Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:18][CH3:19])[CH:12]=3)=[CH:9][N:8]([CH:20]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:27](Cl)(=[O:36])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1.ClCCl>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:27](=[O:36])[CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:13]([O:18][CH3:19])[CH:12]=3)=[CH:9][N:8]([CH:20]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1cc(-c2cn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1NC(=O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a solution of 4-[4-amino-5-(4-amino-3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanone (0.8 g, 2.3 mmol) in pyridine (13 mL) and dichloromethane (32 mL) at 0° C. was added hydrocinnamoylchloride (0.57 g, 3.4 mmol) in dichloromethane (5 mL) under nitrogen. The solution was stirred at 0° C. for 2 hr, warmed to room temperature and quenched by addition of saturated aqueous citric acid solution (50 mL). The organic layer was washed with saturated aqueous citric acid solution (2×50 mL), dried (sodium sulphate), filtered and evaporated to leave N1-{4-[4-amino-7-(4-oxocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-3-phenylpropanamide (1.0 g, 92% crude) as a brown foam. 1H NMR (d6 DMSO, 400 MHz):9.17(1H, s), 8.18(1H, s), 8.06(1H, d), 7.51(1H, s), 7.18-7.29(6H, m), 7.09(1H, m), 6.99(1H, d), 6.21(2H, bs), 5.18 (1H, m), 3.88(3H, s), 1.99-2.93(12H, m). HPLC: (5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min.) tr=14.48 min, 92.2%.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]#[N:15])[NH:9]2.[F:17][CH:18]([F:39])[O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1>CO>[F:39][CH:18]([F:17])[O:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:27]2[CH2:32][CH2:31][N:30]([CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]3[CH:13]=[CH:12][CH:11]=[C:10]4[C:6]=3[CH:7]=[C:8]([C:14]#[N:15])[NH:9]4)[CH2:29][CH2:28]2)=[CH:24][CH:25]=1
Reactant: N#Cc1cc2c(OCC3CO3)cccc2[nH]1
Reactant: FC(F)Oc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CO
Product: N#Cc1cc2c(OCC(O)CN3CCN(C(c4ccccc4)c4ccc(OC(F)F)cc4)CC3)cccc2[nH]1

Procedure:
2.5 g of 4-(2,3-epoxypropoxy)-1H-indole-2-carbonitrile and 3.7 g of 1-((4-difluoromethoxyphenyl)phenylmethyl)piperazine are dissolved in 50 ml of methanol and heated for 3 hours under reflux. The mixture is then concentrated to dryness in vacuo and the residue is triturated with hexane, filtered off with suction and purified by column chromatography on silica gel (eluent: chloroform/methanol 40:2).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH2:17]([O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:15][CH3:16])[N:3]=[C:2]([NH:29][C:28]1[CH:27]=[CH:26][C:25]([O:24][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:31][CH:30]=1)[N:11]=[C:10]2[NH2:12]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: Nc1ccc(OCc2ccccc2)cc1
Product: COc1cc2nc(Nc3ccc(OCc4ccccc4)cc3)nc(N)c2cc1OC
Reaction time: 16 h

Procedure:
2-chloro-6,7-dimethoxy-4-quinazolinamine (1.73 g, 7 mmol) and 4-benzyloxyaniline (2.5 g, 12 mmol) were heated in an s.s. bomb at 145° C. for 16 hrs. Upon cooling the resultant solid was washed well with ether to afford the product. 1H NMR DMSO 3.86 (d, 6H , OCH3), 5.14 (s, 2H, CH2), 6.9-7.5 (m, 11H, ArH)
Reaction SMILES: C([C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=1)#N.[N-]=[N+]=[N-].[Na+].[OH-].[Na+]>CN(C)C=O>[CH:8]1[C:7]2[S:6][C:5]3[C:14](=[CH:15][CH:16]=[CH:3][CH:4]=3)[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1O2
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)Oc1ccccc1S2

Procedure:
2-cyanophenoxathiin (2.25g), sodium azide (0.68g) ammonium chloride (0.59g) and dimethylformamide (30 ml.) were heated for 9 hours at 130° C. The solution was poured onto ice and 2 Normal sodium hydroxide solution, and extracted with chloroform. The aqueous phase was acidified with concentrated hydrochloric acid. The solid was filtered, washed and dried to give 2-5-tetrazolyl)phenoxathiin m.p. 210°-2° C. Recrystallisation from glacial acetic acid raised the melting point to 220°-1° C.
Reaction SMILES: [NH:1]([C:24]([O:26]C(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@@H:11]([CH3:13])[OH:12])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[NH:31]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@H:32](C(O)=O)[CH2:33][CH2:34][CH2:35][CH3:36].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>C(O)(C(F)(F)F)=O.CN(C=O)C>[NH:31]([C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[C@H:32]([C:24]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[C@@H:11]([CH3:13])[OH:12])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:26])[CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@@H](O)[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Boc-Asn-Thr-OBzl (3.1 g) was dissolved in TFA (30 ml), and the solution was allowed to stand at room temperature for 10 minutes, and the solvent was evaporated. The residue was triturated with ether to give powders, which were dissolved in DMF (30 ml) together with TEA (1.5 ml) and to this was added Boc-Nle-ONB which was prepared from Boc-Nle-OH (1.69 g), HONB (1.50 g) and DCC (1.73 g). The mixture was stirred at room temperature for 15 hours and the solvent was evaporated. The residue was triturated with water (50 ml) to give powders, which were collected by filtration and washed with ether. Yield 3.8 g (96.7%); m.p. 160°-163° C. [α]D21.5 -13.6° (c=0.8, DMF); Rf1 0.58
Reaction SMILES: C([O:5][C:6](=O)[N:7]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:8][C@@H:9]([C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])(C)(C)C.C(O)=O.C(OC(=O)C)(=O)C>>[CH2:35]([O:34][N:7]([CH2:8][C@@H:9]([C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)[CH2:18][CH2:17]1)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:6]=[O:5])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)C[C@@H](CN(OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)N1CCN(c2ccc(-c3ccccc3)cc2)CC1
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Product: CC(C)C[C@@H](CN(C=O)OCc1ccccc1)C(=O)N1CCN(c2ccc(-c3ccccc3)cc2)CC1
Yield: 52.2 %

Procedure:
The title product was obtained following the protocol of Example 1 (step c), but starting from tert-butyl(benzyloxy){(2S)-2-[(4-biphenyl-4-ylpiperazin-1-yl)carbonyl]-4-methyl pentyl}carbamate (219 mg, 0.46 mmol) and a preformed mixture of formic acid (875 μL; 23.2 mmol; 50 eq.) and acetic anhydride (220 μl; 2.32 mmol; 5.0 eq.) (mixture formed at 0° C. for 30 min). Purification by column chromatography (Silicagel, gradient from 33% EtOAc up to 50% EtOAc in c-Hex) gave the title product as a white solid (120 mg, 52%). HPLC, Rt: 4.60 min (purity: 99.7%). M+(LC-MS (ESI)): 500.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13].O.[Cl-].[NH4+]>C(O)C.C1COCC1>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH2:11][C:12]([OH:14])=[O:13])[CH:4]=1
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(F)c(CC(=O)O)c1
Temperature: 80 °C

Procedure:
To a suspension of 2-(2-fluoro-5-nitrophenyl)acetic acid (15.0 g, 75.3 mmol) in ethanol (800 mL), THF (400 mL), and water (200 mL) was added ammonium chloride (4.46 g, 83.4 mmol) and ferrous powder (25.04 g, 405.4 mmol). The resulting mixture was heated at 80° C. for 1 hr and the progress of the reaction was monitored by TLC. Upon complete consumption of starting material, the reaction mixture was filtered off while it was hot. The filtrate was evaporated under vacuum and the crude residue was diluted with ethyl acetate (200 mL) and washed with water (3×100 mL). The combined organic layer was washed with brine, dried over Na2SO4 and evaporated under vacuum to afford 2-(5-amino-2-fluorophenyl)acetic acid as a grey solid which was used for the next step without further purification (6.13 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=O.[O:12]=[S:13]([Cl:15])[Cl:14].[NH3:16]>>[Cl:11][C:3]1[C:2]([Cl:1])=[CH:10][C:6]([C:7]#[N:16])=[CH:5][N:4]=1.[O:12]=[S:13]([Cl:15])[Cl:14]
Reactant: N
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Solvent: O=S(Cl)Cl
Product: N#Cc1cnc(Cl)c(Cl)c1

Procedure:
2,3-Dichloro 5-cyano pyridine 4 was prepared from 5,6-Dichloronicotinic acid (ALDRICH). The acid was converted to the acid chloride by treatment with excess SOCl2 and refluxed for 1.5 hours. The intermediate acid chloride was reacted with ammonia (aqueous) to get the primary amide which on dehydration with excess SOCl2 at reflux condition afforded 2, 3-Dichloro 5-cyano pyridine 4. [Ref. George et al J. Org. Chem, 1979, 44, 2697.]
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1.O>C1COCC1.C([Li])CCC.C(OCC)(=O)C>[OH:16][C:13]1([C:2]2[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH2:14][CH2:15][O:10][CH2:11][CH2:12]1
Reactant: O=C1CCOCC1
Reactant: Cc1cc(C)cc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(C2(O)CCOCC2)c1
Reaction time: 1 h
Yield: 63.1 %

Procedure:
Under an atmosphere of argon, to a solution of 5-bromo-m-xylene (5.55 g) in THF (60 mL), n-butyl lithium (17.8 mL) was added at −78° C. The mixture was stirred for 1 hour. Tetrahydropyran-4-on (2.0 g) was added to the reaction mixture, and the mixture was stirred for 3 hours. Water was added to the reaction mixture, and the solution was diluted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:3) to give the title compound (2.6 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[I:11]N1C(=O)CCC1=O>CC(O)=O>[NH2:1][C:2]1[C:9]([I:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: N#Cc1cc(I)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
A mixture of 4-amino-2-chlorobenzonitrile (5.0 g, 0.033 mol) and N-iodosuccinimide (8.28 g, 0.036 mol) in HOAc (35 mL) was stirred at RT overnight. A brown solid formed, which was collected by filtration, washed with hexanes, and dried in vacuo to afford 3.6 g (39%) of 4-amino-2-chloro-5-iodobenzonitrile (236) as a pale brown solid: MS (ESI) m/z=278.8 [M+1]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[C:23]([CH3:25])([CH3:24])[O:22][C:21]([CH3:27])([CH3:26])[C:19]=3[N:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>O1CCOCC1>[ClH:28].[ClH:28].[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[C:23]([CH3:25])([CH3:24])[O:22][C:21]([CH3:27])([CH3:26])[C:19]=3[N:20]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc3c(n2)C(C)(C)OC3(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)OC(C)(C)c2nc(NC3CCNCC3)ncc21

Procedure:
A solution of 4-(5,5,7,7-tetramethyl-5,7-dihydro-furo[3,4-d]pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.23 g, 3.27 mmol) in 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 277.3 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([N:15]2[N:19]=[C:18]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:17]3=[N:16]2)[C:6]=1[OH:25])([CH3:4])([CH3:3])[CH3:2].CN([Zr:29]([N:36]([CH3:38])[CH3:37])([N:33]([CH3:35])[CH3:34])N(C)C)C>CCCCC>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([N:15]2[N:19]=[C:18]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:17]3=[N:16]2)[C:6]=1[O:25][Zr:29]([O:25][C:6]1[C:7]([N:15]2[N:19]=[C:18]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:17]3=[N:16]2)=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:1]([CH3:2])([CH3:3])[CH3:4])([N:33]([CH3:34])[CH3:35])[N:36]([CH3:37])[CH3:38])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Reactant: CN(C)[Zr](N(C)C)(N(C)C)N(C)C
Solvent: CCCCC
Product: CN(C)[Zr](Oc1c(-n2nc3ccc(Cl)cc3n2)cc(C(C)(C)C)cc1C(C)(C)C)(Oc1c(-n2nc3ccc(Cl)cc3n2)cc(C(C)(C)C)cc1C(C)(C)C)N(C)C
Reaction time: 1 h

Procedure:
In a dry box, 2,4-di-tert-butyl-6-(5-chloro-2H-benzo-triazol-2-yl)phenol (25 g, 70.11 mmol) was transferred to a 1 L round bottom flask and dissolved in pentane (150 ml) to from a solution. Tetrakis(dimethylamino)zirconium (9.38 g, 35.05 mmol) in pentane (150 ml) was added to this solution. The mixture was stirred for one hour and then the volatiles were removed under vacuum to obtain yellow solid. The yellow solid was used without further purification (yield, 91%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([CH2:15][CH2:16][CH2:17]Br)=[N:13][NH:12][C:11]=1[NH2:19].NC1NN=C(CCCO)C=1[C:30]1SC2C=CC=C[C:33]=2[N:34]=1.CNC.C1COCC1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([CH2:15][CH2:16][CH2:17][N:34]([CH3:33])[CH3:30])=[N:13][NH:12][C:11]=1[NH2:19]
Reactant: Nc1[nH]nc(CCCO)c1-c1nc2ccccc2s1
Reactant: Nc1[nH]nc(CCCBr)c1-c1nc2ccccc2s1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)CCCc1n[nH]c(N)c1-c1nc2ccccc2s1

Procedure:
The title compound (100 mg) was prepared using 200 mg (0.59 mmol) of 4-benzothiazol-2-yl-5-(3-bromopropyl)-2H-pyrazol-3-ylamine, which was derived from 3-(5-amino-4-benzothiazol-2-yl-1H-pyrazol-3-yl)-propan-1-ol, and 5 mL of a 2 M solution of dimethylamine in THF (10 mmol). MS (m/z, ES+): 302.1 (M+1, 100%).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]#[N:15])=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)[OH:23]>O>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]([NH2:15])=[O:23])=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cn(-c2ccccn2)nc1-c1ccc([N+](=O)[O-])o1
Solvent: O
Product: NC(=O)c1cn(-c2ccccn2)nc1-c1ccc([N+](=O)[O-])o1
Temperature: 0 °C
Yield: 97 %

Procedure:
Stir 2.3 g of 3-(5-nitro-2-furyl)-1-(2-pyridyl)pyrazole-4-carbonitrile with 4.4 ml of concentrated sulfuric acid for 15 hours at from 35° to 40° C. Pour the resulting solution onto 75 g of ice and water; separate the formed precipitate and wash it with water until it is no longer acid to obtain a 97% yield of 3-(5-nitro-2-furyl)-1-(2-pyridyl)pyrazole-4-carboxamide [m.p. 249.5° to 250.5° C (from dimethylformamide/methanol)].
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CON(C)[C:22](=[O:35])[C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=1>O1CCCC1>[CH3:30][O:29][C:27]1[CH:28]=[C:23]([C:22](=[O:35])[C:18]#[C:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:24]=[C:25]([O:33][CH3:34])[C:26]=1[O:31][CH3:32]
Reactant: C#Cc1ccccc1
Reactant: COc1cc(C(=O)N(C)OC)cc(OC)c1OC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: COc1cc(C(=O)C#Cc2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
Place lithium hexamethyldisilazane (3 mL of a 1M solution in tetrahydrofuran, 3 mmol) and tetrahydrofuran (10 mL) under an argon atmosphere and cool to 0° C. Add phenylacetylene (0.33 mL, 3 mmol) and stir at 0° C. for 30 minutes. Add N-methoxy-N-methyl-(3,4,5-trimethoxy)benzamide (0.76 g, 3 mmol), remove the cooling bath and stir at room temperature for 1 hour. Partition between ethyl ether and saturated aqueous sodium chloride, separate the organic phase and dry (MgSO4). Filter and evaporate the solvent in vacuo. Pour onto silica gel and elute with 20% ethyl acetate/hexane to yield a crude solid. Recrystallize (hexane/ethyl acetate) to yield 0.31 g of the title compound; mp 94°-96° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[NH:6][C:7](=O)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21][CH3:22])=[CH:10][CH:9]=2)[CH3:3].O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:21][CH3:22])=[CH:10][CH:9]=2)[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]c(CN(C)C)c(-c3ccccc3)c2c1
Product: COc1ccc2c(Cl)nc(CN(C)C)c(-c3ccccc3)c2c1
Reaction time: 1 h

Procedure:
3-[(dimethylamino)methyl]-6-methoxy-4-phenylisoquinolin-1(2H)-one (50 mg) was combined with 0.600 mL of POCl3, and the reaction was stirred at 90 C for 1 h. After cooling, the reaction was partitioned between saturated aqueous sodium bicarbonate and EtOAc. The organic solution was dried over Na2SO4 and concentrated. Flash chromatography (3% MeOH in CH2Cl2) gave the titled compound.
Reaction SMILES: C([O:4][C:5](=[O:40])[C:6]([CH3:39])([CH3:38])[CH2:7][C:8]1[N:9]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:10]2[C:15]([C:16]=1[S:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:13]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[CH:12][CH:11]=2)C=C.CO.[Li+].[OH-].Cl>C1COCC1>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:9]2[C:10]3[C:15](=[CH:14][C:13]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:12][CH:11]=3)[C:16]([S:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:8]2[CH2:7][C:6]([CH3:39])([CH3:38])[C:5]([OH:40])=[O:4])=[CH:32][CH:33]=1
Reactant: C=CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccccn3)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)Sc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccccn3)cc12
Temperature: 25 °C

Procedure:
The compound from Step 1 (133 mg) was dissolved in THF (5 mL), MeOH (3 mL), and 1N LiOH (1.2 mL) and heated at 55° C. for 1 hour. After cooling to room temperature, the mixture was acidified with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The residue was swished in ether/hexane, affording the title compound as a white solid, m.p. 186.2°-187.7° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]([NH:8][C:9](=O)[C:10]([CH3:13])(C)C)=[N:6][CH:7]=1.C(OCC)C.CN(C)C=CC=O.Cl>C([Li])(C)(C)C.O>[Cl:1][C:2]1[CH:7]=[N:6][C:5]2[C:4]([C:3]=1[CH3:15])=[CH:13][CH:10]=[CH:9][N:8]=2
Reactant: Cc1cc(NC(=O)C(C)(C)C)ncc1Cl
Agent: CN(C)C=CC=O
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Product: Cc1c(Cl)cnc2ncccc12
Temperature: 80 °C
Yield: 69.1 %

Procedure:
N-(5-chloro-4-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (18.3 g, 0.081 mol) from Step 2 was placed in a flame-dried three-neck 1 L flask fitted with an overhead stirrer, under nitrogen. To this solid was added anhydrous diethyl ether (170 mL) and the mixture stirred until a solution, whereupon it was cooled in a dry ice/acetone bath for 20 min (slurry formed). To the resulting slurry was dropped in tert-butyl lithium (1.7 M in pentane, 100 mL) via cannula over an 8 min period. The flask was removed from the cooling bath and allowed to stir until it reached RT, at which time 3-dimethylamino-propenal (10 mL, 0.10 mol) was added neat. The resulting mixture was stirred overnight at RT under a nitrogen stream; by morning a dry powder resulted. To this was added water (80 mL) followed by slow addition of conc. HCl (40 mL) while cooling the flask in an ice/water bath. After the acid addition, the ice bath was removed and the flask was heated to 80° C. for 1 h, cooled in an ice/water bath and treated with NaOH (solid pellets) until basic. The basic aqueous mixture was subsequently extracted with DCM (4×100 mL)—patience and brine were required to help break the resulting emulsions. The combined extracts were dried over Na2SO4 and concentrated under vacuum to yield crude product, which was further purified by SGC (EtOAc eluant) to yield pure 3-chloro-4-methyl-[1,8]naphthyridine (10 g, 0.056 mol). Note: owing to weak UV activity, it was found more efficacious to monitor column fractions with MS rather than UV. MS (ESI+) for m/z 179 (M+H)+. 1H NMR (CDCl3) δ 9.06 (m, 1 H), 8.96 (s, 1 H), 8.34 (d, 1 H), 7.51 (m, 1H), 2.72 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7](CC3C=CC(OC)=CC=3)[C:6]=2[N:25]=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][NH:7][C:6]=2[N:25]=1
Reactant: COc1ccc(CN2CC(F)(F)C(=O)N(C)c3cnc(Cl)nc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CN1C(=O)C(F)(F)CNc2nc(Cl)ncc21
Yield: 12.8 %

Procedure:
A solution of 0.3 g (0.0082 mole) of 2-chloro-7,7-difluoro-9-(4-methoxy-benzyl)-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-291) and 0.3 mL of anisole in 10 mL of trifluoroacetic acid was heated at 85 degrees in a pressure tube for 24 hours. The mixture was concentrated under reduced pressure, a small amount of methanol was added followed by ether. The resulting solid was collected by filtration and washed with ether to give 0.26 g of 2-chloro-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-292). as a lightly yellow solid.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:3]=1[C:4]([N:6]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:7][C:8]([CH3:10])=[CH2:9])=[O:5].C(O[Na])=O.CC([O-])=O.[Na+]>CN(C=O)C.[N+](CC)(CC)(CC)CC.[Cl-]>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:6]2[CH2:7][C:8]([CH3:10])([CH3:9])[C:2]3[C:3](=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)[C:4]2=[O:5])=[CH:13][CH:14]=1
Reactant: C=C(C)CN(Cc1ccc(OC)cc1)C(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Agent: O=CO[Na]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CC(C)(C)c3ccc([N+](=O)[O-])cc3C2=O)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
2-Bromo-N-(4-methoxy-benzyl)-N-(2-methyl-allyl)-5-nitro-benzamide (23.4 mmol) was dissolved in DMF (150 ml) and Et4NCl (4.25 g), HCO2Na (1.75 g) and NaOAc (4.99 g) were added. N2 was bubbled through the solution for 10 min, then Pd(OAc)2 (490 mg) was added and the mixture was stirred overnight at 70° C. The mixture was extracted with EtOAc, washed with sat'd NH4Cl, dried over MgSO4, filtered and concentrated until the compound precipitated as a white solid.