Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:26]=[CH:25][C:11]([CH2:12][CH:13]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH2:16][CH2:15][N:14]2[CH:23]=[O:24])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(=O)(O)(O)O.S(=O)(=O)(O)O>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][C@H:13]3[N:14]([CH:23]=[O:24])[CH2:15][CH2:16][C@@:17]4([C:25]=2[CH:26]=1)[C@H:22]3[CH2:21][CH2:20][CH2:19][CH2:18]4)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CN1CCC2=C(CCCC2)C1Cc1ccc(Oc2ccccc2)cc1
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Product: O=CN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Temperature: 0 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
(±)-1-(p-Phenoxybenzyl)-2-formyl-1,2,3,4,5,6,7,8-octahydroisoquinoline, 24.5 g (0.07 mol), was combined under stirring with 120 g of phosphoric acid which had been mixed with 1.0 g of concentrated sulfuric acid and the mixture was heated in a nitrogen atmosphere to 70°. The resulting homogeneous solution was kept at 70° for 48 hrs. The mixture was cooled in an ice bath and ice-water was added. The resulting suspension was extracted with ethyl acetate (100 ml). The ethyl acetate solution was washed with water and dried. Removal of the solvent gave 23.3 g (95%) of crude (±)-3-phenoxy-N-formylmorphinan.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:12]1C(C(OCC)=O)=C(C)C=CN=1.[NH4+].[Cl-]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].N>[Cl:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([CH3:12])[CH:5]=[CH:4][N:3]=1
Reactant: NC(=O)c1cccnc1Cl
Reactant: CCOC(=O)c1c(C)ccnc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N
Agent: [Br-]
Product: Cc1ccnc(Cl)c1C(N)=O
Yield: 64 %

Procedure:
In a manner similar to that described for 2-chloro-3-pyridinecarboxamide in Example 13, the title compound (m.p. 168-170) was prepared in 64% yield from 4 g of ethyl 2-chloro-4-methyl-3-pyridinecarboxylate, 1 g of NH4Cl, 30 mL of concentrated aqueous ammonia, and 0.6 of Bu4NBr.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([CH:21]([C:23]1[NH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)[OH:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O:3]CC1C=CC=CC=1)=[O:2].C([NH:39][C@@H:40]([C:52]([OH:54])=O)[CH2:41][CH2:42][CH2:43][NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])(OC(C)(C)C)=O>FC(F)(F)C(O)=O>[C:1]([N:11]([C@@H:12]([CH:21]([C:23]1[NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[N:24]=1)[OH:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:52](=[O:54])[C@H:40]([NH2:39])[CH2:41][CH2:42][CH2:43][NH:44][C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])([O:3][C:15]([CH3:20])([CH3:16])[CH3:14])=[O:2]
Reactant: O=C(N[C@H](CCc1ccccc1)C(O)c1nc2ccccc2[nH]1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCCC[C@@H](N)C(=O)N(C(=O)OC(C)(C)C)[C@H](CCc1ccccc1)C(O)c1nc2ccccc2[nH]1

Procedure:
N-Cbz-(1R)-1-[(RS)-(2-Benzimidazolyl)hydroxymethyl]-3-phenylpropylamine (581 mg) is deprotected in trifluoroacetic acid, and the residue is coupled to N,N′-bis-Boc-D-ornithine to afford the title compound (110 mg): mass spectrum (ES+) m/e 596.3 (M+1); 1H NMR (400 MHz, CDCl3, 3:2 mixture of diastereomers) δ 1.46 (m, 9H), 1.42 (s, 9H), 1.58 (m, 4H), 2.02 (m, 2H), 2.63 (m, 2H), 2.82 (m, 2H), 3.18 (m, 1H), 4.16 (m, 1H), 4.49 (m, 1H), 5.17 (m, 1H), 5.42 (m, 1H), 7.03-7.23 (m, 8H), and 7.57 (m, 1H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:23][CH2:24][CH2:25][OH:26])[CH:12]=[C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br>>[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:26][CH2:25][CH2:24][CH2:23][C:11]1[CH:10]=[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=1
Reactant: OCCCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: BrCCCCCBr
Product: BrCCCCCOCCCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1

Procedure:
(4.98 g) as a colourless oil, from 3,5-bis(phenylmethoxy)benzenepropanol (5.0 g) and 1,5-dibromopentane (5.9 ml) with stirring at room temperature for 16 h. T.l.c. (ER-CX 1:19) Rf 0.13.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[C:23]([C:24]5[CH:29]=[CH:28][N:27]=[C:26](S(C)(=O)=O)[N:25]=5)=[CH:22][N:21]([CH2:34][C:35]#[N:36])[N:20]=4)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:37][CH2:38][C@@H:39]([OH:41])[CH3:40]>C1COCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[C:23]([C:24]5[CH:29]=[CH:28][N:27]=[C:26]([NH:37][CH2:38][C@@H:39]([OH:41])[CH3:40])[N:25]=5)=[CH:22][N:21]([CH2:34][C:35]#[N:36])[N:20]=4)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](O)CN
Reactant: CS(=O)(=O)c1nccc(-c2cn(CC#N)nc2-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)n1
Solvent: C1CCOC1
Product: C[C@H](O)CNc1nccc(-c2cn(CC#N)nc2-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)n1
Temperature: 80 °C
Yield: 71.3 %

Procedure:
A Mixture of the [3-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(2-methanesulfonyl-pyrimidin-4-yl)-pyrazol-1-yl]-acetonitrile (C-1-5) (310 mg, 0.6 mmol) and (S)-(+)-1-amino-2-propanol (134 mg, 1.8 mmol) in THF (5 mL) was heated at 80° C. for 18 hr. The mixture was concentrated onto silica gel then purified on silica gel using a gradient of 0-6% methanol in a mixture of dichloromethane and ethyl acetate (1:1) as eluent to yield 220 mg (72%) of {3-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-[2-((S)-2-hydroxy-propylamino)-pyrimidin-4-yl]-pyrazol-1-yl}-acetonitrile (C-1-6) as a foam from methyl tert-butyl ether. 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.52 (d, J=2.02 Hz, 1H), 8.20 (s, 1H), 8.07-8.17 (m, 4H), 7.81 (d, J=4.04 Hz, 1H), 7.63-7.73 (m, 1H), 7.52-7.60 (m, 2H), 6.75 (d, J=4.04 Hz, 1H), 6.53 (br. s., 1H), 5.67 (br. t, J=4.93 Hz, 1H), 5.24 (s, 2H), 3.56 (br. s., 1H), 2.64-3.28 (br. m, 3H), 0.74 (br. s., 3H).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)(C)(C)C.[NH2:25][C:26]1[C:31]([CH:32]=O)=[CH:30][N:29]=[CH:28][CH:27]=1.[OH-].[Na+]>C(O)C>[C:16]1([C:15]2[C:14]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][OH:6])=[CH:13][CH:12]=3)=[N:25][C:26]3[C:31]([CH:32]=2)=[CH:30][N:29]=[CH:28][CH:27]=3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccncc1C=O
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1ccc(-c2nc3ccncc3cc2-c2ccccc2)cc1
Temperature: 70 °C

Procedure:
To a partial suspension of 1-[4-({[t-butyl-(dimethyl)silyl]oxy}methyl)phenyl]-2-phenylethanone (1.36 gm, 4.0 mmol) and 4-aminonicotinaldehyde (prepared as described in J. Org. Chem. 48, 3401 (1983)) (540 mg, 4.42 mmol) in absolute ethanol (10 mL) was added dropwise 5N NaOH (3 mL, 15 mmol). This mixture was heated at 70° C. for three hours. The solvent was evaporated in vacuo and the residue was partitioned between methylene chloride and aqueous sodium carbonate. The organic layer was dried (Na2SO4), the solution filtered, and the solvent evaporated. This residue was triturated with a small amount of ethyl acetate as the product crystallized out. The mother liquors were chromatographed on silica gel eluting with 0-2% methanol/ethyl acetate (sat'd with ammonia) to give additional product. 1H-NMR (500 MHz, CDCl3): δ 9.32 (1H, s), 8.77 (1H, d, J=5.9 Hz), 8.29 (1H, s), 7.99 (1H, d, J=6.1 Hz), 7.46 (2H, d, J=8 Hz), 7.28-7.33 (5H, m), 7.24-7.26 (2H, m), 4.71 (2H, s),
Reaction SMILES: [C:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Rh]>[CH:1]1([CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: [Rh]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C1CCCCC1
Reaction time: 18 h

Procedure:
A suspension of 5% rhodium on carbon (4.5 g) and diethyl phenylmalonate (30 g) in ethanol (100 ml) was hydrogenated at 60 psi for 18 hours. The suspension was filtered through celite and concentrated to a syrup (quant. yield). Distillation at 90°-94° C. (0.5 mmHg) afforded 28.2 g (92%) of the diethyl cyclohexylmalonate.
Reaction SMILES: [C:1]([O:5]C(=O)CC(C)=O)(C)([CH3:3])[CH3:2].CC[O-].CC[O-].[Mg+2].[CH3:19][C:20]1[C:21]([N+:30]([O-:32])=[O:31])=[C:22]([C:26]([CH3:29])=[CH:27][CH:28]=1)[C:23](Cl)=[O:24].S(=O)(=O)(O)O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:19][C:20]1[C:21]([N+:30]([O-:32])=[O:31])=[C:22]([C:26]([CH3:29])=[CH:27][CH:28]=1)[C:23]([CH2:2][C:1](=[O:5])[CH3:3])=[O:24]
Reactant: Cc1ccc(C)c([N+](=O)[O-])c1C(=O)Cl
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CC(=O)CC(=O)c1c(C)ccc(C)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Then, acetoacetate t-butyl ester in an amount of 8.9 g (56 mmol) was added into 80 ml toluene solution containing magnesium ethylate in an amount of 6.4 g (56 mmol) and the resulting mixture was stirred for 2 hours at 80° C., cooled down to an ambient temperature and added dropwise with 15 ml toluene solution of 3,6-dimethyl-2-nitrobenzoyl chloride in an amount of 10.3 g. The obtained mixture was stirred for 2 hours under heating and reflux, added with 10% sulfuric acid and extracted with ethyl acetate. The resulting organic solvent layer was washed with water and dried with anhydrous magnesium sulfate, and the solvent therein was distillated out under reduced pressure. The residue obtained was dissolved in 100 ml benzene and added with p-toluene sulfonic acid in an amount of 4.9 g (26 mmol), and the mixture was stirred for 2 hours under heating and reflux. Then, the reacted solution was washed with water and dried with anhydrous magnesium sulfate, and the solvent in the reacted solution was distillated out under reduced pressure. The residue obtained was purified by means of silica gei column chromatography to obtain 3,6-dimethyl-2-nitrobenzoylacetone in an amount of 3.9 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[N:10][CH:11]=[C:12]([O:21][CH2:22][C:23]([F:26])([CH3:25])[CH3:24])[CH:13]=3)[O:8][C:5]2=[CH:6][CH:7]=1.CN(C=O)C.C(NC(C)C)(C)C.[CH:39]1([C:42]#[CH:43])[CH2:41][CH2:40]1>O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I.C(OCC)(=O)C>[CH:39]1([C:42]#[C:43][C:2]2[CH:3]=[C:4]3[C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:14]4[C:9](=[N:10][CH:11]=[C:12]([O:21][CH2:22][C:23]([F:26])([CH3:25])[CH3:24])[CH:13]=4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH2:41][CH2:40]1
Reactant: C#CC1CC1
Reactant: CC(C)(F)COc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Agent: I[Cu]I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(F)COc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(C#CC3CC3)ccc1O2
Temperature: 110 °C

Procedure:
A sealable tube was charged with (S)-7-bromo-3-(2-fluoro-2-methylpropoxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (75 mg, 0.178 mmol), copper(i) iodide (3.38 mg, 0.018 mmol), tetrakis(triphenylphosphine)palladium (20.53 mg, 0.018 mmol). Added DMF (355 μL, 0.178 mmol), diisopropylamine (498 μL, 3.55 mmol) and cyclopropylacetylene (75 μL, 0.888 mmol) and the tube was flushed with argon, sealed and heated to 110° C. for 2 hours. More copper iodide (3.38 mg, 0.018 mmol), tetrakis(triphenylphosphine)palladium (20.53 mg, 0.018 mmol), diisopropylamine (498 μL, 3.55 mmol) and cyclopropylacetylene (75 μL, 0.888 mmol) were added and the black mixture was heated at 110° C. for 3 hours. The reaction was diluted with water (100 mL) and poured into a separatory funnel containing ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water and then brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (12 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (S)-7-(cyclopropylethynyl)-3-(2-fluoro-2-methylpropoxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a tan solid.
Reaction SMILES: [CH3:1][C:2]1([CH2:9][OH:10])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[O:3]1.[H-].[Na+].[CH3:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH2:9][O:10][CH2:13][C:14]2[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=2[CH3:16])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[O:3]1
Reactant: CC1(C)CCC(C)(CO)O1
Reactant: Cc1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1COCC1(C)CCC(C)(C)O1
Yield: 80 %

Procedure:
2,5,5-Trimethyl-2-hydroxymethyl tetrahydrofuran (1.6 g) was added slowly to a stirred suspension of sodium hydride (0.4 g of 80% dispersion in oil) in dry toluene (55 ml). After the addition the mixture was heated under reflux for 1 hour. 2-Methylbenzyl chloride (1.8 g) was added and the mixture heated under reflux overnight. The cooled mixture was washed with water (x2) and dried and the solvent was removed under reduced pressure. The product was purified by chromatography on silica using methylene dichloride as eluent. Yield 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-].C(N(CC)CC)C.[Cl:17]C1C=CC=CC=1>>[Cl:17][C:4]1[C:5]([CH3:8])=[CH:6][CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: Cc1ccc(Cl)[n+]([O-])c1
Reactant: Clc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)nc1Cl

Procedure:
101.5 g (0.50 mol) of o-phthaloyl chloride in 50 ml of chlorobenzene are added dropwise under nitrogen to a solution of 35.9 g (0.25 mol) of 2-chloro-5-methylpyridine-1-oxide and 50.6 g (0.50 mol) of triethylamine in 200 ml of chlorobenzene in the course of 30 min. The mixture is subsequently heated under reflux for a further 12 hours, then the precipitate is filtered off with suction, the filter cake is washed with 50 ml of methylene chloride and the solvent is removed by distillation. The bottom is subjected to steam distillation, the pH of 6 being maintained by continuously adding 45 per cent sodium hydroxide solution. The distillate is extracted three times using 100 ml of methylene chloride each time, the solvent is removed by distillation and the residue is recrystallized from hexane.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[Si]([O:31][CH2:32][C:33]1[C:34]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:35]([C:38]([O:40][CH3:41])=[O:39])[O:36][CH:37]=1)(C(C)(C)C)(C)C.C(Cl)(Cl)Cl>O>[OH:31][CH2:32][C:33]1[C:34]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:35]([C:38]([O:40][CH3:41])=[O:39])[O:36][CH:37]=1
Reactant: COC(=O)c1occ(CO[Si](C)(C)C(C)(C)C)c1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)c1occ(CO)c1-c1ccccc1
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
Tetrabutylammonium fluoride (1 M THF solution: 7.62 ml) was added at 25° C. to a THF (10 ml) solution of methyl 4-(tert-butyldimethylsilyloxymethyl)-3-phenyl-2-furancarboxylate (2.20 g), and stirred for 0.5 hours. Chloroform and water were added to the reaction solution, the organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0%→30% ethyl acetate/hexane gradient, thereby giving 1.00 g of the desired compound.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH3:16][O:17][C:18]([C:20]1[C:21]2[CH:22]=[CH:23][NH:24][C:25]=2[CH:26]=[CH:27][CH:28]=1)=[O:19].C([O-])(=O)C.[Na+]>C(Cl)CCl>[CH3:16][O:17][C:18]([C:20]1[C:21]2[C:22]([CH:9]=[O:10])=[CH:23][NH:24][C:25]=2[CH:26]=[CH:27][CH:28]=1)=[O:19]
Reactant: CN(C=O)c1ccccc1
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)c1cccc2[nH]cc(C=O)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of N-methylformanilide (15.6 g) and phosphorus oxychloride (17.7 g) is added ethylene dichloride (75 g) followed by 4-indolecarboxylic acid methyl ester (17.5 g), described by F. C. Uhle, J. Amer. Chem. Soc., 71, 761 (1949). The reaction mixture is stirred at room temperature for 11/2 hr., then at 45° - 50°C for 30 minutes more. The mixture is now poured into a solution of 75 g of sodium acetate in 150 ml of ice-water. More ethylene dichloride is added. The layers are separated and the organic phase is washed with water, dried (Na2SO4) and evaporated under reduced pressure. The brown residue is treated repeatedly with boiling water from which the title compound separates on cooling. The title compound has mp 135°C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:39])[CH2:41][OH:42])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)CO)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f2) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH3:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1.[CH2:27]([O:34][CH2:35][C@@H:36]1[CH2:41][C:40]([F:43])([F:42])[CH2:39][CH2:38][C@H:37]1[CH:44]=[O:45])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[NH4+].[Cl-]>C1COCC1>[CH2:27]([O:34][CH2:35][CH:36]1[CH2:41][C:40]([F:43])([F:42])[CH2:39][CH2:38][CH:37]1[CH:44]([OH:45])[CH:21]([C:18]1[CH:17]=[CH:16][C:15]([S:14][CH3:13])=[CH:20][CH:19]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)Cc1ccc(SC)cc1
Reactant: O=C[C@@H]1CCC(F)(F)C[C@H]1COCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(c1ccc(SC)cc1)C(O)C1CCC(F)(F)CC1COCc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A 2.1 M solution of n-BuLi (11 mL, 23 mmol) in hexanes was added slowly to a 0° C. solution of diisopropylamine (4.0 mL, 28 mmol) in THF (10 mL). Stirring was continued at this temperature for an additional 10 min prior to cooling to −78° C. A solution of ethyl [4-(methylthio)phenyl]acetate (4.64 g, 18.9 mmol) in THF (15 mL) was then introduced and the mixture was stirred at −78° C. for 10 min, −40° C. for 10 min and finally at 0° C. for 5 min. The solution was recooled to −78° C. and a solution of (1R,2R)-2-[(benzyloxy)methyl]-4,4-difluorocyclohexanecarbaldehyde (4.64 g, 18.9 mmol) in THF (15 mL) was added down the flask wall over 5 min. Stirring was continued at −78° C. for 30 min then at −40° C. for 1 h. A saturated aqueous solution of NH4Cl was added and the reaction mixture was warmed to rt and partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous NaCl solution and dried over Na2SO4. Concentration in vacuo and flash chromatography on silica gel eluting with 3/7 ethyl acetate/hexanes gave ethyl 3-{2-[(benzyloxy)methyl]-4,4-difluorocyclohexyl}-3-hydroxy-2-[4-(methylthio)phenyl]propanoate as a faint-yellow, thick syrup. 1H NMR (400 MHz, d6-acetone) δ 7.43-7.33 (5H, m), 7.33-7.29 (2H, m), 7.15-7.11 (2H, m), 4.66 (1H, m), 4.57-4.49 (2H, m), 4.16-4.00 (2H, m), 3.74 (2H, d, J= 10.7 Hz), 3.45 (1H, dd, J=2.8, 9.5 Hz), 2.46 (3H, s), 1.84-1.75 (2H, m) 13.5 Hz), 1.73-1.63 (1H, m), 1.17 (3H, t, 7= 7.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[C:13]3[N:14]=[CH:15][C:16]([CH2:18][N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[CH:17][C:12]=3[C:11]3=[N:32][CH:33]=[N:34][N:10]3[C:9]2=[O:35])=[CH:5][CH:4]=1.BrC1C=NC2N(CC3C=CC(OC)=CC=3)C(=O)N3N=CN=C3C=2C=1.C(OC(N1CCN(C[B-](F)(F)F)CC1)=O)(C)(C)C.[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13]3[N:14]=[CH:15][C:16]([CH2:18][N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:17][C:12]=3[C:11]3=[N:32][CH:33]=[N:34][N:10]3[C:9]2=[O:35])=[CH:36][CH:37]=1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc32)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)OC(=O)N1CCN(C[B-](F)(F)F)CC1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(CN4CCNCC4)cnc32)cc1
Temperature: 80 °C
Yield: 29 %

Procedure:
tert-Butyl 4-((6-(4-methoxybenzyl)-5-oxo-5,6-dihydropyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-9-yl)methyl)piperazine-1-carboxylate. 9-Bromo-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (Example 1, 562.00 mg; 1.46 mmol), potassium ((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)trifluoroborate (568.00 mg; 1.86 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (60.00 mg; 0.13 mmol;), Pd(OAc)2 (30.00 mg; 0.13 mmol), Cs2CO3 (1.76 g; 5.40 mmol), and degassed dioxane-water (9:1; 10 mL) were combined in that order and heated at 80° C. for 4 days. The mixture concentrated under reduced pressure. Purification (FCC, SiO2, 20-100% EtOAc/hexanes) afforded the title compound (216 mg, 29%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[N:8]([CH2:9][OH:10])[C:6](=[O:7])[NH:5][C:3]1=[O:4].[CH2:12]=[O:13]>>[CH3:1][C:2]1([CH3:11])[N:8]([CH2:9][OH:10])[C:6](=[O:7])[N:5]([CH2:12][OH:13])[C:3]1=[O:4].[CH2:3]=[O:4]
Reactant: CC1(C)C(=O)NC(=O)N1CO
Agent: C=O
Product: CC1(C)C(=O)N(CO)C(=O)N1CO

Procedure:
DMDMH is a formaldehyde donor which is the diformylated product of DMH and formaldehyde. MDMH is first formed as an intermediate. MDMH, itself, is a formaldehyde scavenger containing about 19% by weight of bound, but available, formaldehyde. Subsequent reaction of MDMH with formaldehyde yields DMDMH which theoretically contains 31.9% of bound but available, formaldehyde.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[CH:11]=2)[N:3]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.[OH-].[Na+].OP([O-])(O)=O.[K+]>CC(C)=O.CC#N.CO.O>[Cl:8][C:6]1[N:7]=[C:2]([NH:22][CH:19]2[CH2:21][CH2:20]2)[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[CH:11]=2)[N:5]=1
Reactant: COc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1F
Reactant: NC1CC1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(C)=O
Product: COc1ccc(Nc2nc(Cl)nc(NC3CC3)n2)cc1F

Procedure:
To 124 (2.01 g, 7.0 mmol) dissolved in acetone (40 mL) was added a solution of cyclopropylamine (0.5 mL, 7 mmol) in acetone (5 mL) followed by addition of NaOH (2.8 mL, 2.5 N, 7.0 mmol) and 8 mL of water. The reaction was stirred and heated at reflux for 3 hours. The reaction mixture was poured over crushed ice. The solid that formed was collected by vacuum filtration and was dried overnight under vacuum to afford unpurified E10 (1.8 g). {A separate reaction [124, (2.00 g, 7 mmol) and cyclopropylamine (0.5 mL, 7 mmol)] yielded unpurified E10 (1.9 g).} The two lots (1.8 g and 1.9 g) were combined for purification. Column chromatography (50:50 v:v hexane:ethyl acetate) yielded a faint yellow solid (E10) (2.89 g, 67%); mp 186° C.; HPLC: Inertsil ODS 3V C18, 40:30:30 [KH2PO4 (0.01 M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 16.6 min, 94.9% purity; MS (TOF ES+) m/z 310 (M+H, 100), 312 (44.4).