Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][NH:5][C:4]2[CH:8]=[CH:9][C:10]([OH:12])=[CH:11][C:3]1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19]([O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31](Cl)=[CH:32][CH:33]=[N:34]2)=[CH:29][C:28]=1[O:38][CH3:39])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([O:12][C:10]3[CH:9]=[CH:8][C:4]4[NH:5][CH2:6][CH2:7][O:2][C:3]=4[CH:11]=3)=[CH:32][CH:33]=[N:34]2)=[CH:29][C:28]=1[O:38][CH3:39])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Oc1ccc2c(c1)OCCN2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4c(c3)OCCN4)ccnc2cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 17 h
Yield: 40.5 %

Procedure:
A solution of 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol hydrochloride (0.626 g, 3.34 mmol), cesium carbonate (4.35 g, 13.3 mmol), and 7-(benzyloxy)-4-chloro-6-methoxyquinoline (1.000 g, 3.34 mmol) in DMF (10.0 mL) was stirred at 80° C. After 17 h, additional 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol hydrochloride (0.626 g, 3.34 mmol) was added, and the mixture stirred at 80° C. for 20 h. Additional 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol hydrochloride (0.6259 g, 3.336 mmol) and cesium carbonate (4.35 g, 13.3 mmol) were added, and the mixture stirred at 80° C. for 3 days. The reaction mixture was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford an orange-brown oil. This material was purified twice via column chromatography (RediSep 120 g column, gradient elution with 0-5% methanol-dichloromethane) to afford an orange oil. Trituration with methanol and filtering the resulting suspension afforded 7-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.560 g, 40.5% yield) as a tan solid. MS (MH+) 415.1; Calculated 414 for C25H22N2O4.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:39][CH2:38][C:37]2[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Solvent: O
Solvent: CCO
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NCc4ccc(F)cc4)ncnc32)[C@]1(C)F
Yield: 54.8 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.2 g, 0.43 mmol) in ethanol (about 5 ml) was added 4-fluorobenzylamine (about 0.39 ml, 3.46 mmol) and refluxed for about 2 hours. Completion of the reaction monitored by thin-layer chromatography and water added to the reaction mixture. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compound (0.13 g) as a colorless gummy mass. Yield: 56%; 1H NMR (300 MHz, CDCl3): δ 8.74 (s, 1H), 8.38 (d, 1H, J=3.9 Hz), 8.06-8.03 (m, 2H), 7.58-7.56 (m, 1H), 7.47-7.42 (m, 2H), 6.46 (d, 1H, J=20.1 Hz), 4.94-4.72 (m, 2H), 4.66-4.59 (m, 1H), 2.11 (s, 3H), 1.79 (s, 3H), 1.41 (m, 3H); Mass: [M+Na]+: 485 (40%), [M+1]+ 463 (45%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:16]=[C:15]3[C:17]([C:28]([O:30]C)=[O:29])=[CH:18][N:19](COC(=O)C(C)(C)C)[C:14]3=[N:13][CH:12]=2)=[N:3]1.[OH-].[K+]>O.O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:16]=[C:15]3[C:17]([C:28]([OH:30])=[O:29])=[CH:18][NH:19][C:14]3=[N:13][CH:12]=2)=[N:3]1
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3nn(C)c4ccccc34)nc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccccc21
Temperature: 25 °C
Yield: 113.7 %

Procedure:
A mixture of methyl 2-(1-methyl-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (150 mg, 0.36 mmol), potassium hydroxide (280 mg, 5 mmol) in 2.5 mL of water and 5 mL of 1,4-dioxane was heated to reflux for 90 mins. The reaction mixture was cooled to room temperature, evaporated, acidified with 1N HCl, then filtered and dried to give 2-(1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (120 mg, crude) as a brown solid. LCMS: (M+H)+=294. Used into the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:19]1[CH2:20][O:21][C:22](=[O:24])[CH:23]=1.[Br:25]N1C(=O)CCC1=O>C(Cl)Cl>[Br:25][C:23]1[C:22](=[O:24])[O:21][CH2:20][C:19]=1[N:3]1[CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=CC(=O)OC1)C2=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(Br)C(=O)OC1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl 1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (I-16, Step A) (2.73 g, 8.12 mmol) was dissolved in DCM (70 mL) and was treated with N-bromosuccinimide (1.73 g, 9.74 mmol) at 25° C. and the resulting mixture was stirred overnight at room temperature. The next day, the reaction mixture was diluted with DCM and was washed with water and brine then dried over Na2SO4. Removing solvent gave crude product that was purified by silica gel column chromatography (80 g RediSep Gold Column) using (25-80) % EtOAc/Hexanes as mobile phase to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[N:10]=1.S(=O)(=O)(O)[OH:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]([NH2:20])=[O:24])=[CH:17][CH:16]=2)[N:10]=1
Reactant: N#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: O=S(=O)(O)O
Product: NC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1

Procedure:
A solution of 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzonitrile (1.0 g, 0.003 mol) in conc. sulphuric acid (10 mL) was heated to 70° C. for 15 h. The reaction mixture was quenched in ice water. The reaction mass was basified till pH ˜6-6.5 with dilute NaOH. The obtained solid was filtered off, washed with water and suck dried to afford 0.300 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 7.36 (br s, 1H), 7.84 (t, 1H), 7.57 (d, 1H), 7.67 (d, 1H), 7.98 (m, 5H), 12.70 (br s, 1H); MS (m/z): 333.11 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[N:8][CH:9]=1)([O-])=O.Br[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:12]1([O:10][C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(OC2CCCC2)nc1
Temperature: 80 °C

Procedure:
A mixture of 5-nitropyridin-2-ol (14.0 g), bromocyclopentane (8.0 g), potassium carbonate (14 g) and DMF (200 mL) was heated at 80° C. for 6 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel. The resulting product (2-cyclopentyloxy-5-nitropyridine) was hydrogenated in ethanol using palladium(II) hydroxide as catalyst. The product with the molecular weight of 178.24 (C10H14N20) was obtained in this way; MS (ESI): 179 (M+H+).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[O:11][C:12]=1[CH3:13])(=O)=O.O[C:20]1[CH:29]=[C:28]2[C:23]([CH2:24][CH:25]([C:30]([O:32]C(C)(C)C)=[O:31])[CH2:26][O:27]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N.C(OCC)C>[C:23]([CH:26]1[CH:25]([C:30]([OH:32])=[O:31])[CH2:24][C:23]2[C:28](=[CH:29][C:20]([O:5][CH2:6][CH2:7][C:8]3[N:9]=[C:10]([C:14]4[S:15][CH:16]=[CH:17][CH:18]=4)[O:11][C:12]=3[CH3:13])=[CH:21][CH:22]=2)[O:27]1)([CH3:28])([CH3:24])[CH3:22]
Reactant: CC(C)(C)OC(=O)C1COc2cc(O)ccc2C1
Reactant: Cc1oc(-c2cccs2)nc1CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc2c(c1)OC(C(C)(C)C)C(C(=O)O)C2
Temperature: 25 °C

Procedure:
2-(5-methyl-2-thien-2-yl-1,3-oxazol-4-yl)ethyl methanesulfonate (947 mg, 3.3 mmol), tert-butyl 7-hydroxychromane-3-carboxylate (750 mg, 3 mmol) and potassium carbonate (1.24 g, 9 mmol) were mixed in CH3CN and refluxed under N2 atmosphere overnight. After the completion of the reaction (TLC), the reaction mixture was cooled to room temperature and diluted with 30 ml of diethyl ether and passed through a small pad of silica. Silica was washed with 100 ml of ether and the ether solution was evaporated to give the product which was purified by column chromatography on silica using ethyl acetate and hexanes as eluent (699 mg, 53%).
Reaction SMILES: [C:1]1([C:7]2[C:20](=[O:21])[N:11]3[CH2:12][CH2:13][S:14][C:15]4[CH:19]=[CH:18][S:17][C:16]=4[C:10]3=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:22][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:20](=[O:21])[N:11]2[C:10]=1[C:16]1[S:17][CH:18]=[CH:19][C:15]=1[S:14][CH2:13][CH2:12]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1c(-c2ccccc2)ccc2n1CCSc1ccsc1-2
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1c(-c2ccccc2)cc(Cl)c2n1CCSc1ccsc1-2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4.95 g of 5,6-dihydro-9-phenyl-8H-pyrido[1,2-d]thieno[2,3-f][1,4]thiazepin-8-one were added under argon to 2.35 g of N-chlorosuccinimide in 50 ml of carbon tetrachloride. The mixture was stirred at room temperature for 2.5 hours, treated with an additional 0.21 g of N-chlorosuccinimide and stirred for an additional 1 hour. After evaporation in vacuo, the residue was chromatographed on silica gel. By recrystallization from acetonitrile, there was obtained 11-chloro-5,6-dihydro-9-phenyl-8H-pyrido[1,2-d]thieno[2,3-f][1,4]thiazepin-8-one as yellow crystals of m.p. 179°.
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH:13]([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[OH:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH:13]([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCOC2C
Yield: 95.6 %

Procedure:
Hydrogenolysis of intermediate 14, ethyl 3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate, (0.610 g, 1.77 mmol) in a mixture of ethyl acetate (75 ml) and ethanol (75 ml) at 25° C. over 10% palladium on activated carbon (0.20 g) under 1 atm of hydrogen for 2 h gave 0.430 g (95% yield) of the title ester as white crystals; mp 119–121° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ ppm: 1.46 (3H, t, J=7.1 Hz, CH3), 1.67 (3H, d, J=6.6 Hz, CH3), 3.90 (2H, m, CH2), 4.13–4.32 (2H, m, CH2), 4.51 (2H, m, OCH2), 4.70 (1H, q, J=6.6 Hz, CH), 10.7 (1H, broad, OH). Anal. Calcd for C11H14N2O5: C, 51.96; H, 5.55; N, 11.01. Found: C, 51.60; H, 5.61; N, 10.70.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7](OCC)=[O:8].[CH:20]([NH2:22])=O>CN(C=O)C.C(O)=O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[NH:3][C:2]3[N:1]=[CH:20][N:22]=[C:7]([OH:8])[C:6]=3[CH:5]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)[nH]c1N
Reactant: NC=O
Solvent: CN(C)C=O
Solvent: O=CO
Product: COc1ccc(-c2cc3c(O)ncnc3[nH]2)cc1

Procedure:
Under a protective gas, 611 mg (2.3 mmol) of 2-amino-3-ethoxycarbonyl-5-(4-methoxy-phenyl)-1H-pyrrole in 5 ml of formamide, 2.5 ml of DMF and 1.25 ml of formic acid are heated at 150° C. overnight. Working-up analogously to Step 8.2 yields the title compound; m.p.>300° C.; FAB-MS: (M+H)+ =242.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].C([O-])(=[O:26])C.[Na+].O.N(S([O-])(=O)=O)(S(O)(=O)=O)O.[K+].[K+]>CO>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:3]1[C:2](=[O:1])[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[C:5](=[O:26])[C:4]=1[CH3:12]
Reactant: COc1cc(C)c(CCCCCCCCCCO)c(O)c1OC
Reactant: CC(=O)[O-]
Agent: O=S(=O)([O-])N(O)S(=O)(=O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O
Yield: 93.9 %

Procedure:
In methanol (110 l) was dissolved 10-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)decan-1-ol (6.84 kg). To this solution were added sodium acetate (27.4 kg) and water (110 l). To the mixture was then added dipotassium nitrosodisulfonate (23.5 kg, content 69.9%), which was stirred at 50°±3° C. for 3 hours. After confirming disappearance of the starting material by means of thin-layer chromatography, water (550 l) was added to the mixture, which was stirred at 10° C. or below for 30 minutes or longer, then precipitating crystals were separated by centrifuge. Wet crystals thus collected were dissolved in ethyl acetate (40 l), followed by washing with water (25). The ethyl acetate layer was concentrated under reduced pressure to obtain a crude product 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (6.70 kg, yield 93.9%). Reference examples using dipotassium nitrosodisulfonate (Fremy's salt) are described in Table 3.
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[C:19]([O:23][C:24]([N:26]1[CH2:37][CH2:36][C:29]2([C:33](=[O:34])[NH:32][C:31](=[O:35])[CH2:30]2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH2:28][C:29]2([C:33](=[O:34])[N:32]([CH2:2][C:3]3[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]4[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=4[CH:4]=3)[C:31](=[O:35])[CH2:30]2)[CH2:36][CH2:37]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)NC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(CN2C(=O)CC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.1 %

Procedure:
6-Bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (1.0 g, 3.25 mmol) and 1,3-dioxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (0.82 g, 3.42 mmol) are dissolved in DMF (15 ml) and potassium carbonate (0.58 g, 4.23 mmol) is added to the solution. The reaction mixture is stirred at room temperature for 15 h and quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined extracts are washed with H2O, brine and dried over magnesium sulfate. Chromatography on silica gel (eluent; n-hexane:ethyl acetate=2:1) gives 1.56 g of desired 2-[2-cyano-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-1,3-dioxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester in 97% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]([NH:5][C:6]([NH2:8])=[S:7])=[O:4].O.[OH-].[Na+].I[CH2:14][CH3:15]>CO>[CH3:1][N:2]([CH3:9])[C:3](=[O:4])[NH:5][C:6](=[NH:8])[S:7][CH2:14][CH3:15]
Reactant: CN(C)C(=O)NC(N)=S
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCSC(=N)NC(=O)N(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 58.5 parts of 1,1-dimethyl-4-thiobiuret in 200 parts of water, 200 parts of methanol and 32 parts of 50% aqueous sodium hydroxide are added at 25° C. within 10 minutes 62.5 parts of iodoethane. The reaction mass is then stirred at 25° C. for 2 hours. Evaporation of the methanol and part of the water under vacuum gives 64 parts of crude ethyl 4,4-dimethylthioallophanimidate (a compound of formula II), which is recrystallized from water-methanol (50:50) and shows a melting point of 90°-93° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[N:6][CH:7]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:14]1([S:20]([NH:1][C:2]2[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[N:6][CH:7]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(N)cnc1CCCC#N
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(NS(=O)(=O)c2ccccc2)cnc1CCCC#N

Procedure:
A solution of 5-amino-2-(3-cyanopropyl)-3-methylpyridine* (5 g) in chloroform (50 ml) was treated with benzenesulphonyl chloride (7.35 ml) and triethylamine (3 ml) for 96 hours. The chloroform layer was extracted with dilute sodium hydroxide solution (2×50 ml). The chloroform layer was discarded and the combined aqueous extracts were adjusted to pH=5 and extracted with chloroform (3×50 ml). The combined extracts were dried over magnesium sulphate, the solvent was removed and the residue was chromatographed on silica gel eluted with 2% v/v methanol in chloroform to give the title compound (3.28 g) as white prisms. m.p. 119°-120° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[NH:12][C@H:11]([CH2:13][OH:14])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.Cl[C:16]1[CH:21]=[CH:20][N:19]2[N:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:18]2[N:17]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:9][CH2:10][C@@H:11]([CH2:13][OH:14])[N:12]2[C:16]2[CH:21]=[CH:20][N:19]3[N:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:18]3[N:17]=2)[CH:5]=[N:6][CH:7]=1
Reactant: OC[C@@H]1CC[C@H](c2cncc(F)c2)N1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn2ccc(N3[C@H](CO)CC[C@@H]3c3cncc(F)c3)nc12
Temperature: 90 °C
Yield: 14 %

Procedure:
A mixture of ((2S,5R)-5-(5-fluoropyridin-3-yl)pyrrolidin-2-yl)methanol (0.910 g, 4.64 mmol), ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, 1.05 g, 4.64 mmol) and DIEA (1.10 mL, 6.00 mmol) in isopropyl alcohol (1.0 mL) was heated at 90° C. for 16 hours. The reaction mixture was concentrated and the residue was purified by reverse phase column chromatography (0-50% acetonitrile/water) followed by normal phase column chromatography (2-5% MeOH/DCM) to afford ethyl 5-((2R,5S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.250 g, 14% yield) as a viscous, clear oil. MS (apci) m/z=386.0 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6](O)=O)=[CH:4][C:3]=1[CH3:12].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:24][C:25]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:26]=1[C:27]([NH2:29])=[O:28]>C(Cl)Cl>[Br:34][C:31]1[CH:30]=[C:26]2[C:25](=[CH:33][CH:32]=1)[N:24]=[C:6]([C:5]1[CH:9]=[C:10]([CH3:11])[C:2]([OH:1])=[C:3]([CH3:12])[CH:4]=1)[NH:29][C:27]2=[O:28]
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Reactant: NC(=O)c1cc(Br)ccc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(-c2nc3ccc(Br)cc3c(=O)[nH]2)cc(C)c1O
Reaction time: 1.25 h
Yield: 94.8 %

Procedure:
To a solution of 4-hydroxy-3,5-dimethylbenzoic acid (2.00 g, 12.0 mmol) in CH2Cl2 (60.2 mL) cooled to 0-5° C. was added oxalyl chloride (1.47 mL, 16.8 mmol) followed by dropwise addition of DMF (93.3 μL, 1.20 mmol). The mixture was stirred for 1.25 h, the volatiles were removed under vacuum to give crude acid chloride, which was used immediately without further purification. A mixture of 2-amino-5-bromobenzamide (1.99 g, 9.23 mmol) and the acid chloride (crude residue described above) in THE (92.3 mL) was stirred at room temperature for 17 h, then heated at reflux for 4 h. The volatiles were removed under vacuum, the residue was triturated with EtOAc, and filtered to afford the amide (3.02 g, 90%) as a yellow solid. A mixture of the amide (3.01 g, 8.29 mmol), 2 M NaOH (20.0 mL), water (40.0 mL), and MeCN (20.0 mL) was heated at reflux for 15 h, cooled to 5° C., and neutralized with 2 M aqueous HCl. After stirring for 30 min, the white solid was filtered, triturated with acetone, and filtered again to afford 6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (2.28 g, 80%). Selected data: 1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, J=2.29 Hz, 1H), 7.93 (dd, J=8.72, 2.42 Hz, 1H), 7.86 (s, 2H), 7.63 (d, J=8.70 Hz, 1H), 5.75 (s, 1H), 2.24 (s, 6H); MS (APCI) m/z 346 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([O:17][CH3:18])=[C:12]([CH3:19])[CH:11]=2)=[C:6]([OH:21])[N:5]=[C:4]([S-:22])[N:3]=1.[Na+].[OH-].[Na+].I[CH3:27].Cl>O.CN1CCCC1=O>[OH:21][C:6]1[C:7]([NH:8][C:9](=[O:20])[C:10]2[CH:11]=[C:12]([CH3:19])[C:13]([O:17][CH3:18])=[C:14]([CH3:16])[CH:15]=2)=[C:2]([OH:1])[N:3]=[C:4]([S:22][CH3:27])[N:5]=1
Reactant: COc1c(C)cc(C(=O)Nc2c(O)nc([S-])nc2O)cc1C
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1c(C)cc(C(=O)Nc2c(O)nc(SC)nc2O)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
19.1 g of sodium 4,6-dihydroxy-5-(4-methoxy-3,5-dimethylbenzoylamino)pyrimidine-2-thiolate in 190 ml of water and 80 ml of N-methylpyrrolidin-2-one were cooled to 0° C. With cooling, 5.9 g of sodium hydroxide were added, after which the mixture was stirred at 0° C. for 30 min. A solution of 3.7 ml of iodomethane in 4.3 ml of N-methylpyrrolidin-2-one was then added. After the reaction had ended (2 h), the mixture was acidified with concentrated hydrochloric acid. The precipitate obtained was filtered off with suction, washed with water and dried under reduced pressure. This gave 10.1 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([CH3:23])[N:9]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:22])[N:13]=[C:10]32)=[CH:5][CH:4]=1.C(Cl)(Cl)Cl>C1C2C(CCCC2)CCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([CH3:23])[N:9]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:22])[N:13]=[C:10]32)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)-c1nc(-c3ccccc3C)cn1C(C)C2
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: C1CCC2CCCCC2C1
Product: COc1ccc2cc(C)n3cc(-c4ccccc4C)nc3c2c1
Yield: 61.6 %

Procedure:
To a solution of 4.9 g of 9-methoxy-5-methyl-2-(2-methylphenyl)-5,6-dihydroimidazo[2,1-a]isoquinoline in 30 ml of decalin was added 0.97 g of palladium on activated carbon (Pd 10%) and the mixture was refluxed for 6 hours. After being cooled and an addition of 200 ml of chloroform, the mixture was filtered and the filtrate was evaporated in vacuo. The resultant residue was crystallized from a mixture of hexane and ethyl acetate(6:1) to give 3.0 g of the tide compound.
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:11]3(COOC3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH2:18]>C(O)(=O)C>[F:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:11](=[O:18])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccnc1N1CCC2(CC1)COOC2
Reactant: O
Solvent: CC(=O)O
Product: O=C1CCN(c2ncccc2F)CC1

Procedure:
8-(3-fluoro-pyridin-2-yl)-2,3-dioxa-8-azaspiro[4.5]decane 17 (347 g, 1.456 Mol) was dissolved in acetic acid (700 mL) and water (140 mL) and the mixture heated to 85° C. under nitrogen for 18 h. LC/MS shows the reaction at 92% conversion at this stage. The mixture was evaporated to dryness in vacuo, to leave orange oil. This material was used directly in the next step without further purification