Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CC(=O)OB([C:11]2[CH:16]=[C:15]([O:17][C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:13][C:12]=2[O:22][C@H:23]([CH2:25][CH:26]=[CH2:27])[CH3:24])OC(=O)C1.[CH2:29]([O:32][C:33]1([CH3:67])[CH2:38][CH2:37][N:36]([C:39]2[N:44]3[CH:45]=[C:46]([C:48]4[CH:53]=[CH:52][CH:51]=[C:50](Br)[CH:49]=4)[N:47]=[C:43]3[C:42]([CH3:55])=[C:41]([CH3:56])[C:40]=2[C@H:57]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[C:58]([O:60][CH3:61])=[O:59])[CH2:35][CH2:34]1)[CH:30]=[CH2:31].C(OC1(C)CCN(C2N3C=C(C4C=C(C5C=C(F)C(F)=CC=5O[C@H](CC=C)C)C=CC=4)N=C3C(C)=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C>>[CH2:29]([O:32][C:33]1([CH3:67])[CH2:34][CH2:35][N:36]([C:39]2[N:44]3[CH:45]=[C:46]([C:48]4[CH:49]=[C:50]([C:11]5[CH:16]=[C:15]([O:17][C:18]([F:19])([F:20])[F:21])[CH:14]=[CH:13][C:12]=5[O:22][C@H:23]([CH2:25][CH:26]=[CH2:27])[CH3:24])[CH:51]=[CH:52][CH:53]=4)[N:47]=[C:43]3[C:42]([CH3:55])=[C:41]([CH3:56])[C:40]=2[C@H:57]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[C:58]([O:60][CH3:61])=[O:59])[CH2:37][CH2:38]1)[CH:30]=[CH2:31]
Reactant: C=CC[C@H](C)Oc1ccc(OC(F)(F)F)cc1B1OC(=O)CN(C)CC(=O)O1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(Br)c4)cn23)CC1
Agent: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5cc(F)c(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5cc(OC(F)(F)F)ccc5O[C@@H](C)CC=C)c4)cn23)CC1
Yield: 92 %

Procedure:
Prepared from (S)-6-methyl-2-(2-(pent-4-en-2-yloxy)-5-(trifluoromethoxy)phenyl)-1,3,6,2-dioxazaborocane-4,8-dione and (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate in 92% yield following the same procedure as (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′,5′-difluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. LCMS (ESI, M+1): 746.85.
Reaction SMILES: F[C:2](F)(F)C(O)=O.C([Zn]CC)C.ICI.[I:16][C:17](=[CH2:37])[CH2:18][C@H:19]([CH2:28][O:29][Si:30]([CH3:36])([CH3:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:20][Si:21]([CH3:27])([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>ClCCCl>[I:16][C:17]1([CH2:18][C@H:19]([CH2:28][O:29][Si:30]([CH3:36])([CH3:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:20][Si:21]([CH3:27])([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:2][CH2:37]1
Reactant: C=C(I)C[C@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: O=C(O)C(F)(F)F
Agent: CC[Zn]CC
Solvent: ClCCCl
Solvent: ICI
Product: CC(C)(C)[Si](C)(C)OC[C@@H](CC1(I)CC1)O[Si](C)(C)C(C)(C)C
Reaction time: 0.58 h
Yield: 76.7 %

Procedure:
Trifluoroacetic acid (TFA; 281 mg, 2.47 mmol) was added to a solution of diethyl zinc (ZnEt2, 2.5 mL, 2.5M in hexane) in DCE (1 mL) at 0° C. and stirred for 35 mins. Diiodomethane (CH2I2, 66 mg, 2.5 mmol) was then added at 0° C., and the mixture stirred for an additional 20 min. A solution of (R)-5-(2-iodoallyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (step D; 188 mg, 0.41 mmol) in DCE (2 ml) was added and the reaction stirred at room temperature overnight. The reaction was then quenched by addition of a mixture of methanol (5 mL) and brine (0.5 mL). After stirring for an additional hour, the mixture was concentrated under reduced pressure. The crude material was extracted with aq. NH4Cl/CHCl3 and the organic layer washed with brine, dried (MgSO4) and concentrated under reduced pressure. The crude material was triturated in hexane and the solution filtered and evaporated to afford (R)-5-((1-iodocyclopropyl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (148 mg, 77%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Li+]>C1COCC1.O>[CH2:22]([NH:21][C:14]1[CH:13]=[C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)[CH:17]=[CH:16][C:15]=1[N+:18]([O-:20])=[O:19])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Reaction time: 5 h
Yield: 68.1 %

Procedure:
To stirred solution of ethyl-1-(3-(benzylamino)-4-nitrophenyl)piperidine-4-carboxylate (2 g, 6.2 mmol) in 20 ml THF: H2O (3:1) was added lithium hydroxide (0.740 g, 30.9 mmol) at room temperature. The resulting mixture was stirred for 5 h, solvent was evaporated and residue was dissolved in water washed with dichloromethane. The aqueous layer was then neutralised with 2M HCl to get yellow solid 1-(3-(benzylamino)-4-nitrophenyl)piperidine-4-carboxylic acid (1.5 g), 90% yield: 1H NMR (500 MHz, DMSO): δ 1.46 (m, 2H), 1.80 (m, 2H), 3.03 (m, 2H), 3.82 (m, 2H), 4.59 (d, J=5.7 Hz, 2H), 5.94 (d, J=2.5 Hz, 1H), 6.40 (dd, J=2.5 Hz, 1H), 7.27 (m, 1H), 7.37 (m, 2H) 7.42 (m, 2H), 7.90 (d, J=9.8 Hz, 1H), 8.83 (m, 1H). HRMS (ESI) calculated for C19H21N3NaO4: 378.1424, Found: 378.1417.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClCl.[S:11](Cl)(Cl)(=[O:13])=[O:12].[NH3:16]>C(S)C1C=CC=CC=1.CN(C)C=O.CS(C)=O>[Cl:8][C:7]1[C:2]([S:11]([NH2:16])(=[O:13])=[O:12])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Clc1cccnc1Cl
Reactant: N
Agent: ClCl
Agent: SCc1ccccc1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ncccc1Cl

Procedure:
The halopyridine sulfonamide of the present invention is prepared in a two-step process. In step one, benzyl mercaptan is dissolved in a solvent such as dimethylformamide or dimethylsulfoxide, mixed with 2,3-dichloropyridine and heated at about 50°-100° C. for about 2-6 hours. The residue is taken up in a solvent and distilled to give the resulting product, 3-chloro-2-(phenylmethyl)thio)pyridine. In step two, the halophenylmethylthiopyridine prepared in step one is converted by oxidative chlorination to a halopyridine sulfonyl chloride upon exposure to chlorine. The resulting sulfonyl chloride compound is reacted with aqueous ammonia for about 16 hours. The mixture is then acidified to a pH of about 5 and extracted with a suitable solvent, preferably ethyl acetate, and dried for 3-5 hours to yield the novel product, 3-chloro-2-pyridine sulfonamide. The product of the present invention is a colorless, needle-like, crystalline solid with a melting point of 128°-130° C. It is soluble in the usual organic solvents and in warm water.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH2:6]([N:13]1[CH2:22][CH2:21][C:20]2[C:19](=O)[NH:18][CH:17]=[CH:16][C:15]=2[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>C1(OC)C=CC=CC=1.C(#N)C.ClCCl>[CH2:6]([N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[N:18][C:19]=2[Br:3])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=c1[nH]ccc2c1CCN(Cc1ccccc1)C2
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: CC#N
Product: Brc1nccc2c1CCN(Cc1ccccc1)C2

Procedure:
Phosphorous oxybromide (7.5 g, 26 mmol) is added portion wise to a suspension of 6-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one (1.6 g, 6.7 mmol) in anisole (20 mL) and acetonitrile (10 mL). The reaction mixture is stirred under reflux for 4 hours. The cooled mixture is poured onto ice and diluted with dichloromethane. The mixture is slowly neutralized using saturated sodium bicarbonate solution. The aqueous phase is extracted with dichloromethane three times. The organic phase are combined and washed with brine, dried over Na2SO4 and taken to dryness by rotary evaporation. The crude product as purified by column chromatography on silica gel to afford 2-benzyl-5-bromo-1,2,3,4-tetrahydro-2,6-naphthyridine as a white solid. MS m/z 303.1 (M+1).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])=[CH:9][CH:8]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]3=[O:24])=[CH:9][CH:8]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNC1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCI)cc1
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCN2CCCC2)cc1

Procedure:
In a manner similar to that described in Example 207, 3-{[4-(4-Iodo-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and pyrrolidine are converted to the named compound
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1.[OH-].[Na+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O1CCOCC1.C(OCC)C>[CH2:17]([O:16][C:14]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1nc(CC(=O)O)cs1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(O)Cc1csc(NC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
(2-Aminothiazol-4-yl)acetic acid (10 g, 63.2 mmol) was dissolved in 1,4-dioxane (100 mL) and aqueous NaOH (6 M, 100 mL), and the solution was cooled to 0° C. Benzyl chloroformate (20 mL, 82.2 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with diethyl ether, and the layers separated. The water layer was cooled to 0° C., and the pH adjusted to approximately 4 with aqueous HCl (6 M). The white precipitate formed was collected by vacuum filtration, washed with water and diethyl ether, and dried under vacuum to provide (2-benzyloxycarbonylaminothiazol-4-yl)acetic acid (7.5 g, 41%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:14]=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)(=[O:18])=[O:17])[C:12]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[C:11]([O:35][CH3:36])[N:10]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].[OH-:37].[Na+]>CCO>[CH3:36][O:35][C:11]1[C:12]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])=[C:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)(=[O:18])=[O:17])[N:14]=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:1]([NH2:2])=[O:37])[CH:8]=2)[N:10]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C#N)c2)nc1OC
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C(N)=O)c2)nc1OC
Temperature: 0 °C

Procedure:
0.356 g of 5-methyl-pyridine-2-sulfonic acid [2-(2-cyano-pyridin-4-yl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide, product of example 19, dissolved in EtOH (5 ml) were treated at RT with 2N NaOH (0.7 ml) and the solution was refluxed for 30 minutes until the transformation was complete according to TLC analysis. The reaction mixture was cooled to 0° C., the pH adjusted to pH=1. The crystalline solid was filtered off, washed with water and dried in a high vacuum to provide the desired 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid amide as an off-white solid. ISN mass spectrum, m/e 521.1 (M−1 calculated for C24H22N6O6S: 521).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:23][C:24]1[C:25]([N:33]([CH3:42])[CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)=[N:26][C:27]([CH3:32])=[N:28][C:29]=1[NH:30][NH2:31].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH:1]1([CH2:6][C@@H:7]([C:8]([NH:31][NH:30][C:29]2[C:24]([F:23])=[C:25]([N:33]([CH3:42])[CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)[N:26]=[C:27]([CH3:32])[N:28]=2)=[O:10])[CH2:11][N:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nc(NN)c(F)c(N(C)CCc2ccncc2)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N(C)CCc2ccncc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A mixture of (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (230 mg, 0.76 mmol), 5-fluoro-6-hydrazino-N,2-dimethyl-N-[2-(4-pyridinyl)ethyl]-4-pyrimidinamine (210 mg, 0.76 mmol), EDC (180 mg, 0.91 mmol), HOAt (120 mg, 0.91 mmol), and NMM (0.25 mL, 2.28 mmol) in 5 ml DMF was stirred at room temperature overnight. The reaction mixture was then purified via reverse phase HPLC to provide {(2R)-2-(cyclopentylmethyl)-3-[2-(5-fluoro-2-methyl-6-{methyl[2-(4-pyridinyl)ethyl]amino}-4-pyrimidinyl)hydrazino]-3-oxopropyl}[(phenylmethyl)oxy]formamide (290 mg, 67%). LCMS: (M+H)+: 564.3.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][C:16]([C:23]#[C:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)([OH:27])[CH3:26])=[CH:17][CH:18]=2)[C:13]=1[C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][C:16]([C:23]#[C:24][C:25]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)([OH:27])[CH3:26])=[CH:17][CH:18]=2)[C:13]=1[C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2ccc(C#CC(C)(O)c3ccc(F)cc3)cc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2ccc(C#CC(C)(O)c3ccc(F)cc3)cc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of (2S)-ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-(4-fluorophenyl)-3-hydroxybut-1-ynyl)-3-methylnaphthalen-2-yl)acetate (22 mg, 0.045 mmol) in 2:2:1 THF/MeOH/H2O (1 mL total) was added a NaOH solution (4 M, 0.2 mL). The reaction mixture was stirred at 60° C. for 2 h. The mixture was partially concentrated and diluted with MeCN and H2O and purified by reverse phase HPLC (MeCN/H2O) to give the titled compound. 1H-NMR: 400 MHz, (CD3OD) δ: 7.75 (d, J=8 Hz, 1H), 7.67 (m, 4H), 7.56 (m, 2H), 7.43 (m, 1H), 7.35 (s, 1H), 7.31 (d, J=8 Hz, 1H), 7.05 (m, 2H), 5.12 (s, 1H), 2.62 (s, 3H), 1.74 (s, 1H), 0.96 (s, 9H). LCMS-ESI+ (m/z): [M-OH]+ calcd for C33H29ClFO3: 527.2. Found: 527.2.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:6]2[N:5]=[CH:4][C:3]=1[C:24]([O:26]CC)=[O:25].[OH-].[Na+].C(O)C.Cl>O>[OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[CH:13][C:14]([S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[CH:4][C:3]=1[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)c1cnc2c(-c3ccc(Sc4ccccc4)cc3)cnn2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnc2c(-c3ccc(Sc4ccccc4)cc3)cnn2c1O
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A mixture of 10.30 g of 7-hydroxy-6-ethoxycarbonyl-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine, 6.59 g of sodium hydroxide, 300 ml of ethanol and 300 ml of water was heated and stirred for 2 hours. To the reaction mixture, 400 ml of water was added, and hydrochloric acid was also added while ice-cooling to adjust the pH to 1 to 2, and after stirring for 30 minutes, the precipitate was filtered, washed in water, and dried, thereby obtaining the title compound (9.42 g ).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][Cl:8].Cl.[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[Cl-:8].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][P+:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: ClCc1ccccn1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: [Cl-]
Product: c1ccc([P+](Cc2ccccn2)(c2ccccc2)c2ccccc2)cc1

Procedure:
2-Picolyl chloride (7.4 g, 58 mmol) (from the hydrochloride) and triphenyl phosphine (16.7 g, 64 mmol) in toluene (100 ml) were heated at reflux for 18 hours. The reaction mixture was cooled in an ice-bath, the precipitated product filtered off and washed with toluene to yield the dried product.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[CH:8]=[CH:9][S:10][C:4]=2[CH2:3]1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([O-:13])=[O:12].O1CCOC[CH2:22]1.C(O)(=O)C(O)=O>C(O)C>[OH:20][C:17]1[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][C:16]=1[CH2:22][N:7]1[CH:2]([CH3:1])[CH2:3][C:4]2[S:10][CH:9]=[CH:8][C:5]=2[CH2:6]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC1Cc2sccc2CN1
Reactant: C1COCCO1
Agent: *CO*
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: CC1Cc2sccc2CN1Cc1cc([N+](=O)[O-])ccc1O
Temperature: 80 °C
Reaction time: 4 h
Yield: 27 %

Procedure:
A mixture of 6-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (6.3 g; 41 mmoles), p-nitro-phenol (5.7 g; 41 mmoles), polyoxymethylene (2.5 g; 83 mmoles) and dioxan (50 cc) is stirred at 80° C. during 4 hours. After concentration in vacuo, the residue is dissolved in ether and then treated with 0.5 equivalent oxalic acid in ethanol solution. The resulting semi-oxalate is filtered, washed with boiling methanol-water (1:3), filtered again and dried (M.p.= 214° C.; yield: 27%).
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[C@@:11]([CH:31]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([CH2:12][O:13][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[O:10][C@@H:9]([N:48]2[CH:56]=[C:54]([CH3:55])[C:52](=[O:53])[NH:51][C:49]2=[O:50])[CH2:8]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>O1CCCC1>[C:34]1([CH2:33][NH:32][CH:31]([C@:11]2([CH2:12][OH:13])[O:10][C@@H:9]([N:48]3[CH:56]=[C:54]([CH3:55])[C:52](=[O:53])[NH:51][C:49]3=[O:50])[CH2:8][C@@H:7]2[OH:6])[NH:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)(C(NCc3ccccc3)NCc3ccccc3)O2)c(=O)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](O)[C@](CO)(C(NCc3ccccc3)NCc3ccccc3)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
3′-O-[(tertbutyl)dimethylsilyl]-5′-O-[(tertbutyl)diphenylsilyl]-4′-C-(1,1′-diphenylmethylaminomethyl)thymidine (2) (1.2 g, 1.5 mmol) was dissolved in tetrahydrofuran (50 mL) at ambient temperature. A solution of tetrabutylammonium fluoride in tetrahydrofuran (4.5 mL) was then added to the solution. The resulting mixture was stirred for 3 hours at ambient temperature. Methanol (5 mL) was then added and the reaction mixture concentrated under vacuum. The residue was purified by flash column chromatography (95:5 dichloromethane:methanol) to give the title compound (3) as an amorphous white solid (0.65 g, 100%) on removal of solvent from the appropriate fractions. δH(300 MHz, d6-DMSO) 11.23(1H, s, br, N3—H), 7.75(1H, s, H-6), 7.41–7.15(10H, m, Ph2CHNH), 6.21(1H, dd, H-1′), 5.57(1H, d, br, 3′-OH), 5.21(1H, t, 5′-OH), 4.78(1H, s, Ph2CHNH), 4.35(1H, m, H-3′), 3.61(2H, 2d, H-5′), 2.54(2H, 2d, 4′-C—CH2), 2.18(2H, m, H-2′), 1.75(3H, s, 5-CH3); δC(75.45 MHz, d6-DMSO) 150.46, 144.53, 144.28, 136.28, 128.36, 126.99, 126.74, 109.17, 88.39, 83.18, 66.79, 64.10, 54.91, 12.27.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[C:11]=1[CH2:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>CN(C)C=O.ClCCl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[C:11]=1[CH2:12][CH2:13][CH2:14][NH:15][C:26]([CH:23]1[CH2:25][CH2:24]1)=[O:27]
Reactant: O=C(Cl)C1CC1
Reactant: NCCCc1c(Cl)ccc2c1CCO2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCc1c(Cl)ccc2c1CCO2)C1CC1
Reaction time: 0.33 h
Yield: 50 %

Procedure:
A mixture of 3-(5-chloro-2,3-dihydro-benzofuran-4-yl)-propylamine hydrochloride (142 mg), dimethylformamide (5 drops), triethylamine (0.64 ml) and dichloromethane (5 ml) was stirred in ice for 20 minutes. Cyclopropanecarbonyl chloride (66 mg) was added and stirring continued for 5 hours. The mixture was purified by chromatography on silica eluting with ethyl acetate/hexane (1:1) to give the title compound as a white solid (80 mg).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.[F-].[K+]>C1COCC1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH3:10])=[CH:3][CH:4]=1)=[O:7]
Reactant: Cc1ccccc1B(O)O
Reactant: O=Cc1ccc(Cl)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc(C=O)cc1
Yield: 94.4 %

Procedure:
4-Chlorobenzaldehyde (144 mg, 1.02 mmol) reacted with 2-methylphenylboronic acid (204 mg, 1.50 mmol) using 1/2 mol % of Pd(OAc)2/Ph5FcP(t-Bu)2 and KF (180 mg, 3.10 mmol) in THF at 50° C. to give the title compound (189 mg, 96%) as a white solid: 1H-NMR (400 MHz, CDCl3): δ 9.98 (s, 1H), 7.85 (d, 2H, J=8.2 Hz), 7.41 (d, 2H, J=8.1 Hz), 7.22-7.13 (m, 4H), 2.19 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 191.98, 148.36, 140.51, 135.06, 134.87, 130.54, 129.88, 129.55, 129.42, 128.03, 125.94, 20.34. GC/MS(EI): m/z 196 (M+), 165, 167, 152. Anal. Calcd for C14H12O: C, 85.68; H, 6.16. Found: C, 85.64; H, 6.39.
Reaction SMILES: [Cl-].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:13][C:14]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:15]O.[OH-].[Na+]>O>[F:13][C:14]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:15][O:10][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:12])=[CH:7][CH:6]=1)(=[O:11])=[O:9]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)(F)F)cc1
Temperature: 50 °C
Yield: 82.3 %

Procedure:
To p-toluenesulfonate chloride (400.66 gm/2.10 mol) in water at 25° C. was added 2,2,3,3,3-pentafluoro-1-propanol (300.8 gm). The mixture was heated in a 5 liter, 3-neck separatory funnel type reaction flask, under mechanical stirring, to a temperature of 50° C. Sodium hydroxide (92.56 gm/2.31 mol) in 383 ml water(6M solution) was added dropwise to the reaction mixture via addition funnel over a period of 2.5 hours, keeping the temperature below 55° C. Upon completion of this addition, when the pH of the aqueous phase was approximately 6, the organic phase was drained from the flask while still warm, and allowed to cool to 25° C. The crude product was recrystallized from petroleum ether to afford white needles of 2,2,3,3,3-pentafluoropropyl-p-toluenesulfonate (500.7 gm/1.65 mol, 82.3%).
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[C:9](=[O:20])[N:10]([CH2:14][C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][CH:13]=1)=[O:6])[CH:2]=[CH2:3].FC(F)(F)C(O)=O>ClCCl.C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([NH:7][C:8]1[C:9](=[O:20])[N:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)Nc1cccn(CC(=O)OCC)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=CCOC(=O)Nc1cccn(CC(=O)O)c1=O

Procedure:
The compound of example 60 (1.00 g) is treated with 50% trifluoroacetic acid in dichloromethane (10 mL) for 1 hour at 0° C., and 3 hours at room temperature. The solution is diluted with toluene (50 mL) and the solvent is removed in vacuo to afford the title compound.