Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1.Br[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[F:36]>C(#N)C>[F:36][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:28]=1[CH2:27][N:3]1[C:2]([I:1])=[CH:6][N:5]=[CH:4]1)[C:32]#[N:33]
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1ccc(CBr)c(F)c1
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2I)c(F)c1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of 4-iodo-1-trityl-1H-imidazole (17.1 g, 39.2 mmol) and 4-bromomethyl-3-fluorobenzonitrile (9.65 g, 45.08 mmol) in 150 mL of dry acetonitrile is stirred at room temperature for 7 days. After concentration, the residue is mixed with methanol, and heated to reflux for 1.5 h. The solvent is subsequently removed and the residue is treated with 1M HCl (300 mL). The resulting suspension is filtered and the washed with HCl (1 M). The combined solution is adjusted to PH 9-10 by saturated NaHCO3 solution. The resulting precipitation is collected by filtration, dried in vacuum oven. MS (ESI) m/z (M+H) 328.1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=O)(C)(C)C.Cl>ClCCl.O1CCOCC1>[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CCCNC1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (12.25 mmol) in dichloromethane (84 mL) was added a solution of hydrogen chloride in 1,4-dioxane (28 mL, 4M). The reaction mixture was stirred at 30° C. for 2 h. The solvent was removed under reduced pressure to afford (R)-piperidine-3-carboxylic acid which was used without further purification.
Reaction SMILES: C([Si](C)(C)OC(CC1C=CC=CC=1)CCC1NC(=O)CC1)(C)(C)C.C([O:27][C:28](=[O:55])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]2[C:42](=[O:43])[CH2:41][CH2:40][CH:39]2[CH2:44][CH2:45][CH:46]([OH:54])[CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[CH:31][CH:30]=1)C.[OH-].[Na+]>>[OH:54][CH:46]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:45][CH2:44][CH:39]1[CH2:40][CH2:41][C:42](=[O:43])[N:38]1[CH2:37][CH2:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([C:28]([OH:55])=[O:27])=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1ccc(OCCN2C(=O)CCC2CCC(O)Cc2ccccc2)cc1
Agent: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCCN2C(=O)CCC2CCC(O)Cc2ccccc2)cc1
Yield: 85.6 %

Procedure:
Analogous to the procedure described for Compound 1A, Step F, 4-{2-[2-(3-hydroxy-4-phenyl-butyl)-5-oxo-pyrrolidin-1-yl]-ethoxy}-benzoic acid ethyl ester (52 mg, 0.122 mmol) was hydrolyzed with 6N NaOH (1 mL) to yield the title compound (41.5 mg). 1H NMR (CDCl3) δ 7.98 (d, 2H), 7.32-7.16 (m, 5H), 6.85 (m, 2H), 4.13 (m, 2H), 3.92 (m, 1H), 3.81 (m, 1H), 3.75 (m, 1H), 3.40 (m, 1H), 2.82 (m, 1H), 2.66 (m, 1H), 2.36 (m, 2H), 2.10 (m, 2H), 1.70-1.34 (m, 5H); MS 398.4 (M+1), 396.3 (M−1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].[CH2:8](O)[CH2:9][CH2:10][OH:11]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:7]1[CH2:8][CH2:9][CH2:10][O:11][CH:6]1[C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: OCCCO
Reactant: O=Cc1nccs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1csc(C2OCCCO2)n1
Yield: 73 %

Procedure:
2-Thiazolecarboxaldehyde (1 g) was dissolved in toluene (50 ml), followed by the addition of trimethylene glycol (3.36 g) and p-toluenesulfonic acid (17 mg). The resulting mixture was heated under reflux with a Dean-Stark apparatus for 4 hr. After cooling as it was, the reaction mixture was washed sequentially with an aqueous solution of saturated sodium bicarbonate and brine, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a brown solid (1.104 g, yield; 73%).
Reaction SMILES: [Cl-].[Ca+2:2].[Cl-].[C:4]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2([C:18]([O-:20])=[O:19])[CH2:17][O:16]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Na+]>O>[Ca:2].[C:4]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2([C:18]([O-:20])=[O:19])[CH2:17][O:16]2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [Ca+2]
Agent: O=C([O-])C1(CCCCCc2ccccc2)CO1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: [Ca]

Procedure:
A solution of 400 mg calcium chloride in 5 ml of water is added dropwise to a solution of 1.0 g of sodium 2-(5-phenylpentyl)oxirane-2-carboxylate in 30 ml of water. The mixture is stirred thoroughly. The solution is decanted from the viscous precipitate which has separated out. The precipitate is stirred again with water and decanted. After drying over phosphorus pentoxide 820 mg of the title compound (softening at 270° C. and melting at about 300° C. under decomposition) are obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[OH-].[Ca+2:34].[OH-]>O1CCCC1.O>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[Ca:34]
Reactant: [Ca+2]
Agent: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: [Ca]
Reaction time: 72 h

Procedure:
A physical mixture of Raltegravir free hydroxy (25.8 mg) and calcium hydroxide (˜4.6 mg) was suspended in 70/30 tetrahydrofuran/water. The mixture was shaken well and the resulting suspension was temperature cycled between room temperature and 50° C. using a Heidolph shaker and incubator with a power source programmed to switch on and off every 4 hours. After approximately 72 hours, excess solvent was decanted off using a syringe and the solid residue was dried at ambient temperature under vacuum for approximately 24 hours. The product was characterised by XRPD.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[Cl-].[Ca+2:15].[Cl-]>O>[Ca:15].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: [Ca+2]
Agent: O=C(O)c1cc(Cl)cc(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: [Ca]

Procedure:
To 3000 g of water, 191 g (1 mole) of 3,5-dichlorobenzoic acid and 40 g (1 mole) of sodium hydroxide were added and dissolved in water with stirring. An aqueous solution with 56.6 g (0.51 mole) of calcium chloride dissolved in 500 g of water was then added dropwise to the first solution under stirring, thereby obtaining a precipitate having a white color. The thus-obtained precipitate was filtered, washed with water, dewatered and then dried under reduced pressure at room temperature to obtain calcium salt of 3,5-dichlorobenzoic acid as white fine powder. The calcium content of these salts was determined by ion chromatography and was found to be 9.7 wt. %. It was hence found that calcium di(3,5-dichlorobenzoate) accounted for about 100% of these salts.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([N:20]([CH3:24])[C:21](=[O:23])[CH3:22])[C:18]3[CH:25]=[CH:26][CH:27]=[CH:28][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.[IH:32]>C(OCC)C>[IH:32].[CH3:24][N:20]([N:19]1[C:18]2[CH:25]=[CH:26][CH:27]=[CH:28][C:17]=2[N:16]=[C:15]1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1)[C:21](=[O:23])[CH3:22]
Reactant: CC(=O)N(C)n1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: I
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)N(C)n1c(N2CCCNCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(N-methylacetamido)-1H-benzimidazol-2-yl)[1,4]diazepane (0.18 g, 0.48 mmol) and dichloromethane (10 mL). Add hydriodic acid (0.17 mL, 57%, 0.95 mmol) and warm to 40° C. After 3 hours, cool to ambient temperature and evaporate in vacuo to give a residue. Combine the residue and diethyl ether with stirring to give a solid. Collect the solid by filtration to give, after drying, the title compound.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].Br[CH2:11][CH2:12][CH2:13][Cl:14]>C1COCC1>[Cl:14][CH2:13][CH2:12][CH2:11][N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9]
Reactant: O=C1CCCCN1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCCCN1CCCCl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.8 %

Procedure:
Sodium hydride (60% suspension in oil, 26 mg, 0.65 mmol) was added to a solution of 2-piperidone (54 mg, 0.54 mmol) in dry THF (2 mL) under argon atmosphere. After 15 minutes stirring at rt the reaction mixture was cooled to 0° C. over 15 minutes. A solution of 1-bromo-3-chloropropane (160 μL, 1.62 mmol) was added dropwise to the cold mixture and stirring was continued overnight at rt. The mixture was partitioned between water and ethyl acetate, the organic layer dried over sodium sulphate, filtered and evaporated to dryness. Purification of the residue on silica gel column chromatography, eluting with a stepwise gradient of 60-80% ethyl acetate in n-heptane, afforded 1-(3-chloropropyl)piperidin-2-one (33 mg, 35%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][NH:8][C:9](=O)[CH2:10][C@H:11]([OH:17])[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1.O.[OH-].[Na+]>O1CCCC1>[CH3:7][NH:8][CH2:9][CH2:10][C@@H:11]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[OH:17]
Reactant: CNC(=O)C[C@H](O)c1cccs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNCC[C@H](O)c1cccs1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
1728 ml of dry tetrahydrofuran are initially charged with 52 g of lithium aluminium hydride and heated to reflux. At the same time, dropwise addition of 86.4 g of N-methyl-(3S)-3-hydroxy-3-(2-thienyl)propanamide dissolved in 692 g of tetrahydrofuran is commenced. Once dropwise addition is complete, stirring is continued under reflux overnight. The reaction mixture is then cooled to room temperature and 1037 ml of water are cautiously added dropwise. 173 ml of a 10% sodium hydroxide solution were then added dropwise and the solution was filtered. The solvent was removed under reduced pressure. The crude solution was admixed with 346 ml of 1 N sodium hydroxide solution and extracted 3 times with 345 ml of toluene each time. The organic phases are combined and the volatile constituents are removed under reduced pressure to obtain 76 g of (1S)-3-(methylamino)-1-(2-thienyl)-1-propanol (84% purity, 80% of theory).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C=C(C#N)C=CC=3OCC2=O)CC1.[F:52][C:53]1[CH:58]=[CH:57][C:56]([F:59])=[CH:55][C:54]=1[CH:60]1[CH2:62][CH:61]1[CH:63]=O.C([BH3-])#N.[Na+]>>[F:52][C:53]1[CH:58]=[CH:57][C:56]([F:59])=[CH:55][C:54]=1[CH:60]1[CH2:62][CH:61]1[CH2:63][NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1
Reactant: N#Cc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Reactant: O=CC1CC1c1cc(F)ccc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2c(c1)N(CCN1CCC(NCC3CC3c3cc(F)ccc3F)CC1)C(=O)CO2
Yield: 42 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 58) (1 mmol), 2-(2,5-difluorophenyl)cyclopropanecarbaldehyde (Intermediate 68) (200 mg, 1.1 mmol) and sodium cyanoborohydride (125 mg, 2 mmol) were reacted as described under Example 21 to give 196 mg (42%) product as a gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[C:14](=[O:15])[CH:13]=[CH:12][NH:11][CH:10]=2)=[CH:5][CH:4]=1.F[C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][N:20]=1>CS(C)=O.CCOC(C)=O>[I:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([N:11]2[CH:12]=[CH:13][C:14](=[O:15])[C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=3)=[CH:10]2)[CH:24]=1
Reactant: COc1ccc(COc2c[nH]ccc2=O)cc1
Reactant: Fc1cc(I)ccn1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(COc2cn(-c3cc(I)ccn3)ccc2=O)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one (7.30 g, 31.6 mmol), 2-fluoro-4-iodopyridine (10.56 g, 47.35 mmol), and K2C03 (10.9 g, 79 mmol) in DMSO (80 mL) was heated at 80° C. overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2S04), filtered and concentrated. The residue was washed with EtOAc and filtered, and the collected solid dried to give 4′-iodo-3-[(4-methoxybenzyl)oxy]-4H-1,2′-bipyridin-4-one. 1H-NMR (DMSO, 400 MHz) (5 8.41 (dd, J=8.0, 2.4 Hz, 1H), 8.30 (s, 1H), 8.20 (m, 2H), 7.81 (dd, J−4.0, 0.8 Hz, 1H), 7.35 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.28 (d, J=7.6 Hz, 1H), 4.96 (s, 2H), 3.72 (s, 3H). MS (M+H)+ 435.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1[OH:12].CO.C[O-].[Na+].C(O)C.[CH2:21]([OH:24])[CH:22]=[CH2:23].C1(C)C=CC=CC=1>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[C:8]([C:4]1[CH:5]=[C:6]([CH2:23][CH2:22][CH2:21][OH:24])[CH:7]=[C:2]([CH3:1])[C:3]=1[OH:12])([CH3:9])([CH3:11])[CH3:10]
Reactant: C=CCO
Reactant: Cc1cccc(C(C)(C)C)c1O
Agent: [Ti+4]
Agent: CC[O-]
Agent: C[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CO
Product: Cc1cc(CCCO)cc(C(C)(C)C)c1O
Temperature: 210 °C
Reaction time: 7 h
Yield: 78 %

Procedure:
A pressure container was charged with 62.4 g (0.38 mol) of 2-methyl-6-t-butylphenol, 14.7 g (0.076 mol) of a methanol solution containing 28% sodium methoxide and 17.4 g (0.076 mol) of titanium tetraethoxide. The mixture was heated under reduced pressure to distill a mixture of 13.0 g (0.41 mol) of methanol and 14.1 g (0.31 mol) of ethanol out of the reaction system. Thereafter, 53.2 g (0.92 mol) of allyl alcohol and 38.7 g (0.42 mol) of toluene were added to the reaction system and the atmosphere in the reaction system was replaced by nitrogen. Then, the reaction system was tightly closed, heated up to 210° C. and kept at that temperature for 7 hours. Then, the reaction system was cooled to room temperature. A sample of the reaction solution was analyzed by gas-chromatography. The desied product, 3-(3-t-butyl-4-hydroxy-5-methylphenyl)propanol was obtained in a yield of 78%.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[C:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[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>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:26]4[CH:27]=[CH:28][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(C(C)(C)C)cc4)cc3CC[C@@H]12
Yield: 69.4 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 4-t-butylphenylboronic acid (139 mg, 0 .78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 16 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 163 mg (69%) of the title compound as an amorphous solid. mp 141°-147° FDMS: m/e=361 α[D]589 =+67.88 (c=1.05, chloroform).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]1([S:16]([O-:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na+]>CS(C)=O>[C:10]1([S:16]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1F
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Product: O=Cc1ccccc1S(=O)(=O)c1ccccc1
Temperature: 95 °C
Yield: 21.2 %

Procedure:
A mixture of 2-fluorobenzaldehyde (4.67 g, 37.6 mmol), sodium benzenesulfinate (6.79 g, 41.3 mmol), and dimethylsulfoxide (30 mL) was heated at 95° C. for 18 hours. The reaction mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The organic phase was dried over MgSO4, filtered, and concentrated to give a white solid. NMR analysis of this crude mixture indicated unreacted 2-fluorobenzaldehyde to be the major component. The crude mixture was redissolved in dimethylsulfoxide (30 mL), then sodium benzenesulfinate (5.0 g, 30 mmol) was added. The resulting mixture was heated at 95° C. for another 16 hours. The reaction mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The organic phase was dried over MgSO4, filtered, and concentrated. A solution of this crude product and dichloromethane was evaporated over silica gel, and the resulting silica gel supported crude product was loaded onto an Analogix SuperFlash™ column. Flash chromatography (5%-35% ethyl acetate in hexanes) provided 1.96 g (23%) of 2-(benzenesulfonyl)-benzaldehyde as a clear, colorless oil which partially solidified over time.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[CH:39][CH:40]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1.C(Cl)Cl>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH:41][C:7]3[N:8]=[CH:9][C:4]4[C:3]([CH3:21])=[C:2]([Br:1])[C:14](=[O:15])[N:13]([CH:16]5[CH2:20][CH2:19][CH2:18][CH2:17]5)[C:5]=4[N:6]=3)=[CH:39][CH:40]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Temperature: 110 °C
Yield: 12.7 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.2 g, 0.54 mmol, prepared according to Example 5 in WO 01/70741) and 4-(6-Amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.6 g, 2.16 mmol) were combined in toluene (3 mL) and heated to 110° C. overnight. The reaction was quenched by the addition of succinic anhydride (0.2 g) and allowed to cool giving a solid. This solid was suspended in CH2Cl2 and filtered to give a white solid. The filtrate was washed with saturated aqueous sodium bicarbonate then saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The crude product was purified by silica gel chromatography eluting with 75% ethyl acetate:25% hexanes to provide 4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.04 g, 13%). MS (APCI) M++1: Calc'd, 584.19. Found, 584.1.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9]C(=O)OC(C)(C)C)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[NH2:9][CH2:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([OH:1])[CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC[C@H]1CC[C@H](O)CC1

Procedure:
Tert-butyl trans-(4-hydroxycyclohexyl)methylcarbamate (1 g) in dichloromethane (10 ml) was treated with trifluoroacetic acid (10 ml) at 0° C. for two hours. The reaction mixture was concentrated and the residue was dried under vacuum to provide the title compound.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:8][CH:9]=1.[B-](F)(F)(F)[F:23].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:23][CH:5]1[C:4](=[O:3])[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6]1
Reactant: C[Si](C)(C)OC1=CCN(C(=O)OCc2ccccc2)CC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of benzyl 4-[(trimethylsilyl)oxy]-3,6-dihydropyridine-1(2H)-carboxylate (800 g, 2.61 mol) in acetonitrile was added Selectfluor™ (932.8 g, 2.63 mol) in small portions under nitrogen at 0° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred overnight. TLC (EtOAc/petroleum ether=1:1) indicated the reaction was complete, and the solvent was removed in vacuo. The residue was triturated with ethyl acetate (5 L, 3 L) for 30 min and filtered. The filtrate was concentrated and the syrup was purified by column chromatography (EtOAc/petroleum ether=1:10 to 2:3) to afford benzyl 3-fluoro-4-oxopiperidine-1-carboxylate. 1H NMR (600 MHz, CDCl3-D6) 7.40-7.30 (m, 5H); 5.20 (s, 2H); 5.00-4.70 (d, 1H); 5.20-4.90 (d, 1H); 4.30-4.20 (m, 1H); 3.40-3.20 (m, 2H); 2.50 (s, 2H).
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>>[CH2:1]([C:14]1[CH:15]=[C:10]([Cl:9])[CH:11]=[CH:12][C:13]=1[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: OCc1ccccc1
Product: Oc1ccc(Cl)cc1Cc1ccccc1
Temperature: 200 °C
Yield: 25.4 %

Procedure:
A German patent, Ger.Offen 2,547,030 (1977), disclosed the preparation of o-benzyl toluenes by the reaction of o-methylbenzyl halides with substituted benzenes in the presence of Al-silicate. The 2-CH3C6H4CH2Cl was stirred with toluene and Al-silicate (25% Al2O3) at 110° C. to give 81% 2-methylbenzyltoluene. According to a Japanese patent, JP 59,186,937 (1984), o-benzylphenol was prepared by the liquid phase reaction of benzyl alcohol with phenol in the presence of γ-Al2O3. For example 7.5 g γ-Al2O3 was added to a mixture of 32.5 g benzyl alcohol and 47 g phenol at 190° C. under stirring to give a product-containing 49.9% o-benzylphenol. A German Patent, Ger. Offen DE 3,700,917 (1988), disclosed the preparation of p-substituted o-benzylphenols by alkylation of p-substituted phenols with benzylalcohol in the presence of Na—Y type zeolite. A mixture of 0.5 mole 4-ClC6H4OH, 0.1 mole C6H5CH2OH and 0.6 g of Na—Y type zeolite was heated at 200° C. for 3 hrs to give 25.4% 2-benzyl-4-chlorophenol.
Reaction SMILES: CS(C)=O.[Br:5][C:6]1[CH:7]=[N:8][C:9](Cl)=[N:10][CH:11]=1.[C-:13]#[N:14].[Na+]>O.CCOC(C)=O>[Br:5][C:6]1[CH:7]=[N:8][C:9]([C:13]#[N:14])=[N:10][CH:11]=1
Reactant: [C-]#N
Reactant: Clc1ncc(Br)cn1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ncc(Br)cn1
Yield: 82.5 %

Procedure:
To a room temperature DMSO solution (20.0 mL) of 5-bromo-2-chloropyrimidine (1.02 g, 5.27 mmol) was added sodium cyanide (0.284 g, 5.80 mmol). After 70 minutes the reaction mixture was diluted with water (300 mL) and EtOAc (150 mL). The organic layer was washed three times with half brine, then once with brine. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain a residue, which was subject to silica gel chromatography. Collection of the product containing fractions and removal of solvent provided 5-bromopyrimidine-2-carbonitrile (0.800 g) as a white crystalline solid, giving proton NMR and LC/MS data consistent with theory.