Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1NC2C=CC=CC=2S[C@H](C2C=CC=CC=2)[C@@H]1NC(=O)[C@H](C)NC(=O)CC1C=CC=CC=1.Br.[NH2:35][C@H:36]1[C:42](=[O:43])[NH:41][C:40]2[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=2[S:38][C@H:37]1[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[F:54][C:55]1[CH:56]=[C:57]([CH2:62][C:63]([NH:65][C@H:66]([C:70](O)=[O:71])[CH:67]([CH3:69])[CH3:68])=[O:64])[CH:58]=[C:59]([F:61])[CH:60]=1>>[F:54][C:55]1[CH:56]=[C:57]([CH2:62][C:63]([NH:65][C@H:66]([C:70]([NH:35][C@@H:36]2[C:42](=[O:43])[NH:41][C:40]3[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=3[S:38][C@@H:37]2[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:71])[CH:67]([CH3:68])[CH3:69])=[O:64])[CH:58]=[C:59]([F:61])[CH:60]=1
Reactant: N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1ccccc1
Reactant: CC(C)[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Br
Agent: C[C@H](NC(=O)Cc1ccccc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1
Product: CC(C)[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1

Procedure:
A method similar to the one described for (97) was used except that (2,3-cis)-3-amino-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrobromide (9d) (105 mg) was used as the amine component and N-[(3,5-difluorophenyl)acetyl]-L-valine (81 mg) 107b was used as the acid component to afford the title compound in 1:1 mixture with the (2S,3S) diastereomer (91 mg), white solid, m.p. 110-115° C. 1H NMR (300 MHz, d6-DMSO) δ 4.76 (t, 1H, J=7 Hz), 5.12(d, 1H, J=7 Hz), 6.91-7.49 (m, 12H), 7.67 (d, 1H, J=7 Hz), 8.25 (s, 1H),10.49 (s, 1H). MS APCI, m/z=524(M+1). LC/MS: 2.54 min.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)([CH3:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.B(F)(F)F.[CH3:16][CH2:17][O:18]CC.[OH-].[Na+].C(#[N:25])C>>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:25][C:17](=[O:18])[CH3:16])([CH3:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: CC(C)(O)c1cccc(Br)n1
Reactant: CC#N
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)NC(C)(C)c1cccc(Br)n1
Temperature: 25 °C
Yield: 26 %

Procedure:
Dissolve 2-(6-bromo-pyridin-2-yl)-propan-2-ol (10.6 g, 50 mmol) in acetonitrile (40 mL). Add BF3-Et2O (20 mL, 125 mmol) and reflux for 3 days. Cool to room temperature, add ice and neutralize the reaction with 5N NaOH and extract with dichloromethane. Purify over silica (120 g) eluting with 0 to 100% EtOAc:hexanes to give N-[1-(6-bromo-pyridin-2-yl)-1-methyl-ethyl]-acetamide (3.3 g, 26%), MS (m/z): 257 and 259 (M+H)+ and recovered 2-(6-bromo-pyridin-2-yl)-propan-2-ol (3.7 g, 34%).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH:67]([C:69]1[CH:70]=[C:71]([CH:81]=[CH:82][CH:83]=1)[CH2:72][NH:73][C:74](=[O:80])[O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=O>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:67]([C:69]3[CH:70]=[C:71]([CH:81]=[CH:82][CH:83]=3)[CH2:72][NH:73][C:74](=[O:80])[O:75][C:76]([CH3:79])([CH3:77])[CH3:78])[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C=O)c1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)c1
Reaction time: 18 h
Yield: 73.3 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (200 mg, 0.51 mmol), DMF (0.45 mL), ethanol (2.55 mL), 1M Na2S2O4 (3 eq, 1.53 mmol, 1.53 mL) and tert-butyl N-(3-formylbenzyl)carbamate (1.1 eq, 0.21 mmol, 132 mg). After 18 h, concentration in vacuo and column chromatography (CH2Cl2-MeOH, 95:5) gave the product (89 mg, 30%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.38 (s, 9H, C(CH3)3), 2.62 (s, br, 4H, piperazine N(CH2)2), 3.61 (s, 2H, NCH2Ar), 3.66 (s, br, 4H, piperazine N(CH2)2), 4.22 (d, J=6.0 Hz, 2H, CH2NH—BOC), 7.36 (d, J=7.7 Hz, 1H, phenyl H-4 or H-6), 7.39 (dd, J=7.7, 2.7 Hz, 1H, pyridine H-5), 7.45 (t, br, J=5.7 Hz, 1H, NH—BOC), 7.48 (t, J=7.7 Hz, 1H, phenyl H-5), 7.78 (d, J=7.6 Hz, 1H, pyridine H-4), 8.01 (d, J=7.7 Hz, 1H, phenyl H-4 or H-6), 8.10 (s, br, 1H, phenyl H-2), 8.25 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.50 (d, br, J=3.5 Hz, 1H, pyridine H-6), 8.57 (s, br, 1H, pyridine H-2), 13.52 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [C:1]1([CH:7]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:11][CH:10]3[C:8]2([C:23]([OH:25])=O)[CH2:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:28])=O>CN(C=O)C.C1(C)C=CC=CC=1>[C:1]1([CH:7]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:11][CH:10]3[C:8]2([C:23]([Cl:28])=[O:25])[CH2:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC3CC3(C(=O)O)C2c2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CC3CC3(C(=O)Cl)C2c2ccccc2)cc1
Temperature: 25 °C
Yield: 101.4 %

Procedure:
To a stirring solution of racemic 2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid (1.5 g, 4.2 mmol) (Intermediate 2) and one drop DMF in 10 mL of toluene at 0° C. was added thionyl chloride (8.6 mL, 11.8 mmol). The reaction was allowed to warm to room temperature and then heated to 73° C. for 2.5 hours. The solvent and excess thionyl chloride were evaporated at reduced pressure to leave 2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hexane-1-carbonyl chloride (1.6 g, 100% crude yield).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:25]=[O:26])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[BH4-].[Na+].C(O)(=O)C>CO>[CH3:1][C:2]1[NH:3][C:4]([CH2:25][OH:26])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)NC(CO)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Yield: 21.3 %

Procedure:
A solution of dimethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (3.60 g) in methanol (72 ml) was cooled at 0° C., and sodium borohydride (0.2271 g) was added bit by bit thereto under cooling with stirring. The mixture was stirred at the same temperature for 15 minutes. The reaction mixture was adjusted to about pH 6 with 50% acetic acid and the methanol was distilled off under reduced pressure below 30° C. The residual solution was diluted with water (100 ml) and extracted with ethyl acetate. The extract was washed with water, an aqueous sodium bicarbonate solution and water in turn, dried over magnesium sulfate and then evaporated to dryness. The residual oil (3.70 g) was crystallized by triturating with diisopropyl ether to give crude crystals (2.74 g), which were recrystallized in first from methanol (8 ml) and then from ethyl acetate (10 ml) to give pure crystals of dimethyl 2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (770 mg), mp 164.5 to 165° C. The whole mother liquor of above recrystallizations were combined together and concentrated. The crystalline residue was collected by filtration and washed with methanol (5 ml) to give additional crystals (1.72 g), which were recrystallized from ethyl acetate to give additional pure specimen of the same product obtained above, (840 mg) m.p. 164.5° to 165° C. Total yield, 1.61 g.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:18]([OH:20])=[O:19])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]2([CH3:17])[CH3:16])([CH3:3])[CH3:2].[CH2:21]([O:28][C:29](=[O:39])[CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1.CCCCCC>[CH2:21]([O:28][C:29]([CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][C:35]([O:19][C:18]([C:6]2[CH:7]=[C:8]3[C:13](=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]3([CH3:17])[CH3:16])=[O:20])=[CH:34][CH:33]=1)=[O:39])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(C=Cc1ccc(O)cc1)OCc1ccccc1
Reactant: CC(C)c1cc(C(=O)O)cc2c1OC(C)(C)CC2(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)c1cc(C(=O)Oc2ccc(C=CC(=O)OCc3ccccc3)cc2)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
A solution of 8-isopropyl-2,2,4,4-tetramethyl-chroman-6-carboxylic acid (Intermediate 34, 0.05 g, 0.18 mmol) and 3-(4-hydroxy-phenyl)-acrylic acid benzyl ester (described in Journal of Natural Products, 1990, 53 (4), p 821–824, Bankova V., 0.046 g, 0.18 mmol) in anhydrous dichloromethane (5 mL) was treated with 4-(dimethylamino)pyridine (0.052 g, 0.27 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.044 g, 0.36 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then subjected to flash column chromatography using 20% ethyl acetate in hexane as the eluent to afford the title compound as a white solid (0.076 g, 83%).
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[CH3:20][NH2:21].CO>C(Cl)(Cl)Cl>[CH3:20][NH:21][C:4]([C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=1[C:1]([NH:5][CH2:6][S:7][C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1)=[O:19])=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1CSc1ccncc1
Reactant: CN
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNC(=O)c1ccccc1C(=O)NCSc1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.1 %

Procedure:
To a solution of 6.76 g (25.0 mmol) of 4-phthalimidomethylthiopyridine in 100 ml of chloroform, 5 ml of 40% methylamine-methanol solution was added, and the mixture was stirred at room temperature for 3 hours. Additional 5 ml of 40% methylamine-methanol solution was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10), and the resulting crude product-was crystallized from methylene chloride-diethylether to give 2.645 g of the desired compound (35.1% yield, yellow crystals), mp. 118°-121° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][CH2:14][C:15](O)=[O:16])[CH:12]=2)=[CH:4][C:3]=1[C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C>CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][CH2:14][C:15]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:16])[CH:12]=2)=[CH:4][C:3]=1[C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1
Reactant: C1CCNC1
Reactant: Nc1ncc(-c2cnn(CCC(=O)O)c2)cc1-c1nc2ccccc2s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ncc(-c2cnn(CCC(=O)N3CCCC3)c2)cc1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-[4-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-pyrazol-1-yl]-propionic acid (7.0 mg, 0.013 mmol), pyrrolidine (9 mg, 0.1 mmol), TBTU (8.24 mg, 0.0257 mmol), DIPEA (0.02 mL, 0.1 mmol), and DMF (2 mL, 0.02 mol) was stirred at rt for 10 min. The solution was transferred to a separatory funnel, diluted with EtOAc and washed 3× with water. The organic layer was concentrated in vacuo and loaded onto a prep TLC plate, eluting with 5% MeOH/DCM. The band containing the pure product was filtered off using 1:1 MeOH/DCM, and the filtrate was concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=1.85 (q, J=6.4 Hz, 2H), 1.88-1.96 (m, 2H), 2.92 (t, J=6.6 Hz, 2H), 3.39 (q, J=7.1 Hz, 4H), 4.49 (t, J=6.6 Hz, 2H), 7.39-7.44 (m, 1H), 7.47-7.52 (m, 1H), 7.81 (s, 1H), 7.94-7.97 (m, 2H), 8.00 (d, J=7.8 Hz, 1H), 8.12 (d, J=2.3 Hz, 1H), 8.27 (d, J=2.3 Hz, 1H). MS (ES+): m/z=419.13 (100) [MH+]. HPLC: tR=2.99 min (ZQ3, polar—5 min).
Reaction SMILES: B.[C:2]1([CH:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])C(O)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O:22]1CCC[CH2:23]1>O>[C:2]1([CH2:8][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:23][OH:22])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCC(C(=O)O)c1ccccc1
Reactant: C1CCOC1
Agent: B
Agent: Cl
Solvent: O
Product: OCCCCCCCCCCCc1ccccc1
Reaction time: 5.5 h

Procedure:
To 200 ml. of 1 M borane in tetrahydrofuran, cooled in an ice bath under nitrogen, is added dropwise over 35 minutes, a solution of 52.5 g. of phenylundecanoic acid in 150 ml. of tetrahydrofuran. The solution is allowed to stand at room temperature for 5.5 hours and poured onto ice. To the mixture is added 8 ml. of concentrated hydrochloric acid and the mixture is diluted with water to 2.2 liters. The mixture is extracted with ether (ca 500 ml.) and the extracts dried over magnesium sulfate. Concentration in vacuo gives a colorless oil.
Reaction SMILES: C([Zn][CH2:4][CH3:5])C.FC(F)(F)C(O)=O.ICI.[C:16]12([CH2:26][O:27][C:28]3[C:40](/[CH:41]=[CH:42]/C)=[CH:39][C:31]([C:32]([O:34]C(C)(C)C)=[O:33])=[C:30]([F:44])[CH:29]=3)[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.Cl>ClCCl>[C:16]12([CH2:26][O:27][C:28]3[C:40]([C@@H:41]4[CH2:42][C@H:4]4[CH3:5])=[CH:39][C:31]([C:32]([OH:34])=[O:33])=[C:30]([F:44])[CH:29]=3)[CH2:23][CH:22]3[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]3)[CH2:17]1)[CH2:25]2
Reactant: C/C=C/c1cc(C(=O)OC(C)(C)C)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Reactant: CC[Zn]CC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ICI
Product: C[C@@H]1C[C@H]1c1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 10.7 %

Procedure:
To a mixture of diethylzinc (1.0 M solution in heptane, 6.75 mL, 6.75 mmol) in anhydrous dichloromethane (2 mL) was added a solution of trifluoroacetic acid (0.52 mL, 6.80 mmol) in anhydrous dichloromethane (3 mL) at 0° C. and the reaction mixture was stirred for 10 minutes at 0° C. A solution of diiodomethane (0.54 mL, 6.75 mmol) in dichloromethane (2 mL) was added to the reaction mixture at 0° C. and stirring was continued for 10 minutes at 0° C. To the reaction mixture was then added a solution of tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-prop-1-en-1-yl)benzoate (0.90 g, 2.25 mmol) in anhydrous dichloromethane (3 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 4 hours. After addition of 1 N hydrochloric acid (10 mL), the mixture was diluted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate gave a residue which was purified by reverse-phase preparative HPLC to afford the title compound as an off-white solid (0.086 g, 11%): MS (ES−) m/z 357.3 (M−1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]2[S:16][C:15]([CH3:17])=[N:14][C:13]=2[CH3:18])[C:3]=1[CH3:19].C1C=C(Cl)C=C(C(OO)=[O:28])C=1.[OH-:31].[Na+]>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([S:8]([CH3:9])(=[O:28])=[O:31])[N:5]=[C:4]([NH:10][CH2:11][C:12]2[S:16][C:15]([CH3:17])=[N:14][C:13]=2[CH3:18])[C:3]=1[CH3:19]
Reactant: CSc1nc(Cl)c(C)c(NCc2sc(C)nc2C)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(C)c(CNc2nc(S(C)(=O)=O)nc(Cl)c2C)s1
Reaction time: 1 h
Yield: 87 %

Procedure:
6-chloro-N-[(2,4-dimethylthiazol-5-yl)methyl]-5-methyl-2-methylsulfanyl-pyrimidin-4-amine F4 (1.36 g, 4.32 mmol) was placed in a 250 mL flask and diluted with dichloromethane (100 mL). To the resultant slurry was added mCPBA (1.49 g, 8.64 mmol), and the solution was stirred for 1 hr. 1 N aqueous NaOH (100 mL) was then added, and the organic layer was separated and concentrated in vacuo to give 1.3 g (87%) of F5 as a white foam. MS (Electrospray): m/z 347.8 (MH+).
Reaction SMILES: [CH2:1]([C@@H:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C@@H:4]([CH3:8])[C:5](O)=[O:6])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[CH3:24][NH:25][CH3:26].C(N(CC)CC)C.Cl>ClCCl>[CH2:1]([C@@H:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C@@H:4]([CH3:8])[C:5]([N:25]([CH3:26])[CH3:24])=[O:6])[CH3:2]
Reactant: CNC
Reactant: CC[C@@H](c1cccc(OC)c1)[C@@H](C)C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](c1cccc(OC)c1)[C@@H](C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
The product of Example 14 (2.2 g, 10 mmol) was dissolved in dichloromethane (10 ml), oxalyl chloride (2.6 ml, 30 mmol) was added dropwise, and the reaction was carried out at room temperature for 1 hr, then the reaction solution was concentrated to give a pale yellow oil which was thereafter dissolved in dichloromethane, and then the resulted solution was added dropwise to an ice bath cooled solution of dimethylamine hydrochloride (1.6 g, 20 mmol) and triethylamine (4.3 ml, 30 mmol) in dichloromethane. Then it was slowly warmed to room temperature to make the reaction carry out for 1 hour. The pH was adjusted to about 7 with 1N hydrochloric acid, then the reaction solution was extracted with dichloromethane, and the organic phases were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate concentrated, and recrystallized with petroleum ether and ethyl acetate to give a white solid 2.3 g, yield: 92%. 1HNMR (300 MHz, CDCl3): δ 7.2 (1H, t, J=7.9, 15.6), 6.6-6.8 (3H, m), 3.7 (3H, s), 2.8-2.9 (1H, m), 2.7-2.8 (1H, m), 2.6 (3H, s), 2.5 (3H, s), 1.7-1.8 (1H, m), 1.4-1.6 (1H, m), 1.1 (3H, d, J=6.2), 0.8 (3H, t, J=6.8, 14.3). ESI-MS: 250.4 (M+H).
Reaction SMILES: OC(C(F)(F)F)=O.Br[C:9]1[CH:10]=[C:11]2[C:18]3([O:22][N:21]([CH3:23])[C:20]([NH2:24])=[N:19]3)[CH2:17][CH:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:15][C:12]2=[CH:13][CH:14]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][N:21]1[C:20]([NH2:24])=[N:19][C:18]2([C:11]3[C:12](=[CH:13][CH:14]=[C:9]([C:33]4[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=4)[CH:10]=3)[O:15][CH:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17]2)[O:22]1
Reactant: OB(O)c1cccnc1
Reactant: CN1OC2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: CN1OC2(CC(c3ccccc3)Oc3ccc(-c4cccnc4)cc32)N=C1N
Temperature: 100 °C
Yield: 35.1 %

Procedure:
To a solution of 6-bromo-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine TFA salt (65 mg, 0.13 mmol), 3-pyridineboronic acid (64 mg, 0.52 mmol) and Cs2CO3 (127 mg, 0.39 mmol) in 1,4-dioxane (3 mL) and H2O (0.5 mL) in a 10 mL CEM microwave test tube was added PdCl2(PPh3)2 (10 mg). After degassing by purging with N2, the mixture was heated to 100° C. for 5 min in a CEM microwave reactor. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 2′-methyl-2-phenyl-6-(pyridin-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (17 mg) as a TFA salt. MS ESI +ve m/z 393 (M+H)+. 1H-NMR (400 MHz, CD3OD): 9.19 (br s, 1H), 8.87 (d, J=7.6 Hz, 1H), 8.78 (br s, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.11 (t, J=6.4 Hz, 1H), 7.91 (dd, J=8.8, 2.4 Hz, 1H), 7.54-7.38 (m, 5H), 7.21 (d, J=8.8 Hz, 1H), 5.37 (d, 12.8 Hz, 1H), 3.43 (s, 3H), 2.88 (dd, J=14.4, 2.0 Hz, 1H), 2.42 (dd, J=14.4, 12.8 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][C:4]=1[CH3:12].Br[C:14]1[CH:19]=[C:18]([CH2:20][O:21][CH2:22][CH3:23])[CH:17]=[C:16]([Br:24])[CH:15]=1.C([Li])CCC>>[Br:24][C:16]1[CH:15]=[C:14]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:12])[CH:5]=2)([OH:11])[CH3:10])[CH:19]=[C:18]([CH2:20][O:21][CH2:22][CH3:23])[CH:17]=1
Reactant: CCOCc1cc(Br)cc(Br)c1
Reactant: COc1ccc(C(C)=O)cc1C
Agent: [Li]CCCC
Product: CCOCc1cc(Br)cc(C(C)(O)c2ccc(OC)c(C)c2)c1

Procedure:
In an analogous reaction sequence to that described for Building Block C, the treatment of 1-(4-methoxy-3-methyl-phenyl)-ethanone with 1,3-dibromo-5-ethoxymethyl-benzene beforehand reacted with n-butyllithium, yielded the (RS)-1-(3-bromo-5-ethoxymethyl-phenyl)-1-(4-methoxy-3-methyl-phenyl)-ethanol which was used as crude material in the following elimination reaction with a catalytic amount of p-toluenesulfonic acid to yield the title compound (yield: 86% of theory) as a colourless oil. Mass (calculated) C19H21BrO2 [360]; (found) [M+H]+=361, 363.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[N:10]=[C:11]([NH:14][C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=3)[O:26][CH2:27][C:28]([OH:30])=O)=[CH:19][CH:18]=[CH:17][N:16]=2)[S:12][CH:13]=1.C(N(CC)CC)C.[Cl:41]C(OCC)=O.Cl.[NH2:48][CH2:49][C:50]([O:52]C(C)(C)C)=[O:51].Cl>>[ClH:41].[CH3:8][C:9]1[N:10]=[C:11]([NH:14][C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=3)[O:26][CH2:27][C:28]([NH:48][CH2:49][C:50]([OH:52])=[O:51])=[O:30])=[CH:19][CH:18]=[CH:17][N:16]=2)[S:12][CH:13]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1csc(Nc2ncccc2OCc2cccc(OCC(=O)O)c2)n1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(Nc2ncccc2OCc2cccc(OCC(=O)NCC(=O)O)c2)n1
Yield: 66.2 %

Procedure:
2-(3-((2-(4-Methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)acetic acid trifluoroacetate (prepared according to Example 26; 70 mg, 0.14 mmol), triethylamine (0.10 mL, 0.72 mmol), ethyl chloroformate (0.035 mL, 0.36 mmol) and tert-butyl 2-aminoacetate hydrochloride (120 mg, 0.72 mmol) were reacted according to the method of Example 30 to provide 2-(2-(3-((2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)acetamido)acetic acid hydrochloride (43.1 mg, 61.1% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 10.75 (bs, 1H), 8.54 (t, 1H), 7.95 (d, 1H), 7.55 (d, 1H), 7.35 (d, 1H), 7.22 (m, 1H), 7.17 (d, 1H), 7.06 (dd, 1H), 6.96 (dd, 1H), 6.78 (s, 1H), 5.29 (s, 2H), 4.57 (s, 2H), 3.90 (d, 1H), 3.62 (s, 2H), 2.30 (s, 3H). Mass spectrum (apci) m/z=443.0 (M+H-HCl).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH3:29]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:28][CH3:29])[CH2:19]1
Reactant: CCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCN(CC)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(3-piperidinyl)propyl]-9H-purin-6-amine and iodoethane.