Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[ClH:6].[CH3:7][N:8]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)O)[CH3:9].[OH-].[Na+]>>[ClH:6].[CH3:7][N:8]([CH3:9])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]=[C:12]1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CN(C)CC1CCCCC1(O)c1cccnc1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CN(C)CC1CCCC=C1c1cccnc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 57.7 %

Procedure:
40 ml 96% strength sulfuric acid were added to 7.8 g dimethylaminomethyl-1-pyridin-3-yl-cyclohexanol hydrochloride, while cooling with ice. When the evolution of gas had ended, the mixture was stirred at room temperature for 45 minutes. The solution was subsequently poured on to approx. 400 g of crushed ice. It was then rendered alkaline by addition of sodium hydroxide lozenges, while cooling with ice, and the mixture was extracted 3× with a total of 600 ml ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated to dryness on a rotary evaporator in vacuo at 50° C. 4.2 g dimethyl-(2-pyridin-3-yl-cyclohex-2-enylmethyl)amine hydrochloride were obtained in this way.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1O.[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14]>O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: Oc1ccc(F)cc1Br
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1ccc(F)cc1Br

Procedure:
2-Bromo-4-fluorophenol (28 g) was added to a solution of sodium hydroxide (7 g) in water (100 ml), and methyl chloroformate was dropwise added thereto at a temperature of below 10° C. Precipitated crystals were collected by filtration and washed with water to give methyl (2-bromo-4-fluorophenyl)formate (41 g). M.P., 80.7° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1.CO.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl>[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[CH:7]=[CH:8][C:9]4=[O:16])[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: COc1ccc2ccc(=O)n(CC=O)c2c1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A solution of [7-(methyloxy)-2-oxo-1(2H)-quinolinyl]acetaldehyde (65 mg, 0.3 mmol) and 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (for a synthesis see WO2004/058144 Example 99(h)) (105 mg, 0.3 mmol) in chloroform (3 ml) and MeOH (3 ml) was stirred at rt for 1 h. The mixture was then treated with NaBH(OAc)3 (190.8 mg, 0.9 mmol), stirred at rt for 0.5 h. 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (52 mg, 0.15 mmol) and NaBH(OAc)3 (127 mg, 0.6 mmol) were added and the reaction stirred at rt for 1 hour. The solvents were then removed and the residue was subjected to column chromatography on silica gel eluting with 0-10% methanol-DCM to afford the desired compound (92 mg, 56%).
Reaction SMILES: [Na].[NH2:2][C:3]1[CH:4]=[C:5]2[CH2:11][C:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:6]2=[N:7][CH:8]=1.[CH2:19]=O.[BH4-].[Na+].[OH-].[K+]>CO>[CH3:19][NH:2][C:3]1[CH:4]=[C:5]2[CH2:11][C:10]3([CH:16]4[CH2:15][CH2:14][N:13]([CH2:18][CH2:17]4)[CH2:12]3)[O:9][C:6]2=[N:7][CH:8]=1
Reactant: C=O
Reactant: Nc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CNc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Temperature: 50 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
Under a nitrogen atmosphere, sodium (50 mg, 2.17 mmol) was slowly added (exothermic) to methanol (1 mL) and stirred for 1 hour. 5'-Aminospiro[1-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine] (115 mg, 0.5 mmol) and paraformaldehyde (35 mg, 1.17 mmol) were added and stirred for 16 hours. The reaction was heated at 50° C. for 4 hours, sodium borohydride (53 mg, 1.4 mmol) was added, and heated at reflux for 1 hour. Then, 1 N aqueous potassium hydroxide (0.4 mL) was added and continued at reflux for 2 hours more. The solvent was evaporated under reduced pressure, the residue was partitioned between water (1 mL) and chloroform (4 mL), separated and extracted the aqueous phase with chloroform (2×4 mL). The combined organic layers were washed with brine (1 mL), dried (MgSO4), evaporated under reduced pressure, and purified by flash chromatography through silica gel (eluting with ammoniated chloroform/methanol, 95:5) to obtain the title compound (78 mg, 0.32 mmol, 64%) as an off-white solid: electrospray MS (m/z, relative intensity) 246 ([MH]+, 100).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:30]([F:31])=[C:29]([NH:32]C(=O)C(C)(C)C)[C:9]2[C:10](=[O:28])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20]C(=O)C(C)(C)C)=[C:16]([F:27])[CH:15]=3)[O:13][C:8]=2[C:7]=1[F:39])=[O:5])[CH3:2].S(=O)(=O)(O)O>>[NH2:32][C:29]1[C:9]2[C:10](=[O:28])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:27])[CH:15]=3)[O:13][C:8]=2[C:7]([F:39])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:30]=1[F:31]
Reactant: CCOC(=O)c1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Yield: 0.1 %

Procedure:
740 mg (1.36 mol) of the above 7-ethoxycarbonyl-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-4H-1-benzopyran-4-one was subjected to the depivaloylation with concentrated sulfuric acid substantially in the same manner as that in Example 87 (2). The resulting solution was adjusted to pH 7 and extracted once with ethyl acetate. The organic layer was washed once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform) and recrystallized from ethyl acetate/n-hexane to give 259 mg of Compound 92 (yield: 50%) .
Reaction SMILES: [C:1]1([C:7]2O[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][C:11](=[O:17])[C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[CH3:26][NH2:27].C(O)(=O)C>O>[C:1]1([C:7]2[N:27]([CH3:26])[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][C:11](=[O:17])[C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1c(-c2ccccc2)oc(-c2ccccc2)cc1=O
Reactant: CN
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)n(C)c(-c2ccccc2)cc1=O

Procedure:
3.0 gms of 2,6-diphenyl-3-methoxycarbonyl-pyr-4-one, 33 mls of methanol, 13.3 mls of 40% aqueous methylamine and 2 mls of glacial acetic acid were mixed at room termperature. The next day the mixture was diluted with water. Filtration of the resulting suspension yielded 2.5 gms of methyl 2,6-diphenyl-1-methyl-4-oxonicotinate. Recrystallization from methanol provided material at 255°-7°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:26]#[C:27][CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=1)[CH2:7]2.[H][H].C(Cl)(Cl)Cl.CO>C(O)C.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][CH2:32][CH2:33]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=1)[CH2:7]2
Reactant: O=C1c2c(Cl)cc(C#CCN3CCCC3)cc2CN1Cc1ccc(Oc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCO
Product: O=C1c2c(Cl)cc(CCCN3CCCC3)cc2CN1Cc1ccc(Oc2ccccc2)cc1
Yield: 49.3 %

Procedure:
A mixture of 7-chloro-2-(4-phenoxy-benzyl)-5-(3-pyrrolidin-1-yl-prop-1-ynyl)-2,3-dihydro-isoindol-1-one (0.049 g, 0.11 mmol) and 10% palladium-carbon (0.015 g) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 7-chloro-2-(4-phenoxy-benzyl)-5-(3-pyrrolidin-1-yl-propyl)-2,3-dihydro-isoindol-1-one (0.025 g, 50%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.80 (m, 6H), 2.5 (m, 6H), 2.68 (t, 2H), 4.22 (s, 2H), 4.74 (s, 2H), 6.88-7.38 (m, 11H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]2[S:49][C:50](Br)=[CH:51][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:54]([C:56]1[CH:57]=[C:58](B(O)O)[CH:59]=[CH:60][CH:61]=1)#[N:55].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]2[S:49][C:50]([C:60]3[CH:59]=[CH:58][CH:57]=[C:56]([C:54]#[N:55])[CH:61]=3)=[CH:51][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(Br)s1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: N#Cc1cccc(-c2ccc(Cc3cc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)ccc3Cl)s2)c1

Procedure:
A mixed solution of 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene 53 (1.24 g) obtained in Example 119-(6), 3-cyanophenylboronic acid (270 ml), bis(triphenylphosphine)palladium (II) dichloride (54 mg) and 2M aqueous sodium carbonate solution (2.3 ml) in 1,2-dimethoxyethane (12 ml) was heated under reflux for 4 hours. The mixture was diluted with ethyl acetate and washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine. The mixture was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1-5:1) to give 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene (1.12 g) as colorless oil. APCI-Mass m/Z 849/851 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene was used and treated in a manner similar to Example 3-(3) to give the target compound as colorless powder. APCI-Mass m/Z 489/491 (M+NH4).
Reaction SMILES: Cl[C:2]1([S:8](Cl)(=[O:10])=[O:9])[NH:6][C:5]([Cl:7])=[CH:4][S:3]1.[CH3:12][C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15]>>[CH3:12][C:13]([CH3:17])([CH3:16])[CH2:14][N:15]([NH:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH3:12])[S:8]([C:2]1[S:3][CH:4]=[C:5]([Cl:7])[N:6]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)C1(Cl)NC(Cl)=CS1
Reactant: CC(C)(C)CN
Product: CC(C)(C)CNN(CC(C)(C)C)S(=O)(=O)c1nc(Cl)cs1
Yield: 67 %

Procedure:
In analogy to Example 13, the N-(2,2-dimethylpropyl)-2-N-(2, 2-dimethyl-propylamino)-4-chlorothiazolesulphonamide was prepared by reacting 2,4-dichlorothiazolesulphonyl chloride from Example 1 with 2,2-dimethylpropylamine. Following recrystallization from toluene, the product of m.p. 157° C. was obtained in 67% yield.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1)#[N:4].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:3]#[N:4])=[N:6]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1n[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1nn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.6 %

Procedure:
420 mg of NaH (60% in oil, 10.3 mmol) were added in portions to 1.0 g of 3-cyanoindazole (7.0 mmol) and 1.7 ml of benzyl bromide (14.0 mmol) in 6 ml of THF, and the mixture was stirred at room temperature for 15 hours. The reaction was quenched with 2 drops of water, the mixture was concentrated and the residue was chromatographed (SiO2; petroleum ether:ethyl acetate 3:1). 1.3 g of a solid were obtained.
Reaction SMILES: O.O.[Sn](Cl)Cl.CC1C=C(C([N:15]2[C:21]3[CH:22]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[CH:24]=[CH:25][C:20]=3[CH2:19][N:18]3[CH:30]=[CH:31][CH:32]=[C:17]3[CH2:16]2)=O)C=CC=1C1C=CC=CC=1C(F)(F)F.CO>Cl>[CH3:29][O:28][C:26]([C:23]1[CH:24]=[CH:25][C:20]2[CH2:19][N:18]3[CH:30]=[CH:31][CH:32]=[C:17]3[CH2:16][NH:15][C:21]=2[CH:22]=1)=[O:27]
Reactant: COC(=O)c1ccc2c(c1)N(C(=O)c1ccc(-c3ccccc3C(F)(F)F)c(C)c1)Cc1cccn1C2
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc2c(c1)NCc1cccn1C2
Temperature: 40 °C
Reaction time: 2 h
Yield: 426.9 %

Procedure:
To a stirred solution of tin(II) chloride dihydrate (23 g, 3.5 eq) in 2 N hydrochloric acid (106 mL) was added the [4-(2-formyl-1H-pyrrole-1-yl)methyl]-3-nitro]-benzoic acid methyl ester of Step A (8 g). Methanol (200 mL) was then added to this solution and the reaction mixture was stirred at 40° C. for 2 hours. The reaction was then cooled to room temperature, quenched by the addition of saturated aqueous sodium carbonate (20 mL) and filtered through Celite. The filter pad was washed with methanol and hot ethyl acetate. The filtrate and washings were combined, concentrated in vacuo to a volume of 300 mL and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a volume of 200 mL. Acetic acid (1 g) and 10% palladium on charcoal (1.5 g) were added and the mixture was hydrogenated overnight at atmospheric pressure. The reaction was then filtered through Celite and the solvent removed in vacuo to give a dark brown crystalline solid (16.4 g). This was dissolved in dichloromethane and filtered through a silica pad eluting with dichloromethane to provide the title compound as a yellow crystalline solid (11.7 g). Recrystallization from 1,2-dichloroethane yielded a yellow crystalline solid (5.7 g), m.p. 198–200° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@H:6]3[CH2:13][O:14][CH:15]([CH3:17])[CH2:16][N:5]3[C:4]=2[N:3]=1.[H-].[Na+].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>CN(C=O)C.CCOC(C)=O.O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:7](=[O:12])[C@H:6]3[CH2:13][O:14][CH:15]([CH3:17])[CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: BrCC1CC1
Reactant: CC1CN2c3nc(Cl)ncc3NC(=O)[C@H]2CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CN2c3nc(Cl)ncc3N(CC3CC3)C(=O)[C@H]2CO1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 99.4 %

Procedure:
To a solution of (R)-2-chloro-9-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (103 mg, 0.404 mmol) in DMF (2.5 mL) at 0° C. was added sodium hydride (21 mg, 0.526 mmol, 60% in oil). After 35 minutes at 0° C., (bromomethyl)cyclopropane (0.051 mL, 0.526 mmol) was added. The mixture was stirred at 0° C. for 30 minutes, then at room temperature for 45 minutes and then sealed and heated at 90° C. (bath temperature) for 2 hours. More (bromomethyl)cyclopropane (0.250 mL) was added and heated at 90° C. for another 24 hours. The mixture was cooled to room temperature, and more sodium hydride (excess) was added followed by (bromomethyl)cyclopropane (0.1 mL). Heating was continued at 90° C. for another 6 hours. Then the mixture was diluted with EtOAc and water, extracted with EtOAc (3×), and dried over Na2SO4. Solvent was removed in vacuo to give crude (R)-2-chloro-5-(cyclopropylmethyl)-9-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one as a brown oil (124 mg). MS [M+H] found 309.2.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]=[O:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:14]2)[C@@H:10]1[F:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Mg+].[Br-].[CH3:33]C(OC(OC(OC(C)(C)C)=O)=O)(C)C>C1COCC1.CCOCC>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]([OH:19])[CH3:33])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[S:14]2)[C@@H:10]1[F:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@H](F)[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)[C@H]1O[C@@H]2SC(N(C)C(=O)OC(C)(C)C)=N[C@@H]2[C@H](F)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.3 %

Procedure:
To a solution of tert-butyl ((3aR,5S,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (2.0 g, 4.7 mmol) in anhydrous THF (40 mL), at 0° C. and under N2, was added MeMgBr (1.4 M in THF/toluene, 8.0 mL, 11.2 mmol). After addition the mixture was stirred at room temperature for 3 h. The reaction was diluted with Et2O (50 mL) and then quenched with saturated NaHCO3 aqueous solution (50 mL). The organic layer was collected, and the aqueous was extracted with DCM (3×40 mL). The combined extract was dried over anhydrous Na2SO4. After filtration the solvent was evaporated under reduced pressure, and the residue was dissolved in DCM (40 mL) and Boc2O (2.0 g, 9.2 mmol) was added. The mixture was stirred at room temperature for 16 h. After concentration the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:2 to 3:2), affording tert-butyl ((3aR,5R,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-(1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (1.0 g, 48%), as a mixture of diastereomers.
Reaction SMILES: C1(C(C2C=CC=CC=2)C(O[CH2:11][Cl:12])=O)C=CC=CC=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29]([OH:31])=[O:30].C(Cl)(=O)C(Cl)=O.C1C2C(=CC=CC=2)C=CC=1C(Cl)=O.C=O>[Cl-].[Zn+2].[Cl-]>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29]([O:31][CH2:11][Cl:12])=[O:30]
Reactant: O=C(OCCl)C(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc2ccccc2c1
Agent: C=O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)c1ccc2ccccc2c1
Product: O=C(OCCl)c1ccc2ccccc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
A similar procedure (Lu, M. C. et al. J. Med. Chem. 1987, 30, 273-278 and Iyer, R. P. et al. Synth. Commun. 1995, 25, 2739-2749) to that described for the preparation of 50 was followed using 2-naphthoic acid (1.0 g, 5.8 mmol) and oxalyl chloride (2 mL), under reflux for 2 h. A mixture of crude 2-naphthoyl chloride, paraformaldehyde (174 mg, 5.8 mmol) and zinc chloride (6 mg, 0.04 mmol) was then stirred at 80° C. for 2 h. Purification by flash chromatography (hexane/ethyl acetate 4:1) afforded chloromethyl 2-naphthoate (53) as a colourless oil (80 mg, 0.36 mmol, 6%); 1H NMR (400 MHz, CDCl3) δ 5.98 (2H, s, CH2), 7.53-7.64 (2H, m, Ar), 7.87-7.96 (3H, m, Ar), 8.05-8.10 (1H, m, Ar), 8.65 (1H, s, Ar).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[N:9][C:8]([CH2:20][NH:21][CH:22]=O)=[CH:7][N:6]=1)=[O:4].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH:22]=[N:21][CH:20]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4]
Reactant: COC(=O)c1ncc(CNC=O)nc1Nc1ccc(I)cc1F
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Temperature: 95 °C
Yield: 41.2 %

Procedure:
To a suspension of 3-(2-fluoro-4-iodo-phenylamino)-5-formylaminomethyl-pyrazine-2-carboxylic acid methyl ester (480 mg, 1.12 mmol) in toluene (18 mL) was added phosphorous oxychloride (0.42 mL, 4.4 mmol, 4.0 eq.), and the reaction mixture was heated at 95° C. for 1 hour. The reaction mixture was cooled to RT and then quenched with a saturated aqueous solution of sodium bicarbonate (2 mL). The resultant residue was dissolved in ethyl acetate and washed with water and brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 20%, methanol in ethyl acetate) to give a yellow oil. Crystallization from dichloromethane—ether—hexane afforded the desired product as a yellow solid (190 mg, 41.3%). LCMS (method C): RT=2.45 min, [M+H]+=413.
Reaction SMILES: Cl[C:2]1[C:3]([C:26]2[CH:27]=[N:28][N:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=23)=[N:4][C:5]([NH:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([N:17]3[CH2:21][CH2:20][C@@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18]3)=[C:11]([NH2:25])[CH:10]=2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1.C[C:70]([N:72](C)C)=O>[C-]#N.[Zn+2].[C-]#N.[Zn]>[NH2:25][C:11]1[C:12]([N:17]2[CH2:21][CH2:20][C@@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18]2)=[CH:13][C:14]([O:15][CH3:16])=[C:9]([NH:8][C:5]2[N:4]=[C:3]([C:26]3[CH:27]=[N:28][N:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=34)[C:2]([C:70]#[N:72])=[CH:7][N:6]=2)[CH:10]=1
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: CC(=O)N(C)C
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(CCC)c1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1ncc(C#N)c(-c2cnn3ccccc23)n1
Temperature: 95 °C
Yield: 65 %

Procedure:
A mixture of N-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine (Intermediate 18, 250 mg, 0.52 mmol), zinc cyanide (36.8 mg, 0.31 mmol), zinc powder (3.41 mg, 0.05 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (‘XPhos’ 49.8 mg, 0.10 mmol) was stirred in DMA (2 mL) and purged with N2 for 0.25 h. Tris(dibenzylidene-acetone)dipalladium(0) (47.8 mg, 0.05 mmol) was then added and the mixture was heated at 95° C. for 2 h. The cooled mixture was then absorbed onto an SCX column, washed with CH3OH and eluted with 7M methanolic ammonia solution. Appropriate fractions were combined and concentrated in vacuo. The resulting residue was suspended in CH3OH then the mixture was filtered. The collected solid was dried on the filter to give the title compound (160 mg, 65%) as a tan powder; 1H NMR: (100° C.) 1.78-1.92 (1H, m), 2.00-2.15 (1H, m), 2.26 (6H, s), 2.95-3.02 (1H, m), 3.02-3.07 (1H, m), 3.07-3.13 (1H, m), 3.16-3.27 (2H, m), 3.68 (3H, s), 6.74 (1H, s), 6.95 (1H, s), 7.13 (1H, td), 7.33-7.43 (1H, m), 8.37 (1H, d), 8.64 (1H, s), 8.77 (1H, dt), 8.84 (1H, s), 8.91 (1H, s); m/z: ES+ MH+ 470.60.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([O:20][CH3:21])(=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16].[H-].[Na+]>CN(C=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([CH:14]([C:13]([O:20][CH3:21])=[O:19])[C:15]([O:17][CH3:18])=[O:16])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)#[N:7]
Reactant: COC(=O)CC(=O)OC
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ccc(C#N)cc1[N+](=O)[O-]
Yield: 39.4 %

Procedure:
To a solution of 4-fluoro-3-nitrobenzonitrile (300 mg) and dimethyl malonate (286 mg) in DMF was added 60% NaH at 0° C., followed by reaction at room temperature to obtain dimethyl (4-cyano-2-nitrophenyl)malonate (198 mg).