Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:8]1([NH:11][C:12]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:39])OC5C=CC=CC=5)[CH:25]=4)=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)=[O:13])[CH2:10][CH2:9]1.C1(NC(N2C3C(=CC(OC4C=CN=C(NC(N5CCC(N6CCCC6)CC5)=O)C=4)=CC=3)C=C2)=O)CC1>CN(C)C=O>[CH:8]1([NH:11][C:12]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([N:5]5[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]5)=[O:39])[CH:25]=4)=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)=[O:13])[CH2:9][CH2:10]1
Reactant: OC1CCNCC1
Reactant: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)Oc1ccccc1
Agent: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)N1CCC(N2CCCC2)CC1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)N1CCC(O)CC1
Reaction time: 8 h
Yield: 46.5 %

Procedure:
N,N-Dimethylformamide (5 ml) and 4-hydroxypiperidine (433 mg, 4.29 mmol) were added to a mixture (470 mg) of phenyl N-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate obtained in Example 68; the reaction mixture was stirred overnight; the reaction mixture was partitioned between ethyl acetate and water; and the organic layer was concentrated to yield the title compound as white crystals (220 mg, 0.51 mmol, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([CH:25]=O)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl-].[NH4+].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([CH2:25][N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: NC(=O)c1sc(-n2cnc3ccc(C=O)cc32)nc1-c1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Product: NC(=O)c1sc(-n2cnc3ccc(CN4CCCCC4)cc32)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.150 g (0.39 mmole) of 4-(3-chloro-phenyl)-2-(6-formyl-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.2a), 0.078 mL of piperidine, 0.414 g of sodium triacetoxyborohydride and 5 mL of dichloromethane was stirred at room temperature for 24 hours, after which 1 mL of saturated aqueous ammonium chloride solution was added. The mixture was stirred at room temperature for 30 minutes, made basic by addition of saturated potassium carbonate solution and partitioned between 30 mL of dichloromethane and 30 mL of dilute potassium carbonate solution. The aqueous layer was extracted twice with 30 mL of dichloromethane. The combined dichloromethane layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with dichloromethane to give a pink solid. Further purification by SFC (methanol) gave 0.050 g of 4-(3-chloro-phenyl)-2-(6-piperidin-1-ylmethyl-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.8) as a yellow solid. MH+/Z=452
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]([OH:14])=[O:13])[CH2:4][CH2:3]1.[C:16]1(C)C=CC(S(O)(=O)=O)=C[CH:17]=1>>[CH2:16]([O:13][C:12]([CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:15])([CH3:1])[CH2:3][CH2:4]1)=[O:14])[CH3:17]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1(C)CCC(C(=O)O)c2ccccc21
Product: CCOC(=O)C1CCC(C)(C)c2ccccc21
Yield: 63 %

Procedure:
248 g of 1,1-dimethyl-tetralin-4-carboxylic acid in 1.740 liters of absolute alcohol are held at reflux temperature for 6 hours with 24.8 g of paratoluenesulphonic acid in a 3-liter flask provided with a thermometer, stirrer and reflux condenser. The excess alcohol is then distilled off under a slight vacuum and the residue is poured into ice/water. The mixture is extracted with ether, washed neutral, dried, filtered, evaporated and distilled, there being thus obtained 177 g of 1,1-dimethyl-tetralin-4-carboxylic acid ethyl ester of boiling point 74° C./0.03 mmHg; nD20 =1.5153; yield 63%. Odour: faint, jasmone-like.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])[C:8]#[N:9].[OH2:18].N>O>[NH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])[C:8]([NH2:9])=[O:18]
Reactant: N#CC(N)c1ccc(F)cc1F
Reactant: O
Agent: N
Agent: O=S(=O)(O)O
Product: NC(=O)C(N)c1ccc(F)cc1F
Reaction time: 3 h
Yield: 61 %

Procedure:
Then, 51 g of concentrated sulfuric acid was added to 2.67 g of water, to which 40 g of 2-amino-2-(2,4-difluorophenyl)acetonitrile was added under ice cooling, and the mixture was heated at 50° to 60° C. under stirring for 3 hours. After completion of the reaction, the reaction mixture was poured into 250 ml of concentrated ammonia water cooled with ice in such a manner that the temperature of the solution became not higher than 20° C. The precipitated crystals were collected by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was combined with the previously collected crystals, followed by recrystallization, which afforded 27.2 g (yield, 61%) of 2-amino-2-(2,4-difluorophenyl)acetamide, m.p. 142.9° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.CC([O-])=O.[K+].Br[C:39]1[CH:40]=[C:41]([C:58]([NH2:60])=[O:59])[C:42]2[NH:43][C:44]3[CH:45]=[C:46]([N:52]4[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)[CH:47]=[CH:48][C:49]=3[C:50]=2[N:51]=1.CC1(C)C(C)(C)OB(C2C=CC(CN3CCOCC3)=NC=2)O1.C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O.N>CO.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].C(Cl)Cl.O.COCCOC>[O:55]1[CH2:56][CH2:57][N:52]([C:46]2[CH:47]=[CH:48][C:49]3[C:50]4[N:51]=[C:39]([C:2]5[CH:7]=[N:6][C:5]([CH2:8][N:9]6[CH2:14][CH2:13][O:12][CH2:11][CH2:10]6)=[CH:4][CH:3]=5)[CH:40]=[C:41]([C:58]([NH2:60])=[O:59])[C:42]=4[NH:43][C:44]=3[CH:45]=2)[CH2:53][CH2:54]1
Reactant: NC(=O)c1cc(Br)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Reactant: Brc1ccc(CN2CCOCC2)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: NC(=O)c1cc(-c2ccc(CN3CCOCC3)nc2)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 100 °C
Yield: 35.7 %

Procedure:
A microwave vial containing a mixture of 4-((5-bromopyridin-2-yl)methyl)morpholine (537 mg, 2.09 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (583 mg, 2.30 mmol), KOAc (410 mg, 4.18 mmol) and PdCl2(dppf)-CH2Cl2 adduct (85 mg, 0.10 mmol) was flushed with nitrogen, dioxane (5 mL) was added. and the vial was sealed and heated at 100° C. for 6 hr. The reaction was filtered and the solid was washed with EtOAc. The filtrate was and washed with water, brine, and dried over MgSO4. Removal of the solvent left 750 mg of crude 4-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)morpholine (750 mg) as a brown thick oil that was used as such. A microwave vial containing a mixture of 2-bromo-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide (60 mg, 0.14 mmol), 4-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)morpholine (130 mg, 0.171 mmol), PdCl2(dppf)-CH2Cl2 adduct (12 mg, 0.014 mmol) was flushed with nitrogen. DME (2.5 mL) and Na2CO3 (0.36 mL, 0.72 mmol, 2.0 M aq. solution) were added and the vial was sealed and heated at 100° C. for 5 hr. Preparative HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; Solvent B=90% Methanol, 10% H2O, 0.1% TFA; gradient of 0 to 60% B over 10 min at 42 mL/min) followed by SCX capture and release with 2 N NH3 in MeOH gave 7-morpholino-2-(6-(morpholinomethyl)pyridin-3-yl)-5H-pyrido[3,2-b]indole-4-carboxamide (25 mg, 0.050 mmol, 35% yield) as a solid. MS (ESI) m/z 473.21 (M+H). 1H NMR (500 MHz, Acetone) δ ppm 10.75 (1H, s), 9.36 (1H, d, J=2.14 Hz), 8.58 (1H, dd, J=8.09, 2.29 Hz), 8.35 (1H, s), 8.10-8.22 (2H, m), 7.62 (1H, d, J=7.93 Hz), 7.29 (1H, d, J=2.14 Hz), 7.18 (1H, br. s.), 7.07 (1H, dd, J=8.85, 2.14 Hz), 3.80-3.87 (4H, m), 3.71 (2H, s), 3.64-3.69 (4H, m), 3.28-3.35 (4H, m), 2.47-2.57 (4H, m).
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][N:15]2[C:18]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=4)[N:22]=3)=[CH:19][N:20]=[C:14]2[N:13]=1)([O:4][Si](CC)(CC)CC)[CH3:3]>CCO.Cl>[N+:33]([C:29]1[CH:28]=[C:27]([C:23]2[N:22]=[C:21]([C:18]3[N:15]4[CH:16]=[CH:17][C:12]([C:2]([OH:4])([CH3:1])[CH3:3])=[N:13][C:14]4=[N:20][CH:19]=3)[CH:26]=[CH:25][N:24]=2)[CH:32]=[CH:31][CH:30]=1)([O-:35])=[O:34]
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4cccc([N+](=O)[O-])c4)n3)cnc2n1
Agent: Cl
Solvent: CCO
Product: CC(C)(O)c1ccn2c(-c3ccnc(-c4cccc([N+](=O)[O-])c4)n3)cnc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 28 %

Procedure:
7-(1-Methyl-1-triethylsilanyloxyethyl)-3-[2-(3-nitrophenyl)-pyrimidin-4-yl]imidazo[1,2-α]pyrimidine in EtOH (10 ml) was treated with conc. HCl (10 drops) and stirred at room temperature for 12 h. The crude mixture was poured onto an SCX cartridge (2 gram) and washed firstly with MeOH (20 ml) to remove the impurities and then 2N NH3 in MeOH (20 ml) to elute the desired compound. Removal of the solvent under reduced pressure afforded 2-{3-[2-(3-nitrophenyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol (66 mg, 28%): 1H NMR (360 MHz, CDCl3) δ 10.31 (1H, d, J 7.3), 9.31 (1H, t, J 1.8), 8.83 (1H, d, J 5.5), 8.80 (1H, d, J 8.0), 8.55 (1H, s), 8.40 (1H, d, J 8.0), 7.75 (1H, t, J 8.0), 7.66 (1H, d, J 5.5), 7.40 (1H, d, J 7.3), 1.68 (6H, s); m/z (ES+) 377 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1.Cl.[F:15][C:16]1[CH:17]=[C:18]([CH2:24][CH2:25][NH2:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].C(N(CC)CC)C.Cl>ClCCl>[F:15][C:16]1[CH:17]=[C:18]([CH2:24][CH2:25][NH:26][C:11]([C:8]2([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:10][CH2:9]2)=[O:12])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(CCN)cc1F
Reactant: O=C(Cl)C1(c2ccccc2Cl)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(=O)C2(c3ccccc3Cl)CC2)cc1F
Reaction time: 1 h

Procedure:
A solution of 1-(2-chlorophenyl)cyclopropane carbonyl chloride (25 g) in dichloromethane (100 ml) was added dropwise to a vigorously stirred mixture of 2-(3-fluoro-4-methoxyphenyl)ethylamine hydrochloride (23.9 g), triethylamine (70 ml) and dichloromethane (400 ml) and the mixture was then stirred for 1 hour. Excess 6N hydrochloric acid was then added. The resulting solution was washed with water, dried over potassium carbonate, and the solvent removed in vacuo to give N-[2-(3-fluoro-4-methoxyphenyl)ethyl]-1-(2-chlorophenyl)cyclopropane carboxamide which was added molten to polyphosphate ester (365 g) under nitrogen. The mixture was heated at 100° C. for 17 hours, then added to water (600 ml) and washed with ether (600 ml). 20% Aqueous ammonia solution was added to the aqueous phase to give pH 8-9.The resulting precipitate was collected by filtration, washed with water, dried in air and recrystallised from boiling acetonitrile to give 1-[1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7 -methoxy-3,4-dihydroisoquinoline, m.p. 172°-176° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[CH:17][N:18]=[CH:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][CH2:17][NH:18][CH2:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3cnccc23)CC1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CCNC3)CC1
Temperature: 25 °C
Yield: 44 %

Procedure:
4-Isoquinoline-5-yl-piperazine-1-carboxylic acid tert-butyl ester (1.5 g) from Step 2 was dissolved in 5 mL of tetrahydrofuran (THF), and excess borane (BH3) in THF was added thereto. The mixture was brought to reflux for 1 hour, and allowed to cool to room temperature. The mixture was then further cooled in an ice bath, and water was carefully added to the reaction mix to consume excess borane. The reaction mix was then diluted with EtOAc, washed with saturated aqueous sodium bicarbonate (NaHCO3), dried over MgSO4, and chromatographed to provide 4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester as a viscous oil (0.668 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:37]=[CH:36][C:20]2[N:21]([CH2:25][C:26]3[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=3)[C:29]([O:31][CH3:32])=[O:30])[CH2:22][CH2:23][O:24][C:19]=2[CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:37]=[CH:36][C:20]3[N:21]([CH2:25][C:26]4[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=4)[C:29]([O:31][CH3:32])=[O:30])[CH2:22][CH2:23][O:24][C:19]=3[CH:18]=2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: COC(=O)c1cccc(CN2CCOc3cc(N)ccc32)c1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCc1[nH]c(C(=O)Nc2ccc3c(c2)OCCN3Cc2cccc(C(=O)OC)c2)nc1Cl
Yield: 65.7 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.21 g, 1.2 mmol), thionyl chloride (4 mL), methyl 3-[(7-amino-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methyl]benzoate obtained in Example (100b) (0.28 g, 0.97 mmol) and pyridine (5 mL). The resulting solid was washed with dichloromethane/hexane=1/1 to obtain 0.29 g of the title compound as a colorless solid (66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:6]=[CH:7][CH:8]=1.Cl[CH2:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=2)[CH:28]=[N:29][CH:30]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:24][C:25]2[CH:26]=[C:27]([C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH:28]=[N:29][CH:30]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Reactant: COc1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Product: COc1ccccc1N(Cc1cncc(-c2cc(OC)c(OC)c(OC)c2)c1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
4-(o-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13]([OH:15])=O)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C@@H:64]1[C:67](=[O:68])[NH:66][C@@H:65]1[CH2:69][N:70]1[N:74]=[N:73][C:72]([CH2:75][NH:76][C:77](=[O:83])[O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[N:71]1>C(Cl)Cl.CN(C=O)C>[C:79]([O:78][C:77]([NH:76][CH2:75][C:72]1[N:73]=[N:74][N:70]([CH2:69][C@@H:65]2[C@H:64]([NH:63][C:13](=[O:15])/[C:12](=[N:11]\[O:10][C:7]([CH3:8])([CH3:9])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:29])/[C:16]3[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[S:19][CH:20]=3)[C:67](=[O:68])[NH:66]2)[N:71]=1)=[O:83])([CH3:82])([CH3:80])[CH3:81]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)NCc1nnn(C[C@H]2NC(=O)[C@H]2N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1nnn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(NC(=O)OC(C)(C)C)n2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a solution of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (938 mg, 2.18 mmol) in DCM:DMF (5:1, 8.5 mL) at 0° C. was added DIPEA (953 μL, 5.46 mmol) followed by HATU (830 mg, 2.18 mmol). To the resulting solution was added a solution of tert-butyl ((2-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-2H-tetrazol-5-yl)methyl)carbamate (541 mg, 1.82 mmol) in DCM:DMF (5:1, 8.5 mL). The solution was stirred at rt for 1 h then concentrated in vacuo, dissolved in EtOAc and washed with brine. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine (3×), dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (Acetone-DCM, 30-50%), affording the title compound (897 mg, 70%) as a purple solid. LCMS: Rt=1.01 min, m/z=709.3 (M+1) Method 2m_acidic.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH:4]=[CH:3][NH:2]1.S(=O)(=O)(O)O.[N+:12]([O-])([OH:14])=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>>[N+:12]([C:3]1[NH:2][O:1][CH:6]=[CH:5][CH:4]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: C1=CNOC=C1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])C1=CC=CON1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The oxazine of formula XI (0.1 mmol) was added portionwise to concentrated sulfuric acid (2 ml) at 22° C. The solution obtained was cooled to 0° C. and treated with red fuming nitric acid (0.058 ml) and stirring was continued at 0° C. for 2 hours. For the workup, the reaction mixture was slowly added to crushed ice and the pH was adjusted to 10 using a saturated solution of sodium carbonate. The aqueous layer was extracted with ethyl acetate, the organic layer was dried over sodium sulphate and evaporated to afford the pure nitro-oxazine of formula XII. Alternatively, the crude product was purified by flash chromatography on silica-NH2 gel using mixtures of heptane or cyclohexane and ethyl acetate as the eluent to yield the pure nitro-oxazines of formula XII.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]#[N:21].[CH:22]([CH:24]([CH:30]=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=O>CCO.CC(O)=O>[C:20]([C:3]1[C:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)=[N:5][N:6]2[CH:30]=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:22]=[N:1][C:2]=12)#[N:21]
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Reactant: CCOC(=O)C(C=O)C=O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)nn2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (276 mg, 1.0 mmol) in EtOH (10 mL) was added ethyl 2-formyl-3-oxopropanoate (144 mg, 1.0 mmol) and HOAc (5 drops). After stirring at RT for 16 hr, the mixture was filtered. The cake was washed with H2O (10 mL×2) and dried to afford 250 mg (65%) of ethyl 3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-6-carboxylate as a yellow solid. MS (ESI) m/e [M+1]+ 384.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]4[CH2:21][NH:22][CH2:23][CH2:24][O:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].CCN(C(C)C)C(C)C>C(#N)C.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]4[CH2:21][N:22]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:23][CH2:24][O:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)OCCNC4)no2)cc1Cl
Reactant: CC(C)(C)OC(=O)CBr
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)OCCN(CC(=O)OC(C)(C)C)C4)no2)cc1Cl
Temperature: 70 °C
Yield: 86.4 %

Procedure:
A mixture of 8-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (Example 13) (0.127 g, 0.301 mmol), 1,1-dimethylethyl bromoacetate (0.117 g, 0.601 mmol) and DIPEA (0.210 ml, 1.203 mmol) in acetonitrile (5 ml) was stirred and heated at 70° C. for one hour. The cooled reaction mixture was diluted with EtOAc/water (30 ml of each) and the organics dried (magnesium sulphate), evaporated and purified by flash chromatography eluting with 1:2 EtOAc/iso-hexane to give the title compound (130 mgs) as a colourless gum. MS (ES) C28H3835ClN3O5 requires 499; found 500 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[SH:15])=[CH:12][CH:11]=[C:10]([Cl:16])[CH:9]=2)(=O)[CH3:2].[OH-].[Na+]>O>[Cl:16][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[S:15][C:1]([CH3:2])=[N:4][C:5]=3[CH:6]=[N:7][C:8]=2[CH:9]=1
Reactant: CC(=O)Nc1cnc2cc(Cl)ccc2c1S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2cnc3cc(Cl)ccc3c2s1
Temperature: 20 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
A mixture of 12.56 g (0.05 mole) of 3-acetamido-7-chloro-4-mercapto-quinoline and 120 g of polyphosphoric acid is heated to 140°-160° C. The reaction mixture is stirred at this temperature for 2 hours, cooled to 90° C., whereupon 700 ml of water are added under vigorous stirring. When the reaction mixture has cooled to 20° C., it is made alkaline by adding a sodium hydroxide solution. The resulting mixture comprising a precipitate is extracted three times with 150 ml of chloroform each. The chloroform layers are united and evaporated to 60 ml, whereupon 300 ml of ethanol are added. 9.3 g of 7-chloro-2-methyl-thiazolo[4,5-c]quinoline are obtained in the form of needle crystals. Yield 80%, m.p.: 181°-183° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3]1.[CH2:12](OC1C=CC=C2C=1NC=C2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OC)(=O)C(OC)=O.CC(C)([O-])C.[K+].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:12]([O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cn1ccc2cccc(O)c21
Reactant: c1ccc(COc2cccc3cc[nH]c23)cc1
Agent: CC(C)(C)[O-]
Agent: COC(=O)C(=O)OC
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cn1ccc2cccc(OCc3ccccc3)c21
Temperature: 110 °C
Reaction time: 8 h

Procedure:
1-Methyl-indol-7-ol: A mixture of 7-benzyloxyindole (300 mg, 1.34 mmol), dimethyl oxalate (317 mg, 2.68 mmol) and potassium tert-butoxide (302 mg, 2.68 mmol) in 5 mL DMF was stirred at 110° C. overnight. The solution was poured into NaHCO3 saturated solution (20 mL) and extracted with EtOAc. The organic layer was separated, washed with brine and dried over Na2SO4. The solvent was removed in vacuo to yield 200 mg of 7-benzyloxy-1-methylindole, which was hydrogenated by 5% Pd/C in 20 mL methanol under H2 (50 psi) to yield 90 mg (45.5%) of the title compound. 1H NMR (CDCl3): 7.19–7.16 (m, 1H), 6.94 (d, J=3 Hz, 1H), 6.86 (t, J=7.5 Hz, 1H), 6.48–6.46 (m, 1H), 6.40 (d, J=3 Hz, 1H), 5.05 (s, 1H), 4.07 (s, 3H).