Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]([CH2:18]C)[CH2:14][CH2:15][O:16][CH3:17])=[N:10][C:9]=2[C:20]2[C:21]([F:36])=[C:22]([NH:26][S:27]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1.[NH4+:37].[OH-]>O.Cl.C(Cl)Cl>[NH2:37][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:20]2[C:21]([F:36])=[C:22]([NH:26][S:27]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)(=[O:28])=[O:29])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCN(CCOC)c1nc(-c2cccc(NS(=O)(=O)C3CCCCC3)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)C3CCCCC3)c2F)n1
Temperature: 120 °C
Yield: 41 %

Procedure:
N-[3-(5-(2-Chloro-4-pyrimidinyl)-2-{ethyl[2-(methyloxy)ethyl]amino}-1,3-thiazol-4-yl)-2-fluorophenyl]cyclohexanesulfonamide (148 mg, 0.275 mmol) was suspended in NH4OH (4 mL) and heated in microwave reactor at 120° C. for 48 min. The reaction was diluted with water and neutralized with 5% aqueous HCl and solid formed. A solid was diluted with DCM and water. The organic layer was dried over Na2SO4, filtered, added silica gel and concentrated. The crude product was chromatographed on silica gel eluting with 100% DCM to 1:1 [DCM:(9:1 EtOAC:MeOH)]. The clean fractions were combined and concentrated. The product was triturated in diethyl ether and filtered to obtain the title compound as a yellow powder (58 mg, 41% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.67 (s, 1H), 7.87 (d, J=5.3 Hz, 1H), 7.43-7.62 (m, 1H), 7.09-7.41 (m, 2H), 6.35-6.74 (m, 2H), 5.80 (d, J=5.3 Hz, 1H), 3.68 (t, J=4.6 Hz, 4H), 3.43 (t, J=4.6 Hz, 4H), 2.81-3.02 (m, 1H), 1.69 (d, J=12.5 Hz, 2H), 1.51 (br. s., 1H), 1.33 (qd, J=12.1, 2.2 Hz, 2H), 0.89-1.22 (m, 5H). MS (ESI): 518.9 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH3:5])C.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>CO>[CH3:13][N:14]([CH3:16])[CH:15]=[CH:5][C:4](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[O:3][CH3:1]
Reactant: COC(OC)N(C)C
Reactant: CCOC(C)=C(C#N)C#N
Solvent: CO
Product: COC(C=CN(C)C)=C(C#N)C#N
Temperature: 25 °C
Yield: 36.6 %

Procedure:
To a mixture of D1 (34 g, 250 mmol) in MeOH (300 ml) was added N,N-dimethylformamide dimethyl acetal (44.68 g, 375 mmol). The reaction mixture was heated at reflux for 2 h. The mixture was then cooled to room temperature and a dark red solid precipitated upon cooling. The solid was filtered off, washed with cold methanol and dried in vacuo to yield compound D2 (16.2 g, 38%) as a red solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([NH2:21])=O)=[CH:15]2)(=[O:8])=[O:7].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19](=[S:31])[NH2:21])=[CH:15]2)(=[O:8])=[O:7]
Reactant: NC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: NC(=S)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 40 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.66 g), Lawesson's reagent (0.88 g) and tetrahydrofuran (20 mL) was stirred at 40° C. overnight. The reaction mixture was concentrated, the obtained residue was subjected to silica gel column chromatography, and the title compound (0.61 g, yield 86%) was obtained as yellow crystals from a fraction eluted with tetrahydrofuran-hexane (3:2, volume ratio). melting point 249-250° C. (decomposition).
Reaction SMILES: [Br-].[Na+].[C:3]([O-:11])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Na+].Cl[CH2:14][CH:15]1[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]1>CN(C)C=O>[C:3]([O:11][CH2:14][CH:15]1[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC1(C)OCC(CCl)O1
Reactant: O=C([O-])c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(COC(=O)c2ccccc2)O1
Temperature: 150 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
Then, sodium bromide (43.01 g, 0.42 mol) and sodium benzoate (60.24 g, 0.42 mol) were added to a mixture of the above 4-chloromethyl-2,2-dimethyl-1,3-dioxolane (60.02 g, 0.39 mol) and N,N-dimethylformamide (600 ml) and the resulting mixture was stirred for 15 hours at 150° C. After cooling the salt was filtered off and N,N-dimethylformamide was removed in vacuo and water was added to the residue and extracted with toluene. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and condensed in vacuo to give crude 4-benzoyloxymethyl-2,2-dimethyl-1,3-dioxolane (yield 90%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[O:10][C:11]([CH3:14])=[CH:12][CH:13]=2)O1.Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:32]3[C:27](=[CH:28][C:29]([S:33]([NH:36][C:37]4[CH:42]=[CH:41][N:40]=[CH:39][N:38]=4)(=[O:35])=[O:34])=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)=[C:19]([O:43][CH3:44])[CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:44][O:43][C:19]1[CH:18]=[C:17]([C:9]2[O:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[C:32]2[C:27](=[CH:28][C:29]([S:33]([NH:36][C:37]3[CH:42]=[CH:41][N:40]=[CH:39][N:38]=3)(=[O:34])=[O:35])=[CH:30][CH:31]=2)[CH:26]=[CH:25][N:24]=1
Reactant: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)o1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2ccc(C)o2)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 150 °C

Procedure:
A microwave vial charged with Pd(Amphos)2Cl2 (0.012 g, 0.018 mmol), 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolane (0.073 g, 0.351 mmol), 1-(4-chloro-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (From Example 160; 0.075 g, 0.176 mmol), potassium phosphate (0.149 g, 0.703 mmol), 1.5 mL dioxane and 0.25 mL water was heated to 150° C. in the microwave for 30 minutes. LC/MS showed mostly product. The aqueous layer was removed, and the reaction mixture was treated with HCl (4N in dioxane). Purification of the crude residue by reverse phase column chromatography [RediSep Gold C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave the titled compound.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>C(O)C>[N:20]1([C:2]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNC1
Reactant: Cc1ccccc1Nc1nc(Cl)nc2ccccc12
Solvent: CCO
Product: Cc1ccccc1Nc1nc(N2CCCC2)nc2ccccc12
Yield: 65.2 %

Procedure:
2-chloro-4-(2-methylphenylamino)quinazoline (5 g, 0.0185 mol) and pyrrolidine (6.59 g, 0.093 mol) were dissolved in ethanol (65 ml) placed in a sealed vessel and heated to 135° for 5 hours. After cooling, the reaction mixture was dissolved in ethanol and then evaporated in vacuo. The oily residue afforded crystals of 2-pyrrolidino-4-(2-methylphenylamino)quinazoline (3.67 g, 65%) from ethanol/water, m.p. 152°-154°.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:44][CH:45]([F:47])[F:46])=[C:12]([C:14]2[C:18]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[N:27][C:26]=34)=[O:21])=[CH:17][N:16]([CH2:31][C:32]([N:34]3[CH2:39][CH2:38][CH:37]([C:40]([O:42]C)=[O:41])[CH2:36][CH2:35]3)=[O:33])[N:15]=2)[CH:13]=1.Cl>O.CO>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:44][CH:45]([F:46])[F:47])=[C:12]([C:14]2[C:18]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[N:27][C:26]=34)=[O:21])=[CH:17][N:16]([CH2:31][C:32]([N:34]3[CH2:35][CH2:36][CH:37]([C:40]([OH:42])=[O:41])[CH2:38][CH2:39]3)=[O:33])[N:15]=2)[CH:13]=1
Reactant: COC(=O)C1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(Nc1cn(CC(=O)N2CCC(C(=O)O)CC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
K2CO3 (500 mg, 3.59 mmol) in H2O (5 mL) was added to methyl 1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate (500 mg, 0.85 mmol) in methanol (10 mL). The resulting solution was stirred at 50° C. overnight and acidified with 1 N HCl to pH 2. The solids were collected by filtration. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (30.0% MeCN up to 34.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 30.0% in 2 min); Detector, UV 254/220 nm. This resulted in 390 mg (80%) of 1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-acetyl)piperidine-4-carboxylic acid as a light yellow solid. LCMS (Method 28) [M+H]+=574.1, RT=1.11 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 12.34 (s, 1H), 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.29-5.19 (m, 2H), 4.28-4.18 (m, 1H), 3.87-3.84 (m, 1H), 3.19-3.13 (m, 1H), 2.83-2.77 (m, 1H), 1.86-1.85 (m, 2H), 1.60-1.57 (m, 1H), 1.43-1.41 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:11]2[N:6]([C:7]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][C:17]4=[O:22])=[CH:12][C:8]=3[O:9][CH2:10]2)[C:5](=[O:23])[O:4]1.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][CH2:2][C@H:3]2[C@H:11]3[N:6]([C:7]4[CH:15]=[CH:14][C:13]([N:16]5[CH2:21][CH2:20][O:19][CH2:18][C:17]5=[O:22])=[CH:12][C:8]=4[O:9][CH2:10]3)[C:5](=[O:23])[O:4]2)=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12)c1ccc(Cl)cc1
Yield: 83.68 %

Procedure:
Using compound (3S,3aS)-3-aminomethyl-7-(3-oxomorpholin-4-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1(3H)-one (the product of step (e) in Example 1) (60 mg, 0.188 mmol), p-chlorobenzoic acid (35 mg, 0.225 mmol), HATU (107 mg, 0.282 mmol), and TEA (38 mg, 0.376 mmol) as starting materials, preparation following the method as described in Example 11 (g) afforded white solid compound 72 mg, yield: 83.68%.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[C:14]1([CH2:20][CH2:21]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O.C(OCC)C>[C:14]1([CH2:20][CH2:21][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(CCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
A solution of diethyl malonate (6.07 ml, 40 mmol) in dimethyl formamide (60 ml) at 0° C. was treated portionwise with sodium hydride (1.6 g, 40 mmol, 60% dispersion in oil) and stirred for 0.25 h. 2-Phenylethyl bromide (5.48 ml, 40 mmol) in dimethylformarnmide (30 ml) was added dropwise. The mixture was warmed to room temperature and stirred for 1 h. The mixture was diluted with diethyl ether (300 ml), washed with water (4×200 ml), saturated brine (100 ml), dried (MgSO4) and evaporated. Flash chromatography on silica, eluting with 1% ethyl acetate in hexane, gave the title compound as a colourless oil (7.55 g, 71%); νmax (CH2Cl2), 1726 cm-1 ;
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)=[O:6].[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[O:6]=[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[CH2:4][CH2:3][CH2:2][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCl)c1ccc(Oc2ccccc2)cc1
Product: CCC(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(Oc4ccccc4)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(4-phenoxyphenyl)-1-butanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 471.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([O:29][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OS(C)(=O)=O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
8-(5-Fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 14-1, 61.1 mg, 0.136 mmol) was dissolved in anhydrous dichloromethane (1 mL), and triethylamine (44 μL, 0.319 mmol) and methanesulfonyl chloride (13 μL, 0.168 mmol) were added thereto successively. The reaction mixture was stirred at room temperature for hours and 15 minutes. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (68.3 mg) as a colorless amorphous product. (Yield 98%)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27](I)[CH:28]=[CH2:29].O>CN(C=O)C>[CH2:29]([N:13]1[C:14]2=[N:15][CH:16]=[N:17][C:18]([NH2:20])=[C:19]2[C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:12]1)[CH:28]=[CH2:27]
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1nc(-c2ccc3ccccc3c2)c2c(N)ncnc21
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.21 mmol) was dissolved in DMF (1.5 mL) and K2CO3 (110 mg, 0.8 mmol) and allyl iodide (23 μL, 0.25 mmol) were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 302.1, found 302.2.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH2:5][NH2:6])=[CH:14][CH:13]=1
Reactant: NCc1cccc(I)c1
Reactant: COc1ccc(S)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: COc1ccc(Sc2cccc(CN)c2)cc1
Yield: 88.9 %

Procedure:
The general procedure in example 39 was followed. 3-Iodobenzylamine (133 μL, 1.0 mmol), 4-methoxythiophenol (123 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 3-(4-methoxyphenyl)sulfanylbenzylamine (218 mg, 89% yield) as light yellow liquid. Column chromatographic solvent (CH2Cl2 (saturated with NH3)/MeOH=30/1). Rf=0.4 (CH2Cl2 (saturated with NH3)/MeOH=30/1), (Note: same Rf value as the starting material). 1H NMR (CDCl3, 300 MHz) δ 7.40 (dt, 2 H, J=1.8 Hz, 8.7 Hz), 7.19 (t, 1 H, J=7.8 Hz), 7.06-7.13 (m, 2 H), 7.01 (dt, 1 H, J=1.5 Hz, 7.5 Hz), 6.89 (dt, 2 H, J=2.1 Hz, 8.7 Hz), 3.82 (s, 3 H), 3.79 (s, 2 H), 1.40 (brs, 2 H). 13C NMR (CDCl3, 75 MHz) δ 159.9, 144.3, 139.0, 135.6, 129.3, 126.9, 126.7, 124.8, 124.3, 115.2, 55.7, 46.6. IR (neat, cm−1) 3373 (broad), 3072, 3060, 2939, 2836. MS (EI) m/z (relative intensity) 245 (100), 106 (60). HRMS (EI), Cald. for C14H15NOS 245.0869; Found 245.0862.
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.[CH3:8][N:9]1[C:13]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Cl)=[N:12][N:11]=[N:10]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][S:14][C:13]2[N:9]([CH3:8])[N:10]=[N:11][N:12]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCCCCCCCCCl
Reactant: Cn1nnnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCCCCCCSc1nnnn1C
Yield: 56.5 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g) is dissolved in acetone (50 ml). To the solution are added 1-methyl-5-(8-chlorooctyl)thio-1,2,3,4-tetrazole (4.1 g) and potassium carbonate (1.5 g) and the mixture is refluxed for 4 hours. Acetone is distilled off and water is added to the residue. The mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off and the residue is recrystallized from ethyl acetate-hexane to obtain 1-methyl-5-[8-(1-methyl-1,2,3,4-tetrazol-5-yl)thiooctyl]thio-1,2,3,4-tetrazole (2.0 g) as colorless needles, m.p. 52°-54° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[N:7]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:24]2[C:32]3[C:31]([CH:33]4[CH2:35][CH2:34]4)=[N:30][CH:29]=[N:28][C:27]=3[N:26]([S:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:38])=[O:37])[CH:25]=2)[OH:23])=[C:18]([F:45])[N:17]=1)[C:8]1[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]([O:5][C:6](=[O:46])[N:7]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[C:32]3[C:31]([CH:33]4[CH2:34][CH2:35]4)=[N:30][CH:29]=[N:28][C:27]=3[N:26]([S:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:37])=[O:38])[CH:25]=2)=[O:23])=[C:18]([F:45])[N:17]=1)[C:8]1[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn(S(=O)(=O)c4ccccc4)c4ncnc(C5CC5)c34)c(F)n2)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(=O)c3cn(S(=O)(=O)c4ccccc4)c4ncnc(C5CC5)c34)c(F)n2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
{5-[(7-Benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl}-(6-methoxy-pyridin-3-yl)-carbamic acid tert-butyl ester (75, 0.350 g, 0.541 mmol) is alternatively dissolved in 10.0 mL of dichloromethane, and Dess-Martin periodinane (0.211 g, 0.498 mmol) is added. The reaction is stirred at room temperature for 30 minutes, then concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 10-100% ethyl acetate in hexane. Appropriate fraction are combined and concentrated under vacuum to provide the desired compound (77, 340 mg). MS (ESI) [M+H+]+=645.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][N:6]([N:8]=O)[C:5]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:4]=2[O:3]1.[OH-].[Na+]>CO.O>[NH2:8][N:6]1[C:5]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:4]=2[O:3][C:2]([CH3:17])([CH3:1])[CH2:7]1
Reactant: CC1(C)CN(N=O)c2cc([N+](=O)[O-])ccc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CN(N)c2cc([N+](=O)[O-])ccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.6 %

Procedure:
In 69 ml of methanol was dissolved 2.29 g of 3,4-dihydro-2,2-dimethyl-6-nitro-4-nitroso-2H-1,4-benzoxazine and the solution was cooled on an ice bath. After addition of a solution of 1.16 g of sodium hydroxide in 8.1 ml of water to the above solution, 3.13 g of formamidinosulfinic acid was gradually added. The mixture was stirred at room temperature overnight and, then, concentrated. The concentrate was subjected to column chromatography (eluent: hexane;ethyl acetate=9:1) to give 0.4 g of 4-amino-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[CH2:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([NH:14][C@H:15]4[CH2:20][CH2:19][C@H:18]([CH2:21][NH:22]C(=O)OC(C)(C)C)[CH2:17][CH2:16]4)=[N:11][C:10]=3[C:4]=2[CH:3]=1>CCOC(C)=O.Cl.O1CCOCC1>[NH2:22][CH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([NH:14][C:12]2[S:13][C:9]3[CH2:8][CH2:7][CH2:6][C:5]4[CH:30]=[CH:31][C:2]([F:1])=[CH:3][C:4]=4[C:10]=3[N:11]=2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NC[C@H]1CC[C@H](Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1

Procedure:
A solution of trans-tert-butyl N-({4-[(9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazol-2-yl)amino]cyclohexyl}-methyl)carbamate (34.5 g, 77.0 mmol) in 200 ml EtOAc and 100 ml 4N HCl in dioxane was stirred at room temperature for 2 hours. The resulting solid was collected by filtration and the solid product washed with Et2O and dried under vacuum to yield 25.9 g of the desired product as a pale yellow solid. An additional 1.43 g of the product was obtained by allowing the filtrate to stand in a closed flask for several days. The overall yield was 85%: 1H-NMR (CD3OD) δ 1.25 (2H, m), 1.51 (2H, m), 1.70 (1H, broad), 1.95 (2H, m), 2.18 (4H, m), 2.80 (6H, m), 3.63 (1H, broad), 7.11 (1H, dt, J=2.5 Hz, 8.4 Hz), 7.36 (2H, m); 346 (ESMS, MH+).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[CH:6]([OH:29])[CH:7]([NH:11][C:12]([C@@H:14]2[C@H:18]3[CH2:19][CH2:20][CH2:21][C@H:17]3[CH2:16][N:15]2C(OC(C)(C)C)=O)=[O:13])[CH2:8][CH2:9][CH3:10])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5](=[O:30])[CH:6]([OH:29])[CH:7]([NH:11][C:12]([C@@H:14]2[C@H:18]3[CH2:19][CH2:20][CH2:21][C@H:17]3[CH2:16][NH:15]2)=[O:13])[CH2:8][CH2:9][CH3:10])[CH2:3][CH2:2]1
Reactant: CCCC(NC(=O)[C@@H]1[C@H]2CCC[C@H]2CN1C(=O)OC(C)(C)C)C(O)C(=O)NC1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(NC(=O)[C@H]1NC[C@@H]2CCC[C@@H]21)C(O)C(=O)NC1CC1

Procedure:
Compound 12 (0.845 g, 2 mmol) is treated with TFA (5 ml) in DCM (10 ml) at 0° C. for 2 hr. The mixture is evaporated to dryness. The yellow syrup so obtained is dissolved in DCM (20 ml) to make a stock solution of 13 (0.1 M) for the next step.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=1F>O1CCCC1>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=1[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1
Reactant: Nc1ccc(Br)c(F)c1[N+](=O)[O-]
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccc(Br)c(OCC2CC2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
A solution of cyclopropyl carbinol (0.269 mL, 3.40 mmol) in tetrahydrofuran (6.9 mL) at 0° C. was treated with sodium hydride (0.0860 g, 3.40 mmol) and stirred at RT for 30 min. The reaction mixture was cooled to 0° C., treated with 4-bromo-3-fluoro-2-nitroaniline (0.400 g, 1.70 mmol) [Combi-Blocks, AN-2785] and stirred at RT for 15 h. The reaction mixture was cooled to 0° C. and quenched with saturated ammonium chloride solution. The reaction mixture was diluted with ethyl acetate (50 mL) and water (40 mL). The organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated to give crude oil. Purification by flash column chromatography (100% hexanes to 40% EtOAc/hexanes) gave the desired product (0.365 g, 75%). LCMS calculated for C10H12BrN2O3 (M+H)+: m/z=287.1. found: 286.8.