Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:40])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:42][C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:40])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])[N:28]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccc(F)c(F)c3)n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3ccc(F)c(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4.000 g 4-((S)-4-tert-Butoxycarbonyl-2-{[1-(3,4-difluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 26 ml DMF were added 1.172 ml benzyl bromoacetate and 4.607 g cesium carbonate. After stirring at RT for 12 h the solution was diluted with 100 ml ethyl acetate and extracted with aqueous LiCl (4% w/w) and aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent reaction.
Reaction SMILES: [OH-].[Na+:2].[F:3][C@@H:4]1[CH2:8][N:7]([C:9](=[O:28])[CH2:10][C:11]2[CH:27]=[CH:26][C:14]3[N:15]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])[O:17][C:13]=3[CH:12]=2)[C@H:6]([CH2:29][O:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH2:5]1>C(O)C>[F:3][C@@H:4]1[CH2:8][N:7]([C:9](=[O:28])[CH2:10][C:11]2[CH:27]=[CH:26][C:14]3[N:15]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])[O:17][C:13]=3[CH:12]=2)[C@H:6]([CH2:29][O:30][CH2:31][CH2:32][CH2:33][C:34]([O-:36])=[O:35])[CH2:5]1.[Na+:2]
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)N3C[C@@H](F)C[C@H]3COCCCC(=O)O)cc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)N3C[C@@H](F)C[C@H]3COCCCC(=O)[O-])cc2o1
Yield: 78.1 %

Procedure:
Methyl 4-((2S,4S)-4-fluoro-1-(2-(2-methylphenylamino)-6-benzoxazolylacetyl)-2-pyrrolidinylmethoxy-n-butyrate (378 mg, 0.782 mmol) was dissolved in THF (20 ml). To the resulting solution was added 0.25N NaOH (20 ml) and the mixture was stirred at 50° C. for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was acidified with 1N HCl, followed by extraction with a chloroform/methanol (10/1) mixture. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was then purified by thin-layer silica gel column chromatography (TLC), whereby from chloroform/methanol (10/1) eluate fractions, 4-((2S,4S)-4-fluoro-1-(2-(2-methylphenylamino)-6-benzoxazolylacetyl)-2-pyrrolidinylmethoxy)-n-butyric acid (99 mg, 27%) was obtained as a yellow oil. Ethanol (3 ml) and 1N NaOH (211 μl, 0.211 mmol) were added to the resulting 4-((2S,4S)-4-fluoro-1-(2-(2-methylphenylamino)-6-benzoxazolylacetyl)-2-pyrrolidinylmethoxy)-n-butyric acid (99 mg, 0.211 mmol) under stirring to dissolve the latter in the former. The resulting solution was concentrated to dryness. Ether was added to crystallize the residue, whereby sodium 4-((2S,4S)-4-fluoro-1-(2-(2-methylphenylamino)-6-benzoxazolylacetyl)-2-pyrrolidinylmethoxy)-n-butyrate (81 mg) was obtained as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH2:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17]C=2)[CH:3]=1.[Sn](Cl)Cl.[CH2:24](O)C>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][CH2:12][C:13]([C:14]2[CH:15]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH2:24])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1OCC=Cc1ccccc1
Reactant: CCO
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(COc1cc(Cl)ccc1N)c1ccccc1

Procedure:
The compound of Step A (7.2 g) was added to a suspension of tin (II) chloride (28 g) in ethanol (45 ml). The mixture was refluxed for 1.5 h. The reaction was diluted with ethyl acetate and neutralized by careful addition of saturated sodium bicarbonate solution. The organic solution was washed with brine and the solvent was dried over magnesium sulfate. Evaporation of the solution left a thick oil of the title compound (5.8 g).
Reaction SMILES: [Na].[NH2:2][C:3]1[NH:4][C:5](=[S:17])[C:6]([C:15]#[N:16])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1.Br[CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23]>C(O)C>[CH2:20]([O:21][C:22]([C:23]1[S:17][C:5]2[N:4]=[C:3]([NH2:2])[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[C:15]=1[NH2:16])=[O:24])[CH3:19]
Reactant: CC(=O)OCCBr
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=S
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1sc2nc(N)nc(-c3ccccc3)c2c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium (0.010 g, 0.438 mmol, 1 eq) was dissolved in 4 ml anhydrous ethanol under nitrogen. 2-Amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile (0.100 g, 0.438 mmol, 1 eq) was added and the reaction was stirred at room temperature for 1 hour. 2-Bromoethylacetate (0.073 g, 0.438 mmol, 1 eq) was added. The reaction was stirred for further 30 minutes at room temperature. Then sodium (0.010 g, 0.438 mmol, 1 eq) dissolved in 1 ml anhydrous ethanol was added. The reaction was then refluxed for 5 hours. The reaction was cooled to room temperature and quenched with water. The precipitate was filtered off and triturated with diethyl ether to yield 2,5-diamino-4-phenyl-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:21]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45].Cl>ClCCl.CO>[ClH:28].[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:21]=2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(OCCN(C)C)nc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(OCCN(C)C)nc1
Yield: 146 %

Procedure:
Following general procedure F, 1-(6-bromo-4-(6-(2-(dimethylamino)ethoxy)pyridin-3-ylamino)quinolin-3-yl)ethanone (5.0 g, 12.0 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (3.7 g, 13.0 mmol) to obtain the free base. The purified product was suspended in dichloromethane/methanol (1:1, 300 mL) after which HCl (30 mL, 1.25 M in methanol) was added to form a solution. The solution was concentrated to dryness to obtain desired product (5.2 g, 74% over two steps) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.27 (s, 1H), 8.29 (d, J=2.9 Hz, 1H), 8.20-8.10 (m, 1H), 8.06-7.96 (m, 1H), 7.87-7.77 (m, 2H), 7.20 (s, 2H), 7.17-7.08 (m, 1H), 4.81-4.71 (m, 2H), 3.64 (t, J=5.1 Hz, 2H), 3.01 (s, 6H), 2.80 (s, 3H); ESI MS m/z 511 [C26H24Cl2N4O3+H]+; HPLC>99% (AUC), tR=6.86 min.
Reaction SMILES: [P:1]([S-:9])([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[S:2].[K+].[Cl:11][C:12]1[C:13](=[O:20])[N:14]([CH2:18]Cl)[O:15][C:16]=1[CH3:17]>>[P:1]([S:9][CH2:18][N:14]1[C:13](=[O:20])[C:12]([Cl:11])=[C:16]([CH3:17])[O:15]1)(=[S:2])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5]
Reactant: CCOP(=S)([S-])OCC
Reactant: Cc1on(CCl)c(=O)c1Cl
Agent: [K+]
Product: CCOP(=S)(OCC)SCn1oc(C)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.8 %

Procedure:
To the solution obtained in step (b) above was added dropwise the isoxazolinone solution obtained in step (a) above, with stirring, over a period of 5 minutes at ambient temperature. The mixture was then stirred for a further 30 minutes, also at ambient temperature. After distilling off the solvent, 100 ml of benzene and 25 ml of water were added to the residue and the benzene phase was washed, in turn, with 25 ml of a 5% w/w aqueous sodium bicarbonate solution and twice with 100 ml of a saturated aqueous sodium chloride solution. The benzene solution was then dried over anhydrous sodium sulphate and the solvent was distilled off. The residue was then purified as described in step (b) of Example 3, affording 28.5 g (85.8% of theory) of O,O-diethyl S-(4-chloro-5-methyl-3-oxo-4-isoxazolin-2-ylmethyl) phosphorodithioate, in the form of a yellow oil, n20D =1.5457.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14]1(C)C=CC=C[CH:15]=1>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:14][CH3:15])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
4-chloro-3-nitrobenzoic acid (40.0 g, 0.2 mol) was refluxed in thionyl chloride (150 ml) for 6 hours. After cooling toluene (50 ml) was added and the mixture was evaporated to dryness. Abs. ethanol (500 ml) was added to the cooled residue, and the resulting mixture was refluxed overnight. The excess of ethanol was removed under reduced pressure and the product crystallized upon addition of aqueous sodium bicarbonate (1M). Yield: 42.5 g (93%).
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH:3]([C:5](OC)=[O:6])[CH2:2]1.CO.[Li+].[BH4-].O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1.CCOC(C)=O>[OH:6][CH2:5][CH:3]1[CH2:4][N:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(CO)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
1-tert-butyl 3-methyl azetidine-1,3-dicarboxylate (1055 mg, 4.90 mmol) was dissolved in THF (17 mL) and then cooled to 0° C. MeOH (0.397 mL, 9.80 mmol) and LiBH4 (14.7 mmol) were added sequentially. The reaction was warmed to room temperature over 3 h. Then 10% aqueous potassium sodium tartrate tetrahydrate (Rochelle's Salt) (30 mL) and EtOAc (30 mL) were added and the solution stirred at room temperature over 30 minutes. The organic layer was separated and then dried (Na2SO4) and concentrated to afford 674 mg of t-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (1-3) as a crude product (clear oil). The product was used directly in the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[OH:27])(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[CH3:29][S:30][C:31]1[N:35]([CH2:36][C@@H:37](O)[CH3:38])[C:34]2[CH:40]=[CH:41][CH:42]=[CH:43][C:33]=2[N:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(O)C=CC=CC=1>C1COCC1.C(OCC)(=O)C.CCCCCCC>[C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[O:27][C@H:37]([CH3:38])[CH2:36][N:35]1[C:34]2[CH:40]=[CH:41][CH:42]=[CH:43][C:33]=2[N:32]=[C:31]1[S:30][CH3:29])(=[O:18])=[O:19])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CSc1nc2ccccc2n1C[C@H](C)O
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Oc1ccccc1
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1O[C@H](C)Cn1c(SC)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of (S)-3-(4-amino-2-hydroxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester (200 mg, 0.48 mmol), (2S)-1-[2-(methylsulfanyl)-1H-benzo[d]imidazol-1-yl]propan-2-ol (150 mg, 0.67 mmol) and resin bound triphenyl phosphine (1 g, 1 mmol) in THF (5 mL) was added diisopropyl azodicarboxylate (600 uL, 3 mmol). This mixture was shaken at room temperature for 2 h. TLC 50% ethyl acetate/heptane shows no phenol rf 0.2. The reaction mixture was filtered, the resin was washed with dichloromethane, the organics were combined, the solvent was evaporated under reduced pressure. (S)-3-{4-amino-2-[(R)-1-methyl-2-(2-methylsulfanyl-benzoimidazol-1-yl)-ethoxy]-benzenesulfonylamino}-4,4-diethoxy-butyric acid tert-butyl ester was purified by silica gel chromatography ethyl acetate/heptane (132 mg, 44%). RP-HPLC (10 to 9O % acetonitrile in 0.1 N aqueous ammonium acetate over 10 min at 2 mL/min using a Waters Symmetry C18 150×4.6 mm column) 9.8 min.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[N:12]=[CH:13][C:14]([C:21]2[CH:22]=[N:23][N:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH:25]=2)=[C:15]2[C:19]([Cl:20])=[CH:18][O:17][C:16]=12.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[NH2:10][C:11]1[N:12]=[CH:13][C:14]([C:21]2[CH:22]=[N:23][N:24]([CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)[CH:25]=2)=[C:15]2[C:19]([Cl:20])=[C:18]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:17][C:16]=12
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c4occ(Cl)c34)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5ccccc5)c(Cl)c34)cn2)CC1

Procedure:
A solution of phenylboronic acid (35.0 mg, 287 μmol), tert-butyl 4-[4-(7-amino-3-chlorofuro[2,3-c]pyridin-4-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (65 mg, 144 μmol), (1,1′-bis(diphenylphosphino)ferrocene)palladium dichloride (10.5 mg, 14.4 μmol), potassium carbonate (29.8 mg, 216 μmol) in 1,4-dioxane (785 μL) and H2O (259 μL) was evacuated and filled with argon three times. The mixture was irradiated in a microwave reactor at 100° C. for 40 min. The reaction mixture was partitioned between EtOAc and brine/water and separated. The aqueous layer was extracted with EtOAc (3×) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (60 to 100% EtOAc:hexanes) to afford tert-butyl 4-[4-(7-amino-3-chloro-2-phenylfuro[2,3-c]pyridin-4-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate. MS (ESI): 494.16 [M+H]+; HPLC tR=3.11 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[S:20][C:21]([C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25])=[N:22][N:23]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH2:11][NH:18][C:19]1[S:20][C:21]([C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25])=[N:22][N:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCNC(=O)c1nnc(N)s1
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Solvent: Cc1ccccc1
Product: CCCNC(=O)c1nnc(NCc2cc(Br)ccc2OCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-benzyloxy-5-bromobenzaldehyde (4.2 g) and 2-amino-N-propyl-1,3,4-thiadiazole-5-carboxamide (2.7 g) in toluene (200 mL) was heated under reflux for 2 hours. The solvent was evaporated and residue was dissolved in ethanol (100 mL) and was heated under reflux for 3 hours then allowed to cool to ambient temperature. Sodium borohydride (0.53 g) was added and the reaction mixture was stirred for 16 hours then poured into water (500 mL). The aqueous mixture was extracted 4 times with ethyl acetate (50 mL each time), the combined extracts were washed 3 times with water (100 mL each time) and dried (MgSO4). The residue obtained on removal of the solvent was subjected to chromatography on silica, eluting with a mixture of ethyl acetate and dichloromethane (1/5 v/v), to give 2-[N-(2-benzyloxy-5-bromobenzyl)amino]-N-propyl-1,3,4-thiadiazole-5-carboxamide, yield 0.81 g, mp 154° C.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=2[N:3]=1.CS(C)=O.N1CCOCC1>C1COCC1.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(C)c(=O)n2CCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n(C)c(=O)c2[nH]c(Cl)nc21
Reaction time: 5 h

Procedure:
Tetrakis(triphenylphosphine)palladium (1.0, 0.90 mmol) was placed in a flask which was evacuated and then filled with nitrogen (×3). A solution of 8-chloro-1-methyl-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (2.78 g, 8.96 mmol) in 50 ml of THF was added and the flask evacuated once more and nitrogen introduced. DMSO (4.5 ml) and morpholine (7.8 ml, 89.6 mmol) was added and the solution stirred for 5 h. The solution was partitioned between ethyl acetate and 2N HCl solution and the organic fraction washed with brine, dried (MgSO4) and concentrated. The crude was purified with an aminopropyl SPE eluting with first methanol then methanol containing 0-15% acetic acid to provide the title compound as a white solid, 1.12 g, 46%. NMR δH (400 MHz, d6-DMSO) 0.86 (t, 3H, J=7 Hz), 1.21-1.35 (m, 4H), 1.59-1.68 (m, 2H), 3.22 (s, 3H), 3.91 (t, 2H, J=7.5 Hz), NH not observed; m/z 271 [MH+].
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[C:20]([C:23]2[N:27]([CH2:28][CH3:29])[N:26]=[N:25][N:24]=2)[CH2:21][OH:22])=[CH:15][CH:14]=1>C(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)=[C:20]([C:23]2[N:27]([CH2:28][CH3:29])[N:26]=[N:25][N:24]=2)[CH:21]=[O:22])=[CH:15][CH:14]=1
Reactant: CCn1nnnc1C(CO)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCn1nnnc1C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
Pyridinium chlorochromate (0.9 g) was added to a solution of 0.8 g (2.3 mmoles) of the 3,3-bis(4-fluorophenyl)-2-(1-ethyl-1H-tetrazol-5-yl)-2-propenol in methylene chloride. The solution became bright yellow and then darkened with the formation of a dark gummy precipitate. After stirring at room temperature for 16 hours, the mixture was poured directly onto a silica gel column and eluted with methylene chloride to give 0.65 g (83%) of the title compound; m.p. =144°-145° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:19][O:20][C:21]([CH3:23])=[O:22]>CS(C)=O.C1(C)C=CC=CC=1>[CH3:19][O:20][C:21]([C:23]1[CH:11]=[CH:10][C:9]([N:15]2[CH2:16][CH2:17][C:10]3([CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][CH2:11]3)[CH2:13][CH2:14]2)=[N:8][CH:6]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: CCOC(C)=O
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N2CCC3(CCN(C(=O)OC(C)(C)C)C3)CC2)nc1
Temperature: 85 °C

Procedure:
To a solution of methyl 6-chloronicontinate (200 mg, 1.16 mmol) in DMSO/PhMe (2 mL of a 1:1 solution) was added t-butyl-2,8-diazaspiro[4.5]decane-2-carboxylate (700 mg, 2.91 mmol). The reaction mixture was heated at 85° C. for 6 hours and then diluted with EtOAc (10 mL). The organic layer was washed with NaHCO3 (1×5 mL) and brine (1×5 mL), dried over Na2SO4, and then concentrated. The crude residue was purified by reverse-phase flash chromatography (10-100% MeCN/H2O with 0.05% TFA) to give t-butyl 8-[5-(methoxycarbonyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate: MS (ESI+): cal'd [M+H]+ 376.2, obs'd 376.2. This intermediate was then treated with TFA (3 mL) in CH2Cl2 (6 mL). The reaction mixture was concentrated after 30 minutes of stirring at room temperature and the crude residue was purified by reverse-phase flash chromatography (10-75% MeCN/H2O with 0.05% TFA) to give the methyl 6-(2,8-diazaspiro[4.5]dec-8-yl)nicotinate: MS (ESI+): cal'd [M+H]+ 276.2, obs'd 276.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=[C:4]([C:9]2[C:10]3[CH:19]=[CH:18][N:17](S(C4C=CC(C)=CC=4)(=O)=O)[C:11]=3[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[C:35](OCC)(OCC)(OCC)[CH3:36]>>[CH:32]1([CH2:31][O:30][C:3]2[C:2]3[N:1]=[C:35]([CH3:36])[NH:8][C:7]=3[CH:6]=[CH:5][C:4]=2[C:9]2[C:10]3[CH:19]=[CH:18][NH:17][C:11]=3[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)[CH2:33][CH2:34]1
Reactant: CCOC(C)(OCC)OCC
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc(N)c(N)c4OCC4CC4)cn(C)c(=O)c32)cc1
Product: Cc1nc2c(OCC3CC3)c(-c3cn(C)c(=O)c4[nH]ccc34)ccc2[nH]1

Procedure:
This compound was synthesized according to the procedure of Example 2 using 4-[3,4-diamino-2-(cyclopropylmethoxy)phenyl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting material and triethyl orthoacetate instead of ethyl orthoformate. 1H NMR (300 MHz, DMSO-d6) δ 12.23 (s, 1H), 11.99 (s, 0.3H), 11.93 (s, 0.7H), 7.33-7.19 (m, 1.2H), 7.18-7.00 (m, 2.8H), 6.17-6.10 (m, 0.3H), 6.10-6.02 (m, 0.7H), 4.37 (d, J=6.8 Hz, 2H), 3.62-3.51 (m, 3H), 1.09-0.89 (m, 1H), 0.41-0.25 (m, 2H), 0.17-0.06 (m, 1.4H), −0.01-−0.12 (m, 0.6H); LCMS calculated for C20H21N4O2 (M+H)+: m/z=349.2. found: 349.1.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][C:12]([CH3:15])([O-:14])[CH3:13].[K+]>C1COCC1>[C:12]([O:14][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])([CH3:15])([CH3:13])[CH3:11]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cc(Br)ccc1C#N
Reaction time: 0.67 h
Yield: 98.4 %

Procedure:
To a solution of 2-fluoro-4-bromobenzonitrile (2.0 g, 10 mmol) in 10 mL of THF, cooled to −15° C., was added a solution of potassium t-butoxide (10 mL, 10 mmol) over 7 min. The cooling bath was removed, and the reaction stirred for another 40 min. The reaction was poured into ether/10% HCl, and the ether layer was separated. The ether layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated to give 2.5 g of 2-t-butoxy-4-bromobenzonitrile.