Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[N+:30]([C:33]1[CH:60]=[CH:59][C:36]([CH2:37][O:38][C:39]([NH:41][CH2:42][CH2:43][S:44]([NH:47][CH2:48][C:49]([C:51]2[N:52]=[CH:53][N:54]3[CH:58]=[CH:57][S:56][C:55]=23)=[O:50])(=[O:46])=[O:45])=[O:40])=[CH:35][CH:34]=1)([O-:32])=[O:31].[Cl-].[NH4+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[N+:30]([C:33]1[CH:34]=[CH:35][C:36]([CH2:37][O:38][C:39]([NH:41][CH2:42][CH2:43][S:44]([NH:47][CH2:48][C:49]([C:51]2[N:52]=[CH:53][N:54]3[CH:58]=[C:57]([Sn:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])[S:56][C:55]=23)=[O:50])(=[O:46])=[O:45])=[O:40])=[CH:59][CH:60]=1)([O-:32])=[O:31]
Reactant: O=C(NCCS(=O)(=O)NCC(=O)c1ncn2ccsc12)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)CNS(=O)(=O)CCNC(=O)OCc3ccc([N+](=O)[O-])cc3)c2s1
Reaction time: 0.5 h

Procedure:
Tri-n-butylstannyl chloride (0.83 ml) and 7.3 ml of a 1.0 N lithiumbis(trimethylsilyl)amide/THF solution were sequentially added at −73° C. in an argon atmosphere to a solution of 682 mg of 7-[2-(4-Nitrobenzyloxycarbonyl)aminoethane-sulfonylamino]acetylimidazo[5,1-b]thiazole in 16 ml of THF and 3 ml of HMPA. The mixture was stirred at the same temperature for 30 min. An aqueous ammonium chloride solution was added to the reaction solution. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1-1:2) to give 327 mg of the title compound.
Reaction SMILES: Cl.C([N:9]1[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1)C1C=CC=CC=1.O>CO.[Pd]>[C:17]1([CH:11]2[C:12](=[O:16])[CH2:13][CH2:14][CH2:15][NH:9][CH2:10]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCCN(Cc2ccccc2)CC1c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1CCCNCC1c1ccccc1

Procedure:
22.1 g of 1-benzyl-3-phenyl-perhydro-azepin-4-one hydrochloride are dissolved in 250 ml of methanol and 10 ml of water and hydrogenated with 2.5 g of Pd/C (10%) for 3 hours under 5 bar of H2. Then another 2.5 g of catalyst are added and the hydrogenation step is repeated. The catalyst is filtered off and the mixture is evaporated down. The residue is recrystallised from ethanol. Yield: 8.2 g
Reaction SMILES: [NH2:1][CH:2]1[CH2:17][C:6]2[C:7]3[NH:8][C:9](=[O:16])[C:10](=[O:15])[NH:11][C:12]=3[CH:13]=[CH:14][C:5]=2[CH2:4][CH2:3]1.[N+:18]([O-])([OH:20])=[O:19]>FC(F)(F)C(O)=O>[NH2:1][CH:2]1[CH2:17][C:6]2[C:7]3[NH:8][C:9](=[O:16])[C:10](=[O:15])[NH:11][C:12]=3[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:5]=2[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])O
Reactant: NC1CCc2ccc3[nH]c(=O)c(=O)[nH]c3c2C1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
A mixture of 9-amino-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione and trifluoroacetic acid (10 mL) was cooled in an ice bath and then treated with fuming nitric acid (0.5 mL) and stirred for 3 h at 0° C. and then 1 h at room temperature. After removing the solvent by rotoevaporation, the residue was triturated with acetone and the resulting solid collected by filtration to give the product (0.22 g, 93% yield). The solid was stirred in 2N HCl for 15 min, collected by filtration and dried to give the hydrochloride salt. Anal. calc'd for C12H12N4O4.HCl.H2O--C, 43.58; H, 4.57; N, 16.94; found -C, 43.56; H, 4.08; N, 16.51.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[C:12](=[O:20])[C:11]([CH3:22])([CH3:21])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:23]([CH:25]1[O:27][CH2:26]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:23][CH:25]4[O:27][CH2:26]4)=[CH:16][CH:17]=3)[C:12](=[O:20])[C:11]([CH3:22])([CH3:21])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: ClCC1CO1
Reactant: CC1(C)CC(c2ccc(Cl)c(Cl)c2)c2ccc(O)cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CC(c2ccc(Cl)c(Cl)c2)c2ccc(OCC3CO3)cc2C1=O
Yield: 94 %

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-7-hydroxy-2,2-dimethyl-1-tetralone (2.9 g), epichlorohydrin (10 ml) and potassium carbonate (2 g) was heated under reflux in acetone (10 ml) for 24 hr. The hot mixture was filtered and evaporation of the filtrate in vacuo gave 4-(3,4-dichlorophenyl)-7-(2,3-epoxypropoxy)-2,2-dimethyl-1-tetralone as a yellow gum (3.2 g, 94%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br/[CH:41]=[CH:42]/[CH2:43][C:44]([CH2:55][CH3:56])([O:47][Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50])[CH2:45][CH3:46].[H-].[Na+].C1OCCOCCOCCOCCOC1>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24]/[CH:41]=[CH:42]/[CH2:43][C:44]([CH2:55][CH3:56])([O:47][Si:48]([CH2:53][CH3:54])([CH2:49][CH3:50])[CH2:51][CH3:52])[CH2:45][CH3:46])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(CC)(C/C=C/Br)O[Si](CC)(CC)CC
Reactant: CC(C)(O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(C/C=C/OC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)O[Si](CC)(CC)CC
Yield: 61.6 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene (400 mg, 0.698 mmol), 1-bromo-4-ethyl-4-triethylsilyloxy-(2E)-hexene (0.897 g, 2.79 mmol), sodium hydride (60% in oil, 0.168 g, 4.188 mmol), 15-crown-5 (0.14 ml, 0.698 mmol) and tetrahydrofuran (12 ml) were subjected to reaction using a procedure similar to that of Example 5(1) (3 hours), worked up and purified by column chromatography (hexane:toluene=2:1) to give the titled compound (0.35 g, 62%) as a yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][CH2:22][CH2:23]OS(C)(=O)=O)=[CH:18][CH:19]=2)[C:14]([CH3:30])([CH3:29])[O:13]1.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32]>O1CCOCC1.CCOC(C)=O>[CH2:31]([N:33]([CH2:34][CH3:35])[CH2:23][CH2:22][CH2:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[C:12](=[C:5]1[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]1=[O:11])[O:13][C:14]2([CH3:29])[CH3:30])[CH3:32]
Reactant: CC1(C)OC(=C2C(=O)Nc3ccc(F)cc32)c2ccc(CCCOS(C)(=O)=O)cc21
Reactant: CCNCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCN(CC)CCCc1ccc2c(c1)C(C)(C)OC2=C1C(=O)Nc2ccc(F)cc21
Yield: 55.2 %

Procedure:
A solution of methanesulfonic acid 3-[1-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene)-3,3-dimethyl-1,3-dihydro-isobenzofuran-5-yl]-propyl ester (170 mg, 0.39 mmol) and diethylamine (0.30 ml, 2.92 mmol) in dioxane (1.6 ml) was heated at 75° C. in a pressure tube for 36 hours. The mixture was evaporated, dissolved in EtOAc, and the EtOAc washed with H2O and brine. The aqueous layer was also extracted with CHCl3. The organic layers were combined, dried over anhydrous Na2SO4, and then evaporated to a yellow film. The sample was passed through a plug of silica gel eluting with 10% methanol in CHCl3 to give a yellow-orange solid. The solid was dissolved in EtOAc, washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, and evaporated to a yellow solid. The solid was chromatographed eluting with CHCl3/MeOH to give the title compound as a yellow solid (88 mg, 54%).
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.C(N(CC)CC)C.[Cl:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([NH:37][NH2:38])=O)=[CH:33][CH:32]=1>C(O)C>[Cl:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]2[NH:6][C:5]([C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[NH:12][N:11]=[C:10]4[C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:38][N:37]=2)=[CH:33][CH:32]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2n[nH]c3ccc(-c4nnc(-c5ccc(Cl)cc5)[nH]4)cc23)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 12.6 %

Procedure:
To a sealed tube containing ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (300 mg, 0.94 mmol) dissolved in ethanol (15 mL) and triethylamine (0.3 μL, 2.82 mmol) was added 4-chlorobenzoic hydrazide (213 mg, 1.25 mmol). The tube was sealed and allowed to stir at 75° C. overnight. The solvent was removed and the material was purified by HPLC to yield the title compound (46 mg, 19% yield). 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 8.75 (s, 1H), 8.0–8.2 (m, 5H), 7.76 (d, 1H), 7.6 (m, 2H), 7.4–7.42 (t, 2H), ES-MS (m/z) 390 [M+1]+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]3[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=3)[C:19]#[N:20])[CH:8]=2)[NH:3]1.[CH2:25]([O:27][CH:28](OCC)[O:29][CH2:30][CH3:31])[CH3:26]>>[CH2:25]([O:27][CH:28]([O:29][CH2:30][CH3:31])[N:3]1[C:4]2[C:9](=[CH:8][C:7]([C:16]3[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=3)[C:19]#[N:20])=[CH:6][CH:5]=2)[C:10]2([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[C:2]1=[O:1])[CH3:26]
Reactant: N#Cc1cc(F)cc(-c2ccc3c(c2)C2(CCCCC2)C(=O)N3)c1
Reactant: CCOC(OCC)OCC
Product: CCOC(OCC)N1C(=O)C2(CCCCC2)c2cc(-c3cc(F)cc(C#N)c3)ccc21
Yield: 56.4 %

Procedure:
A solution of 3-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile (1.0 eq, 0.27 g, 0.84 mmol) in triethylorthoformate (2 mL, 12 mmol) was heated to 150° C. for 1 h. The reaction mixture was allowed to cool, the excess triethylorthoformate was removed in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 10% EtOAc/hexane) to give the title compound (0.2 g, 56%) as a white powder, mp 146° C. 1H NMR (DMSO-d6; 400 MHz) δ 1.13 (t, 6H, J=7 Hz), 1.60-1.96 (m, 10H), 3.48 (m, 2H), 3.66 (m, 2H), 6.17 (s, 1H), 7.35 (d, 1H, J=8.3 Hz), 7.68 (dd, 1H, J=2.0, 8.3 Hz), 7.77 (ddd, 1H, J=1.3, 2.4 Hz), 7.89 (d, 1H, J=2.0 Hz), 7.92 (dt, 1H, J=2.4, 10.5 Hz), 8.08 (dd, 1H, J=1.3, 2.9 Hz). MS ((+)−EI) m/z 422 [M+]. Anal. Calcd for C25H27FN2O3: C, 71.07; H, 6.44; N, 6.63. Found: C, 70.75; H, 6.48; N, 6.52.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([O:11]C)[C:8]([C:13]2[N:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([C:26]([NH:28][CH3:29])=[O:27])[CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][N:6]=1)([CH3:3])[CH3:2].I[Si](C)(C)C.C(Cl)Cl.C1COCC1>ClCCCl>[CH:1]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([C:13]2[N:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([C:26]([NH:28][CH3:29])=[O:27])[CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: CNC(=O)c1cc(Oc2ccc(-c3cnc(NC(C)C)nc3OC)nc2)ccn1
Agent: C[Si](C)(C)I
Solvent: ClCCCl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Oc2ccc(-c3cnc(NC(C)C)[nH]c3=O)nc2)ccn1
Temperature: 50 °C
Yield: 23 %

Procedure:
A solution of 4-((6-(2-(isopropylamino)-4-methoxypyrimidin-5-yl)pyridin-3-yl)oxy)-N-methylpicolinamide (0.072 g, 0.183 mmol) in DCE (10 mL) was treated with iodotrimethylsilane (0.497 mL, 3.65 mmol), heated at 50° C. for 20 h, treated with additional iodotrimethylsilane (0.25 mL, 1.84 mmol) and heated at 60° C. for 20 h. The mixture was cooled to RT, treated with DCM/THF (5:1), washed with satd. NaHCO3, 10% sodium bisulfite, then brine. The combined aqueous washes were back-extracted with DCM/THF (5:1) (1×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified by preparatory TLC (EtOAc) to afford 4-((6-(2-(isopropylamino)-6-oxo-1,6-dihydropyrimidin-5-yl)pyridin-3-yl)oxy)-N-methylpicolinamide (16 mg, 23%). 1H NMR (400 MHz, DMSO-d6): δ 10.89 (br s, 1H), 8.79 (d, J=5.2 Hz, 1H), 8.66 (s, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.47 (d, J=2.9 Hz, 1H), 8.44 (d, J=8.8 Hz, 1H), 7.67 (dd, J=8.8, 2.9 Hz, 1H), 7.42 (d, J=2.6 Hz, 1H), 7.21 (dd, J=5.6, 2.6 Hz, 1H), 6.74 (br s, 1H), 4.08 (m, 1H), 2.77 (d, J=4.8 Hz, 3H), 1.16 (d, J=6.5 Hz, 6H); MS (ESI) m/z: 381.2 (M+H+).
Reaction SMILES: F[B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+]([F:21])(CC1)CC2.[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][N:32]=1)[N:29]=[CH:28][CH:27]=[C:26]2[N:33]1[CH2:38][CH2:37][CH2:36][C@H:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:34]1>CC#N>[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][N:32]=1)[N:29]=[CH:28][C:27]([F:21])=[C:26]2[N:33]1[CH2:38][CH2:37][CH2:36][C@H:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:43])([CH3:45])[CH3:44])[CH2:34]1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3cnc(Cl)cc23)C1
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(F)cnc3cnc(Cl)cc23)C1
Reaction time: 18 h
Yield: 15 %

Procedure:
1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.0 equiv.) was added to a solution of (S)-tert-butyl 1-(6-chloro-1,7-naphthyridin-4-yl)piperidin-3-ylcarbamate (1.0 equiv.) in MeCN (0.14 M). After stirring for 18 hours, Na2CO3(sat.) was added to quench. The solution was partitioned between EtOAc and Na2CO3(sat.) washed further with NaCl(sat.), dried over MgSO4, concentrated and purified by silica gel chromatography (25-50-100% EtOAc/hexanes w/0.1% DIEA eluant) to yield (S)-tert-butyl 1-(6-chloro-3-fluoro-1,7-naphthyridin-4-yl)piperidin-3-ylcarbamate (15%), as well as recovered (S)-tert-butyl 1-(6-chloro-1,7-naphthyridin-4-yl)piperidin-3-ylcarbamate (55%). LCMS (m/z): 381.1/383.0 (MH+); LC Rt=4.20 min.
Reaction SMILES: [OH-].[NH4+].[C:3]([NH:10][C:11]1[C:20]([N+:21]([O-:23])=O)=[CH:19][CH:18]=[C:17]2[C:12]=1[CH2:13][CH2:14][CH2:15][CH2:16]2)([C:5](OCC)=[O:6])=[O:4]>O.CN(C)C=O.O1CCCC1.[Pt]>[OH:23][N:21]1[C:20]2[CH:19]=[CH:18][C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]=2[NH:10][C:3](=[O:4])[C:5]1=[O:6]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])ccc2c1CCCC2
Agent: [Pt]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2c3c(ccc2n(O)c1=O)CCCC3
Yield: 47.4 %

Procedure:
A solution of 25% ammonium hydroxide in water (0.7 ml) was added to a solution of 5-ethoxalylamino-1,2,3,4-tetrahydro-6-nitronaphthalene (0.30 g, 1 mmol) in a mixture of 10 ml of N,N-dimethylformamide and 30 ml of tetrahydrofuran. The mixture was hydrogenated at atmospheric pressure and room temperature in the presence of 5% platinum on carbon, until the starting material had disappeared. The mixture was filtered and the filtrate was discarded. Now the filter was washed with 5% aqueous potassium hydroxide, and the filtrate was acidified with 4N hydrochloric acid. The white precipitate was isolated by filtration and washed with water and ethanol to give 0.11 g (46%) of the title compound. M.p. >225° C. dec.; 1H-NMR (DMSO-d6): 1.57-1.90 (m, 4H, 2CH2), 2.50-2.93 (m, 4H, 2CH2), 6.95 (d, J=9 Hz, 1H, ArH), 7.30 (d, J=9 Hz, 1H, ArH); appr. 11.1 (very broad s, 1H, NH); IR (KBr): 1670 cm-1 ; MS (m/e): 232 (M+, 87%).
Reaction SMILES: [C]=O.Br[C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:30])[C:9]=1[NH:10][C:11]1[C:20]2[C:15](=[C:16]([O:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[O:14][C:13](=[O:29])[CH:12]=1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C.CO>[Cl:30][C:8]1[CH:7]=[N:6][CH:5]=[C:4]([C:9]=1[NH:10][C:11]1[C:20]2[C:15](=[C:16]([O:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[O:14][C:13](=[O:29])[CH:12]=1)[C:13]([O:14][CH3:15])=[O:29]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Br)cc(=O)oc2c1OC1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cncc(Cl)c1Nc1cc(=O)oc2c(OC3CCCC3)c(OC)ccc12
Temperature: 80 °C

Procedure:
Carbon monoxide was bubbled through a mixture of 4-(3-bromo-5-chloropyridin-4-ylamino)-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one (0.240 g, 0.514 mmol, Example 11), Pd(OAc)2 (11 mg, 0.051 mmol), DPPP (21 mg, 0.051 mmol), triethylamine (0.22 mL, 1.5 mmol), methanol (1 mL), and anhydrous DMF (4 mL). The reaction was heated at 80° C. for 2 d under an atmosphere of CO and then allowed to cool to rt. The mixture was filtered though Celite, washed with EtOAc, and concentrated to give methyl 5-chloro-4-(8-(cyclopentyloxy)-7-methoxy-2-oxo-2H-chromen-4-ylamino)nicotinate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([I:12])[N:11]=1)=[O:5])[CH3:2].[CH3:24][C:25]([CH3:30])([CH3:29])[C:26](Cl)=[O:27].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:23][C:26](=[O:27])[C:25]([CH3:30])([CH3:29])[CH3:24])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([I:12])[N:11]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)c1nc(I)c2snc(-c3ccc(Cl)cc3)c2c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1nc(I)c2snc(-c3ccc(Cl)cc3)c2c1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of 3-(4-chloro-phenyl)-4-hydroxy-7-iodo-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (0.47 mmol) in CH2Cl2 (2.38 mL) was added trimethylacetyl chloride (0.57 mmol) and Et3N (0.71 mmol). The reaction mixture was stirred at r.t. for 2 h before the mixture was filtered. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography on silica gel. Eluting with 0-20% EtOAc/CH2Cl2, gave the title compound (225 mg) as a white solid: MS (m/z) 544.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2=[N:9][C@@H:10]([CH2:24][C:25]([O:27]C)=[O:26])[C:11]3[N:12]([C:20]([CH3:23])=[N:21][N:22]=3)[C:13]3[S:17][C:16]([CH3:18])=[C:15]([CH3:19])[C:14]2=3)=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2=[N:9][C@@H:10]([CH2:24][C:25]([OH:27])=[O:26])[C:11]3[N:12]([C:20]([CH3:23])=[N:21][N:22]=3)[C:13]3[S:17][C:16]([CH3:18])=[C:15]([CH3:19])[C:14]2=3)=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2c(sc(C)c2C)-n2c(C)nnc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)O)c1nnc(C)n1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
Methyl 2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (see e.g., WO 2006129623) (100.95 mg, 0.243 mmol was suspended in 1 mL methanol to which was added a freshly prepared solution of lithium hydroxide monohydrate (0.973 mL, 0.5 M, 0.487 mmol) and shaken at ambient temperature for 3 hours. The methanol was evaporated and the pH adjusted with aqueous hydrochloric acid (1 M, 0.5 mL, 0.5 mmol) and extracted four times with ethyl acetate. The combined ethyl acetate layers were dried over magnesium sulfate and concentrated to afford 2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (85.3 mg, 87.0%); ESI-MS m/z=401.1 [(M+H)+] which was used directly in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:12]=1[CH2:13][NH2:14].C(N(C(C)C)CC)C>CCCCO>[Br:9][C:5]1[N:6]=[C:7]([NH:14][CH2:13][C:12]2[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:11]=2[Cl:10])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: NCc1c(F)ccc(F)c1Cl
Agent: CCN(CC)C(C)C
Solvent: CCCCO
Product: Nc1ncc(Br)nc1NCc1c(F)ccc(F)c1Cl
Yield: 70 %

Procedure:
A solution of 2-amino-3,5-dibromopyrazine (29 mmol, 7.35 g), 2-chloro-3,6-difluorobenzylamine (29 mmol, 5.16 g), and N, N-diethylisopropylamine (32 mmol, 5.6 mL) in n-BuOH (20 mL) was refluxed for 72 hrs. After volatile components were removed on rotavap, EtOAc and water were added to the residue to facilitate the extraction. The combined organic layers were combined, dried, concentrated, and then subjected to a silica gel column chromatography by using hexanes/EtOAc (4:1) as eluents, furnishing 5-bromo-N3-(2-chloro-3,6-difluorobenzyl)pyrazine-2,3-diamine in 70% yield (7.14 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([CH:11]=O)=[CH:9][CH:8]=[C:7]([O:13][CH3:14])[C:5]=2[N:6]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O>[CH3:14][O:13][C:7]1[C:5]2[N:6]=[C:2]([NH2:1])[S:3][C:4]=2[C:10]([CH2:11][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(C=O)c2sc(N)nc12
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CN2CCOCC2)c2sc(N)nc12
Temperature: 20 °C
Reaction time: 48 h
Yield: 73.3 %

Procedure:
To a suspension of 2-amino-4-methoxy-benzothiazole-7-carbaldehyde (440 mg, 2.1 mmol) in THF (100 ml) was added morpholine (276 mg, 3.2 mmol), acetic acid (190 mg, 3.2 mmol) followed by NaBH(OAc)3 (672 mg, 3.2 mmol). This mixture was stirred vigorously at 20° C. for 48 hours, after which time water (50 ml) and 5% NaHCO3 solution (50 ml) were added and the mixture agitated vigorously. After separating the organic and aqueous layers, the aqueous phase was extracted with EtOAc (50 ml) and the combined organic phase was washed with saturated NaCl solution (100 ml) then dried with Na2SO4, filtered and evaporated. The solid residue was suspended in ether (20 ml) and filtered then the filter cake was washed with ether (10 ml), and dried under vacuum (0.05 mmHg, 50° C.) to afford the title compound as a yellow solid (430 mg, 73% yield), MS: m/e=280.2 (M+).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:19])C(=O)C1>CN(C=O)C>[Br:19][C:10]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=1
Reactant: CC(C)(C)c1ccccc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Br)ccc1N
Reaction time: 2 h

Procedure:
To a solution of 2-tert-butylaniline (7.5 g, 50 mmol) in DMF (80 mL) was added NBS (8.9 g, 50 mmol) at 0° C. The reaction mixture was stirred for 2 h, quenched with ice water, extracted with EA (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC to give compound P13a (9.1 g, 80%) as a white solid.