Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:14](Cl)(=O)=O)[C:12]=1[Cl:13])[C:7]([OH:9])=[O:8])([O-])=O>C(O)(=O)C.Cl>[ClH:13].[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([SH:14])[C:12]=1[Cl:13])[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: CC(=O)O
Product: Nc1cc(C(=O)O)cc(S)c1Cl

Procedure:
A solution of 3-nitro-4-chloro-5-chlorosulfonylbenzoic acid (33 g.; 0.11 mole) in acetic acid (550 ml.) is warmed to 70° C. on a water bath and treated in one portion with a solution of stannous chloride dihydrate (226 g.; 1.0 mole) in concentrated hydrochloride acid (190 ml.). The reaction is stirred at 70°-80° C. for one-half hour, chilled in ice and the tin complex which separates is filtered, rinsed with acetic acid and dissolved in water (300 ml.). The solution is treated with concentrated hydrochloric acid (150 ml.) whereupon 3-amino-4-chloro-5-mercaptobenzoic acid hydrochloride separates, m.p. = 239.5° C.; yield, 20.5 g. (77%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[CH:14]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.N1C=CC=CC=1>O>[CH:14]1([NH:22][C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[O:12])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCCCCC1
Reactant: O=C(Cl)c1cnc2ccccc2n1
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC1CCCCCCC1)c1cnc2ccccc2n1
Yield: 39.2 %

Procedure:
Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), cyclooctylamine (123 μL, 114 mg, 0.90 mmol), pyridine (5 mL), and water (100 mL) yielding 100 mg (39%) of (228):
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[N:9].[CH3:10][O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][CH2:16][C:17]2=O.B(F)(F)F.CCOCC>>[NH2:9][C:8]1[C:16]2[CH2:15][CH2:14][C:13]3[C:12]([O:11][CH3:10])=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]=2[N:1]=[C:2]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: N#Cc1ccccc1N
Reactant: COc1cccc2c1CCCC2=O
Agent: FB(F)F
Solvent: CCOCC
Product: COc1cccc2c1CCc1c-2nc2ccccc2c1N

Procedure:
2-amino-1-cyano-benzene (5.0 g, 42.3 mmol), 3, 4-dihydro-5-methoxy-[2H)-napthalen-1-one) (Aldrich Chemicals) (8.1 g, 46.0 mmol) and boron trifluoride diethyl etherate (1M, 5.7 ml, 46.6 mmol) were treated according to general procedure described herein to give the title compound.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][C:7](=[CH2:24])[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.CCCCCC>C(OCC)(=O)C>[CH3:24][C:7](=[CH2:6])[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1
Reactant: C=C(C)CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl[Sn]Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)CN1CCN(c2ccc(N)cc2)CC1
Yield: 73.5 %

Procedure:
Tin (II) chloride dihydrate (67.0 g, 297 mmol) was added in portions to a solution of 1-(2-methyl-allyl)-4-(4-nitro-phenyl)-piperazine (prepared as described in Reference Example 40, 13 g, 50 mmol) in ethyl acetate (200 mL) at room temperature. The mixture was heated to reflux for 4 hours then the solvent was evaporated under reduced pressure. The resulting residue was diluted with water and basified with 10% sodium hydroxide solution to pH ˜10 then extracted with ethyl acetate (4×100 mL). The combined organic layers were washed twice with saturated brine then dried over sodium sulfate. Filtration and concentration in vacuo gave a gummy mass which was washed repeatedly with small volumes of 1:3 ether/hexane to afford a solid. This was slurried with hexane, filtered and dried under vacuum at room temperature to afford 1-(2-methyl-allyl)-4-(4-amino-phenyl)-piperazine (8.5 g, 74%) as light yellow solid.
Reaction SMILES: NC1C2N(C3C=CC(NC(C4N(C)C5C(C=4)=CC=CC=5)=O)=C(OC)C=3)N=C(C3CCNCC3)C=2N=CN=1.C(=O)C.[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]\[C:44]([OH:46])=[O:45].[NH2:49][C:50]1[C:51]2[N:58]([C:59]3[CH:64]=[CH:63][C:62]([NH:65][C:66]([C:68]4[N:69]([CH3:77])[C:70]5[C:75]([CH:76]=4)=[CH:74][CH:73]=[CH:72][CH:71]=5)=[O:67])=[C:61]([O:78][CH3:79])[CH:60]=3)[N:57]=[C:56]([CH:80]3[CH2:85][CH2:84][N:83]([CH:86]4CCOC[CH2:87]4)[CH2:82][CH2:81]3)[C:52]=2[N:53]=[CH:54][N:55]=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]\[C:44]([OH:46])=[O:45].[NH2:49][C:50]1[C:51]2[N:58]([C:59]3[CH:64]=[CH:63][C:62]([NH:65][C:66]([C:68]4[N:69]([CH3:77])[C:70]5[C:75]([CH:76]=4)=[CH:74][CH:73]=[CH:72][CH:71]=5)=[O:67])=[C:61]([O:78][CH3:79])[CH:60]=3)[N:57]=[C:56]([CH:80]3[CH2:85][CH2:84][N:83]([CH2:86][CH3:87])[CH2:82][CH2:81]3)[C:52]=2[N:53]=[CH:54][N:55]=1
Reactant: COc1cc(-n2nc(C3CCN(C4CCOCC4)CC3)c3ncnc(N)c32)ccc1NC(=O)c1cc2ccccc2n1C
Agent: CC=O
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Agent: COc1cc(-n2nc(C3CCNCC3)c3ncnc(N)c32)ccc1NC(=O)c1cc2ccccc2n1C
Solvent: CC#N
Product: CCN1CCC(c2nn(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)c3c(N)ncnc23)CC1

Procedure:
The title compound was prepared from N2-{4-[7-amino-3-(4-piperidyl)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide and acetaldehyde in the manner described for the preparation N2-{4-[7-amino-3-(1-tetrahydro-2H-4-pyranyl-4-piperidyl)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide maleate: 1H NMR (DMSO-d6, 400 MHz) δ 9.49 (s, 1H), 9.10 (bs, 1H), 8.33 (s, 1H), 8.13 (d, 1H), 7.71 (d, 1H), 7.59 (d, 1H), 7.28-7.35 (m, 3H), 7.15 (m, 2H), 6.80 (bs, 2H), 6.01 (s, 2H), 4.04 (s, 3H), 3.94 (s, 3H), 3.62 (m, 2H), 3.38 (m, 1H), 3.16 (m, 4H), 2.26 (m, 4H), 1.27 (t, 3H); RP-HPLC (Hypersil HS C18, 5 μm, 100 A, 250×4.6 mm; 5%-100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 15.77 min; MS: MH+ 525.0, M−H+ 523.0
Reaction SMILES: I[C:2]1[C:3]([NH:14][C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:23][C:24]1[N:29]=[C:28]([S:30][CH3:31])[N:27]=[C:26]([Sn](CCCC)(CCCC)CCCC)[N:25]=1.[F-].[Cs+].O1CCOCC1>O.[Cu]I.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>[CH3:22][O:21][C:18]1[N:17]=[CH:16][C:15]([NH:14][C:3]2[C:2]([C:26]3[N:25]=[C:24]([CH3:23])[N:29]=[C:28]([S:30][CH3:31])[N:27]=3)=[CH:7][N:6]=[C:5]([N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[N:4]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(Nc2nc(N3CCCCC3)ncc2I)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C)nc(SC)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Nc2nc(N3CCCCC3)ncc2-c2nc(C)nc(SC)n2)cn1
Temperature: 140 °C
Yield: 21.7 %

Procedure:
A glass microwave reaction vessel was charged with 5-iodo-N-(6-methoxypyridin-3-yl)-2-(piperidin-1-yl)pyrimidin-4-amine (161 mg, 0.391 mmol), 2-methyl-4-(methylthio)-6-(tributylstannyl)-1,3,5-triazine (168 mg, 0.391 mmol), cesium fluoride (119 mg, 0.783 mmol), copper(I) iodide (15 mg, 0.078 mmol), tetrakis(triphenylphosphine)palladium(0) (45.2 mg, 0.039 mmol) and dioxane (2 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 30 min. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an orange solid. The crude product was purified by silica gel chromatography eluting with 40% EtOAc/Hexanes to give N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-2-(piperidin-1-yl)pyrimidin-4-amine (36 mg, 0.085 mmol, 21.66% yield). 1H NMR (300 MHz, CDCl3) δ 11.61 (s, 1H); 9.41 (s, 1H); 7.99 (d, J=8.48 Hz, 1H); 6.77 (d, J=8.77 Hz, 1H); 3.95 (s, 3H); 3.78-3.91 (m, 4H); 2.59 (s, 3H); 2.56 (s, 3H); 1.56-1.78 (m, J=2.63 Hz, 6H). m/z (ESI, +ve ion) 425.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCCCCCO)cc1
Temperature: 100 °C

Procedure:
2.44 g (0.02 mol) of 4-hydroxybenzaldehyde, 2.73 g (0.02 mol) of 6-chlorohexanol, 1.66 g (0.012 mol) of potassium carbonate and 20 ml of N,N-dimethylformamide were put in a three-neck 50 ml-flask equipped with a stirrer and a thermometer and heated at 100° C. for 2 hours with stirring. The reaction mixture was cooled to room temperature, poured into water containing ice and extracted with ethyl acetate. The resulting extract was dried with anhydrous sodium sulfate, and ethyl acetate was removed therefrom by distillation. The oily residue was allowed to stand at room temperature, whereupon it gradually crystallized. By silica gel thin layer chromatography (using a developer of ethyl acetate), the purity of the crystals was high. The yield of the product was 4.4 g (99.0%).
Reaction SMILES: CN(C)[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])=[O:6].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=1.O>CCO>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH:24][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])=[O:6])[CH3:23])=[CH:18][CH:17]=1
Reactant: CN(C)CCC(=O)c1ccccc1F
Reactant: C[C@H](N)c1ccc(Br)cc1
Solvent: CCO
Solvent: O
Product: C[C@H](NCCC(=O)c1ccccc1F)c1ccc(Br)cc1
Yield: 3.3 %

Procedure:
A solution of 3-dimethylamino-1-(2-fluoro-phenyl)-propan-1-one (17 g, 0.087 mol) and (S)-1-(4-bromophenyl)ethanamine (17 g, 0.087 mol) in EtOH (50 mL)/H2O (50 mL) was refluxed at 80° C. over night. The solvent was removed under vacuum. The residue was purified by column chromatography to afford (S)-3-(1-(4-bromophenyl)ethylamino)-1-(2-fluorophenyl)propan-1-one (1 g, 3%).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([OH:21])=[O:20])=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH2:5][CH2:6][CH3:7]>C(Cl)Cl>[CH2:4]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([O:21][CH3:3])=[O:20])=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH2:5][CH2:6][CH3:7]
Reactant: C=[N+]=[N-]
Reactant: CCCCc1c[nH]c2cc(C(=O)O)ccc2c1=O
Solvent: ClCCl
Product: CCCCc1c[nH]c2cc(C(=O)OC)ccc2c1=O

Procedure:
Diazomethane was added to a solution in methylene chloride of the product of Step D until a persistent yellow color was obtained. The excess diazomethane was destroyed with acetic acid and the medium was evaporated t dryness to obtain the expected product.
Reaction SMILES: C=C[C@@H]1[C@@H]2C[C@@H]([C@H](O)C3C4C(=CC=CC=4)N=CC=3)N(CC2)C1.[CH2:23]([CH:29]([N:33]1[CH:37]=[C:36]([N+:38]([O-:40])=[O:39])[N:35]=[CH:34]1)[C:30]([OH:32])=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].Cl>O.C(N(CC)CC)C.C(O)C>[CH2:23]([C@@H:29]([N:33]1[CH:37]=[C:36]([N+:38]([O-:40])=[O:39])[N:35]=[CH:34]1)[C:30]([OH:32])=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCC(C(=O)O)n1cnc([N+](=O)[O-])c1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCC[C@H](C(=O)O)n1cnc([N+](=O)[O-])c1
Temperature: 85 °C

Procedure:
To a suspension of 5.89 g (0.02 mol) of (-)-cinchonidine in 80 mL water was added 2.78 mL (2.02 g, 0.02 mol) triethylamine. The mixture was warmed to about 40°-45° C. A solution of 10.21 g (0.04 mol) of a racemic mixture of α-hexyl-4-nitro-1H-imidazole-1-acetic acid in 40 mL technical grade ethanol was added to the warm suspension with stirring. (The pH of the mixture was adjusted to 6.9-7.4 by addition of triethylamine or aqueous hydrochloric acid as required.) The resulting suspension was then heated to about 85° C. The resulting solution was allowed to cool gradually to ambient temperature with slow stirring. The precipitated salt was filtered, washed with about 30 mL of ethanol --H2O(1:2), and dried at 50° C. in vacuo to constant weight. The reaction produced 9 g of (R)-α-hexyl-4-nitro-1H-imidazole-1-acetic acid)-cinchonidine salt. A portion of the product was converted to the free acid and then derivatized as the methyl ester (diazomethane) and analyzed by HPLC on a chiral column. The analysis indicated that the acid derived from the product had an ee of 94%. Recrystallization of the product salt from ethanol--water 1:1 (13:1 volumes) provided 7.4 g of the pure salt, ee>99% (HPLC), M.Pt. 205° C. (dec). (NMR).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5][SH:6])[CH3:2].[H-].[Na+].Br[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>CN(C=O)C>[CH:15]([C:14]1[CH:17]=[CH:18][C:11]([S:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:7])=[CH:12][CH:13]=1)=[O:16]
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ccc(C=O)cc1
Reaction time: 0.17 h
Yield: 59.9 %

Procedure:
The compound was prepared according to general procedure E. To a solution of ethyl-2-mercaptoacetate (1.7 mmol) in dry DMF (5 ml), sodium hydride (2.0 mmol) was added at 0° C. After 10 minutes, 4-bromobenzaldehyde (1.4 mmol) was added and the mixture was heated for 3 hours. After cooling, the solvent was removed under reduced pressure. The residue was chromatogaphed on a silica gel column (cyclohexane/ethyl acetate 9/1 as eluent) to give 188 mg of ethyl 2-(4-formylphenythio)acetate (yield 59%). 1H NMR (250 MHz, CDCl3): δ 1.23 (t, J=7.5 Hz, 3H), 3.73 (s, 2H), 4.18 (q, 2H), 7.42 (d, J=8.75 Hz, 2H), 7.76 (d, J=8.75 Hz, 2H), 9.93 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[NH:10][N:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:2]2[CH:3]=[C:4]3[NH:10][N:9]=[CH:8][C:5]3=[N:6][CH:7]=2)[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1
Reactant: Brc1cnc2cn[nH]c2c1
Reactant: COc1cc(OC)cc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(OC)cc(-c2cnc3cn[nH]c3c2)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
A mixture of 6-bromo-1H-pyrazolo[4,3-b]pyridine (0.3 g, 2 mmol)(Annova Chem Cat. No. L05238), (3,5-dimethoxyphenyl)boronic acid (0.33 g, 1.8 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (100 mg, 0.1 mmol), and potassium phosphate (0.64 g, 3.0 mmol) in 1,4-dioxane (1 mL) and water (0.12 mL) was degassed and sealed. It was stirred at 85° C. overnight. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.38 g). LCMS (M+H)+=256.2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][S:20]([N:23]1[CH2:28][CH2:27][NH:26][C:25]([CH3:30])([CH3:29])[CH2:24]1)(=[O:22])=[O:21]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:26]3[CH2:27][CH2:28][N:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH2:24][C:25]3([CH3:30])[CH3:29])=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)CN(S(C)(=O)=O)CCN1
Product: CC1(C)CN(S(C)(=O)=O)CCN1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and 1-methanesulfonyl-3,3-dimethyl-piperazine using procedure C yielded 2-chloro-6-(4-methanesulfonyl-2,2-dimethyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This compound was subjected to procedure A to yield the desired final compound which was purified using flash chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CN(C)C=O.CC1(C)C2CCC1(CS(O)(=O)=O)C(=O)C2.[NH:34]1[CH2:38][CH2:37][C@@:36]2([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[C:40](=[O:47])[O:39]2)[CH2:35]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:34]3[CH2:38][CH2:37][C@@:36]4([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=5[C:40](=[O:47])[O:39]4)[CH2:35]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Reactant: O=C1O[C@]2(CCNC2)c2ccccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(Br)cc4)CC3)C2)c2ccccc21
Reaction time: 17 h
Yield: 89.9 %

Procedure:
To a stirred solution of 1-(4-bromophenyl)cyclopropanecarboxylic acid (1.616 g, 0.006704 mol) in anhydrous N,N-dimethylformamide (12.0 mL, 0.155 mol) at room temperature was added (7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid -(1R)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (1:1) (2.569 g, 0.006095 mol, example 96, steps 1-2), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (3.057 g, 0.006704 mol), followed by N,N-diisopropylethylamine (4.27 mL, 0.0244 mol). The resulting clear solution was stirred at temperature for 17 hours. LCMS showed that the reaction was complete. The reaction was quenched with saturated aqueous NaHCO3 (50 mL), and the reaction miture was extracted with EtOAc (2×). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by Combiflash with 30-70% EtOAc/hexanes to give the product as a colorless solid (2.258 g, 90% in yield). LC/MS (M+H+)=412.1.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Cl>>[CH2:7]([O:6][P:4]([O:3][CH2:1][CH3:2])([CH:9]([CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([O:18][CH3:17])[CH:20]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:5])[CH3:8]
Reactant: COc1cccc(CCl)c1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(Cc1cccc(OC)c1)P(=O)(OCC)OCC
Yield: 76 %

Procedure:
By working in a way similar to that described in example 11 and by using ethyl diethoxyphosphinylacetate (59 g; 0.26 moles), sodium hydride at 60% (9.33 g; 0.233 moles) and 3-methoxybenzyl chloride (20.62 g; 0.13 moles), ethyl 2-diethoxyphosphinyl-3-(3-methoxyphenyl)-propionate (34 g; 76% yield) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N+:13]([C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27])([O-:15])=[O:14]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:26]([C:17]2[CH:18]=[CH:19][C:20]([C:22]([F:24])([F:25])[F:23])=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])(=[O:27])=[O:28])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: Nc1ccc(Cl)c2cccnc12
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Yield: 99.3 %

Procedure:
In a similar fashion using route 14 general procedure 26, 5-chloroquinolin-8-amine (Intermediate 27) (50 mg, 0.28 mmol), 2-nitro-4-(trifluoromethyl)benzene-1-sulfonyl chloride (162 mg, 0.56 mmol) gave the title compound (120 mg, 50%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4]Cl.[C:8]([O-:16])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[K+].[I-].[K+].CN(C)C=O>C(OCC)(=O)C.O>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][O:16][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C([O-])c1ccccc1
Reactant: COC(CCl)OC
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(COC(=O)c1ccccc1)OC
Temperature: 25 °C
Yield: 72.3 %

Procedure:
Chloroacetaldehyde dimethyl acetal (50.0 g), potassium benzoate (70.7 g), potassium iodide (6.66 g) and DMF (N,N-dimethylformamide) (250 mL) were placed in a three-neck flask, followed by refluxing. Twenty hours later, the reaction mixture was cooled to room temperature, and water (250 mL) and ethyl acetate (250 mL) were added thereto, followed by stirring. After filtration, the filtrate was extracted with ethyl acetate (500 mL). The organic layer was subjected to vacuum concentration and then to vacuum distillation at 132-135° C. and at 5 mmHg and thereby yielded the target compound (61.0 g) in a yield of 72%.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[C:14]2[NH:13][C:12](=[O:15])[N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10]=2[CH:9]=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C>[C:20]([O:19][C:17](=[O:18])[CH2:16][N:11]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[C:14]=2[N:13]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:12]1=[O:15])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)CCCBr
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2c([N+](=O)[O-])cccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCn1c(=O)n(CC(=O)OC(C)(C)C)c2cccc([N+](=O)[O-])c21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (26.7 mg of a 60% dispersion in mineral oil, 0.66 mmol) was added to a solution of tert-butyl (4-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate from Step A (96 mg, 0.327 mmol) in DMF (5 mL). After 10 min, methyl 4-bromobutyrate (178 mg, 0.98 mmol) was added and the reaction was stirred at room temperature for 18 h. The mixture was quenched with H2O and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=394 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].C[NH:13][C@@H:14]1[CH2:19][CH2:18]CC[C@H:15]1[NH:20][CH3:21].BrC1C=C(N)C=NC=1>[Cu](I)I.O.CN(C)C(=O)C>[N:1]1([C:18]2[CH:19]=[C:14]([NH2:13])[CH:15]=[N:20][CH:21]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CN[C@@H]1CCCC[C@H]1NC
Agent: I[Cu]I
Agent: Nc1cncc(Br)c1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1cncc(-n2ccnc2)c1
Temperature: 150 °C
Reaction time: 14.5 h
Yield: 31 %

Procedure:
Imidazole (42 mg), cesium carbonate (340 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (74 mg), and copper iodide (50 mg) were added to a tube containing a N,N-dimethylacetamide (2 ml) solution containing 5-bromopyridin-3-amine (90 mg) in a nitrogen atmosphere and the tube was sealed, followed by stirring at 150° C. for 14.5 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (chloroform:methanol=1:0 to 10:1), and a brown solid of 5-(1H-imidazol-1-yl)pyridin-3-amine (25.8 mg) was thus obtained.