Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:18]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][OH:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:29][CH2:28][C:27]3[CH:30]=[CH:31][CH:32]=[C:25]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:26]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: N=C(OCc1cccc(Oc2ccccc2)c1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and m-phenoxybenzyl alcohol, there is obtained m-phenoxybenzyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e:M+ 420 (14), 327 (13), 237 (35), 194 (100);
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:26])([CH3:25])[C:19]=3[CH:27]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH:28]O>>[CH3:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:25])([CH3:26])[C:19]=3[CH:27]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1C
Reactant: OO
Product: Cc1ccc(S(=O)CCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1C

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dimethyl-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=O)[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[S:25])[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(F)cc2C2CCCC12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: Fc1ccc2c(c1)C1CCCC1C(=S)N2
Yield: 79.7 %

Procedure:
Analogously to Example 4, 8-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (280 mg, 1.36 mmol) is reacted with Lawesson's reagent (608 mg, 1.5 mmol) to form 240 mg (80%) of product.
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=3[OH:20])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[CH2:21]1COCC1>>[C:3]12([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=3[O:20][CH3:21])[CH2:4][CH:5]3[CH2:11][CH:9]([CH2:8][CH:7]([CH2:6]3)[CH2:12]1)[CH2:10]2
Reactant: Oc1cc(Br)ccc1C12CC3CC(CC(C3)C1)C2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COc1cc(Br)ccc1C12CC3CC(CC(C3)C1)C2

Procedure:
1.6 g (53 mmol) of sodium hydride (80% in oil) and 50 ml of THF are introduced into a round-bottomed flask and a solution of 15 g (49 mmol) of the phenol obtained above in (a), dissolved in 100 ml of DMF, is added dropwise. The mixture is stirred until gaseous evolution has ceased and 3.1 ml (49 mmol) of methyl iodide are then introduced. The mixture is stirred at room temperature for four hours, the reaction medium is poured into water and the organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated. The residue obtained is ground in the minimum amount of hexane and filtered off. 12.6 g (80%) of 2-(1-adamantyl)-5-bromoanisole, melting point 159°-160° C., are collected.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]([NH:8][CH2:9][CH2:10][C:11]2[N:12]([CH3:30])[C:13](=[O:29])[C:14]3[C:19]([C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][C:17]([O:27][CH3:28])=[CH:16][CH:15]=3)=[O:7])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:38][O:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1>CN(C)C=O>[CH3:38][O:39][C:40]1[CH:48]=[CH:47][C:43]([C:44]([NH:2][C:3]2([C:6]([NH:8][CH2:9][CH2:10][C:11]3[N:12]([CH3:30])[C:13](=[O:29])[C:14]4[C:19]([C:20]=3[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:18][C:17]([O:27][CH3:28])=[CH:16][CH:15]=4)=[O:7])[CH2:5][CH2:4]2)=[O:45])=[CH:42][CH:41]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc2c(=O)n(C)c(CCNC(=O)C3(N)CC3)c(-c3ccccc3)c2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)NC2(C(=O)NCCc3c(-c4ccccc4)c4cc(OC)ccc4c(=O)n3C)CC2)cc1
Reaction time: 72 h

Procedure:
To a solution of 1-amino-N-[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]cyclopropanecarboxamide hydrochloride (30 mg, 0.117 mmol) in 3 mL of dimethylformamide was added triethylamine (0.049 mL, 0.35 mmol), followed by 4-(methoxy)benzoyl chloride (24 mg, 0.14 mmol). After 3 days, the mixture was concentrated in vacuo. Purification by preparative reversed phase HPLC provided the titled compound. ESI+MS: 526.0 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=3)=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>C(O)C>[C:1]1([C:7]2[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=3)=[C:10]3[NH:11][CH2:12][CH2:13][CH2:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(-c2c(-c3ccccc3)nn3cccnc23)ccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2c(-c3ccccc3)nn3c2NCCC3)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
To a mixture of 4-(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-amine (60 mg, 0.2 mmol, 1 eq) in 3 mL of ethanol is added sodium borohydride (17 mg, 0.45 mmol, 2.2 eq). The mixture is stirred at room temperature for 2 h. The mixture is then poured into water, extracted with dichloromethane (3×50 mL), dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. 29 mg (47%) of 4-(2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-amine are obtained as a white solid which is used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@:9]1([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:24]>C1COCC1.CO>[CH3:24][O:14][C:13]([C@:9]1([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:15]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(Cc1ccccc1)C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@]1(Cc2ccccc2)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 81 %

Procedure:
To a stirred solution of (R)-2-benzyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.23 g, 4.0 mmol) in THF (10 mL) and methanol (10 mL) at 0° C. under nitrogen was added TMS-diazomethane (5.0 mL of a 2.0 M solution in hexanes, 5.0 mmol) dropwise. The reaction mixture was warmed to ambient temperature then concentrated in vacuo to an oil (1.36 g). Purification by chromatography (silica, 5-15% EtOAc in hexanes) gave (R)-2-benzyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.03 g, 3.23 mmol, 81%) as an oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@@H:6]1Br)(=[O:3])[CH3:2].[SH:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(#N)C.[O-2].[Zn+2]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[S:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: N#Cc1ccc(S)cc1
Agent: [O-2]
Agent: [Zn+2]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc(C#N)cc2)SC[C@H]1OC(C)=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
A suspension of 16.9 g (47.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 6 g (43.10-3 mol) of 4-mercaptobenzonitrile and 3.5 g (43.10-3 mol) of zinc oxide (ZnO) in 120 ml of anhydrous toluene and 120 ml of acetonitrile is stirred under an inert atmosphere, in the presence of a molecular sieve (1 mm), for 18 hours, at 50° C. After the reaction medium has been filtered on Celite® in ethyl acetate, the organic phase obtained is washed with a 1N solution of HCl twice, a 1N solution of sodium hydroxide and finally water, dried over magnesium sulfate and evaporated under reduced pressure. After precipitation in ether, 11.30 g (yield: 64%) of the expected product are obtained.
Reaction SMILES: [F:1][C:2]1([F:43])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[S:21][CH:22]=[N:23][N:24]=3)(=[O:18])=[O:17])=[C:11]([F:36])[CH:10]=2)[C@@H:5]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:43][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[S:21][CH:22]=[N:23][N:24]=3)(=[O:17])=[O:18])=[C:11]([F:36])[CH:10]=2)[C@@H:5]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(C)c(O[C@H]3CC(F)(F)CC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Nc2nncs2)c(F)cc1O[C@H]1CC(F)(F)CC[C@@H]1c1ccnn1C
Yield: 80.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (78.8 mg, 0.124 mmol) prepared in Example 125b, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (48.6 mg, 81%) as a colorless solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:15])=[O:7].[Br:16]C1OC(C(O)=O)=CC=1>>[Br:16][C:5]1[O:1][C:2]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])=[O:7])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: O=C1CCCCCN1C(=O)c1ccco1
Product: O=C1CCCCCN1C(=O)c1ccc(Br)o1

Procedure:
Synthesized as for N-(2-furoyl)caprolactam (Example X) using 5-bromo-2-furoic acid in place of 2-furoic acid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([Cl:15])[C:8]2[NH:13][CH:12]=[C:11]([I:14])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:16](C1N=C(Cl)C2NC(C)=CC=2N=1)CCC>>[CH2:1]([C:5]1[N:6]=[C:7]([Cl:15])[C:8]2[NH:13][C:12]([CH3:16])=[C:11]([I:14])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c2[nH]cc(I)c2n1
Reactant: CCCCc1nc(Cl)c2[nH]c(C)cc2n1
Product: CCCCc1nc(Cl)c2[nH]c(C)c(I)c2n1

Procedure:
Prepared similarly to Intermediate 4 from. 2-butyl-4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>ClCCl.C(N(CC)CC)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:18](=[O:19])[C:17]3[CH:21]=[CH:22][C:14]([Br:13])=[CH:15][CH:16]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Br)cc1)N1CCN(c2ccncc2)CC1
Reaction time: 2 h
Yield: 59.7 %

Procedure:
A solution of 1-(4-pyridyl)piperazine (0.49 g) in dry dichloromethane (20 ml) and triethylamine (0.7 ml) was treated slowly with a solution of 4-bromobenzoyl chloride (0.7 g) in dry dichloromethane (10 ml). The reaction mixture was then stirred under argon for 2 hours. The dichloromethane solvent was removed by evaporation and the residue dissolved in ethyl acetate. The organic extracts were then washed with aqueous sodium hydrogen carbonate solution, water, brine, dried (Na2SO4) and evaporated to yield a colourless oil. The residual oil was then triturated with diethyl ether and recrystallised from ethyl acetate/isohexane to give 1-(4-pyridyl)-4-(4-bromobenzoyl)piperazine (0.62 g) as a solid, m.p. 128-129° C.; microanalysis, found: C, 55.7; H, 4.7; N, 12.0%; C16H16N3OBr requires: C, 55.5; H, 4.7; N, 12.1%; NMR: (CDCl3) 3.36(s,4H), 3.73(s,4H), 6.67(dd,2H), 7.33(dd,2H), 7.58(dd,2H), 8.34(dd,2H); MS: m/z 346 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:39])(=[O:15])=[O:14])=[CH:9][C:8]=1[OH:40])([CH3:4])([CH3:3])[CH3:2].[C:42](O)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[N:45][CH:44]=1.[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:39])(=[O:14])=[O:15])=[CH:9][C:8]=1[O:40][C:42]([C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1)=[O:49])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Reactant: O=C(O)c1cccnc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(OC(=O)c2cccnc2)c1
Temperature: 75 °C
Yield: 74.5 %

Procedure:
A stirred solution containing 4-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.508 g, 0.863 mmol), nicotinic acid (0.108 g, 0.863 mmol), 2-chloro-1-methylpyridinium iodide (0.272 g, 1.04 mmol) and triethylamine (0.288 mL, 2.07 mmol) in CH2Cl2 (8.63 mL) was heated at 75° C. in a sealed tube for 3 days. The reaction was cooled to ambient temperature and concentrated. The crude product was purified on Biotage KP-Sil eluting with a 10 & 15% acetone/hexane step gradient to give 0.446 g (74%) of the title compound. 1H NMR (DMSO-d6) δ 1.35 (s, 9 H), 1.58 (s, 3 H), 2.18 (s, 6 H), 2.35 (s, 3 H), 7.18 (s, 2 H), 7.36-7.46 (m, 3 H), 7.68-7.72 (m, 1 H), 7.98 (d, 1 H), 8.15 (dd, 1 H), 8.22-8.26 (m, 2 H), 8.50-8.53 (m, 2 H), 8.95 (dd, 1 H), 9.30 (d, 1 H).
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[N:13]([CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N+:14]=[N-:15]>>[ClH:1].[C:19]1([CH2:18][CH2:17][CH2:16][N:13]2[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]3[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=3)[N:15]=[N:14]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C#CCCCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCCCc1ccccc1
Agent: Cl
Product: Nc1nc(CCCc2cn(CCCc3ccccc3)nn2)c[nH]1
Yield: 34.1 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.050 g, 0.269 mmol) was reacted with (3-azido-propyl) benzene (0.044 g, 0.273 mmol) following the general procedure for click reactions outlined above to produce 4-{3-[1-(3-Phenyl-propyl)-1H-[1,2,3]triazol-4-yl]-propyl}-1H-imidazol-2-ylamine hydrochloride (0.0318 g, 34%) as a pale yellow solid. 1H NMR (300 MHz, DMSO) δ 7.91 (s, 1H), δ 7.29-7.17 (m, 5H), δ 6.62 (s, 2H), δ 6.57 (s, 1H), δ 4.29 (t, 2H), δ 2.59 (t, 2H), δ 2.53 (t, 2H), δ 2.43 (t, 2H) δ 2.09 (m, 2H), δ 1.83 (m, 2H) ppm; 13C NMR (75 MHz, DMSO) δ 163.6, 156.2, 155.1, 147.4, 146.9, 141.4, 129.1, 127.1, 126.7, 122.6, 109.4, 49.4, 32.6, 32.0, 28.1, 24.9, 24.2 ppm; HRMS (ESI) calcd for C17H22N6 (M+) 310.1978. found 310.1977.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O)#[CH:2].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:15]1[C:11](=[O:21])[C:12]2[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14]1=[O:16])#[CH:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C#Cc1ccccc1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C#Cc1ccccc1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.8 %

Procedure:
To a solution of 2-ethynylbenzyl alcohol (1.00 g), phthalimide (2.20 g) and triphenylphosphine (3.96 g) in tetrahydrofuran (30 mL), a solution of diisopropyl azodicarboxylate (1.9 mol/L) in toluene (7.9 mL) was added under ice cooling, and the mixture was stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, 96 to 66% hexane in ethyl acetate) to obtain 2-(2-ethynylbenzyl)isoindoline-1,3-dione (F8, 1.44 g) as pale orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH2:10])=[O:4].[O:17]1[CH2:21][CH2:20][C@H:19]([O:22][CH:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)[CH2:18]1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH:10][C@H:26]1[CH2:25][CH2:24][C@H:23]([O:22][CH:19]2[CH2:20][CH2:21][O:17][CH2:18]2)[CH2:28][CH2:27]1)=[O:4]
Reactant: O=C1CCC(O[C@H]2CCOC2)CC1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N[C@H]1CC[C@H](OC2CCOC2)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 3-amino-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (2.41 g, 10.2 mmol), 4-(tetrahydro-furan-3(S)-yloxy)-cyclohexanone (1.6 g, 8.5 mmol), TFA (2.6 mL, 34 mmol) and triethylsilane (2.7 mL, 17 mmol) in CH2Cl2 (12 mL) was stirred for 22 h at room temperature. The reaction was concentrated in vacuo and the crude oil was dissolved in toluene (50 mL) and concentrated (repeat) to give a yellow solid. The crude solid was purified by column chromatography (10-25% ethyl acetate/hexanes) to give 5-(3,3-dimethyl-but-1-ynyl)-3-[4-(tetrahydro-furan-3-yloxy)-trans-cyclohexylamino]-thiophene-2-carboxylic acid methyl ester (1.09 g, 2.69 mmol) as a single isomer.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:22])[C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.Cl[C:24]1[C:25]2[N:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=2[N:27]=[CH:28][N:29]=1>CC(O)C.C(Cl)Cl>[Cl:34][C:31]1[CH:32]=[N:33][C:25]2[C:24]([NH:1][C:2]3[CH:3]=[C:4]([CH3:22])[C:5]([F:21])=[C:6]([C@:8]4([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:15])[F:16])[O:11][C:10]([NH2:18])=[N:9]4)[CH:7]=3)=[N:29][CH:28]=[N:27][C:26]=2[CH:30]=1
Reactant: Clc1cnc2c(Cl)ncnc2c1
Reactant: Cc1cc(N)cc([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1F
Solvent: ClCCl
Solvent: CC(C)O
Product: Cc1cc(Nc2ncnc3cc(Cl)cnc23)cc([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1F
Temperature: 100 °C
Yield: 50 %

Procedure:
To a mixture of (4S,6S)-4-(5-amino-2-fluoro-3-methylphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.044 g, 0.136 mmol) and 4,7-dichloropyrido[3,2-d]pyrimidine (0.030 g, 0.150 mmol) in iPrOH (2 mL) was added a catalytic amount of concentrated H2 SO4 and the resulting mixture was heated in microwave at 100° C. for 45 min. The mixture was diluted with DCM, washed with 1 N NaOH and extracted with DCM. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-4% MeOH/DCM to afford a light brown solid as (4S,6S)-4-(5-((7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-fluoro-3-methylphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.033 g, 0.068 mmol, 49.8% yield). MS m/z=486.9 [M+H]+. Calculated for C20H16ClF5N6O: 486.10.
Reaction SMILES: [CH2:1]([CH:4]1[C:9](=O)[CH2:8][CH2:7][S:6][CH2:5]1)[CH2:2][CH3:3].Cl.[NH2:12][OH:13]>>[N:12](=[C:9]1[CH2:8][CH2:7][S:6][CH2:5][CH:4]1[CH2:1][CH2:2][CH3:3])[OH:13]
Reactant: CCCC1CSCCC1=O
Reactant: NO
Agent: Cl
Product: CCCC1CSCCC1=NO

Procedure:
Employing the procedure described in Example 2, step A, 3-propyl-tetrahydrothiopyran-4-one was reacted with hydroxylamine hydrochloride to form 4-oximino-3-propyl-tetrahydrothiopyran and was used directly in the subsequent reaction.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:14].[Na+]>C(O)(=O)C>[C:2]1([C:1]([C:8]2[CH:13]=[CH:12][N:11]=[N:10][CH:9]=2)=[O:14])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: c1ccc(Cc2ccnnc2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1ccnnc1
Temperature: 100 °C

Procedure:
To a 100° C. suspension of SeO2 (4.75 g, 0.043 mole) in acetic acid (216 mL) was added dropwise to a solution of 4-benzylpyridazine (11; 7.6 g, 0.044.6 mole) in acetic acid (216 mL). The mixture was heated for 1 hour at 100° C. The reaction mixture was cooled to room temperature and was neutralized to a pH ˜6-7 with 50% NaOH. The neutralized mixture was extracted twice with CH2Cl2. The combined extracts were dried over MgSO4 and were evaporated to dryness. The crude product was purified by crystallization in refluxing isopropyl alcohol (10 vol). The yield of phenylpyridazin-4-yl-methanone (12) obtained was 5.8 g or 66%. MS (ESI+): [M+H]+=185.33; 1H NMR (300 MHz, CDCl3), δ ppm: 7.5-7.60 (m, 2H), 7.64-7.83 (m, 4H), 9.42-9.51 (m, 2H).
Reaction SMILES: C[N:2]([CH3:32])/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[C:9]([S:17]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([N:27]3[CH:31]=[N:30][N:29]=[CH:28]3)[CH2:22]2)(=[O:19])=[O:18])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)=O.N[C:34]1[CH:38]=C[NH:36][N:35]=1>C(O)(=O)C>[N:35]1[N:36]2[C:5]([C:7]3[CH:8]=[C:9]([S:17]([NH:20][C@H:21]4[CH2:26][CH2:25][CH2:24][C@@H:23]([N:27]5[CH:28]=[N:29][N:30]=[CH:31]5)[CH2:22]4)(=[O:18])=[O:19])[CH:10]=[C:11]([C:13]([F:14])([F:16])[F:15])[CH:12]=3)=[CH:4][CH:3]=[N:2][C:32]2=[CH:38][CH:34]=1
Reactant: CN(C)/C=C/C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N[C@H]2CCC[C@@H](n3cnnc3)C2)c1
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Product: O=S(=O)(N[C@H]1CCC[C@@H](n2cnnc2)C1)c1cc(-c2ccnc3ccnn23)cc(C(F)(F)F)c1
Temperature: 110 °C

Procedure:
A mixture of 9b (40.0 mg, 0.085 mmol) and 3-aminopyrazole (8.5 mg, 0.102 mmol) in acetic acid (1.50 mL) was placed in a sealed tube and heated in a microwave reactor at 110° C. for 20 min. After cooling to rt, the reaction mixture was concentrated in vacuo, resuspended in 10% NH4OH/MeOH and reconcentrated. The crude residue was purified by preparative thin layer chromatography on silica gel (10% MeOH/DCM as eluent) to afford the title compound, 9c. m/z (ES) 492 (MH)+; IC50=5.9 nM
Reaction SMILES: [OH:1][C@@H:2]([C@@H:9]([CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)[C:10]([O:12]C(C)C)=[O:11])[C:3]([O:5]C(C)C)=[O:4].[OH-].[K+].Cl>C1COCC1.O>[OH:1][C@@H:2]([C@@H:9]([CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:23][CH:24]=1)[C:10]([OH:12])=[O:11])[C:3]([OH:5])=[O:4]
Reactant: CC(C)OC(=O)[C@@H](O)[C@@H](CCCc1ccc(OC(F)(F)F)cc1)C(=O)OC(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H](O)[C@@H](CCCc1ccc(OC(F)(F)F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 110.9 %

Procedure:
To a solution of diisopropyl (2S,3R)-2-hydroxy-3-{3-[4-(trifluoromethoxy)phenyl]propyl}butanedioate (6.98 g; 16.6 mmol; 1.0 eq.) in THF/water (3/1; 140 mL) was added potassium hydroxide (5.59 g; 99.6 mmol; 6.0 eq.). The reaction mixture was then stirred for 14 h at RT. The aq. layers were acidified with an aqueous solution of HCl to pH 2, extracted with EtOAc. The combined organic layers were then dried over MgSO4 and evaporated to give the title compound as an oil (6.19 g), used in the next steps without further purification.