Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:30])=[C:4]([F:29])[C:5]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[Cl:28])=[C:6]([CH:19]=1)[C:7]([NH:9][O:10][CH2:11][CH:12]1[CH2:16][O:15]C(C)(C)[O:13]1)=[O:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[Cl:1][C:2]1[C:3]([F:30])=[C:4]([F:29])[C:5]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[Cl:28])=[C:6]([CH:19]=1)[C:7]([NH:9][O:10][CH2:11][CH:12]([OH:13])[CH2:16][OH:15])=[O:8]
Reactant: CC1(C)OCC(CONC(=O)c2cc(Cl)c(F)c(F)c2Nc2ccc(I)cc2Cl)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: O=C(NOCC(O)CO)c1cc(Cl)c(F)c(F)c1Nc1ccc(I)cc1Cl

Procedure:
To a stirring solution of 5-chloro-2-(2-chloro-4-iodo-phenylamino)-N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-benzamide (3.7 g, 6.45 mmol) in methanol (20 mL) and water (2 mL) was added p-toluenesulfonic acid (0.12 g, 0.65 mmol). After 20 hours the reaction was concentrated in vacuo. The afforded residue was partitioned between ethyl acetate and water. The organic layer was washed twice with saturated NaHCO3 solution and twice with saturated brine solution. The organic layers were collected, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by crystallization with methanol/water and the solids were dried in a vacuum oven at 40° C. to afford 5-chloro-2-(2-chloro-4-iodo-phenylamino)-N-(2,3-dihydroxy-propoxy)-3,4-difluoro-benzamide: m.p.=152-154° C.; 1NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H), 8.83 (s, 1H), 7.76 (s, 1H), 7.66 (d, 1H, J=6.8), 7.47 (d, 1H, J=8.5), 6.68 (t, 1H, J=6.6), 4.83 (bs, 1H), 4.60 (bs, 1H), 3.89-3.92 (m, 1H), 3.68-3.76 (m, 2H), 3.30 (2H, partially hidden by HDO); MS(APCI+)=533.0/535.0; Anal. calcd/found for C16H13Cl2F2IN2O4: C, 36.05/36.23; H, 2.46/2.40; N, 5.25/5.03; F, 7.13/7.14.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][S:9][C:4]2=[CH:3][CH:2]=1.[Li+].CCC[CH2-].[C:15](=[O:17])=[O:16]>CCOCC>[CH:1]1[CH:6]=[C:5]2[CH:7]=[C:8]([C:15]([OH:17])=[O:16])[S:9][C:4]2=[CH:3][CH:2]=1
Reactant: O=C=O
Reactant: c1ccc2sccc2c1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCOCC
Product: O=C(O)c1cc2ccccc2s1

Procedure:
Thionaphthene was treated in a carboxylation reaction in accordance with the procedure described by D. A. Shirley and M. D. Cameron, in J. Am. Chem. Soc., 72, 2788, 1950 using N-butyllithium in ether, followed by carbonation with dry ice, and hydrolysis to the acid. The product had a melting point of 238°-239° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:15][S:16]([C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17].S(Cl)(Cl)(=O)=O.N12CCN(CC1)CC2>CC(C)=O>[F:15][S:16]([C:19]1[CH:20]=[C:21]([S:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:6][CH:7]=2)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:18]
Reactant: O=S(=O)(F)c1cccc(S(=O)(=O)Cl)c1
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Agent: C1CN2CCN1CC2
Solvent: CC(C)=O
Solvent: O=S(=O)(Cl)Cl
Product: N#CC=CS(=O)(=O)c1ccc(NS(=O)(=O)c2cccc(S(=O)(=O)F)c2)cc1
Temperature: 25 °C

Procedure:
To an acetone solution of 10.4 g (0.05 mol) 2-cyanovinyl 4-aminophenyl sulfone is added 12.8 g (0.05 mol of 3-fluorosulfonylbenzenesulfonyl chloride at room temperature, with agitation. The sulfonyl chloride dissolves immediately, giving a clear yellow solution. To this mixture is added over a ten minute period an acetone solution of 1,4-diazabicyclo[2.2.2]-octane (11.2 g, 0.05 mol). A light yellow precipitate forms almost at once; the reaction mixture is maintained at about 25° C for 30 minutes with stirring. Precipitation in water and workup affords a bright yellow powder, 2-cyanovinyl 4-(3-fluorosulfonylbenzenesulfonamido)phenyl sulfone: ##SPC44##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:24][CH2:23]4)[CH:12]=[CH:11][C:10]=2[C:35]([F:38])([F:37])[F:36])=[CH:5][CH:4]=1.CO.O.[Li+].[OH-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([OH:32])=[O:31])[CH2:24][CH2:23]4)[CH:12]=[CH:11][C:10]=2[C:35]([F:37])([F:38])[F:36])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3ccc(C(F)(F)F)c(-c4ccc(OC)cc4)n3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(NCCCOc3ccc4c(c3)CC[C@H]4CC(=O)O)ccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.4 %

Procedure:
To a solution of ethyl [(1S)-5-(3-{[6-(4-methoxyphenyl)-5-(trifluoromethyl)-2-pyridinyl]amino}propoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 304, 0.05 g, 0.09 mmol) in a mixture of THF (1 mL), methanol (1 mL), and water (0.5 mL) was added LiOH (0.02 g, 0.85 mmol). The mixture was stirred at rt for 18 h, and then concentrated under reduced pressure. The residue was taken up in water and acidified with 5% H3PO4. The aqueous solution was extracted with ethyl acetate. The combined organic phases dried (Na2SO4), filtered, and concentrated under reduced pressure to give the product (0.038 g, 88%). 1H NMR (400 MHz, CD2Cl2) δ 7.65 (d, 1H), 7.35 (d, 2H), 7.05 (d, 1H), 6.92 (d, 2H), 6.73 (s, 1H), 6.66 (dd, 1H), 6.49 (d, 1H), 4.02 (t, 2H), 3.84 (s, 3H), 3.55 (t, 3H), 3.45 (qt, 1H), 2.92-2.65 (m, 3H), 2.40-2.30 (m, 2H), 2.10-2.02 (m, 2H), 1.80-1.68 (m, 1H); LC-MS: RT=3.02 min, (M+H)+ 531.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[N:17][CH:16]=3)[CH:9]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].C(=O)([O-])[O-].[K+].[K+].[Cl:31][C:32]1[C:33](F)=[CH:34][C:35]([F:58])=[C:36]([S:38]([N:41]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=2[O:56][CH3:57])[C:42]2[S:43][CH:44]=[N:45][N:46]=2)(=[O:40])=[O:39])[CH:37]=1>CS(C)=O>[Cl:31][C:32]1[C:33]([O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:21]([F:22])([F:24])[F:23])[CH:4]=3)=[CH:9][C:10]=2[C:15]2[CH:20]=[CH:19][N:18]=[N:17][CH:16]=2)=[CH:34][C:35]([F:58])=[C:36]([S:38]([N:41]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=2[O:56][CH3:57])[C:42]2[S:43][CH:44]=[N:45][N:46]=2)(=[O:39])=[O:40])[CH:37]=1
Reactant: Oc1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(Cl)c(C(F)(F)F)c4)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
4′-Chloro-3-(pyridazin-4-yl)-3′-(trifluoromethyl)biphenyl-4-ol (Preparation 56, 88 mg, 0.25 mmol) was dissolved in DMSO (1 mL), potassium carbonate (69 mg, 0.5 mmol) was added followed by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 127 mg, 0.27 mmol). The reaction was stirred at room temperature for 3 hours and then partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was separated and washed with water (2×50 mL), dried over MgSO4, filtered and evaporated. The crude product was chromatographed on silica eluting with a gradient of heptane:ethyl acetate 100:0 to 20:80 to give the title compound (135 mg, 0.17 mmol, 69%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.CS(C)=O.[NH2:13][C:14]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20](F)[C:19]([Br:26])=[C:18]([CH3:27])[C:15]=1[C:16]#[N:17].C(N(CC)CC)C>O>[NH2:13][C:14]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)[C:19]([Br:26])=[C:18]([CH3:27])[C:15]=1[C:16]#[N:17]
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(Br)c(F)c([N+](=O)[O-])c(N)c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(Br)c(N2CC[C@H](N(C)C)C2)c([N+](=O)[O-])c(N)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (140 μl, 1.10 mmol) was added to a dimethyl sulfoxide (2 ml) solution of 2-amino-5-bromo-4-fluoro-6-methyl-3-nitrobenzonitrile (I-266) (274 mg, 1.00 mmol) and triethylamine (209 μl, 1.50 mmol), followed by stirring at room temperature for 30 minutes. The reaction liquid was poured into water, and the precipitated solid was collected by filtration, washed with water, and dried to obtain the entitled compound (359 mg, 97%) as a yellow solid.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH2:11][C:10]2=O.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C:18]1=[O:26].N1CCCCC1.Cl>CN(C)C=O.O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13]([C:12](=[C:19]3[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[NH:17][C:18]3=[O:26])[CH2:11][CH:10]2[CH2:2][C:1]([OH:4])=[O:3])=[CH:14][CH:15]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: O=C1Cc2ccccc2N1
Reactant: CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(CC(=O)O)CC2=C1C(=O)Nc2ccccc21
Temperature: 130 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
A mixture of 0.66 g 5-methoxyindan-3-one acetic acid, 2.4 g oxindole and 1.0 ml piperidine in 3 ml of dimethylformamide was heated in a sealed tube at 130° C. for 14 hours. Three ml of 6N hydrochloric acid was added to the cooled reaction mixture followed by 3 ml of water. The supernatant was then decanted. The oily residue was heated in 5 ml of ethanol until it dissolved, the solution was then cooled and water was added. After standing overnight, a solid formed which was filtered and washed with ethanol. The solid was slurried in 4 ml of ethyl acetate at 70° C. for 45 minutes, filtered and suctioned dried to give 300 mg of [6-methoxy-3-(2-oxo-1,2-dihydroindol-3-ylidene)-indan-1-yl]-acetic acid.
Reaction SMILES: N1C=N[C:3]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=N1.BrCC1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1.[NH:25]1[CH:29]=[N:28][CH:27]=[N:26]1>C(#N)C.C(Cl)(Cl)Cl>[CH:13]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]([CH:6]([N:25]2[N:26]=[CH:27][N:28]=[CH:29]2)[C:3]2[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=2)[CH:14]=1
Reactant: c1nc[nH]n1
Reactant: N#Cc1ccc(Cc2nc[nH]n2)cc1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(C(c2ccc(C#N)cc2)n2cncn2)cc1

Procedure:
U.S. Pat. No. 5,473,078 (“the '078 patent”) describes a method of preparing 4-[1-(1,2,4-triazolyl)methyl]benzonitrile by refluxing a solution of α-bromo-4-tolunitrile with 1,2,4-triazole for 15 hours in a mixture of acetonitrile and chloroform. The intermediate is purified by chromatography on silica gel, eluting with chloroform and isopropanol, and then reacted with 4-fluorobenzonitrile and potassium tert-butoxide in DMF, to obtain letrozole. An exemplary process described in the '078 patent is generally depicted in Scheme 1.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH3:11])[CH2:3]1.[C:12](O)(=O)C.P(=O)(O)(O)O.[ClH:21]>O>[CH3:11][CH:4]1[C:5]2[C:10](=[CH:9][C:8]([CH2:12][Cl:21])=[CH:7][CH:6]=2)[CH:2]([CH3:1])[CH2:3]1
Reactant: CC1CC(C)c2ccccc21
Reactant: Cl
Reactant: CC(=O)O
Agent: O=P(O)(O)O
Solvent: O
Product: CC1CC(C)c2cc(CCl)ccc21
Reaction time: 24 h

Procedure:
a mixture of 73 g of 1,3-dimethyl-indane, 28 g of trioxymethylene, 64 ml of acetic acid, 41 ml of 85% strength phosphoric acid and 100 ml of concentrated hydrochloric acid is stirred for 24 hours at between 58° and 60° C. The reaction mixture is taken up in a mixture of water and ice and the organic products are extracted with ether. The ether phase is washed with water and dried over sodium sulphate. After evaporation of the ether, the residue obtained is distilled in vacuo. 44.8 g of 1,3-dimethyl-5-chloromethylindane are thus obtained in the form of a colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1)=[O:8].[NH2:26][C:27]1[S:31][N:30]=[CH:29][N:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])[CH2:5][NH:6][C:7](=[O:8])[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:26][C:27]2[S:31][N:30]=[CH:29][N:28]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Nc1ncns1
Reactant: O=C(NCc1ccc(C(F)(F)F)c(Cl)c1)c1ccc(S(=O)(=O)Cl)cc1
Product: O=C(NCc1ccc(C(F)(F)F)c(Cl)c1)c1ccc(S(=O)(=O)Nc2ncns2)cc1
Yield: 16 %

Procedure:
The title compound was prepared from 4-({[3-chloro-4-(trifluoromethyl)benzyl]amino}carbonyl)benzenesulfonyl chloride (Preparation 30) and 5-amino-1,2,4-thiadiazole in 16% yield following the Method H described for Example 6.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])#[CH:2].[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([Cl:22])=[CH:17][N:16]=1.CCN(CC)CC>O1CCOCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:14][C:15]1[N:20]=[C:19]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])[C:18]([Cl:22])=[CH:17][N:16]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: C#Cc1ccccc1C(C)C(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C(N)=O)c1ccccc1C#Cc1nc(Cl)ncc1Cl
Temperature: 60 °C

Procedure:
To a solution of 2-(2-ethynylphenyl)propanamide K7 (2.5 g, 14 mmol) and 2,4,5-trichloropyrimidine (2.2 mL, 19 mmol) in 1,4-dioxane (27 mL) and Et3N (8.1 mL, 58 mmol) containing CuI (0.055 g, 0.29 mmol) was added PdCl2(PPh3)2 (0.10 g, 0.14 mmol). The reaction mixture was heated at 60° C. for 2.5 hours under a nitrogen atmosphere. The solvent was removed in vacuo and the residue was diluted with 20% Et2O in cyclohexane. The precipitate was filtered, washed with water and dried in vacuo to give the title compound A29 as a light brown solid (4.52 g, 98%). LCMS-C: rt 5.10 min; m/z 320 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH3:36])[C:5]2[C:11]([OH:12])=[CH:10][C:9](=[O:13])[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[N:31](C(C)(C)C)[N:30]=[N:29][N:28]=4)=[CH:17][CH:16]=3)[C:6]=2[N:7]=1.CS(O)(=O)=[O:39].[OH-:42].[K+]>C1(C)C=CC=CC=1>[OH2:12].[CH3:1][C:2]1[N:3]=[C:4]([CH3:36])[C:5]2[C:11]([OH:12])=[CH:10][C:9](=[O:13])[N:8]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:28][N:29]=[N:30][N:31]=4)=[CH:19][CH:20]=3)[C:6]=2[N:7]=1.[OH2:39].[OH2:42].[CH3:1][C:2]1[N:3]=[C:4]([CH3:36])[C:5]2[C:11]([OH:12])=[CH:10][C:9](=[O:13])[N:8]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:28][N:29]=[N:30][N:31]=4)=[CH:19][CH:20]=3)[C:6]=2[N:7]=1
Reactant: [OH-]
Reactant: Cc1nc(C)c2c(O)cc(=O)n(Cc3ccc(-c4ccccc4-c4nnnn4C(C)(C)C)cc3)c2n1
Reactant: CS(=O)(=O)O
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1nc(C)c2c(O)cc(=O)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c2n1
Product: O
Yield: 52 %

Procedure:
A mixture of 2,4-dimethyl-5-hydroxy-8-[2'-(1-tert-butyl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-8H-pyrido[2,3-d]pyrimidin-7-one (925 mg, 1.92 mmol), methanesulfonic acid (1.84 g, 19.2 mmol), and toluene (10 mL) was heated under reflux for 28 h. 1N KOH (25 mL) was added and the mixture was extracted twice with EtOAC (discarded). The aqueous phase was acidified to pH 4 with 1N HCl and the precipitate (560 mg) was collected by filtration. Recrystallizationfrom EtOH/water gave 424 mg (52%) of product as an off-white solid, mp 278-280 (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10](/[CH:13]=[N:14]/[S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])=[N:9]2)=[CH:4][CH:3]=1.[CH3:21][Mg]Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C@H:13]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH3:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccn(-c2ccc(Cl)cc2)n1
Reactant: C[Mg]Br
Solvent: ClCCl
Product: C[C@@H](N[S@](=O)C(C)(C)C)c1ccn(-c2ccc(Cl)cc2)n1
Temperature: -40 °C
Reaction time: 3 h
Yield: 49.8 %

Procedure:
To a solution of (R,E)-N-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)methylene)-2-methylpropane-2-sulfinamide (2.12 g, 6.84 mmol) in DCM (40 ml) at −40° C. was added methylmagnesium bromide (9.12 ml, 27.4 mmol). The reaction was stirred at −40° C. for 3 hours. The reaction mixture was then quenched with saturated NH4Cl solution (20 mL). The aqueous layer was adjusted to pH=8 with HCl (1M) and extracted with DCM (2×200 mL). The combined organic was dried (Na2SO4) and concentrated. The residue was then purified via silica gel chromatography (EtOAC/heptane) to give (R)—N—((R)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.11 g). LCMS (B) m/z 326.3 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:15]([C:17]3[C:18]([O:36][CH2:37][CH3:38])=[C:19]([CH:25]4[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]4)[C:20]([F:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:9]=[C:10]([CH:11]([OH:14])CO)[C:3]=12.C(O)(=O)C.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:15]([C:17]3[C:18]([O:36][CH2:37][CH3:38])=[C:19]([CH:25]4[CH2:26][N:27]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:28]4)[C:20]([F:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:9]=[C:10]([CH:11]=[O:14])[C:3]=12
Reactant: CCOc1c(C(C)n2nc(C(O)CO)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOc1c(C(C)n2nc(C=O)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-(3-{1-[4-amino-3-(1,2-dihydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-fluorophenyl)azetidine-1-carboxylate (0.754 g, 1.37 mmol) in THF (10 mL) and water (6 mL) was added acetic acid (20 μL, 0.36 mmol) and sodium periodate (0.878 g, 4.10 mmol) at 0° C. After stirring overnight, water was added to the reaction and extracted with dichloromethane (3×). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to yield the crude product. LCMS calculated for C24H29ClFN6O4 (M+H)+: m/z=519.2; Found:519.2.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][N:10]1[CH:15]2[CH2:16][CH2:17][CH:11]1[C:12](=[O:18])[CH2:13][CH2:14]2>O1CCCC1>[CH3:9][N:10]1[CH:15]2[CH2:16][CH2:17][CH:11]1[C:12]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:18])[CH2:13][CH2:14]2
Reactant: Br[Mg]c1ccccc1
Reactant: CN1C2CCC(=O)C1CC2
Solvent: C1CCOC1
Product: CN1C2CCC1C(O)(c1ccccc1)CC2
Temperature: 0 °C
Reaction time: 5 h
Yield: 65.1 %

Procedure:
To 5.4 ml (5.39 mmol) of a 1M phenyl-magnesium bromide solution under nitrogen at 0° C., was added drop-wise a solution of 500 mg 8-methyl-8-aza-bicyclo[3.2.1]octan-2-one (CAS 78477-91-5) in 5 ml tetrahydrofuran over mol-sieve. The reaction mixture was stirred at 0° C. for 5 hours. The mixture was quenched under ice bath cooling with a 20% ammonium chloride solution (5 ml). The organic layer was separated and the aqueous layer was extracted once with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica (20 g) eluting with a gradient formed from n-heptane and ethyl acetate (0 to 100%) to provide 508 mg (65.1%) of the title compound as a light yellow oil. MS (m/e): 218.4 (M+H+).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=NC(C)=N[CH:13]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].[F:35][C:36]1C=C(C=[C:42]([F:44])[CH:43]=1)C=O>>[F:35][C:36]1[CH:13]=[C:8]([CH:9]=[C:42]([F:44])[CH:43]=1)[CH2:7][N:5]1[CH2:6][C@@H:2]([CH3:1])[C@H:3]([C:15]2[NH:16][C:17](=[O:30])[C:18]3[CH:23]=[N:22][N:21]([CH:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[C:19]=3[N:20]=2)[CH2:4]1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Reactant: O=Cc1cc(F)cc(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@@H]1CN(Cc2cc(F)cc(F)c2)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyanoborohydride and 3,5-difluorobenzaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.03 (s, 1H), 6.93-6.90 (m, 2H), 6.73-6.69 (m, 1H), 4.81-4.80 (m, 1H), 4.14-4.10 (m, 2H), 3.79-3.67 (m, 2H), 3.62-3.55 (m, 2H), 3.30-3.26 (m, 1H), 3.10-3.07 (m, 1H), 2.95-2.92 (m, 1H), 2.83-2.79 (m, 1H), 2.26-2.53 (m, 1H), 2.38-2.32 (m, 2H), 2.18-2.14 (m, 1H), 1.91-1.85 (m, 2H), 1.18 (d, J=7.1 Hz, 3H). MS: (M+H m/z 430.4).
Reaction SMILES: [C@@H:1]1([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=O)[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH3:33]>N1C=CC=CC=1>[NH2:17][C:16]1[N:18]=[C:19]2[C:12]([N:11]=[CH:10][N:9]2[CH:1]2[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]2)=[C:13]([NH2:33])[N:15]=1
Reactant: N
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Nc1nc(N)c2ncn(C3C[C@H](O)[C@@H](CO)O3)c2n1
Yield: 34 %

Procedure:
To 2 mmol of deoxyguanosine, dried by evaporation of pyridine and suspended in 20 mL of dry pyridine was added dropwise 2.3 mL (16 mmol) of trifluoroacetic anhydride, with cooling in an ice bath. After ten minutes 20 mL of cold, concentrated aqueous ammonia was added. After a further 11/2 hours the mixture was evaporated to dryness, the residue dissolved in water and the solution filtered through a 100 mL portion of Bio Rad AG 1-X2, hydroxide from resin to remove colored impurities. The resin was washed with 40% methanol in water to elute crude 2,6-diamino-9-(2-deoxy-Beta-D-erythro-pentofuranosyl)purine, which was further purified on the reversed-phase column described above using a gradient of 2-15% acetonitrile in water. Evaporation of appropriate fractions gave 192 mg (34%) of 2,6-diamino-9-(2-deoxy-D-erythro-pentofuranosyl)purine, a sample crystallized from water gave a mp of 148°. UVmax (MeOH) 282 nm, UVmin 256 nm; 1H NMR (DMSO-d6) delta (ppm) 7.91 (s, 1,H8), 6.73 (br s, 2, NH2), 6.17 ("t", 1, Japp =6 Hz, H1'), 5.73 (br s, 2, NH2), 5.25 (m, 2, 3'-OH & 5'-OH), 4.35 (m, 1, H3'), 3.84 (m, 1, H4'), 3.54 (m,2,H5',5"), 2.59 & 2.17 (m & m, 1 & 1, H2' & H2"). Anal. Calcd. for C10H14N6O3.H2O: C, 42.25; H, 5.67; N, 29,56. Found: C, 42.54; H, 5.33; N, 29.56.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][CH:7]=1.C(OC(C1(C(OC(C)C)=O)CC(OC)(OC)C1)=O)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:8]2)=[CH:6][CH:7]=1
Reactant: O=C(C=C(Nc1cccc(Cl)c1)c1ccccc1)C(F)(F)F
Agent: COC1(OC)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C1
Product: FC(F)(F)c1cc(-c2ccccc2)nc2cc(Cl)ccc12
Temperature: 0 °C

Procedure:
4-(3-Chloro-phenylamino)-1,1,1-trifluoro-4-phenyl-but-3-en-2-one (2.8 g, 0.0086 mole) and polyphosphoric acid (60 mL) in a 250 mL 3 neck round bottom flask was stirred mechanically under an atmosphere of Nitrogen at 165° C. internal temperature for 3 h. The reaction was poured over stirring ice water (600 ml). The product precipitated, and was collected by suction filtration, washed with water, and air dried overnight. The solids remaining in the Buchner funnel, and beaker from aqueous quench were rinsed into a flask concentrated in vacuo, then combined with the filtered sample and chromatographed on silica gel with 3:1 Hexanes/methylene chloride to afford the title compound as a white solid; 1H NMR (CDCl3, 400 MHz) δ 7.53-7.59 (m, 3H), 7.60-7.63 (dd, 1H, J=2.2 & J=9.1 Hz), 8.06-8.09 (dq, 1H, J=1.9 & J=9.0 Hz), 8.16-8.20 (m, 3H), 8.29 (d, 1H, J=2.1 Hz); 19F NMR δ −61.48; MS(ES+): 308.0 (100) [MH+], 310.0 (30) [M+2H+].