Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C:14]2[C:15]([CH3:27])([CH3:26])[C:16](=[O:25])[N:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:18]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:13])[CH3:3].[CH2:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([CH3:45])=[C:40]([CH:44]=1)[C:41](O)=[O:42])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([CH3:45])=[C:40]([C:41]([N:22]2[CH2:23][CH2:24][CH:19]([N:17]3[C:16](=[O:25])[C:15]([CH3:27])([CH3:26])[C:14]([C:7]4[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH3:13])=[C:5]([O:4][CH2:2][CH3:3])[CH:6]=4)=[N:18]3)[CH2:20][CH2:21]2)=[O:42])[CH:44]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OCC
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Agent: Cl
Product: CCOc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCc5ccccc5)ccc4C)CC3)C(=O)C2(C)C)cc1OCC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-diethoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B2) and 5-(benzyloxy)-2-methylbenzoic acid (compound F1) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by a second chromatography (silica gel and cyclohexane/EA=6:4) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][C@@H:13]1[CH2:18][O:17][CH2:16][CH2:15][NH:14]1.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][C@H:13]2[CH3:12])[N:3]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: C[C@@H]1COCCN1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Temperature: 80 °C
Yield: 31.2 %

Procedure:
A mixture of 2,6-dichloro-9H-purine (2.18 g, 11.53 mmol), (R)-3-methylmorpholine (1.40 g, 13.84 mmol) and DIPEA (2.57 mL, 14.99 mmol) in IMS (50 mL) were heated at 80° C. for 8 h. The reaction mixture was concentrated in vacuo to a reduced volume and the residue partitioned between EtOAc and H2O. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) affording the title compound as an off-white solid (914 mg, 31%). LCMS (method H): RT 2.53 min [M+H]+ 254.3
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])[N:8]=1.[CH:14](Cl)(Cl)Cl>O>[CH3:1][N:2]([CH2:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])[N:8]=1)[CH3:14]
Reactant: ClC(Cl)Cl
Reactant: CNCc1nc(CSCCN)cs1
Solvent: O
Product: CN(C)Cc1nc(CSCCN)cs1

Procedure:
Following the above procedure, 10.1 millimoles of 2-(methylaminomethyl)-4-thiazolemethanol dihydrochloride, 1.15 g. of cysteamine hydrochloride and 15 ml. of 48% aqueous hydrobromic acid were stirred at about 100° C. for about 7.5 hours. Water and hydrobromic acid were removed on a rotary evaporator and the resulting residue comprising 2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine trihydrobromide formed in the above reaction was dissolved in water and the water removed by evaporation. The residue was again taken up in water and the water removed by evaporation. The residue was then dissolved in a small volume of water and a solution of 5.5 g. of potassium carbonate in 15 ml. of water was added. The resulting alkaline solution was evaporated to dryness. The resulting residue, comprising the free base of 2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine, was slurried with ethanol and the ethanol separated and removed by evaporation. The residue was twice slurried with isopropanol. The residue was next extracted with boiling isopropanol several times and the combined isopropanol extracts combined and filtered. Removal of the isopropanol yielded a yellow oil. The yellow oil was dissolved in chloroform and the chloroform solution filtered. Chloroform was evaporated from the filtrate to yield 1.59 g. of a yellow oil comprising 2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine. The compound had the following physical characteristics:
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[CH3:14][O:15][C:16]([C:18]1[S:19][C:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH2:41][CH3:42])([C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([CH3:40])[CH:34]=3)[CH2:31][CH3:32])=[CH:26][C:25]=2[CH3:43])=[C:21]([CH3:23])[CH:22]=1)=[O:17].C(OCC)C>CN(C)C=O>[CH3:14][O:15][C:16]([C:18]1[S:19][C:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[C:35]([CH3:40])[CH:34]=3)([CH2:31][CH3:32])[CH2:41][CH3:42])=[CH:26][C:25]=2[CH3:43])=[C:21]([CH3:23])[CH:22]=1)=[O:17]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(-c2sc(C(=O)OC)cc2C)c(C)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1)c1ccc(-c2sc(C(=O)OC)cc2C)c(C)c1
Reaction time: 0.2 h
Yield: 88285 %

Procedure:
t-Butyldimethylsilyl chloride (36 mg, 0.238 mmol) and imidazole (40.5 mg, 0.595 mmol) were added to a solution of 5-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl}-4-methyl-thiophene-2-carboxylic acid methyl ester (Example 20-(1); 50.3 mg, 0.119 mmol) in N,N-dimethylformamide (0.2 mL) at room temperature, and the mixture was stirred at the same temperature for 0.2 hour. Diethyl ether was added to the reaction solution. The organic layer was washed with distilled water and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=95/5 to ethyl acetate only) to give the title compound (56.4 g, 88.3%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[CH3:8]>C(Cl)Cl.O=[Mn]=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ncc(CO)cc1Br
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1ncc(C=O)cc1Br
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of (5-bromo-6-methyl-3-pyridinyl)methanol (56 mg, 0.277 mmol) in DCM (2 ml), MnO2 (193 mg, 2.217 mmol) was added. After stirring overnight, an excess of MnO2 (120 mg, 1.386 mmol) was added and then the mixture was stirred for 3 h more. The reaction mixture was filtrated and evaporated to afford 30 mg of title compound pure enough to be used in the next step.
Reaction SMILES: C=CCOC(C1C2C(=CC=CC=2)N=CC=1)C1[N+]2(CC3C4C(=CC=CC=4)C=C4C=3C=CC=C4)CC(C=C)C(CC2)C1.[Br-].[F-].[K+].[N+:44]([CH2:47][CH2:48][CH2:49][CH:50]=[CH2:51])([O-:46])=[O:45].[CH2:52]([N:59]([CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[C@@H:60]([CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[CH:61]=[O:62])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C1COCC1>[CH2:70]([N:59]([CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[C@H:60]([C@H:61]([OH:62])[CH:47]([N+:44]([O-:46])=[O:45])[CH2:48][CH2:49][CH:50]=[CH2:51])[CH2:63][C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)[C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1
Reactant: C=CCCC[N+](=O)[O-]
Reactant: O=C[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: C=CCOC(c1ccnc2ccccc12)C1CC2CC[N+]1(Cc1c3ccccc3cc3ccccc13)CC2C=C
Agent: [Br-]
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCCC([C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)[N+](=O)[O-]
Temperature: -10 °C

Procedure:
Cool to −10° C. a well stirred mixture of O-allyl-N-(9-anthracenylmethyl)-cinchonidinium bromide (0.480 g, 0.8 mmol), potassium fluoride (3 gr, 51 mmol), THF (150 mL) and 5-nitropent-1-ene (2.34 g, 20 mmol) and treat with a solution of (S)-2-dibenzylamino-3-phenylpropionaldehyde (2.640 gr, 8 mmol). Allow mixture to warn to room temperature and stir for two days. Concentrate under reduced pressure. Purify on silica gel with hexane/ethyl ether mixtures to give a mixture of two products (2.7 g, 75%).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[NH2:25][C@@H:26]([CH2:31][OH:32])[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>COCCO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:25][C@@H:26]([CH2:31][OH:32])[CH2:27][C:28]([OH:30])=[O:29])=[O:22])[N:4]=1)#[N:2]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: N[C@@H](CO)CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)N[C@@H](CO)CC(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (30 mg, 0.09 mmol), (R)-3-amino-4-hydroxybutanoic acid (67 mg, 0.56 mmol, PepTech) and sodium methoxide (28 mg, 0.53 mmol) were suspended in 2-methoxyethanol (3 mL). The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (15 mL) and EtOAc (15 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/CH2Cl2 with 0.5% formic acid) to give the title compound in 12 mg. MS: (−) m/z 405.97 (M−1).
Reaction SMILES: C(Cl)CCl.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[N:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=O)=[CH:9][CH:8]=1.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]1[CH2:34][NH:35][CH3:36].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]2[N:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([N:35]([CH3:36])[CH2:34][C:26]2[N:25]([CH3:24])[C:33]3[C:28]([CH:27]=2)=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:19])=[CH:11][CH:12]=1
Reactant: COc1ccc(CCc2ncccc2C(=O)O)cc1
Reactant: CNCc1cc2ccccc2n1C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: COc1ccc(CCc2ncccc2C(=O)N(C)Cc2cc3ccccc3n2C)cc1
Reaction time: 8 h
Yield: 90.2 %

Procedure:
EDC (0.60 g, 3.16 mmole) was added to a solution of 2-[2-(4-methoxyphenyl)ethyl]nicotinic acid (0.81 g, 3.16 mmole), 1-methyl-2-(methylaminomethyl)indole (0.50 g, 2.87 mmole), HOBt.H2O (0.43 g, 3.16 mmole), and diisopropylethylamine (0.55 mL, 3.16 mmole) in DMF (15 mL) at RT. The reaction was stirred overnight, then was diluted with H2O and extracted with EtOAc. Drying (Na2SO4), concentration, and flash chromatography on silica gel (5% MeOH/CHCl3) gave the title compound (1.07 g, 90%) as a viscous yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 8.63 (m, 1H), 7.22-7.61 (m, 8H), 6.97 (d, J=8.1 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 6.52 (s, 1H), 3.80 (s, 3H), 3.78 (m, 2H), 3.72 (s, 2H), 3.16 (m, 2H), 3.03 (s, 3H), 2.57 (s, 3H), MS (ES) m/e 414 (M+H)+. Anal. Calcd for C26H27N3O2: C, 75.52; H, 6.58: N, 10.16. Found C, 75.84; H, 6.68; N, 9.76.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:12]([O:14]C)=[O:13])([CH3:4])([CH3:3])[CH3:2].C(O)(C)(C)C>O>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:12]([OH:14])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(Cl)c(OCC(=O)OC(C)(C)C)c1
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)COc1cc(C(=O)O)ccc1Cl
Yield: 89.9 %

Procedure:
Methyl 3-(2-tert-butoxy-2-oxoethoxy)-4-chlorobenzoate (0.7 g) in 9:1 tert butanol:water was subjected to Antarctica B lipase for 6 d. Filtration and evaporation of the solvent yielded the subtitle compound as an off-white solid (0.6 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:16])[CH:8]([C:11]([O:13]CC)=O)[C:9]#[N:10].[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1>C1(C)C(C)=CC=CC=1>[O:16]=[C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)[CH:8]([C:11](=[O:13])[NH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:9]#[N:10]
Reactant: Nc1cccnc1
Reactant: CCOC(=O)C(C#N)C(=O)c1cccn1C
Solvent: Cc1ccccc1C
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1cccnc1
Temperature: 25 °C

Procedure:
The mixture of 1.1 g of 1-methyl-β-oxo-α-ethoxycarbonyl-2-pyrrolepropionitrile (U.S. Pat. No. 4,256,759), 1.2 g of 3-aminopyridine and 60 ml of xylene, is refluxed for 41/2 hours. After standing and cooling to room temperature overnight, the solution is filtered, evaporated and the residue is purified to yield β-oxo-α-(3-pyridylcarbamoyl)-β-(1-methyl-2-pyrrolyl)propionitrile.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:25])=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[CH:18]=2)[C:5]([CH3:16])=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13].CO.[BH4-].[Na+].Cl>O1CCCC1>[F:1][C:2]1[C:3]([CH3:25])=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][OH:24])[CH:18]=2)[C:5]([CH3:16])=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: Cc1cc(OCCCS(C)(=O)=O)c(F)c(C)c1-c1cccc(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCCCS(C)(=O)=O)c(F)c(C)c1-c1cccc(CO)c1
Reaction time: 8 h
Yield: 93.8 %

Procedure:
A solution of 3′-fluoro-2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-carbaldehyde (2.77 g, 8.00 mmol) in a mixed solvent of methanol (10 mL) and tetrahydrofuran (20 mL) was ice-cooled, sodium borohydride (90%, 0.336 g, 8.00 mmol) was added, and the mixture was stirred for 8 hr under nitrogen atmosphere. The reaction mixture was treated with diluted hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=40:60-80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (2.75 g, yield 94%) as colorless crystals.
Reaction SMILES: [CH:1]12[N:8]([C:9]3[CH:14]=[C:13]([CH2:15][N:16]([CH3:18])[CH3:17])[N:12]=[C:11]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH3:29])=[O:27])=[CH:21][CH:20]=4)[N:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.[CH3:30]N=C=O>>[CH:5]12[N:8]([C:9]3[CH:14]=[C:13]([CH2:15][N:16]([CH3:18])[CH3:17])[N:12]=[C:11]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:23][CH:24]=4)[N:10]=3)[CH:1]([CH2:7][CH2:6]1)[CH2:2][O:3][CH2:4]2
Reactant: CNC(=O)Nc1ccc(-c2nc(CN(C)C)cc(N3C4CCC3COC4)n2)cc1
Reactant: CN=C=O
Product: CCNC(=O)Nc1ccc(-c2nc(CN(C)C)cc(N3C4CCC3COC4)n2)cc1
Yield: 21 %

Procedure:
A procedure similar to that used for the preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-methylurea was used, substituting ethylisocyanate for methylisocyanate, to provide the mono-TFA salt of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-ethylurea (0.014 g, 21%) as a white solid. MS: 411.4, M+H.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:27]=[O:28].C(Cl)Cl>O1CCCC1.CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:5]2[N:10]=[C:9]([CH:27]=[O:28])[S:8][C:6]=2[N:7]=1
Reactant: CN(C)C=O
Reactant: Clc1nc(N2CCOCC2)c2ncsc2n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
5-Chloro-7-morpholinothiazolo[5,4-d]pyrimidine was slurried in tetrahydrofuran and cooled to −78° C. under nitrogen. Two equivalents of 2M lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene was added slowly and the solution was stirred for 30 minutes. dimethylformamide (6 eq) was added and the solution was stirred at −78° C. for an additional one hour. The solution was warmed to 0° C. and ice cold 0.1N hydrochloric acid was added and the solution was warmed to room temperature before extraction with methylene chloride. The organic layer was dried with sodium sulfate and concentrated to give 5-chloro-7-morpholinothiazolo[5,4-d]pyrimidine-2-carbaldehyde.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:10]=3[O:11][CH2:12][CH2:13][OH:14])[N:7]=[N:6][N:5]=2)[CH2:3][CH2:2]1>[Pd].CO>[NH2:19][C:17]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][OH:14])=[C:9]([N:8]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[N:5][N:6]=[N:7]2)[CH:18]=1
Reactant: O=[N+]([O-])c1ccc(OCCO)c(-n2nnnc2C2CC2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OCCO)c(-n2nnnc2C2CC2)c1
Yield: 85.5 %

Procedure:
Similarly, 2-(2-(5-cyclopropyl-1H-tetrazol-1-yl)-4-nitrophenoxy)ethan-1-ol (82 mg, 0.3 mmol), palladium on charcoal (16 mg) and MeOH (7 mL) was hydrogenated to give 2-(4-amino-2-(5-cyclopropyl-1H-tetrazol-1-yl)phenoxy)ethan-1-ol (67 mg, 91%) after workup.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])P(OC)(OC)=O.C1CCN2C(=NCCC2)CC1.[CH3:34][O:35][C:36]1[N:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[N:42]=[CH:41][CH:40]=[C:39]2[CH:46]=O.CC(=O)OCC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])/[C:4](/[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[CH:46]/[C:39]1[C:38]2[C:43](=[CH:44][CH:45]=[C:36]([O:35][CH3:34])[N:37]=2)[N:42]=[CH:41][CH:40]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: COc1ccc2nccc(C=O)c2n1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: COC(=O)/C(=C/c1ccnc2ccc(OC)nc12)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
A solution of benzyloxycarbonylamino-(dimethoxy-phosphoryl)-acetic acid methyl ester (2.07 g, 6.25 mmol) in DCM (10 mL) was cooled to 0° C. and DBU (0.95 g, 6.25 mmol) was added dropwise. The mixture was stirred at 0° C. for 15 min and then added via syringe dropwise to a suspension of 6-methoxy-[1,5]naphthyridine-4-carbaldehyde (0.94 g, 5 mmol) in DCM (15 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, diluted with DCM, washed with water, dried over MgSO4 and concentrated. Chromatography on SiO2 (Hex/EA 1:1) gave the product (25:1 Z/E mixture) as a colourless foam (1.92 g, 98% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[NH:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([C:20]([OH:22])=O)[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:34]=[CH:33][C:28]2[NH:29][C:30](=[O:32])[O:31][C:27]=2[CH:26]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[O:32]=[C:30]1[NH:29][C:28]2[CH:33]=[CH:34][C:25]([NH:24][C:20]([C:18]3[CH:17]=[CH:16][C:14]4[N:15]=[C:11]([NH:10][C:9]([NH:8][C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)=[O:23])[S:12][C:13]=4[CH:19]=3)=[O:22])=[CH:26][C:27]=2[O:31]1
Reactant: O=C(Nc1ccc(Cl)cc1)Nc1nc2ccc(C(=O)O)cc2s1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)Nc1nc2ccc(C(=O)Nc3ccc4[nH]c(=O)oc4c3)cc2s1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
Starting material 35 (300 mg, 45% content, 0.4 mmol) and 6-Amino-3H-benzooxazol-2-one (30, 58 mg, 0.4 mmol) were dissolved in 2 ml of dry DMF. Then EDCI (96 mg, 0.5 mmol) and HOBt (76 mg, 0.5 mmol) were added. The reaction was stirred at ambient temperature over night. It was then purred into water and the resulting precipitate was filtered. The isolated precipitate was then stirred in 100 ml warm methanol and the non-soluble crystals filtered and washed with methanol. Thereby the desired product 36 (130 mg, 0.271 mmol, 70%) could be isolated.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])[CH:5]=[CH:4][CH:3]=1.[CH3:25]OC1C=C(C2OC3C=CC=CC=3N=2)C=CC=1B1OC(C)(C)C(C)(C)O1.BrC1C=C(C)C=CN=1>>[CH3:24][O:23][C:9]1[CH:10]=[C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[C:4]([CH3:25])[CH:3]=[CH:2][N:7]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccc(Br)n1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccnc(Br)c1
Product: COc1cc(-c2nc3ccccc3o2)ccc1-c1cc(C)ccn1

Procedure:
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazole (150 mg, 0.43 mmol) was reacted with 2-bromo-4-methylpyridine (47 μL, 0.43 mmol) to afford the desired 2-[3-methoxy-4-(4-methylpyridin-2-yl)phenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.57 (s, 1H), 7.97–7.96 (m, 2H), 7.89 (s, 1H), 7.82–7.79 (m, 2H), 7.63–7.54 (m, 2H), 7.39–7.36 (m, 2H), 4.01 (s, 3H), 2.39 (s, 3H). MS (ESI) 317 (M+H)+.
Reaction SMILES: [CH:1]1([S:4]([NH:7][CH:8]2[CH2:12][CH:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]([CH2:18][CH3:19])[CH2:9]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[F:28]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O.[NH4+].[Cl-]>C1COCC1>[CH:1]1([S:4]([NH:7][CH:8]2[CH2:12][C:11]([F:28])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]([CH2:18][CH3:19])[CH2:9]2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)C1CC(NS(=O)(=O)C2CC2)CC1CC
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(F)CC(NS(=O)(=O)C2CC2)CC1CC
Temperature: -78 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
A solution of ethyl 4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylate (0.630 g, 2.18 mmol, prepared using K from Preparation #Y.1 and cyclopropanesulfonyl chloride) in THF (14.5 mL) was cooled to about −78° C. and then LDA (1.8 M in THF/hexane, 3.63 mL, 6.53 mmol) was added dropwise to the reaction mixture over about 30 min. The reaction mixture was stirred at about −78° C. for about 50 min before a solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (2.06 g, 6.53 mmol) in THF (7.3 mL) was added dropwise over about 30 min. The reaction mixture was stirred at about −78° C. for about 1 h and then was warmed to ambient temperature and stirred for about 16 h. Saturated aqueous NH4Cl (100 mL) was added. The reaction mixture was partitioned with EtOAc (50 mL). The aqueous layer was further extracted with EtOAc (2×50 mL). The combined organic layers were concd under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-60% EtOAc in heptane to yield ethyl 4-(cyclopropanesulfonamido)-2-ethyl-1-fluorocyclopentanecarboxylate (0.41 g, 46%) as clear oil: LC/MS (Table 1, Method b) Rt=2.12 min; MS m/z: 306 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14](Br)[C:13]([C:17]#[N:18])=[N:12]2)=[CH:7][CH:6]=1)[CH3:2].[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=2[O:21]1.C(=O)([O-])[O-].[Na+].[Na+].Cl>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O.O>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:25]3[CH:24]=[CH:23][C:22]4[O:21][CH2:20][O:28][C:27]=4[CH:26]=3)[C:13]([C:17]#[N:18])=[N:12]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(Br)c(C#N)n2)cc1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2cc(-c3ccc4c(c3)OCO4)c(C#N)n2)cc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 26.1 %

Procedure:
A suspension of 4-(4-bromo-3-cyanopyrazole-1-yl)benzoic acid ethyl ester (0.17 g), (3,4-methylenedioxyphenyl)boronic acid (0.11 g), tetrakis(triphenylphosphine) palladium (0.12 g) and sodium carbonate (0.17 g) in a mixed solvent of water (0.5 mL) and N,N-dimethylformamide (5 mL) was stirred at 70° C. for 12 hours. To this reaction mixture was added dilute hydrochloric acid, and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (eluent: ethyl acetate/n-hexane=1/5) to give the title compound (0.05 g).