Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=C2C(=CC=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])([O-])=O.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[CH:34]([N:37](C(C)C)[CH2:38]C)(C)C.CI.[C:45]1(S)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C1C=CN=CC=1)C.FC(F)(F)C(O)=O.C(#N)C>[CH3:34][N:37]([CH3:38])[C:47]1[CH:46]=[C:45]2[C:50](=[CH:49][CH:48]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: Sc1ccccc1
Reactant: CC(=O)NCCc1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CI
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCCc1c[nH]c2ccc(N(C)C)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-[2-(5-Nitro-1H-indol-3-yl)-ethyl]-acetamide (0.6 mmol) is taken into acetonitrile (1 mL) and stirred with a catalytic amount of DMAP and di-t-butyl dicarbonate (0.7 mmol) for 1 h. The solvent is removed in vacuo and the remaining oil chromatographed with ethyl acetate-hexane as eluent. The product is dissolved in ethanol (10 ml) and hydrogenated as above. The residue is dissolved in DMF (2 mL), and diisopropylethylamine (1.4 mmol) followed by methyl iodide (1.4 mmol) added. The mixture is stirred 3 h at 25° C. then filtered, evaporated to dryness, dissolved in ethanol and decolorized with activated charcoal. The residue is dissolved in trifluoroacetic acid with 1 equivalent of thiophenol and stirred 1 h at 20° C. The solvent is removed, the compound dissolved in isopropanol-water (5:1) and treated with 2 equivalents (w/w) of Dowex AG1-X8 ion exchange resin in the hydroxide form. Evaporation of the solvent followed by crystallization affords the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)=[CH:2]1.[NH2:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[N:13]=2)=[CH:2]1
Reactant: Nc1cccc(O)c1
Reactant: Fc1cnc(Cl)nc1NCc1csc2ccccc12
Product: Oc1cccc(Nc2ncc(F)c(NCc3csc4ccccc34)n2)c1

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of benzothiophen-3-ylmethylamine (244 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gave N4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine. The reaction of N4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine and 3-aminophenol (200 mg, 1.83 mmol) gave N4-(benzothiophen-3-ylmethyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. (40 mg, 36%). 1H NMR (CDCl3): δ 4.45 (br, 1H), 4.95 (dd, J=1.2 and 5.4 Hz, 2H), 5.33 (br, 1H), 6.40 (ddd, J=1.2, 2.4 and 8.1 Hz, 1H), 6.85 (ddd, J=0.9, 2.1 and 8.1 Hz, 1H), 6.91 (br, 1H), 7.05 (t, J=8.1 Hz, 1H), 7.26 (m, 1H), 7.39-7.47 (m, 3H), 7.81 (dd, J=1.2 and 5.1 Hz, 1H), 7.84 (d, J=3.3 Hz, 1H), 7.92 (m, 1H); 19F NMR (282 MHz, CDCl3): δ −168.89; LCMS: ret. time: 21.91 min.; purity: 99.34%; MS (m/e): 366.96 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[N:3]1[CH2:21][CH2:22][OH:23].[C:25](OC(=O)C)(=[O:27])[CH3:26].C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:25]([O:23][CH2:22][CH2:21][N:3]1[C:2]([CH3:24])([CH3:1])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:17])([F:18])[F:19])[CH:9]=2)[C:4]1=[O:20])(=[O:27])[CH3:26]
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)OCCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 215 mg of the product of Example 43, 15 mg of 4-dimethylamino-pyridine, 1 ml of pyridine and 0.5 ml of acetic acid anhydride was stirred at room temperature for 30 minutes and was then poured into 20 ml of a saturated aqueous sodium bicarbonate solution. After stirring for 20 minutes, the mixture was extracted with ethyl acetate. The organic phase was washed with water and evaporated to dryness and the pyridine and residual acetic acid were distilled. The residue was chromatographed on silica and eluted with a 65-35 methylene chloride-ethyl acetate mixture. The residue with a Rf=0.35 was taken up in isopropanol, partially concentrated, iced and vacuum filtered to obtain after drying, 210 mg of the desired product melting at 99° C. to 100° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26](O)=[O:27])=[CH:9]2.N1(O)C2C=CC=CC=2N=N1.[CH2:39]([S:46][C:47]([CH3:55])([CH:50]([O:53][CH3:54])[O:51][CH3:52])[CH2:48][NH2:49])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:39]([S:46][C:47]([CH3:55])([CH:50]([O:51][CH3:52])[O:53][CH3:54])[CH2:48][NH:49][C:26]([C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=2[N:15]([CH3:25])[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)(=[O:18])=[O:17])=[O:27])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COC(OC)C(C)(CN)SCc1ccccc1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(C)(SCc3ccccc3)C(OC)OC)cc2c1
Yield: 76.3 %

Procedure:
To a mixture of 5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (1.62 g), 1H-1,2,3-benzotriazol-1-ol (919 mg), 2-(benzylthio)-3,3-dimethoxy-2-methylpropan-1-amine (1.02 g) and N,N-dimethylformamide (30 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.53 g) at room temperature, and the mixture was added overnight at room temperature, and concentrated under reduced pressure. The residue was diluted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give the title compound (1.96 g, yield 76%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[CH3:30][O:31][CH:32]([O:43][CH3:44])[C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[C:35](F)[CH:34]=1>O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:35]2[CH:34]=[C:33]([CH:32]([O:43][CH3:44])[O:31][CH3:30])[CH:38]=[CH:37][C:36]=2[N+:39]([O-:41])=[O:40])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(N)nc1-c1cccc(Cl)c1
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(Nc2cc(C(OC)OC)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Yield: 71.1 %

Procedure:
A mixture of 2.82 g (10 mmole) of 2-amino-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester, 9.75 g (30 mmole) of cesium carbonate, 20 mL of dimethylformamide, and 2.15 g (10 mmole) of 4-dimethoxymethyl-2-fluoro-1-nitro-benzene was heated at 80 degrees for 1 hour. The cooled mixture was diluted with 200 mL of water and extracted three times with 100 mL of dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified with silica gel chromatography, eluting with ethyl acetate-hexanes (gradient 0:100-10:90) to give 3.4 g of 4-(3-chloro-phenyl)-2-(5-dimethoxymethyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid ethyl ester (VI.41a) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[C:48]([CH3:49])=[CH:47][CH:46]=[CH:45][N:44]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:50])=[CH:38][C:39]([C:43]6[C:48]([CH3:49])=[CH:47][CH:46]=[CH:45][N:44]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cccnc1-c1cc(C)c(Br)c(C)c1
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ncccc6C)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-bromo-3,5-dimethyl-phenyl)-3-methyl-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.07 min; Mass spectrum (ESI+): m/z=538 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[C:16](=[O:17])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:14][C:5]2[C:6]3[CH:7]=[N:8][NH:9][C:10]=3[C:11]([Cl:13])=[CH:12][C:4]=2[CH2:3]1.C(N(CC)C(C)C)(C)C.C1C=CC(O[C:39](OC2C=CC=CC=2)=[N:40][C:41]#[N:42])=CC=1.Cl.[NH:51]1[CH2:56][CH2:55][CH:54]([C:57]2[C:58](=[O:67])[NH:59][C:60]3[C:65]([CH:66]=2)=[CH:64][CH:63]=[CH:62][CH:61]=3)[CH2:53][CH2:52]1>CN(C)C=O.CO>[Cl:13][C:11]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:14][N:15]([CH2:18][C:19]([F:21])([F:20])[F:22])[C:16](=[O:17])[C@H:2]([NH:1][C:39]([N:51]3[CH2:52][CH2:53][CH:54]([C:57]4[C:58](=[O:67])[NH:59][C:60]5[C:65]([CH:66]=4)=[CH:64][CH:63]=[CH:62][CH:61]=5)[CH2:55][CH2:56]3)=[N:40][C:41]#[N:42])[CH2:3][C:4]=2[CH:12]=1
Reactant: N[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: N#CN=C(N[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 33 %

Procedure:
(R)-7-Amino-4-chloro-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one (130 mg, 390.7 μmol) was dissolved in N,N-dimethylformamide (5.0 mL). N,N-Diisopropylethylamine (200 μL, 1.1 mmol) was added to the mixture followed by diphenyl N-cyanocarbonimidate (100 mg, 407.1 μmol). Mixture stirred at room temperature for 40 minutes. 3-(Piperidin-4-yl)quinolin-2(1H)-one hydrochloride (125 mg; 472.1 μmol) was added to the vessel with stirring. The mixture was heated to 100° C. and held for 54 hr with stirring. Mixture was cooled to room temperature and then diluted with methanol. Mixture was filtered. Filtrate was purified by reverse phase prep HPLC (acetonitrile-water-ammonium acetate). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was diluted with water. Solids were filtered off and washed with water. Air was pulled through the filter cake for 2 hours. Solids were collected and then dried in vacuo. Title compound was obtained as tan solid in 33% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.62 (s, 1 H) 11.79 (s, 1 H) 8.35 (s, 1H) 7.73 (s, 1 H) 7.66 (d, J=7.94 Hz, 1H) 7.53 (d, J=7.93 Hz, 1H) 7.44 (t, J=7.63 Hz, 1 H) 7.25-7.33 (m, 2 H) 7.16 (t, J=7.48 Hz, 1 H) 5.59-5.71 (m, 1 H) 5.40 (d, J=17.40 Hz, 1 H) 4.90 (d, J=17.70 Hz, 1 H) 4.59-4.77 (m, 1 H) 4.27 (d, J=13.12 Hz, 2H) 4.00-4.15 (m, 1 H) 3.33-3.42 (m, 1 H) 3.03-3.26 (m, 4 H) 1.86-1.98 (m, 2) 1.54-1.71 (m, 2 H). High resolution MS m/e (M+H)+=611.1890.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][NH:6]1)=[O:4].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][OH:20])[CH:15]=[N:16][C:17]=1Cl>>[CH3:1][NH:2][C:3]([CH:5]1[CH2:10][N:9]([C:17]2[C:12]([Cl:11])=[CH:13][C:14]([CH2:19][OH:20])=[CH:15][N:16]=2)[CH2:8][CH2:7][NH:6]1)=[O:4]
Reactant: CNC(=O)C1CNCCN1
Reactant: OCc1cnc(Cl)c(Cl)c1
Product: CNC(=O)C1CN(c2ncc(CO)cc2Cl)CCN1

Procedure:
Piperazine-2-carboxylic acid methylamide from step (c) above (570 mg, 4.0 mmol) and (5,6-dichloro-pyridin-3-yl)-methanol (710 mg, 4.0 mmol, TCI-US) reacted under the conditions of Example 3a to give the title compound as a light-yellow gum. MS ESI, pos. ion) m/e: 285 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:27])[C:10]([NH:24][CH2:25][CH3:26])=[C:11]([C:13]3[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]4[C:14]=3[CH:15]=[CH:16][CH:17]=[N:18]4)[CH:12]=2)=[C:5]([CH3:28])[O:4][N:3]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30].O1CCCC1>CCOC(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([C:13]3[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]4[C:14]=3[CH:15]=[CH:16][CH:17]=[N:18]4)[C:10]3[N:24]([CH2:25][CH3:26])[C:29](=[O:30])[NH:27][C:9]=3[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCNc1c(N)cc(-c2c(C)noc2C)cc1-c1c(C)ccc2ncccc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1c(=O)[nH]c2cc(-c3c(C)noc3C)cc(-c3c(C)ccc4ncccc34)c21
Temperature: 105 °C

Procedure:
4-(3,5-Dimethylisoxazol-4-yl)-N1-ethyl-6-(6-methylquinolin-5-yl)benzene-1,2-diamine (90 mg, 0.24 mmol) and 1,1′-carbonyldiimidazole (86.2 mg, 0.53 mmol) were added to tetrahydrofuran (10 ml) in a sealed vessel and heated to 105° C. overnight. The reaction mixture was the diluted in EtOAc and aqueous ammonium chloride and extracted with EtOAc (3 times). Organics were washed with ammonium chloride, water and brine and dried over sodium sulfate. Solvent was evaporated to dryness Crude material was purified by silica gel chromatography (DCM/MeOH as eluent) then by preparative HPLC to afford 5-(3,5-dimethylisoxazol-4-yl)-1-ethyl-7-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Br:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(N1CCO[C@H](CC2C=CC=C(C=CC3C=NC=CC=3)C=2)C1)(O[C:26](C)([CH3:28])[CH3:27])=O.ICCC.C(O)(C(F)(F)F)=O>>[Br:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:27][CH2:26][CH3:28])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Br)c2)C1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCI
Product: CCCOc1ccc(C[C@@H]2CNCCO2)cc1Br

Procedure:
Example 63 was prepared using the same procedure as described for example 4, starting from N-BOC-(R)-2-(3-bromo-4-hydroxybenzyl)morpholine, example 4, intermediate (a), and 1-iodopropane. The resulting intermediate was deprotected with TFA as described for example 4 to yield the desired morpholine example 63 as a colorless oil (27 mg, 64% over 2 steps) after purification by HPLC.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[CH2:10]([N:17]1[CH2:24][CH:23]2[C:25]([CH3:27])([CH3:26])[CH:19]([CH2:20][NH:21][CH2:22]2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[CH2:10]([N:17]1[CH2:18][CH:19]2[C:25]([CH3:27])([CH3:26])[CH:23]([CH2:22][N:21]([S:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)(=[O:8])=[O:7])[CH2:20]2)[CH2:24]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC1(C)C2CNCC1CN(Cc1ccccc1)C2
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: ClCCl
Product: CC1(C)C2CN(Cc3ccccc3)CC1CN(S(=O)(=O)c1cccs1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
A solution of 2.87 g (=0.015 mol) thiophene-2-sulfonyl chloride in 20 ml dichloromethane was added dropwise with ice cooling to a solution of 3.5 g (=0.014 mol) 7-benzyl-9,9-dimethyl-3,7-diazabicyclo[3,3,1]nonane (=substance No. C8 in the following Table C) in 40 ml dichloromethane. Then the ice bath was removed and the reaction mixture stirred further for 3 hours at room temperature. The reaction mixture was then made alkaline by adding aqueous sodium hydroxide solution, the aqueous phase was separated and extracted twice with dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and the solvent was evaporated. 4.0 g of the title compound (base) were thereby obtained as an oil.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1)=O.[NH2:17][C:18]([NH2:20])=[S:19].[CH3:21][O-].[Na+].CI>C(O)CCC>[CH3:21][S:19][C:18]1[N:20]=[C:5]([C:7]2[N:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[CH:3][N:17]=1
Reactant: NC(N)=S
Reactant: C[O-]
Reactant: CN(C)/C=C/C(=O)c1cnc2ccccn12
Agent: [Na+]
Solvent: CI
Solvent: CCCCO
Product: CSc1nccc(-c2cnc3ccccn23)n1
Temperature: 85 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
1 g of (E)-3-(dimethylamino)-1-imidazo[1,2-a]pyridin-3-yl-2-propen-1-one [1-2] was dissolved in 10 mL of n-butanol, then 354 mg of thiourea and 377 mg of sodium methoxide were added, and the mixture was stirred at 85° C. for 2 hours. After cooling back to the room temperature, 868 μL of methyl iodide was added, and stirred at room temperature for 30 minutes. The solvent was distilled off until the volume is halved, the solid thus produced was taken and washed with diethyl ether and with water in the subsequent order, and then dried under reduced pressure to obtain 728 mg of 3-[2-methylthio-4-pyrimidinyl]imidazo[1,2-a]pyridine [1-3] as a grey solid.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[CH2:4][C:5]([OH:7])=[O:6].[CH2:18](N(CC)CC)C.Cl.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1.O>O1CCCC1>[C:26]([NH:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[CH2:4][C:5]([O:7][CH3:18])=[O:6])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Reactant: O=C(Cl)c1cccnc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC(NC(=O)c1cccnc1)c1ccc(OC)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 22.1 %

Procedure:
To a cooled (0° C.) stirred suspension of 3-amino-3-(3',4'-dimethoxyphenyl)propionate hydrochloride (1.38 grams, 5.0 mmol) and triethylamine (1.5 milliliters , 10.8 mmol) in 20 milliliters of tetrahydrofuran was added nicotinoyl chloride hydrochloride (0.89 grams, 5.0 mmol). The thick slurry was stirred for 15 minutes and then allowed to warm to room temperature and stirring was continued for 2 hours. The reaction mixture was treated with 20 milliliters of water resulting in a brown colored solution. The tetrahydrofuran was removed in vacuo and the aqueous layer was extracted with methylene chloride (3 times, milliliters). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to afford an oil which solidified overnight. The white solid was dried in vacuo (60° C., <1 mm) to afford 0.52 grams (30%) of crude product. The crude product was purified by flash chromatography (silica gel, 5% methanol/methylene chloride) and dried in vacuo (60° C., <1 mm) to afford 0.38 grams (22%) of the product as a white solid: 1H NMR (CDCl3) δ 9.10-9.00(m , 1 H), 8.80-8.69(m , 1 H), 8.19-8.08(m , 1 H), 7.65-7.31(m, 2 H), 6.96-6.76(m, 3 H), 5.64-5.50(m, 1 H), 3.87(s, 3 H), 3.67(s, 3 H), 3.14-2.37(m, 2 H). 13C NMR (CDCl3) δ 6 172.1, 164.6, 152.4, 149.2, 148.7, 148.1, 135.0, 132.8, 129.9, 123.5, 118.1, 111.3, 111.2, 109.9, 109.8, 55.9, 52.0, 49.8, 39.5. HPLC 99.47%.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7](=[O:23])[N:8]2[CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[CH:4][CH:3]=1.Cl.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=1>C1COCC1>[Br:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6]([CH2:31][C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)([CH2:31][C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)[C:7](=[O:23])[N:8]2[CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccncc1
Reactant: Cc1c(Br)ccc2c1N(Cc1ccc3ccccc3c1)C(=O)C2
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(Br)ccc2c1N(Cc1ccc3ccccc3c1)C(=O)C2(Cc1ccncc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-bromo-7-methyl-1-naphthalen-2-ylmethyl-1,3-dihydro-indol-2-one (495.7 mg, 1.36 mmol) in THF (30 ml) was added 4-picolyl chloride hydrochloride (893 mg, 5.45 mmol). The resulting suspension was purged with nitrogen gas for 10 minutes, after which time an aqueous potassium hydroxide (1N, 10.88 ml, degassed for 10 minutes prior to the addition) was added dropwise at room temperature. The dark solution was stirred at room temperature overnight. After removal of THF, the reaction mixture was partitioned between water and ethyl ether. The organic layer was dried over MgSO4, filtered and concentrated under vacuum to give the crude product. It was chromatographed on flash silica gel eluting with ethyl acetate to provide the title compound of 2D (524 mg, 0.956 mmol, 70.3% yield).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][C@@H:30](O)[CH2:31][C@H:32]([OH:34])[CH3:33].COCCOC(N=NC(OCCOC)=O)=O>C1COCC1.O>[C:1]([O:9][C@@H:30]([CH3:29])[CH2:31][C@H:32]([OH:34])[CH3:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](O)C[C@@H](C)O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: O=C(O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)C[C@H](C)OC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
After benzoic acid (300 mg, 2.46 mmol), triphenylphosphine (775 mg, 2.95 mmol), (2R,4R)-2,4-pentanediol (308 mg, 2.95 mmol), and THF (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (691.1 mg, 2.95 mmol) dissolved in THF (6 mL) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for one hour. Water (0.5 ml) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 mL, ×2). Then, the organic layer was washed with water (10 ml) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 40% ethyl acetate-hexane solution) to give (4S,2R)-4-benzoyloxypentane-2-ol as a colorless oily substance (379 mg, yield: 74%/benzoic acid).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.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>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Reactant: OB(O)c1ccc(F)cc1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3ccc(F)cc3)c(=O)n12
Temperature: 100 °C
Yield: 65.5 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.10 g, 0.32 mmol) and 4-fluorophenylboronic acid (53 mg, 0.38 mmol) in 1,4-dioxane (2 mL) was added a 1M solution of sodium carbonate in water (0.38 mL, 0.38 mmol) and tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.016 mmol). The reaction mixture was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with water, brine, dried over MgSO4, and concentrated. The crude mixture was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to give the desired product (69 mg, 66%). LCMS calculated for C15H13FN5OS (M+H)+: m/z=330.1. Found: 330.0.