Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][C@@H:12]([OH:15])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl.Cl[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][C@@H:12]([O:15][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCc2cccnc2)C1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
55% of NaH in mineral oil (160 mg, 6.68 mmol) is added to a solution of (R)-3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.67 mmol) in THF (8 mL) at 0° C. After 15 min, 3-chloromethyl-pyridine HCl salt (526 mg, 3.20 mmol) is added, and the reaction mixture is stirred at 40° C. After completion, the reaction mixture is quenched by H2O, EtOAc is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Silica gel flash chromatography of the residue affords the title compound as a white powder; ES-MS: M+=279.2: AtRet=2.80.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1)#[N:2].[CH3:12][NH:13][NH2:14]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[S:11])[N:13]([CH3:12])[NH2:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: CNN
Reactant: N#Cc1ccc(N=C=S)cc1
Solvent: CCO
Product: CN(N)C(=S)Nc1ccc(C#N)cc1
Yield: 98.9 %

Procedure:
Following procedures similar to those employed in Step A of Example 2, the reaction of 7.8 g (0.049 mole) of 4-cyanophenyl isothiocyanate with 2.24 g (0.0490 mole) of methylhydrazine in 50 ml of ethanol yielded 10.0 g of 4-(4-cyanophenyl)-2-methyl-3-thiosemicarbazide as a solid, mp 178°-179° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:10]([NH:20][C:21](=[O:39])[CH2:22][N:23]2[C:31]3[C:30]([F:33])([F:32])[CH2:29][CH2:28][C:27]([F:35])([F:34])[C:26]=3[C:25]([CH:36]([F:38])[F:37])=[N:24]2)[CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[N:4][C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.BrC1[C:42]([C@@H:51]([NH:61][C:62](=[O:80])CN2C3C(F)(F)CCC(F)(F)C=3C(C(F)F)=N2)CC2C=C(F)C=C(F)C=2)=[N:43][C:44](S(C)(=O)=O)=NC=1.NCCN1CCNC1=O>>[Br:1][C:2]1[C:3]([C@@H:10]([NH:20][C:21](=[O:39])[CH2:22][N:23]2[C:31]3[C:30]([F:33])([F:32])[CH2:29][CH2:28][C:27]([F:34])([F:35])[C:26]=3[C:25]([CH:36]([F:37])[F:38])=[N:24]2)[CH2:11][C:12]2[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:44][N:43]2[CH2:42][CH2:51][NH:61][C:62]2=[O:80])=[N:6][CH:7]=1
Reactant: CNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Reactant: CS(=O)(=O)c1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Agent: NCCN1CCNC1=O
Product: O=C(Cn1nc(C(F)F)c2c1C(F)(F)CCC2(F)F)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(NCCN2CCNC2=O)ncc1Br

Procedure:
The title compound (22A) was prepared according to the method presented for the synthesis of compound 14A of Example 14 utilizing 12C and 1-(2-aminoethyl)imidazolidin-2-one. MS (m/z) 725.15 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:31])=[N:4][CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH3:30])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1.FC1C=CC(C2N=[C:41](C3CCNCC3)[N:42]([CH2:44]CN(C)C)[CH:43]=2)=CC=1C(F)(F)F>>[Br:1][C:2]1[C:3]([NH2:31])=[N:4][CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:30][CH2:41][N:42]([CH3:44])[CH3:43])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:28])([F:29])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2Br)CC1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Product: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2Br)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 2-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)-N,N-dimethylethanamine instead of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS: (M+1=556, obsd.=556).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]#[N:12].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[C:7]([N:6]1[C:2]([N:1]=[CH:15][N:16]([CH3:18])[CH3:17])=[C:3]([C:11]#[N:12])[CH:4]=[N:5]1)([CH3:8])([CH3:9])[CH3:10]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)n1ncc(C#N)c1N
Product: CN(C)C=Nc1c(C#N)cnn1C(C)(C)C

Procedure:
The title compound was prepared from the reaction of 5-Amino-1-tert-butyl-1H-pyrazole-4-carbonitrile with N,N-dimethylformamide dimethyl acetal using the procedure from Example 156B to provide the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C@H:27]1([NH2:34])[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1>CS(C)=O>[NH2:33][C@H:30]1[CH2:31][CH2:32][C@H:27]([NH:34][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:11]=[C:10]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH2:28][CH2:29]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Fc1cccc(CNc2cc(C(F)(F)F)cc(-c3ccnc(F)c3)n2)c1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3cc(C(F)(F)F)cc(NCc4cccc(F)c4)n3)ccn2)CC1
Temperature: 105 °C

Procedure:
To 2′-fluoro-N-(3-fluorobenzyl)-4-(trifluoromethyl)-2,4′-bipyridin-6-amine (34 mg, 0.093 mmol) was added DMSO (1.7 ml) and trans-cyclohexane-1,4-diamine (159 mg, 1.396 mmol). The resulting reaction mixture was stirred at 105° C. until completion as indicated by LCMS, about 40 hours. To the crude reaction mixture was added 0.75 ml of DMSO, filtered and purified by prep LC. After lyophilization, 28.1 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 460.3 (MH+), retention time=0.72 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.40-1.72 (m, 4 H) 2.18 (t, J=13.77 Hz, 4 H) 3.11-3.24 (m, 1H) 3.62-3.76 (m, 1 H) 4.72 (s, 2 H) 6.95 (s, 1 H) 7.12 (d, J=9.96 Hz, 1 H) 7.17-7.24 (m, 1 H) 7.27-7.37 (m, 1 H) 7.40 (s, 1 H) 7.42-7.48 (m, 1 H) 7.69 (s, 1 H) 7.87 (d, J=6.74 Hz, 1 H)
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45]([OH:47])=O)=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1.[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH2:56][NH2:57])[CH:51]=1>>[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45]([NH:57][CH2:56][C:52]4[CH:51]=[N:50][CH:55]=[CH:54][CH:53]=4)=[O:47])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 68 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 68% yield: mp 178-179° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.58 (br s, 1H), 8.51 (br s, 1H), 8.27 (s, 1H), 7.72-7.64 (m, 1H), 7.63-7.54 (m, 2H), 7.51-7.42 (m, 2H), 7.33-7.21 (m, 1H), 6.46 (t, J=5.8 Hz, 1H), 5.04 (s, 2H), 4.59 (d, J=5.8 Hz, 2H), 2.63 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.3, 161.7, 161.0, 153.4, 150.9, 149.9, 149.3, 149.1, 135.7, 130.9, 130.3, 130.2, 121.6, 115.9, 115.7, 48.9, 41.6, 17.2; MS (ES+) m/z 425.3 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([O:10][CH3:11])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.[I:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[N+:22]([O-:24])=[O:23])[NH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[I:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[N+:22]([O-:24])=[O:23])[N:15]([CH2:2][C:3]2[C:4]([O:10][CH3:11])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=2)[N:14]=1
Reactant: COc1nc(C)ccc1CBr
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nc(C)ccc1Cn1nc(I)c2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.9 %

Procedure:
To 3-(bromomethyl)-2-methoxy-6-methylpyridine (500 mg, 2.314 mmol) and 3-iodo-4-nitro-1H-indazole (668.8 mg, 2.314 mmol) in DMF (10 mL) was added K2CO3 (479.7 mg, 3.471 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with EtOAc, washed with water, brine and concentrated under reduced pressure to give the product (1.0 g).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([C@@H:28]([NH2:30])[CH3:29])=[CH:24][N:23]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:30][C@H:28]([C:25]4[CH:24]=[N:23][C:22]([CH3:21])=[N:27][CH:26]=4)[CH3:29])[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: Cc1ncc([C@H](C)N)cn1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(N[C@@H](C)c4cnc(C)nc4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (60 mg, 0.21 mmol) and (S)-1-(2-methylpyrimidin-5-yl)ethanamine (29 mg, 0.21 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (74 μL, 0.42 mmol) was subjected to microwave irradiation at 180° C. for 1 h. The reaction mixture was concentrated and the residue was purified by semi-preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to yield an off-white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH2:10].[O-]CC.[Na+].Cl[C:16]1[C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1.[OH-].[Na+]>O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH:10][C:16]1[C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: NCCSCc1nccs1
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccnc1NCCSCc1nccs1

Procedure:
An intimate mixture of 2-(2-thiazolylmethylthio)ethylamine [prepared from 6.73 g; 0.020 moles of the dihydrobromide salt and sodium ethoxide (from 0.92 g; 0.040 g. atom of sodium in ethanol)] and 2-chloropyridine 3-carboxylic acid (3.15 g; 0.020 moles) was heated to 150° for 3 hours. The resulting brown residue was cooled, dissolved in a little water, and basified to pH5 by dropwise addition of 2 N sodium hydroxide solution, to precipitate an oil. The latter was separated and dried, and chromatographed on a column of silica-gel using chloroform/ethyl acetate, (1:1). The crude product was then recrystallised from isopropanol to give 2-[2-(2-thiazolylmethylthio)ethyl]amino pyridine 3-carboxylic acid as a cream-coloured solid (0.36 g, m.p. 133°-4° (softening above 123°).
Reaction SMILES: [CH:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])([CH3:3])[CH3:2].[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32](O)[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:38]2)=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32]([O:9][C:8](=[O:10])[CH:7]([O:6][C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[CH:1]([CH3:2])[CH3:3])[CH3:11])[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH2:38]2)=[CH:25]1)([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CC(Oc1ccccc1C(C)C)C(=O)O
Product: CC(Oc1ccccc1C(C)C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 97.4 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 749 mg of (2RS)-2-(2-isopropylphenoxy)propionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], give 1.31 g of the title compound as a colorless foam.
Reaction SMILES: C(O[N:9]1[C:13](=C=O)[CH:12]([CH2:16][OH:17])[NH:11][C:10]1=[O:18])C1C=CC=CC=1.[C:19]([OH:24])(=[O:23])[C:20]([OH:22])=[O:21].[OH:25][C:26]1[CH:27]=[CH:28][C:29]2[C:33]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[C:37]([CH3:47])[CH:36]=3)=[C:32]([C:48]3[CH:53]=[CH:52][C:51](OCC4COC(=O)N4)=[CH:50][CH:49]=3)[S:31][C:30]=2[CH:62]=1>C1COCC1>[C:19]([OH:24])(=[O:23])[C:20]([OH:22])=[O:21].[OH:25][C:26]1[CH:27]=[CH:28][C:29]2[C:33]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[C:37]([CH3:47])[CH:36]=3)=[C:32]([C:48]3[CH:53]=[CH:52][C:51]([O:17][CH2:16][CH:12]4[CH2:13][NH:9][C:10](=[O:18])[NH:11]4)=[CH:50][CH:49]=3)[S:31][C:30]=2[CH:62]=1
Reactant: O=C=C1C(CO)NC(=O)N1OCc1ccccc1
Reactant: Cc1cc(Cc2c(-c3ccc(OCC4COC(=O)N4)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Product: Cc1cc(Cc2c(-c3ccc(OCC4CNC(=O)N4)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Yield: 28 %

Procedure:
By essentially following the conditions of Example 2, Part A, the title compound was prepared from 1-benzyloxy-carbonyl-2-oxo-4-hydroxymethylimidazolidine (Saijo et al. Chem. Pharm. Bull. 1980, 28, 1459) and 6-benzyloxy-3-[3-methyl-4-[(1-pyrrolidinyl)methyl]benzyl]-2-(4-hydroxyphenyl)benzo[b]thiophene (Example 8, Part C) in 28% yield following radial chromatography (SiO2; 20% then 25% then 40% THF with 5% TEA in hexanes).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:10])=[O:11])[C:5]([O:8][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cc(Br)cnc1O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2ncc(Br)cc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 100 °C
Yield: 54 %

Procedure:
To a solution of 5-bromo-N-(tert-butyl)-2-hydroxypyridine-3-sulfonamide (2.00 g, 6.47 mmol) in DMF (40 mL) was added 4-methoxybenzyl chloride (1.76 mL, 12.9 mmol) followed by K2CO3 (1.78 g, 12.9 mmol) at ambient temperature. The reaction mixture was heated to 100° C. for 14 h, diluted with cold water (100 mL). The aqueous mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a residue which was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 40 g, 50% EtOAc/hexanes) to obtain 5-bromo-N-(tert-butyl)-2-((4-methoxybenzyl)oxy)pyridine-3-sulfonamide (1.50 g, 54.0%). LCMS Condition B-39: retention time 2.53 min, [M+1]=429.0. 1H NMR (400 MHz, CDCl3) 1.25 (s, 9H), 3.81 (s, 3H), 6.88-6.91 (m, 2H), 7.24-7.30 (m, 4H), 7.55 (d, J=2.8 Hz, 1H), 8.11 (d, J=2.8 Hz, 1H).
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[OH-].[K+].O.[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Br>CN(C=O)C>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[F:14])[N:6]=[C:7]([OH:9])[CH:8]=1
Reactant: Nc1cc(O)nc(S)n1
Reactant: Fc1ccccc1CBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(O)nc(SCc2ccccc2F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a stirred suspension of 4-Amino-6-hydroxy-2-mercaptopyrimidine monohydrate (25 g) in DMF (300 ml) was added potassium hydroxide (10.2 g) and water (50 ml). After a clear solution was obtained, 2-fluorobenzyl bromide (29.3 g) was added and the reaction stirred at room temperature for 30 min. The mixture was poured into water (21) and the resulting precipitate isolated by filtration, washing with isopropanol and diethyl ether, affording the subtitled compound as a white solid (34.7 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:16][OH:17].C([Li])CCC.[CH3:23][C:24]([CH3:26])=[O:25]>CCCCCC.C1COCC1>[Si:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:16][OH:17])=[C:2]([C:24]([OH:25])([CH3:26])[CH3:23])[CH:7]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CO)c(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1CO
Reaction time: 2 h
Yield: 51.4 %

Procedure:
To a solution of [2-bromo-4-[tert-butyl(dimethyl)silyl]oxy-phenyl]methanol (Intermediate 9, 500 mg, 1.5758 mmol) in dry hexane (8 mL) and THF (2 mL) at −15° C. butyllithium 1.6M in hexane (2.17 ml, 3.467 mmol) was slowly added (10 min) and the reaction mixture was stirred at the same temperature for 2 hours. Then a solution of acetone (118.98 mg, 2.0486 mmol) in dry hexane (1 ml) was added at −15° C. and the reaction mixture stirred at the same temperature for additional 1 hour. The reaction was quenched with an aqueous saturated solution of ammonium chloride and extracted with ethyl acetate (100 ml). The organic layer was washed with brine, dried over sodium sulphate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (Biotage system) using a SNAP 50 g as column and cyclohexane/ethyl acetate from 100:0 to 60:40 as eluent in 12 column volumes, to give the title compound (240 mg) as a colourless oil.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=1.[Br:16][C:17]1[CH:18]=[C:19]([C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[C:38]#[N:39])=[N:24]S(C(C)(C)C)=O)[CH:20]=[CH:21][CH:22]=1.Cl.CO>O1CCCC1.CO>[Br:16][C:17]1[CH:18]=[C:19]([C:23]2([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([CH:13]4[CH2:15][CH2:14]4)[CH:8]=3)[C:31]3[C:32](=[C:33]([F:37])[CH:34]=[CH:35][CH:36]=3)[C:38]([NH2:39])=[N:24]2)[CH:20]=[CH:21][CH:22]=1
Reactant: Brc1ccnc(C2CC2)c1
Reactant: CC(C)(C)S(=O)N=C(c1cccc(Br)c1)c1cccc(F)c1C#N
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: NC1=NC(c2cccc(Br)c2)(c2ccnc(C3CC3)c2)c2cccc(F)c21
Temperature: -112.5 °C
Reaction time: 0.75 h
Yield: 38.2 %

Procedure:
Under an atmosphere of argon, tert-butyllithium (0.731 mL, 1.24 mmol) was added drop wise over 3 minutes to tetrahydrofuran (5 mL) in a flask cooled in a liquid nitrogen-pentane bath at an external temperature between −105 to −120° C. To the solution was added drop wise over a period of 6 minutes 4-bromo-2-cyclopropylpyridine (123 mg, 0.62 mmol) dissolved in anhydrous tetrahydrofuran (2 mL). The solution was stirred for 4 minutes before drop wise addition of N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (253 mg, 0.62 mmol) dissolved in anhydrous tetrahydrofuran (2 mL) over a period of 10 minutes. The reaction mixture was stirred at a temperature below −100° C. for 45 minutes. MeOH (5.0 mL) was added at −100° C. and then hydrogen chloride-methanol solution (0.745 mL, 0.93 mmol) was added at −90° C. The reaction was left to stir overnight (17 h) and was allowed to reach ambient temperature. The solvents were evaporated and the residue was partitioned between EtOAc (25 mL) and saturated aqueous NaHCO3 (25 mL). The aqueous layer was extracted with EtOAc (25 mL). The organics were combined, dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography on silica gel and gave 100 mg (38%) of the title compound. MS (ES+) m/z 422, 424 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH2:22].Cl.[OH-].[Na+]>O.C(O)C>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccc2)n1
Reactant: COc1ccc(OC)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(OC)c(Nc2cc(C(F)(F)F)nc(-c3ccccc3)n2)c1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
A mixture of 4-chloro-2-phenyl-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 2,5-dimethoxyaniline (44 mg, 0.290 mmol) and aqueous 2N HCl (150 μl) in water:ethanol (1:1, 10 ml) was refluxed for 48 h. The mixture was cooled to room temperature and then basified with aqueous 2N NaOH to pH 10-12. The resulting precipitate was filtered, washed with water, water:ethanol (2:1) and dried under vacuo to give a gray solid (36 mg, 50%). 1H NMR (CDCl3): 8.51-8.48 (m, 2H), 8.14 (s, 1H), 7.51-7.48 (m, 4H), 6.89 (s, 1H), 6.88 (d, J=9.3 Hz, 1H), 6.66 (dd, J=3.0, 8.7 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[IH:28]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[I:28][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Reactant: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(I)n2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 65.4 %

Procedure:
A mixture of 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1020 mg, 2.65 mmol) and 67% hydriodic acid solution (0.499 mL, 6.63 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 19 h. The reaction mixture was diluted with NaHCO3 (30 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with saturated NaCl (20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow solid. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 50% CH2Cl2/hexanes to give 4-iodo-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (826 mg, 1.734 mmol, 65.4% yield) as a mixture of product and starting material (3:1).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26].B(O)O>>[CH3:23][O:24][C:25](=[O:26])[C:27]1[CH:32]=[CH:31][C:30]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)=[CH:29][CH:28]=1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: OBO
Product: COC(=O)c1ccc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccnc2)cc1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 4-methoxycarbonylphenylboronic acid as a boronic acid, the desired compound was obtained.