Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([C@@H:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[C:19]([F:22])([F:21])[F:20])[CH3:11])[C:6]=2[CH:23]=1.C(O[C:29]([N:31]1[CH2:36][CH:35]=[C:34](B(O)O)[CH2:33][CH2:32]1)=[O:30])(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>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.C(O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C@H:10]([N:7]2[C:6]3[CH:23]=[C:2]([C:34]4[CH2:33][CH2:32][N:31]([C:29]([C@H:32]5[CH2:33][CH2:34][CH2:35][CH2:36][NH:31]5)=[O:30])[CH2:36][CH:35]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[N:8]2)[CH3:11])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B(O)O)CC1
Reactant: C[C@H](c1ccc(Cl)cc1C(F)(F)F)n1nnc2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[C@H](c1ccc(Cl)cc1C(F)(F)F)n1nnc2ccc(C3=CCN(C(=O)[C@H]4CCCCN4)CC3)cc21
Temperature: 100 °C
Yield: 162.5 %

Procedure:
A mixture of (R)-6-bromo-1-(1-(4-chloro-2-(trifluoromethyl)phenyl)ethyl)-1H-benzo[d][1,2,3]triazole (0.32 g, 0.8 mmol), (N-t-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid pincol ester (0.27 g, 0.8 mmol), Pd(PPh3)4 (0.046 g, 0.039 mmol), and 2 M aqueous potassium carbonate (1.2 mL, 2.4 mmol) in 2:1toluene/ethanol (3.6 mL) was purged with nitrogen for 5 min, and then heated at 100° C. for 2 h. After cooling to room temperature, the mixture was extracted with ethyl acetate (15 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. The resulting crude material was purified by flash chromatography (SiO2, 0-100% ethyl acetate in hexanes) to afford the desired product (0.33 g, 0.65 mmol, 83%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[NH2:9][CH2:10][CH:11]([OH:23])[CH2:12][N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:9][CH2:10][CH:11]([OH:23])[CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)[CH:3]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: Fc1cc(Br)ccn1
Solvent: CN(C)C=O
Solvent: O
Product: OC(CNc1cc(Br)ccn1)CN1CCc2ccccc2C1
Temperature: 120 °C
Yield: 82.3 %

Procedure:
A mixture of 4-bromo-2-fluoropyridine (100 mg, 0.57 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (117 mg, 0.57 mmol) and TEA (115 mg, 1.14 mmol) in DMF (5 mL) was stirred at 120° C. under microwave heating for 1 h. Water was added to the mixture which was extracted with DCM. The combined organic layers were concentrated to give the desired compound as a colorless oil (170 mg, Yield 82%) and used directly in the next step. LCMS (m/z): 362.08, 364.08 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH3:35]>>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:51]2[CH2:52][CH2:53][CH2:54][N:48]([C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:49][CH2:50]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 9.1 using 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt to give the title compound.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH:13]2[CH2:15][CH2:16][CH:10]1[CH2:11][N:12]2C)(=O)C1C=CC=CC=1>Cl>[CH3:1][N:9]1[CH2:14][CH:13]2[CH2:15][CH2:16][CH:10]1[CH2:11][NH:12]2
Reactant: CN1CC2CCC1CN2C(=O)c1ccccc1
Agent: Cl
Product: CN1CC2CCC1CN2

Procedure:
A solution of 2-benzoyl-5-methyl-2,5-diazabicyclo[2.2.2]octane (17.2 g, 0.074 mole) in concentrated hydrochloric acid (172 ml) was refluxed 48 hours. The solution was evaporated to dryness in vacuo and the residue triturated with diethyl ether. The supernatant, after centrifugation, was decanted, and the procedure was repeated using absolute ethanol. The hygroscopic residue of 2-methyl-2,5-diazabicyclo[2.2.2]octane . 2HCl (12.1 g, 81.5%) was dried in vacuo. It slowly decomposed above 300°C.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[N:36]O)[NH2:35])=[CH:30][C:29]=1[NH:38][C:39]([C:41]1[N:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]2=[N:43][CH:42]=1)=[O:40]>CN1C(=O)CCC1>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:35]=[C:12]([CH:10]3[CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:11]3)[O:14][N:36]=2)=[CH:30][C:29]=1[NH:38][C:39]([C:41]1[N:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]2=[N:43][CH:42]=1)=[O:40]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: NC(=NO)c1ccc(F)c(NC(=O)c2cnc3ccccn23)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC(c2nc(-c3ccc(F)c(NC(=O)c4cnc5ccccn45)c3)no2)C1
Temperature: 125 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of Boc-azetidine-3-carboxylic acid (162 mg, 0.8 mmol) in anhydrous NMP (4 mL) was added CDI (131 mg, 0.8 mmol). The reaction was stirred for 10 minutes. N-(2-fluoro-5-(N′-hydroxycarbamimidoyl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (50) (125 mg, 0.4 mmol) was added and the reaction was stirred for 15 minutes, then heated via microwave at 125° C. for 15 minutes. The crude was purified via reverse phase HPLC to afford tert-butyl 3-(3-(4-fluoro-3-(imidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F27) as a white solid. MS m/z 479.2 (M+1)+.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].O[NH:26][C:27]([C:29]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1)=[NH:28].C[O-].[Na+]>CO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]2[O:21][N:28]=[C:27]([C:29]3([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:30][CH2:31][CH2:32][CH2:33]3)[N:26]=2)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: N=C(NO)C1(c2ccccc2)CCCC1
Reactant: CCCCn1c(=O)n(CCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCn1c(=O)n(CCCc2nc(C3(c4ccccc4)CCCC3)no2)c(=O)c2[nH]c(Cl)nc21
Yield: 39 %

Procedure:
Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (53 mg, 0.15 mmol), N-hydroxy-1-phenylcyclopentanecarboximidamide (34 mg, 0.165 mmol) and sodium methoxide (20 mg, 0.37 mmol) in dry MeOH (0.75 ml) were heated at 140° C. in the microwave reactor for 10 min. The mixture was then partitioned between ethyl acetate and 2M HCl, the organic phase evaporated and the product purified by MDAP to give the title compound as a solid (29.1 mg).
Reaction SMILES: C(OC([N:8]1[CH2:15][C@H:14]2[N:16](C(OC(C)(C)C)=O)[C@H:10]([CH2:11][C:12]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]4[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=4[Cl:45])=[CH:29][CH:28]=3)=[C:13]2[C:24](O)=[O:25])[CH2:9]1)=O)(C)(C)C.[Cl:46][C:47]1[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][O:60][CH3:61])=[CH:54][C:48]=1[CH2:49][NH:50][CH:51]1[CH2:53][CH2:52]1>>[Cl:46][C:47]1[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][O:60][CH3:61])=[CH:54][C:48]=1[CH2:49][N:50]([CH:51]1[CH2:52][CH2:53]1)[C:24]([C:13]1[C@@H:14]2[NH:16][C@H:10]([CH2:11][C:12]=1[C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]3[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=3[Cl:45])=[CH:31][CH:32]=1)[CH2:9][NH:8][CH2:15]2)=[O:25]
Reactant: COCCc1ccc(Cl)c(CNC2CC2)c1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(C3=C(C(=O)O)[C@H]4CN(C(=O)OC(C)(C)C)C[C@@H](C3)N4C(=O)OC(C)(C)C)cc2)c(Cl)c1
Product: COCCc1ccc(Cl)c(CN(C(=O)C2=C(c3ccc(OCCOc4c(Cl)cc(C)cc4Cl)cc3)C[C@@H]3CNC[C@H]2N3)C2CC2)c1

Procedure:
This compound was synthesized from (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester and [2-chloro-5-(2-methoxy-ethyl)-benzyl]-cyclopropyl-amine as for compound L1, and then Example 1. MS (ESI, Q+) m/z 686.1.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C:17]2[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[NH:10][S@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])=[CH:5][CH:4]=1)=[O:2].[CH3:27][Mg]Br>C1COCC1>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([C:17]2[C:22]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[NH:10][S@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])=[CH:7][CH:8]=1)[CH3:27]
Reactant: C[Mg]Br
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccc(C=O)cc1)c1ncccc1C(F)(F)F
Solvent: C1CCOC1
Product: CC(O)c1ccc([C@H](N[S@@](=O)C(C)(C)C)c2ncccc2C(F)(F)F)cc1

Procedure:
(S)—N—((S)-(4-Formylphenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (0.200 g, 0.520 mmol) was dissolved in dry THF (30 mL) and cooled in an ice bath. Methylmagnesium bromide (3M in Et2O, 0.50 mL, 1.50 mmol) was added dropwise and the reaction stirred. The resulting mixture was stirred for 1 h and then quenched by addition of saturated aqueous NH4Cl (10 mL). H2O (100 mL) and EtOAc (100 mL) were added, and the phases were mixed and separated. The organic layer was dried with MgSO4 and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave impure material which was further purified using reverse phase HPLC to give the desired (S)—N-((1 S)-(4-(1-hydroxyethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:51]=[CH:52][C:53]=1[O:54][CH3:55])[CH2:32][O:33][C:34]([NH:36][C:37]1[NH:38][C:39](=[O:50])[C:40]2[N:41]=[CH:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=2[N:45]=1)=[O:35]>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:47](=[O:48])[CH2:46][N:43]2[CH:42]=[N:41][C:40]3[C:39](=[O:50])[NH:38][C:37]([NH:36][C:34]([O:33][CH2:32][C:31]4[CH:51]=[CH:52][C:53]([O:54][CH3:55])=[C:29]([O:28][CH3:27])[CH:30]=4)=[O:35])=[N:45][C:44]2=3)[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: COc1ccc(COC(=O)Nc2nc3c(ncn3CC(=O)O)c(=O)[nH]2)cc1OC
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COC(=O)Nc2nc3c(ncn3CC(=O)N3CCN(S(=O)(=O)c4nc5ccccc5s4)C(=O)C3)c(=O)[nH]2)cc1OC

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [2-N-(3,4-dimethoxybenzyloxycarbonyl)-guanin-9-yl]-acetic acid as per the procedure of Example 52.1H NMR (500 MHz; DMSO-d6) δ 11.41 (s, 1H), 11.37 (s, 1H), 8.34 (m, 1H), 8.24 (m, 1H), 7.81 (s, 0.6H), 7.77 (s, 0.4H), 7.71 (m, 2H), 7.04 (s, 1H), 6.95 (d, 1H), 6.94 (d, 1H), 5.15 (s, 2H), 5.13 (s, 1.2H), 5.02 (s, 0.8H), 4.51 (s, 0.8H), 4.27 (s, 1.2H), 4.24 (t, 1.2H), 4.07 (t, 0.8H), 4.03 (t, 1.2H), 3.84 (t, 0.8H), 3.75 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=O)[O:11][CH:12]=2)=[C:6]([CH3:16])[CH:5]=[N:4]1)[CH3:2].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][C@@H:51]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([F:71])[CH:66]=1)[CH2:52][N:53]1[C:61](=[O:62])[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]1=[O:63]>C(Cl)Cl>[O:63]=[C:54]1[C:55]2[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:61](=[O:62])[N:53]1[CH2:52][C@@H:51]([NH:50][C:13]([C:10]1[O:11][CH:12]=[C:8]([C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=2[CH3:16])[CH:9]=1)=[O:15])[CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([F:71])[CH:66]=1
Reactant: CCn1ncc(C)c1-c1coc(C(=O)O)c1
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1ncc(C)c1-c1coc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)c1
Reaction time: 0.17 h
Yield: 54 %

Procedure:
To the crude 4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid in DCM (5 mL) at 25° C. was added PyBrOP (370 mg, 0.79 mmol) in one portion, followed by the addition of DIPEA (0.8 mL, 4.58 mmol). After 10 min, 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (220 mg, 0.74 mmol) was added to the reaction solution. After 2 h, the reaction mixture was concentrated and purified via column chromatography (silica, 20-50% EtOAc/Hexane) affording the title compound (164 mg, 54%) as a white solid: LC-MS (ES) m/z 501 (M+H)+.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10](=[O:21])[C:11]#[C:12][C:13]([CH3:20])([O:15][Si](C)(C)C)[CH3:14])[CH:7]=[CH:6][C:5]=12.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10](=[O:21])[C:11]#[C:12][C:13]([OH:15])([CH3:14])[CH3:20])[CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C#CC(=O)c1ccc2nsnc2c1)O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)C#CC(=O)c1ccc2nsnc2c1
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a stirred solution of 1-(benzo[c][1,2,5]thiadiazol-5-yl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one (0.80 g, 2.515 mmol) in DCM (15 mL) was added p-TSA (0.574 g, 3.018 mmol) at RT. The reaction mixture was stirred for 2 h and diluted with water (5 mL). The combined organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford 1-(benzo[c][1,2,5]thiadiazol-5-yl)-4-hydroxy-4-methylpent-2-yn-1-one (0.6 g, 100%) as a colorless oil.
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[C:6]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][C@@H:16]([CH3:20])[CH2:15]1)=[CH:10][C:9]2=[O:21])[CH3:3].[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>CC(N(C)C)=O>[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][CH:2]([C:4]2[CH:5]=[C:6]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][C@@H:16]([CH3:20])[CH2:15]2)=[CH:10][C:9]3=[O:21])[CH3:3])=[CH:30][CH:29]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@@H](C)C3)oc12
Solvent: CC(=O)N(C)C
Product: CC(Nc1ccc(F)cc1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@@H](C)C3)oc12
Yield: 51 %

Procedure:
8-(1-bromoethyl)-N,N-dimethyl-2-((S)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (110 mg, 0.20 mmol) and 4-fluoroaniline in DMA (1 mL) were stirred at 50° C. for 5 hrs. The reaction mixture was purified by preparative HPLC on a Waters X-Bridge system. The fractions containing the desired compound were concentrated. The obtained gum was triturated in diethyl ether and petroleum ether, the resulting solid was collected by filtration and dried to afford 8-(1-(4-fluorophenylamino)ethyl)-N,N-dimethyl-2-((S)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (45 mg, 51%) as a white solid. Mass Spectrum: M+H+ 545. NMR Spectrum (CDCl3): 1.25 (d, 1.5H), 1.26 (d, 1.5H), 1.61 (d, 3H), 2.77-2.88 (m, 1H), 2.83 (bs, 3H), 3.06 (bs, 3H), 3.13-3.22 (m, 1H), 3.64-3.82 (m, 4H), 3.97 (bs, 1H), 3.98-4.06 (m, 1H), 4.91 (q, 1H), 5.56 (s, 1H), 6.37-6.43 (m, 2H), 6.82 (t, 2H), 7.73 (d, 1H), 8.11 (d, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl[C:7]1[S:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([Cl:12])[N:11]=1>CN1CCCC1=O>[Cl:12][C:10]1[N:11]=[C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[S:8][C:9]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Reactant: c1cc[nH]c1
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1sc(-n2cccc2)nc1Cl
Temperature: 70 °C
Yield: 71.9 %

Procedure:
6.7 g (0.1 mol) of pyrrole are added to a solution of 10.0 g (0.05 mol) of 2,4-dichloro-5-nitrothiazole in 100 ml of N-methyl-2-pyrrolidinone at room temperature. The mixture is then heated at 70° C. for 5 hours and subsequently cooled to room temperature and stirred into 1 l of ice-water. The precipitate formed is filtered off, washed with water and dried. 8.25 g (72.0% of theory) of 4-chloro-5-nitro-2-(1-pyrrolyl)-thiazole of melting point 138° C. to 139° C. (yellow needles from toluene) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[N:30][CH:31]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][C:10]=2[F:32])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].[CH3:37]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[N:19]([CH3:37])[CH:20]=[C:21]([CH2:25][C:26]4[CH:31]=[N:30][CH:29]=[N:28][CH:27]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][C:10]=2[F:32])=[CH:4][C:3]=1[C:33]([F:35])([F:36])[F:34]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)[nH]cc1Cc1cncnc1
Solvent: CI
Solvent: ClCCl
Product: Cn1cc(Cc2cncnc2)c(=O)nc1OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.2 %

Procedure:
To a solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3-fluorophenyl) ethyl]oxy}-5-(5-pyrimidinylmethyl)-4(1H)-pyrimidinone (80 mg, 0.154 mmol) and Hunig's base (0.040 mL, 0.230 mmol) in DCM (3.0 mL) was added MeI (0.019 mL, 0.307 mmol) dropwise. The mixture was stirred at room temperature for 2 h. Purification via reverse phase flash chromatography afforded the title compound (15 mg, 18.26% yield). LCMS: rt=3.32 min, [M+H+]=535
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([OH:20])[CH:11]=2)=[CH:4][N:3]=1.[CH2:21](Cl)[C:22]#[CH:23]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:20][CH2:23][C:22]#[CH:21])[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][N:3]=1
Reactant: C#CCCl
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(O)c1OC
Product: C#CCOc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC

Procedure:
The title compound was prepared from 2,4-diamino-5-(3-hydroxy-4,5-dimethoxybenzyl)pyrimidine and propargyl chloride by the procedure of Example 1A. Recrystallization from 95% ethanol gave off-white needles (73%); mp 160°-161°. Anal. Calcd for C16H18N4O3 : C, 61.13; H, 5.77; N, 17.82. Found: C, 60.96; H, 5.80; N, 17.75.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:24]([O:27][C:28]1[CH:38]=[CH:37][C:31]([CH:32]=[CH:33][C:34](O)=[O:35])=[CH:30][CH:29]=1)(=[O:26])[CH3:25].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:24]([O:27][C:28]1[CH:38]=[CH:37][C:31]([CH:32]=[CH:33][C:34]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=2)=[O:35])=[CH:30][CH:29]=1)(=[O:26])[CH3:25]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccc(OC(C)=O)cc1
Yield: 80.4 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.0 g), triethylamine (1.4 mL), 4-acetoxycinnamic acid (2.0 g), WSC.HCl (1.9 g), and methylene chloride (60 mL), to give the captioned compound (2.6 g, 79%) as crystals.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH3:5][C:6]([CH3:19])([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:5][C:6]([CH3:19])([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:3][CH:2]=[CH2:1])=[CH:16][CH:17]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(C)(C)Cc1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(CC(C)(C)C(=O)OC)cc1

Procedure:
Allyl bromide (0.66 ml) was added to a stirred suspension of methyl 2,2-dimethyl-3-(4-hydroxyphenyl)propionate (1.41 g) and potassium carbonate (1.08 g) in butan-2-one (12 ml). The reaction mixture was heated at reflux for 19 hours, cooled, and filtered. The filtrate was evaporated to give methyl 2,2-dimethyl-3-(4-allyloxyphenyl)propionate (1.59 g) as an oil; NMR(CDCl3): 1.17(6H,s), 2.78(2H,s), 3.65(3H,s), 4.50(2H,m), 5.33(2H,m), 6.02(1H,m), 6.70(2H,m) and 7.00(2H,m); m/z 248(M+).
Reaction SMILES: [CH2:1]([C:3]1O[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:2].[CH2:14]([NH2:17])[CH2:15][CH3:16]>>[CH2:1]([C:3]1[N:17]([CH2:14][CH2:15][CH3:16])[C:5](=[O:13])[C:6]2[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:8]=1)[CH3:2]
Reactant: CCc1nc2ccccc2c(=O)o1
Reactant: CCCN
Product: CCCn1c(CC)nc2ccccc2c1=O
Temperature: 110 °C
Yield: 29.1 %

Procedure:
A mixture of 2-ethyl-benzo[d][1,3]oxazin-4-one (541 mg, 3.1 mmol) and propylamine (254 μL, 3.1 mmol) were heated to 110° C. for 1 hour. The crude product was purified by column chromatography (10-40% ethyl acetate-hexanes) to yield the product as a white solid (195 mg, 29%). 1H NMR (CDCl3) δ 1.03 (t, 3H, J=7.4 Hz), 1.41 (t, 3H, J=7.3 Hz), 1.76 (sex, 2H, J=7.7 Hz), 2.86 (q, 2H, J=7.4 Hz), 4.05 (t, 2H, J=7.9 Hz), 7.42 (t, 1H, J=8.1 Hz), 7.63 (d, 1H, J=7.7 Hz), 7.70 (t, 1H, J=7.7 Hz), 8.24 (d, 1H, J=8.1 Hz).
Reaction SMILES: [CH2:1](/[C:3](/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([O:20][CH3:21])[CH:7]=1)=[CH:4]/[CH3:5])[CH3:2].[OH2:22]>>[CH3:21][O:20][C:8]1[CH:7]=[C:6]([CH:3]([CH2:1][CH3:2])[CH:4]([OH:22])[CH3:5])[CH:11]=[CH:10][C:9]=1[O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O
Reactant: C/C=C(/CC)c1ccc(OCc2ccccc2)c(OC)c1
Product: CCC(c1ccc(OCc2ccccc2)c(OC)c1)C(C)O

Procedure:
Addition of H2O to 4-((1Z)-1-ethylprop-1-enyl)-1-benzyloxy-2-methoxybenzene to yield 3-(3-methoxy-4-benzyloxyphenyl)pentan-2-ol.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:14][CH3:15])=[C:5]2[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:6]=12.C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)CCC>O1CCOCC1>[CH3:12][C:8]1([CH3:13])[CH2:7][C:6]2=[C:2]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[S:3][C:4]([S:14][CH3:15])=[C:5]2[C:10](=[O:11])[CH2:9]1
Reactant: CSc1sc(Br)c2c1C(=O)CC(C)(C)C2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: C1COCCO1
Product: CSc1sc(-c2ccccn2)c2c1C(=O)CC(C)(C)C2
Yield: 56 %

Procedure:
1-Bromo-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (300 mg, 1 mmol) was dissolved in dioxane (25 mL), and 2-(tri-n-butylstannyl)pyridine (550 mg, 1.35 mmol) was added. The solution was degassed with nitrogen then tetrakis (tri-phenylphosphine)palladium (30 mg, 0.025 mmol) was added and the solution refluxed for 16 h. The solvent was then removed in vacuo and the residue triturated with a mixture of ethyl acetate and hexane (1:3). After filtration the solid product was washed with a little diethyl ether to give the title compound as a white solid (170 mg, 57%). mp 217-220° C. Found: C, 63.02; H, 5.64; N, 4.47%. C16H17NOS2 requires; C, 63.36; H, 5.61; N, 4.62%. 1HNMR (250 MHz, CDCl3)δ 1.08 (6H, s), 2.44 (2H, s), 2.65 (3H, s), 2.93 (2H, s), 7.18 (1H, m), 7.47 (1H, d, J=8 Hz), 7.71-7.77 (1H, m), 8.61-8.63 (1H, m). MS (ES+) 304 (M+1).