[CH2:33][CH2:32][CH2:31][O:30][C:26]1[CH:25]=[C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:43](=[O:44])[CH2:42][C:38]5[S:37][CH:41]=[CH:40][CH:39]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: CN(C)CCCOc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1
Product: CN(C)CCCOc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1
Yield: 48 %

Procedure:
The title compound was synthesized from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-{[3-(dimethylamino)propyl]oxy}phenyl)-2-pyrimidinamine using acylation with 2-thienylacetyl chloride as described in Example 10, Step E to yield a light brown solid in 48% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.8 (s, 2H) 2.1 (s, 6H) 2.3 (s, 2H) 3.9 (s, 2H) 3.9 (d, J=6.2 Hz, 2H) 6.5 (m, 2H) 7.0 (m, 2H) 7.1 (m, 2H) 7.3 (s, 2H) 7.4 (m, 2H) 7.5 (m, 2H) 7.7 (m, 1H) 7.9 (d, J=2.2 Hz, 1H) 8.2 (d, J=5.3 Hz, 1H) 8.5 (s, 1H) 8.8 (d, J=7.0 Hz, 1H) 9.5 (s, 1H) 10.3 (s, 1H). ES-LC/MS m/z 604 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1>C(O)(=O)C.[Pt]=O>[NH:7]1[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1
Reactant: OCCc1ccncc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: OCCC1CCNCC1
Reaction time: 20 h
Yield: 0 %

Procedure:
A solution of 4-(2-hydroxyethyl)pyridine (1.8 g, 14.6 mol) in acetic acid (15 ml) containing platinum oxide (200 mg) was hydrogenated for 20 hours at 3.3-4 atmospheres pressure. After filtration, the filtrate was evaporated and azeotroped twice with toluene. The residue was triturated with 2N sodium hydroxide and solid sodium hydroxide was added to adjust the pH to 13. The volatiles were removed under vacuum and the residue was triturated with ether, filtered, washed with methylene chloride, and dried under vacuum to give 2-(piperidin-4-yl)-1-ethanol (860 mg, 46%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:28](O)=[O:29]>>[CH3:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: Cc1ccc(C(=O)O)cc1C
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc(C)c(C)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3,4-Dimethyl-benzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[N:12][C:11]=1[C:19]([OH:21])=O.[CH3:22][C:23]1([CH3:31])[O:27][C@@H:26]([CH2:28][O:29][NH2:30])[CH2:25][O:24]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[CH3:22][C:23]1([CH3:31])[O:27][C@@H:26]([CH2:28][O:29][NH:30][C:19]([C:11]2[N:12]=[CH:13][C:14]3[N:15]([CH:16]=[N:17][CH:18]=3)[C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[O:21])[CH2:25][O:24]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C(O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](CONC(=O)c2ncc3cncn3c2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.1 %

Procedure:
To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid (100.0 mg, 0.25 mmol) in anhydrous DMF (2.5 mL) was added, in order, (R)—O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (40.7 mg, 0.28 mmol, 1.1 eq.), HOBt (37.3 mg, 0.27 mmol, 1.1 eq.), EDCI (53.0 mg, 0.27 mmol, 1.1 eq.), and N-methylmorpholine (0.1 mL, 0.91 mmol, 3.6 mmol). The reaction mixture was stirred at room temperature under N2 for 3 days. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with a saturated solution of sodium bicarbonate, water and brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 80% to 100%, ethyl acetate in hexane, followed by gradient 0 to 20% methanol in ethyl acetate) to give a yellow solid (72.6 mg, 54.8%). LCMS (method D1): RT=0.97 min, [M+H]+=528.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[C:16](#[N:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[NH:23])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: N#Cc1ccccc1
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (12 g, 70 mmol) in toluene (400 mL), trimethylaluminum (52.5 ml, 2M solution in toluene, 0.1 mol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 3.5 hours. A solution of benzonitrile (14.5 g, 0.14 mol) in toluene (300 mL) was added over 10 minutes and the reaction mixture heated to 70-75° C. After 17 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue is washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates are concentrated in vacuo and the resulting yellowish solid is stirred with a mixture of hexane/ether (2/1, 1000 mL). The intermediate is filtered and washed with more of hexane/ether (2/1). The yellowish solid N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (16.7 g, 87%) was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][C:19]4[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=4)[O:22][CH2:23][C:24]([OH:26])=[O:25])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:5][CH:4]=1.CO.O.[OH-].[Na+:40]>C1COCC1>[Na+:40].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH:18][C:19]4[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=4)[O:22][CH2:23][C:24]([O-:26])=[O:25])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(OCC(=O)O)c4)c23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(OCC(=O)[O-])c4)c23)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Suspend 2.52 g (5.39 mmol) of 3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenoxyacetic acid in a mixture of 10 ml of THF, 10 ml of methanol and 1 ml of water at RT, add 5.39 ml of 1N sodium hydroxide solution dropwise and stir the resulting solution at RT for 10 min, before filtering off with suction through a fine frit (removal of suspended particles). Concentrate the solution under reduced pressure and treat the residue with ethanol. Filter off the insoluble solid with suction, wash with a little ethanol and dry under reduced pressure, then under high vacuum. Concentrate the filtrate, stir the residue again with a little ethanol and thus obtain a second product batch after filtering off with suction. After combining the two fractions, a total of 2.32 g (87.9% of theory) of the target compound are obtained as a colourless solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[O:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:15][CH:16]=2)=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1COCC1>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[O:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:15][CH:16]=2)=[S:33])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)N1CCN(C(=O)c2ccc(CN3CCCCC3)o2)CC1
Solvent: C1CCOC1
Product: CC(C)N1CCN(C(=S)c2ccc(CN3CCCCC3)o2)CC1
Temperature: 70 °C

Procedure:
A solution of (4-isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-furan-2-yl)-methanone (Example 1, 1 equiv.) and Lawesson's reagent (2.1 equiv.) in THF is heated at reflux (70° C.) for 48 h. The reaction is cooled to room temperature and the solvent is removed in vacuo. Chromatography of the residue on a silica gel column using 1-6% 2 M NH3 in MeOH/DCM) provides the title compound.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[C:7]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]>C(OCC)C>[C:7]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:1](=[O:5])[C:2]([Cl:4])=[O:3])=[CH:17][CH:18]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)c1ccc(CO)cc1
Solvent: CCOCC
Product: CC(C)(C)c1ccc(COC(=O)C(=O)Cl)cc1

Procedure:
To a stirred solution of oxalyl dichloride (100ml) in diethylether (500 ml) at -10° under nitrogen a solution of 4-t-butylbenzyl alcohol (200 ml) in diethylether (100 ml) was added dropwise so as to maintain the temperature between -10° and -5°. The solvent was then evaporated under vacuum to give the title compound (289 g,) as a clear oil (b.p. 120°-122° at 2 mbar).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([OH:26])([CH3:25])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[CH:19]=[N:18][C:17](S(C)(=O)=O)=[N:16][C:15]=3[N:24]=2)[CH:8]=[N:7]1.[CH3:27][N:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([NH:39]C=O)=[C:35]([O:42][CH3:43])[CH:34]=2)=[CH:31][N:30]=[C:29]1[CH3:44]>CN1C(=O)CCC1.C1COCC1>[CH3:27][N:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:17]3[N:18]=[CH:19][C:14]4[CH:13]=[CH:12][C:11]([C:9]5[CH:8]=[N:7][N:6]([CH2:5][C:4]([CH3:25])([OH:26])[CH3:3])[CH:10]=5)=[N:24][C:15]=4[N:16]=3)=[C:35]([O:42][CH3:43])[CH:34]=2)=[CH:31][N:30]=[C:29]1[CH3:44]
Reactant: CC(C)(O)Cn1cc(-c2ccc3cnc(S(C)(=O)=O)nc3n2)cn1
Reactant: COc1cc(-c2cnc(C)n2C)ccc1NC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: COc1cc(-c2cnc(C)n2C)ccc1Nc1ncc2ccc(-c3cnn(CC(C)(C)O)c3)nc2n1
Temperature: 160 °C
Reaction time: 2 h
Yield: 13.8 %

Procedure:
A suspension of NaH (4.3 mg), 2-methyl-1-(4-(2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)propan-2-ol (Preparation 69, 15.5 mg, 0.045 mmol), N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)formamide (Preparation 74, 16.4 mg, 0.067 mmol) in NMP/THF (1/3 mL) was stirred at 160° C. under microwave irradiation for 2 hours. The reaction mixture was filtered, diluted with NaCl solution and extracted with EtOAc. The EtOAc portion was purified by elution through an SCX-2 column using 2M NH3/MeOH to give the title compound as yellow oil (3 mg, 14%).