Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Ca].[C:2]([O:6][C:7]([NH:9][C@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].F[C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C.O>[CH3:26][N:25]([CH3:27])[S:22]([C:19]1[CH:18]=[CH:17][C:16]([N:12]2[CH2:13][CH2:14][C@H:10]([NH:9][C:7](=[O:8])[O:6][C:2]([CH3:5])([CH3:3])[CH3:4])[CH2:11]2)=[CH:21][CH:20]=1)(=[O:23])=[O:24]
Reactant: CN(C)S(=O)(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [Ca]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)cc1
Temperature: 130 °C
Reaction time: 24 h
Yield: 16.9 %

Procedure:
A solution of 50 g of 4-fluorobenzenesulfonyl chloride in 250 ml of THF was cooled to 0° C., and then, 100 ml of an aqueous 50% dimethylamine solution was added dropwise thereto, and the mixture was stirred at room temperature for 1 day. To the reaction mixture were added water and ethyl acetate, the mixture was stirred and then the liquids were separated. The organic layer washed with a saturated aqueous sodium bicarbonate solution and dried, the solvent was evaporated, and diisopropyl ether and hexane were added to the residue. Then, the precipitates were collected by filtration and washed with hexane to obtain 49.9 g of 4-fluoro-N,N-dimethyl-benzenesulfonamide. (2) In 600 ml of DMSO were suspended 25 g of (S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine, 47.9 g of 4-fluoro-N,N-dimethyl-benzenesulfonamide and 139 g of potassium carbonate, and the mixture was stirred at 130° C. for 1 day. To the reaction mixture were added water and ethyl acetate, the resulting mixture was stirred and the liquids were separated. The organic layer washed with water, and then dried, and the solvent was evaporated. The residue was dissolved in chloroform, NH silica gel was added thereto and the mixture was allowed to stand for a while, and silica gel was filtered off. The silica gel was further washed with ethyl acetate. The filtrate and the washed solution were combined, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=80:20→67:33) to obtain 8.39 g of tert-butyl [(S)-1-(4-dimethylsulfamoylphenyl)-pyrrolidin-3-yl]carbamate.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[N:2]1.C(Cl)(=O)C(Cl)=O.[CH3:21][C:22]([CH3:36])([CH3:35])[CH2:23][NH:24][C:25]1[C:30]([C:31]#[CH:32])=[CH:29][N:28]=[C:27]([C:33]#[N:34])[N:26]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.[Cu]I.CCOC(C)=O.CCCCCC>[CH3:21][C:22]([CH3:36])([CH3:35])[CH2:23][NH:24][C:25]1[C:30]([C:31]#[C:32][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[N:2]3)=[CH:14][CH:13]=2)=[CH:29][N:28]=[C:27]([C:33]#[N:34])[N:26]=1
Reactant: C#Cc1cnc(C#N)nc1NCC(C)(C)C
Reactant: O=C(O)c1ccc(-n2ccnn2)cc1
Agent: [Cu]I
Agent: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)CNc1nc(C#N)ncc1C#CC(=O)c1ccc(-n2ccnn2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
4-[1,2,3]Triazol-1-yl-benzoic acid (5.0 mmol) is dissolved in CH2Cl2 (20 ml). Oxalyl chloride (3.5 mmol) and DMF (1 drop) are added at room temperature and the reaction mixture is stirred at room temperature for 3 h, then evaporated. The residue is dissolved in CH2C2 (20 ml) and the mixture is added to 4-(2,2-dimethyl-propylamino)-5-ethynyl-pyrimidine-2-carbonitrile, copper (I) iodide (0.13 mmol) and triethylamine (13.0 mmol) at room temperature. The reaction mixture is stirred for overnight at room temperature. The organic layer is washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give the product in 31% yield. Rf=0.02 (n-hexane:AcOEt=2:1)
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.[Li]CCCC.[Cl:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.CN([CH:31]=[O:32])C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[CH:31]=[O:32]
Reactant: Clc1ccncc1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cnccc1Cl
Reaction time: 1 h

Procedure:
In a flame-dried 3-necked 100 ml r.b. flask fitted with internal thermometer was prepared LDA at -78° using diisopropyl amine (2.8 ml, 19.9 mmol) and 2.5 M n-BuLi (8.32 ml, 20.8 mmol) in dry THF (15 ml). After stirring for min, 4-chloropyridine (2.26 g, 19.9 mmol) in THF (5 ml) was added via a syringe pump at 0.15 ml/min over about 30 min. The mixture was stirred for 1 h, then dry DMF (4.8 ml, 62 mmol) was added via a syringe pump so that the temperature remained at -78°. After complete addition, the mixture was stirred 30 min then allowed to warm to -40° and hydrolyzed with 5% NaHCO3. The mixture was extracted twice with t-butyl methyl ether and washed with 5% NaHCO3, brine, dnred (MgSO4), and concentrated. Chromatography (flash silica gel, 1:1 t-butyl methyl ether/hexanes) afforded the title compound as a white solid. (1.55 g, 55%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:23](=[O:26])[CH2:24]Br)[CH:12]=[C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][NH:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:23]([CH2:24][N:46]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)[OH:26])[CH:12]=[C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CNCCCCCCOCCCCCCc2ccccn2)cc1
Reactant: O=C(CBr)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Solvent: CN(C)C=O
Product: OC(CN(CCCCCCOCCCCCCc1ccccn1)Cc1ccccc1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 66.7 %

Procedure:
A solution of 1-[3,5-bis(phenylmethoxy)phenyl]-2-bromoethanone (1.76 g) in dry DMF (15 ml) was added dropwise to a solution of N-[6-[[6-(2-pyridinyl)hexyl]oxy]hexyl]benzenemethanamine (1.58 g) and DEA (0.56 g) in dry DMF (15 ml) under nitrogen. The mixture was stirred at room temperature for 4.5 h, and the solvent was evaporated. Sodium borohydride (1.75 g) was added portionwise to the ice-cooled solution of the residue in ethanol (40 ml) under nitrogen and the reaction mixture was stirred at room temperature for 16 h and concentrated. The residue was partitioned between ethyl acetate (70 ml) and water (70 ml), the organic layer was washed with brine (70 ml), dried and concentrated to give an oil which was purified by FCC eluting with ethyl acetatehexane-triethylamine (25:75:1) to give the title compound as a colourless oil (2.00 g), t.l.c. (ethyl acetate-hexane (1:2)+ few drops triethylamine) Rf 0.19.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:10](=[O:35])[C:11]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](OC)=[O:32])=[C:12]([CH3:18])[C:13](=[O:17])[C:14]=1[O:15][CH3:16].Cl>CCOCC>[OH:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:11]1[C:10](=[O:35])[C:9]([O:8][CH3:7])=[C:14]([O:15][CH3:16])[C:13](=[O:17])[C:12]=1[CH3:18]
Reactant: COC(=O)CCCCCCCCCCCCC1=C(C)C(=O)C(OC)=C(OC)C1=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCCO)=C(C)C1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Lithium aluminum hydride (740 mg) is suspended in dry ether (80 ml) and to the suspension is added dropwise a solution of 2,3-dimethoxy-5-methyl-6-(12-methoxycarbonyldodecyl)-1,4-benzoquinone (1.06 g) in dry ether (100 ml) under ice-cooling and stirring. After 1.5 hour, ice-water is added to the mixture to decompose excess lithium aluminum hydride. The mixture is acidified with hydrochloric acid and subjected to extraction with ether. The extract is washed with water and concentrated under a reduced pressure. The residue is dissolved in methanol (30 ml) and to the solution is added a solution of ferric chloride (12 g) in water (60 ml) and the mixture is stirred at room temperature for 1.5 hour. The reaction mixture is diluted with water and subjected to extraction with ethyl acetate. The extract is washed with water, and dried. The solvent is distilled off under reduced pressure. The residue is dissolved in chloroform and subjected to column chromatography on silica gel. The crystals obtained from the first-emerging fraction eluted with chloroformethanol (99:1) is recrystallized from ether-hexane. The above procedure yields 6-(13-hydroxytridecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone as yellow needles. (727 mg) Melting point 65°-66° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:46]4[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=4)=[C:15]4[N:45]=[C:18]([C:19]([C:38]5[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=5)=[C:20]5[NH:37][C:23](=[C:24]([C:30]6[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73]>CN(C=O)C>[OH:52][C:49]1[CH:48]=[CH:47][C:46]([C:14]2[C:12]3[NH:13][C:9]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:73][CH2:72][CH2:71][CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH3:60])=[CH:3][CH:4]=4)=[C:28]4[N:29]=[C:25]([C:24]([C:30]5[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=5)=[C:23]5[NH:37][C:20](=[C:19]([C:38]6[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=6)[C:18]6[CH:17]=[CH:16][C:15]=2[N:45]=6)[CH:21]=[CH:22]5)[CH:26]=[CH:27]4)=[CH:10][CH:11]=3)=[CH:51][CH:50]=1
Reactant: Oc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1

Procedure:
5,10,15,20-tetrakis-(4-Hydroxy-phenyl)-porphyrin (170 mg, 0.25 mmol) is dissolved and K2CO3 (0.65 g, mmol) is suspended in DMF (30 mL). To the vigorously stirred reaction mixture a solution of 1-bromotetradecane (0.1 mL, 0.45 mmol) in DMF (10 mL) is added dropwise at 50° C. during 30 mins and the mixture is heated for 1.5 h. After evaporation of solvent, the residue is dissolved in toluene:ethanol (1:1 by vol., ca. 5 mL) and purified by chromatography using a column (5×25 cm) of silica gel (Merck 60) which is washed with toluene. After the elution of the first 3 fractions, elution is continued using toluene:ethyl acetate (2:1 by vol.). The fifth compound eluted is collected, the solvent evaporated and the residue dried under high vacuum to afford product as a violet solid.
Reaction SMILES: [Cl:1][C:2]1[N:13]=[C:12](Cl)[C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1.Cl.[CH3:16][N:17]([CH3:25])[CH:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:13]=[C:12]([NH:24][CH:21]2[CH2:22][CH2:23][CH:18]([N:17]([CH3:25])[CH3:16])[CH2:19][CH2:20]2)[C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1
Reactant: Clc1nc(Cl)c2c3c(sc2n1)CCC3
Reactant: CN(C)C1CCC(N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C1CCC(Nc2nc(Cl)nc3sc4c(c23)CCC4)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
A solution of 10,12-dichloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene (264 mg, 1.08 mmol, 1.00 equiv) in DMF (15 mL) was added 1-N,1-N-dimethylcyclohexane-1,4-diamine hydrochloride (270 mg, 1.51 mmol, 1.40 equiv) and potassium carbonate (450 mg, 3.26 mmol, 3.00 equiv) was stirred overnight at 80° C. in an oil bath under nitrogen. The resulting solution was diluted with of EtOAc and washed with of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to provide the resulted 4-N-[10-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (300 mg, 79%) as a yellow solid. LC-MS: (ES, m/z) 252 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])(=O)C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[N:55]1[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=1[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: Clc1ccn2ccnc2c1
Reactant: Brc1ccccn1
Agent: [Pd+2]
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(-c2ccn3ccnc3c2)nc1
Yield: 111 %

Procedure:
To a round bottomed flask add 7-chloro-imidazo[1,2-a]pyridine (0.25 g, 1.6 mmol), tricyclohexylphosphine (55 mg, 0.12 equiv.), potassium acetate (0.24 g, 1.5 equiv.), bis(pinacolato)diboron (0.46 g, 1.1 equiv.) and dioxane (10 mL). Deoxygenate this mixture thoroughly with N2 then add tris(dibenzylideneacetone)dipalladium (0) (75 mg, 0.05 equiv.) and heat the reaction to 80° C. overnight under N2. Filter the reaction thru Celite® and wash with DCM then concentrate to dryness. To this residue, add 2-bromopyridine (0.14 mL, 1.5 mmol), S-Phos (75 mg, 0.125 equiv.), potassium phosphate (0.62 g, 2 equiv.), dioxane (10 mL), and water (5 mL). Deoxygenate this mixture thoroughly with N2, add palladium (II) acetate (16 mg, 0.05 equiv.), and reflux the reaction overnight. Concentrate the reaction to dryness and slurry in DCM. Filter this slurry thru Celite® and wash with DCM. Concentrate the filtrate then purify by silica column (EtOAc to 5% MeOH: DCM) to give a residue (0.325 g, >100%). MS (ES), m/z 196 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:27]=[C:28]([CH:45]=[C:46]([F:48])[CH:47]=1)[O:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10]([C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:45]=[C:46]([F:48])[CH:47]=[C:26]([F:25])[CH:27]=4)=[CH:35][CH:34]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(I)c2c(N)ncnc21
Reactant: CC1(C)OB(c2ccc(Oc3cc(F)cc(F)c3)cc2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cc(F)cc(F)c3)cc2)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 81 %

Procedure:
Into a 100 mL, 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (2R)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (250 mg, 0.56 mmol, 1.00 equiv), 2-[4-(3,5-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (226 mg, 0.68 mmol, 1.20 equiv), tetrakis(triphenylphosphane) palladium (39 mg, 0.03 mmol, 0.06 equiv), dioxane (50 mL), sodium carbonate (149 mg, 1.41 mmol, 2.50 equiv), and water (10 mL). The resulting solution was stirred for 12 h at 80° C. in an oil bath and then concentrated under vacuum. The resulting solution was extracted with dichloromethane and the organic layers combined, dried and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50/1) to give 0.237 g (81%) of tert-butyl (2R)-2-([4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate as a brown solid which was converted to title compound as described in Reference I above.
Reaction SMILES: [F:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3](OCC)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[F:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:3][OH:4]
Reactant: CCCCCC[C@@H](F)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC[C@@H](F)CO
Reaction time: 16 h

Procedure:
--Ethyl (R)-(+)-2-fluorooctanoate 69 (20.0 g, 105 mol) in dry THF (30 ml) was added dropwise with stirring to a suspension of lithium aluminium hydride (6 g, 0.158 mol) under nitrogen and with water bath cooling. After the final addition the water bath was removed and the mixture was stirred for 16 h. Aqueous THF (50 ml, 1:3) was added dropwise with iced water-bath cooling followed by 20% hydrochloric acid until a clear solution was effected. The mixture was extracted with ether (3 times) and the combined organic solutions were washed with sat. sodium bicarbonate solution (twice) and brine, dried (MgSO4) and evaporated. The yellow oil was distilled to give (R)-(+)-2-fluorooctanol 70 which solidified on cooling (12.9 g, 83%), b.p. 110° C. at 20 mm Hg, [α]D18 =+6.2° (c 4.6 in CHCl3); νmax /cm-1 (film) 3600-3100br (OH), 2920, 2860, 1460, 1375, 1125sh, 1055br and 840; δ 0.90 (3H, t, Me), 1.14-1.80 (10H, m), 2.19 (1H, br s, OH), 3.69 (2H, br d, 3JHF 27, CH2OH), and 4.56 (1H, br d, 2JHF 51, CHF); m/z 149 (M+ 1), 137, 125, 115, 111, 97, 81 and 69.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1O.O[CH:12]([C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)[C:13]([OH:15])=[O:14]>C(OCC)(=O)C.CCCCCC>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([CH:12]2[C:4]3[C:5]([CH3:9])=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[C:3]=3[O:15][C:13]2=[O:14])=[CH:17][CH:18]=1
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Reactant: Cc1cc(C)c(C)c(O)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(C)c2c(c1C)OC(=O)C2c1ccc(Br)cc1
Yield: 43 %

Procedure:
Using 2,3,5-trimethylphenol and hydroxy(4-bromophenyl)acetic acid, the title compound was synthesized in the same manner as in Reference Example 2. Yield 43%. Melting point: 168-169° C. (ethyl acetate-hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[C:4]([F:16])[C:3]=1[O:17][CH3:18].Cl[C:20]1[N:25]=[C:24]([NH:26][CH3:27])[C:23]([C:28]([F:31])([F:30])[F:29])=[CH:22][N:21]=1.C(O)(C(F)(F)F)=O>COCCO>[F:16][C:4]1[C:3]([O:17][CH3:18])=[C:2]([NH:1][C:20]2[N:25]=[C:24]([NH:26][CH3:27])[C:23]([C:28]([F:31])([F:29])[F:30])=[CH:22][N:21]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)=[O:9]
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Reactant: COc1c(N)ccc(C(=O)N2CCOCC2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: COCCO
Product: CNc1nc(Nc2ccc(C(=O)N3CCOCC3)c(F)c2OC)ncc1C(F)(F)F
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A mixture of (4-amino-2-fluoro-3-methoxyphenyl)(morpholino)methanone (0.18 g, 0.72 mmol) and 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (0.10 g, 0.47 mmol) in a solution of 2-methoxyethanol (2 mL) and TFA (0.055 mL) was stirred at 95° C. for 2 hours. The reaction was concentrated and purified by reverse phase HPLC to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:17]([N:20]=CN(C)C)(=[O:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:17]([NH2:20])(=[O:19])=[O:18]
Reactant: CN(C)C=NS(=O)(=O)c1cc(C(=O)c2ccc(O)cc2)ccc1Cl
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)c2ccc(OCCCc3ccccc3)cc2)ccc1Cl
Temperature: 65 °C
Yield: 3.4 %

Procedure:
2-Chloro-N-dimethylaminomethylene-5-(4-hydroxy-benzoyl)-benzenesulfonamide (250 mg, 0.68 mmol) is dissolved in N,N,-dimethylformamide (5 mL). Potassium carbonate (235 mg, 1.7 mmol) is then added followed by (3-bromo-propyl)-benzene (135 mg, 0.68 mmol). The reaction is heated to 65° C. for 18 hours. The reaction mixture is diluted with water and extracted with ethyl acetate, the organic layer is separated and concentrated in vacuo. The crude ether is purified by column chromatography (gradient of ethyl acetate in hexanes 25-75%). The residue is dissolved in ethanol (3 mL), treated with concentrated HCl (400 μl) and heated to reflux for 2.5 hours after which the reaction is allowed to cool to ambient temperature overnight. The volatiles were removed in vacuo and the crude sulfonamide is purified by column chromatography (gradient of ethyl acetate in hexanes 20-70%) affording 10 mg of the title compound. 1H NMR (DMSO) 2.02-2.11 (m, 2H), 2.76 (t, 2H, J=7.16 Hz), 4.10 (t, 2H, J=6.41 Hz), 7.10 (d, 2H, J=8.67 Hz), 7.17-7.32 (m, 5H), 7.75-7.91 (m, 6H), 8.24 (d, 1H, J=1.88 Hz). MS (m/z): 430 (M+1).
Reaction SMILES: Cl[Si](C)(C)C.[O:6]=[C:7]1[N:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:9]2[CH2:20][S:21][CH2:22][C:8]1=2.ClN1C(=O)CCC1=O>N1C=CC=CC=1.O>[O:6]=[C:7]1[N:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:9]2=[CH:20][S:21][CH:22]=[C:8]12
Reactant: O=C(O)c1ccc2nc3c(c(=O)n2c1)CSC3
Agent: C[Si](C)(C)Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1ccc2nc3cscc3c(=O)n2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chlorotrimethylsilane (2.6 ml, 0.02 mol) is added to a cooled (icebath) solution of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno-[3,4-d]pyrimidine-7-carboxylic acid (5.0 g., 0.02 mol) in pyridine (40 ml) under nitrogen. The mixture is stirred at ice bath temperature for one hour and then allowed to warm to room temperature. N-Chlorosuccinimide (2.74 g., 0.02 mol) is added and the mixture is heated at 90°-95° C. for 20 minutes. The mixture is cooled, diluted with water (5 ml) and stirred for 15 minutes. The precipitate is filtered off, dried, washed with boiling acetone (3×100 ml) and recrystallized from dimethylformamide to give the product (3.9 g.), mp 320° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16]C2C=NC(C(=O)N(C)C)=CC=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].Br[C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([Cl:37])[CH:30]=1.COC(C1C=C(O)C2CC(C)(C)OC=2C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([Cl:37])[CH:30]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N(C)C)nc2)c2c(c1)OC(C)(C)C2
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2ccc(C#N)c(Cl)c2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161b, from 4-bromo-2-chlorobenzonitrile (292 mg, 1.35 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (300 mg, 1.35 mmol) to give a white foam (116 mg, 24% yield). 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=8.59 Hz, 1 H) 7.25-7.34 (m, 1 H) 7.23 (d, J=1.01 Hz, 1 H) 7.04 (d, J=2.27 Hz, 1 H) 6.90 (dd, J=8.72, 2.40 Hz, 1 H) 3.88 (s, 3 H) 2.87 (s, 2 H) 1.48 (s, 6 H); LCMS for C19H16ClNO4 m/z 380.00 (M+Na+).