Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C2C=CC=C(C([NH:14][C:15]3[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][N:19]=[C:20]4[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29](C(F)(F)F)[CH:28]=3)=O)C=2C=CN=1.[Cl:37]C1C=CC(N)=CC=1>>[Cl:37][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:20]2[C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[C:15]([NH2:14])[C:16]=3[CH:17]=[CH:18][N:19]=2)=[CH:28][CH:29]=1
Reactant: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1NC(=O)c1cccc2c(N)nccc12
Reactant: Nc1ccc(Cl)cc1
Product: Cc1ccc2c(Nc3ccc(Cl)cc3)nccc2c1N
Yield: 50 %

Procedure:
The procedures of Steps (1) and (2) of Example 18 were repeated step by step, except for using 4-chloroaniline instead of aniline in Step (1) of Example 18 to obtain the title compound (0.83 g, 50%).
Reaction SMILES: O=[C:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[CH2:3][N:4]1[C:10](=O)[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6]2[N:16]=[CH:17][CH:18]=[CH:19][C:5]1=2.C([O-])(=O)C.[NH4+:31].C(OCC)(=O)C.[OH-].[Na+]>C(O)(=O)C>[C:21]1([CH3:26])[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]1[N:31]=[C:10]2[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[NH:7][C:6]3[N:16]=[CH:17][CH:18]=[CH:19][C:5]=3[N:4]2[CH:3]=1
Reactant: Cc1ccccc1C(=O)CN1C(=O)c2ccccc2Nc2ncccc21
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cn2c(n1)-c1ccccc1Nc1ncccc1-2
Temperature: 120 °C
Reaction time: 48 h
Yield: 52.9 %

Procedure:
To a solution of 5-(2-oxo-2-(o-tolyl)ethyl)-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (0.6 g, 1 eq.) in acetic acid (10 mL) was added ammonium acetate (2.7 g, 20 eq.). The reaction was stirred at 120° C. for 48 hours. The reaction was poured onto water (50 mL) and ethyl acetate (150 mL). The pH was adjusted to 9 by the addition of NaOH 1N. The phases were separated and washed with water (1×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (10% ethyl acetate in dichloromethane) gave the 2-(o-tolyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.3 g, 53%). M.p.: 215-217° C.; 1H NMR (DMSO-d6) 400 MHz δ 8.60 (s, 1H), 8.18 (dd, JA=4.4 Hz, JB=1.2 Hz, 1H), 7.99 (dd, JA=8.0 Hz, JB=1.2 Hz, 1H), 7.91-7.85 (m, 2H), 7.82 (s, 1H), 7.34-7.20 (m, 5H), 7.14 (dd, JA=8.0 Hz, JB=4.8 Hz, 1H), 7.05 (t, J=8.4 Hz, 1H), 2.56 (s, 3H); LCMS: 325 [M+H].
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14]/[N:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([C:25]([CH2:52][CH2:53][CH2:54][CH3:55])=[CH:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][C:28]=1[C:40]([N:42]1[CH2:51][CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43]1)=[O:41])([O-])=O>>[C:34]([O:33][C:31]([C:30]1[CH:38]=[CH:39][C:27]([C:26]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:15][N:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[C:25]=2[CH2:52][CH2:53][CH2:54][CH3:55])=[C:28]([C:40]([N:42]2[CH2:51][CH2:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:43]2)=[O:41])[CH:29]=1)=[O:32])([CH3:35])([CH3:36])[CH3:37]
Reactant: CCOC(=O)/C=N/Nc1cccc(Oc2ccccc2)c1
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1cccc(Oc2ccccc2)c1
Yield: 33 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-ethyl 2-(2-(3-phenoxyphenyl)hydrazono)acetate (37 mg, 0.13 mmol) and tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (60 mg, 0.13 mmol) were converted to the title compound (30 mg, 33%) as a pale yellow oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.08 (dd, J=8, 2 Hz, 1H), 8.04-8.02 (m, 1H), 7.44-6.78 (m, 14H), 5.02-4.98 (m, 1H), 4.41-4.35 (m, 1H), 4.31-4.26 (m, 2H), 4.16-3.98 (m, 1H), 3.58-3.28 (m, 1H), 2.81-2.50 (m, 4H), 1.61 (s, 9H), 1.28 (t, J=8 Hz, 1.5H), 1.22 (t, J=8 Hz, 1.5H), 1.13-0.88 (m, 4H), 0.63-0.59 (m, 3H); MS(ESI+) m/z 700.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:18]([CH3:25])[CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5].Cl[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[NH2:37][C:33]1[N:34]=[C:35]([N:22]2[CH2:21][CH2:20][CH:19]([N:18]([CH3:25])[C:16]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH2:9][CH2:8][C@H:7]4[NH:6][C:4](=[O:5])[C:3]3[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=3[Cl:1])=[O:17])[CH2:24][CH2:23]2)[CH:36]=[CH:31][N:32]=1
Reactant: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2)C1CCNCC1
Reactant: Nc1nccc(Cl)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2)C1CCN(c2ccnc(N)n2)CC1
Reaction time: 0.15 h
Yield: 45 %

Procedure:
A mixture of (R)-3-(2-chlorobenzamido)-N-methyl-N-(piperidin-4-yl)-2,3-dihydro-1H-indene-5-carboxamide (stage 2H-214) (200 mg, 0.486 mmol, 1.0 eq), 4-chloro-pyrimidin-2-ylamine (94 mg, 0.728 mmol, 1.5 eq) and DIPEA (0.125 ml, 0.728 mmol, 1.5 eq) in dioxane (10 ml) was refluxed for 16 h. When the reaction was complete according to TLC monitoring, concentration under reduced pressure was carried out, and the reside was taken up in dichloromethane (50 ml) and washed with water (30 ml) and saturated sodium chloride solution (30 ml). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 6% methanol in dichloromethane). Yield: 45% (110 mg, 0.267 mmol) Analytical Data—Single Substances Method 1: Equipment and methods for HPLC-MS analysis: HPLC: Waters Alliance 2795 with PDA Waters 2998; MS: Micromass Quattro Micro™ API; column: Waters Atlantis® T3, 3 μm, 100 Å, 2.1×30 mm; column temperature: 40° C., eluent A: purified water+0.1% formic acid; eluent B: acetonitrile (gradient grade)+0.1% formic acid; gradient: 0% B to 100% B in 8.8 min, 100% B for 0.4 min, 100% B to 0% B in 0.01 min, 0% B for 0.8 min; flow: 1.0 ml/min; ionization: ES+, 25 V; batch: 100 μl/min 70% methanol+0.2% formic acid; UV: 200-400 nm.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[CH2:11][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][C:8]1=[O:18])=O)C.[NH3:19]>CO>[C:4]([CH2:6][N:7]1[CH2:11][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][C:8]1=[O:18])(=[O:3])[NH2:19]
Reactant: CCOC(=O)CN1C[C@@H](c2ccccc2)CC1=O
Reactant: N
Solvent: CO
Product: NC(=O)CN1C[C@@H](c2ccccc2)CC1=O
Yield: 85 %

Procedure:
The solution of N-ethoxycarbonylmethyl-4(R)-phenyl-2-pyrrolidinone (3) (250 mg, 1.01 mM) in methanol (30 ml) saturated by stream of gaseous ammonia for 5 hours. Reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography with ethylacetate-hexane mixture 1:1 silicagel giving N-carbamoylmethyl-4(R)-phenyl-2-pyrrolidinone (4a) (187 mg, 85%). M.p. 107.5-108° C. [α]D20=+8.5° (c=3, MeOH). 1H NMR (CDCl3), δ: 2.61 (1H, d, d, 3-CH2); 2.87 (1H, d, d, 3-CH2); 3.54 (1H, t, 5-CH2); 3.66 (1H, quintet, 4-CH); 3.89 (1H, t, 5-CH2); 4.00 (2H, s, NCH2CO); 5.68 and 6.21 (1H and 1H, br.s and br.s, NH2); 7.20-7.40 (5H, m, C6H5).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Cl[CH2:45][C:46]1[N:47]=[N:48][CH:49]=[CH:50][CH:51]=1.BrCC1OC(C(F)(F)F)=CC=1>>[N:48]1[CH:49]=[CH:50][CH:51]=[C:46]([CH2:45][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([CH2:13][O:12][C:11]4[CH:14]=[C:15]5[C:19](=[CH:20][C:10]3=4)[CH2:18][CH2:17][O:16]5)[C:2]2=[O:21])[N:47]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: ClCc1cccnn1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2cccnn2)c2ccccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 3-(chloromethyl)pyridazine to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-(pyridazin-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (13%) as a colorless solid: mp 81-82° C.; 1H NMR (300 MHz, CDCl3) δ 9.18-9.14 (m, 1H), 7.58-7.44 (m, 2H), 7.28-7.15 (m, 2H), 7.12-7.02 (m, 2H), 6.47 (s, 1H), 6.43 (s, 1H), 5.39-5.22 (m, 2H), 4.84 (ABq, 2H), 4.60-4.49 (m, 2H), 3.10-2.91 (m, 2H); 13C NMR (75 MHz, CDCl3) δ178.1, 161.9, 161.4, 158.4, 151.1, 141.6, 132.4, 129.0, 127.3, 126.0, 123.9, 123.8, 120.0, 119.9, 118.8, 109.6, 93.3, 80.6, 72.4, 57.8, 44.6, 29.0; MS (ES+) m/z 372.3 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[O:10][S:11]([CH3:14])(=[O:13])=[O:12].C(Br)(Br)(Br)[Br:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:16][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[O:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: Cc1ccc(CO)c(OS(C)(=O)=O)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(CBr)c(OS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of methanesulfonic acid 2-hydroxymethyl-5-methylphenyl ester (864 mg, 4 mmol) in DCM (45 mL) is added CBr4 (2.0 g, 6 mmol) and PPh3 (1.57 g, 6 mmol). The mixture is stirred at RT for 6 h. The solvent is removed and the residue is purified to give the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](Br)=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cu][C:20]#[N:21]>CN1CCCC1=O>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([C:20]#[N:21])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1cc(Br)c(C(C)C)cc1OCC
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cc(C#N)c(C(C)C)cc1OCC
Yield: 40.3 %

Procedure:
Ethyl 2-ethoxy-4-iso-propyl-5-bromobenzoate (12 g, 3.8 mmol) was treated with copper (I) cyanide (682 mg, 7.6 mmol) in N-methyl-2-pyrrolidinone (40 ml) as described in Procedure 5 to give the title compound as an oil (400 mg).
Reaction SMILES: CC([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[C:15]([O:17][CH3:18])=[O:16])(=[O:8])=[O:7])(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.[Au]>[NH2:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[C:15]([O:17][CH3:18])=[O:16])(=[O:8])=[O:7]
Reactant: COC(=O)c1c(S(=O)(=O)NC(C)(C)C)ccn1C
Agent: [Au]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(S(N)(=O)=O)ccn1C

Procedure:
To a solution of 3.53 g of methyl 3-[[(1,1-dimethylethyl)amino]sulfonyl]-1-methyl-1H-pyrrole-2-carboxylate in 40 mL of methylene chloride under an nitrogen atmosphere was added 80 ml, of trifluoroacetic acid (TFA). The gold solution was stirred at room temperature overnight ca. 16 hours. The gold solution was concentrated to an oily residue. Diethyl ether was added to the residue and removed by evaporation to remove residual TFA. The resulting solid was suspended in diethyl ether and filtered affording the title compound as a tan solid, m.p. 105°-107° C.
Reaction SMILES: [H-].[Na+].Br.Cl[C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([NH2:14])=[N:12][N:13]=2)[N:10]=1.O.[CH:16]1([OH:20])[CH2:19][CH2:18][CH2:17]1>>[CH:16]1([O:20][C:5]2[CH:6]=[CH:7][C:8]3[N:9]([C:11]([NH2:14])=[N:12][N:13]=3)[N:10]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: Nc1nnc2ccc(Cl)nn12
Reactant: OC1CCC1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Nc1nnc2ccc(OC3CCC3)nn12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Cyclobutanol (2.43 ml) was initially charged at RT with stirring and cooled almost to 0° C. with an ice bath. Subsequently, the mixture was admixed with portions of sodium hydride (146 mg). The suspension formed was heated to 55° C. for 30 min and admixed with portions of 6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.001, 200 mg), suspended in cyclobutanol (5 ml). After stirring at 55° C. for 1.5 h, the mixture was left to stand at RT overnight and then admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 136 mg of the title compound were obtained in solid form. LC-MS rt: 0.82 min [M+1-1]+: 206.2 (met. a)
Reaction SMILES: O.O.O.O.O.O.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].[OH-].[Na+]>CO.O>[N:7]1([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1CNCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCNCC1
Temperature: 25 °C

Procedure:
250 ml of water and 500 ml of methanol are added to 194 g (1 M) of piperazine hexahydrate, while stirring, and the pH is adjusted to 3 with about 163 ml of concentrated hydrochloric acid. The mixture is then cooled to 25° C. and 100 g (0.59 M) of benzyl chloroformate are added dropwise, while stirring, during which the pH is kept between 3 and 4.5 with sodium hydroxide solution (4 M; about 230 ml). About 700 ml are then stripped off on a rotary evaporator and the residue is washed with water, rendered acid with about 1.5 ml of concentrated HCl and extracted twice with 200 ml of toluene each time. The aqueous phase is cooled and brought to pH 12 with about 115 ml of 12.5 N NaOH. The oil which separates out is extracted several times with toluene, and the extract is dried over K2CO3 and concentrated under reduced pressure. Yield: 74 g
Reaction SMILES: O(C([N:10]1[CH2:15][CH2:14][C:13]2([C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:12][CH2:11]1)=O)C1C=CC=CC=1.C(O)C.[OH-].[K+].[ClH:34]>O>[ClH:34].[NH:10]1[CH2:11][CH2:12][C:13]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3[C:28]2=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:15]1
Reactant: O=C(Oc1ccccc1)N1CCC2(CC1)c1ccccc1Oc1ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc2c(c1)Oc1ccccc1C21CCNCC1

Procedure:
A mixture of 1'-phenoxycarbonylxanthene-9-spiro-4'-piperidine (370 mg.), ethanol (80 ml.) and a 50% w/v solution of potassium hydroxide in water (20 ml.) is heated under reflux for 22 hours. The mixture is cooled and concentrated hydrochloric acid (20 ml.) is added and the ethanol is evaporated. The residue is washed with ether, water (50 ml.) is added and the resulting solution made alkaline with 3N sodium hydroxide. The alkaline solution is extracted with chloroform and the chloroform extract is washed with water, dried (MgSO4) and evaporated to dryness. The gummy residue is dissolved in ethanol and treated with ethereal hydrochloric acid. The solid is recrystallised from ethanol-ether to give xanthene-9-spiro-4'-piperidine hydrochloride, m.p. 248°-250° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+].O>CS(C)=O>[CH2:14]([O:13][CH2:12][CH2:11][C:5]1[C:6]2[N:7]([N:8]=[CH:9][N:10]=2)[C:2]2[N:3]([N:22]=[N:23][N:24]=2)[C:4]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOCCc1c(-c2ccccc2)nc(Cl)n2ncnc12
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOCCc1c(-c2ccccc2)n2nnnc2n2ncnc12
Reaction time: 5 h

Procedure:
To a solution containing 30.2 g of 5-chloro-8-(2-ethoxyethyl)-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidine (0.1 moles) dissolved in 200 ml of dimethylsulfoxide is added 20 g of sodium azide (0.3 moles). The resulting reaction mixture is heated to 65°-70° C. and then stirred for 5 hours. The reaction mixture is then stirred overnight at room temperature. The reaction mixture is then stirred into 1 liter of water and a precipitate forms. The mixture is filtered and the precipitate is washed with water and dried yielding a crude product. The crude product is chromatographed on silica gel and recrystallized from diethylether to yield 6-(2-ethoxyethyl)-5-phenyltetrazolo[1,5-a][1,2,4]triazolo[1,5-c]pyrimidine having the structural formula ##STR20## and the azido tautomer thereof as a white solid having a melting point of 114° C. and the following elemental analysis:
Reaction SMILES: CS(O)(=O)=O.C(OC([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:35](=[NH:37])[NH2:36])[CH:31]=2)[CH:26]=1)=[O:23])=O)C1C=CC=CC=1.CS(O)(=O)=O.[H][H]>[C].[Pd].CN(C)C=O>[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:35](=[NH:36])[NH2:37])[CH:31]=2)[CH:26]=1)=[O:23]
Reactant: N=C(N)c1ccc2cc(OC(=O)CCCCCNC(=O)OCc3ccccc3)ccc2c1
Reactant: [H][H]
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CN(C)C=O
Product: N=C(N)c1ccc2cc(OC(=O)CCCCCN)ccc2c1
Yield: 36.6 %

Procedure:
To 40 ml of anhydrous dimethylformamide, were added 4.2 g of 6-amidino-2-naphthyl ε-benzyloxycarbonylaminocaproate methanesulfonate, 1.0 g of methanesulfonic acid, and 0.2 g of 10% palladium-carbon. Hydrogen was passed for 4 hours through the vigorously stirred mixture. After removing the palladium-carbon by filtration, the filtrate was poured into stirred ethyl ether. An oily substance which separated out was washed with ethyl ether and recrystallized from ethanol to obtain 0.87 g of white crystals of 6-amidino-2-naphthyl ε-aminocaproate dimethanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:3]=12.Cl.[NH:15]1[CH2:18][CH2:17][CH2:16]1>>[N:15]1([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[O:13])[CH2:18][CH2:17][CH2:16]1
Reactant: O=C(O)c1cc2nccc(Cl)c2s1
Reactant: C1CNC1
Agent: Cl
Product: O=C(c1cc2nccc(Cl)c2s1)N1CCC1

Procedure:
was prepared from 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid and azetidine hydrochloride following Method A. 1H NMR (300 MHz, DMSO-d6) δ 8.72 (1H, d, J=5.1 Hz), 7.96 (1H, s), 7.70 (1H, d, J=5.1 Hz), 4.62 (2H, t, J=7.4 Hz), 4.12 (2H, t, J=7.7 Hz), 2.34 (2H, tt, J=7.4, 7.7 Hz).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>COCCOC>[CH3:8][S:7][C:4]1[N:3]=[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[F:9])[S:6][N:5]=1
Reactant: OB(O)c1ccccc1F
Reactant: CSc1nsc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1nsc(-c2ccccc2F)n1
Temperature: 80 °C
Reaction time: 12 h
Yield: 85.6 %

Procedure:
To 4 ml of 1,2-dimethoxyethane were added 284 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole, 262 mg of 2-fluorophenylboronic acid, 98 mg of tetrakistriphenylphosphine palladium and 4 ml of a 2 M aqueous sodium carbonate solution, and the mixture was stirred at 80° C. for 12 hours in a nitrogen atmosphere. Then, the reaction mixture was poured into an aqueous saturated sodium chloride solution, and the mixture was extracted with t-butyl methyl ether. The residue obtained by concentration of the organic layer was subjected to silica gel column chromatography to obtain 330 mg of 3-methylthio-5-(2-fluorophenyl)-1,2,4-thiadiazole.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=O)[N:11]=2)=[CH:6][C:3]=1[C:4]#[N:5].[NH2:18][C@@H:19]([CH2:23][OH:24])[CH:20]([CH3:22])[CH3:21].C(O)(=O)C.C([BH3-])#N>CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:18][C@H:19]([CH:20]([CH3:22])[CH3:21])[CH2:23][OH:24])[N:11]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)[C@@H](N)CO
Reactant: N#Cc1cc(-c2cccc(C=O)n2)ccc1F
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)[C@H](CO)NCc1cccc(-c2ccc(F)c(C#N)c2)n1
Reaction time: 2 h
Yield: 52.5 %

Procedure:
To a solution of 6-bromopicolinaldehyde (1.00 g, 5.38 mmol) in dioxane (30 mL) at ambient temperature was added 3-cyano-4-fluorophenylboronic acid (0.887 g, 5.38 mmol), 2M cesium carbonate (8.1 mL, 16.2 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.220 g, 0.269 mmol). The mixture was degassed (3× vacuum/purge N2), then heated at 80° C. overnight. The mixture was cooled, concentrated and partitioned between water and CH2Cl2. The organic layer was concentrated and purified by chromatography (30% ethyl acetate:hexanes) to provide 2-fluoro-5-(6-formylpyridin-2-yl)benzonitrile. To a solution of 2-fluoro-5-(6-formylpyridin-2-yl)benzonitrile (0.500 g, 2.21 mmol) in methanol (20 mL) at ambient temperature was added D-valinol (0.25 mL, 2.2 mmol), acetic acid (0.50 mL, 8.8 mmol) followed by MP-cyanoborohydride (2.49 mmol/g; 1.0 g). After 2 hours, the mixture was filtered, concentrated, and the residue partitioned between ether and 1M NaOH. The organic layer was concentrated and purified by chromatography to provide 362 mg (52%) of the title compound. MS (DCI+) m/z 314 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.62 (dd, J=6.3, 2.3 Hz, 1H), 8.52 (ddd, J=8.9, 5.3, 2.4 Hz, 1H), 7.97-7.84 (m, 2H), 7.66 (t, J=9.0 Hz, 1H), 7.49 (dd, J=7.4, 1.1 Hz, 1H), 3.92 (d, J=3.6 Hz, 2H), 3.52-3.43 (m, 1H), 2.40-2.22 (m, 2H), 1.93-1.76 (m, 1H), 0.89 (dd, J=9.5, 6.9 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17](Br)=[CH:18][CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27].COC(=O)/C=C/C1C=C2C(=CC=1)OC1(CCNCC1)CC2=O>>[CH3:30][O:29][C:25](=[O:28])/[CH:26]=[CH:27]/[C:17]1[CH:16]=[C:15]2[C:20]([C:21](=[O:23])[CH2:22][C:11]3([O:14]2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)=[CH:19][CH:18]=1
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccc(Br)cc1O2
Agent: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Product: COC(=O)/C=C/c1ccc2c(c1)OC1(CCN(C(=O)OC(C)(C)C)CC1)CC2=O

Procedure:
7-Bromo-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylic acid tert-butyl ester (9.1 g, 23 mmol) was treated with methyl acrylate according to the procedure for preparation of Intermediate 1, Step B, giving (E)-3-{1′-tert-butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-7-yl}-acrylic acid methyl ester (7.07 g) as a yellow solid.
Reaction SMILES: Br[CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH2:20][C:21]([NH2:23])=[S:22].C([O-])(=O)C.[Na+]>C(O)C>[CH2:13]([C:2]1[S:22][C:21]([NH2:23])=[N:20][C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(C(=O)C(Br)Cc2ccccc2)cc1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
To a 500 ml eggplant-shaped flask were added 25.00 g (78.32 mmol) 2-bromo-1-(4-methoxy-phenyl)-3-phenyl-propan-1-one prepared in the step 3 and 150 ml anhydrous ethanol, then added 5.96 g (78.32 mmol) thiourea and 6.42 g (78.32 mmol) anhydrous sodium acetate under stirring, the resulting mixture was stirred at room temperature for 1 hour, then refluxed for 2 hours, and cooled to room temperature, and a solid was precipitated, filtered, washed with water, dried to obtain 18.01 g of a product, a single spot was shown by TLC, the product was not further purified in a yield of 77.6%, mp: 177-178□. 1H-NMR (DMSO-d6, 400 MHz) δ: 3.76 (3H, s, OCH3), 4.04 (2H, s, CH2), 6.82 (2H, s, NH2), 6.93 (2H, d, J=9.00 Hz, ArH), 7.18˜7.35 (5H, m, ArH), 7.46 (2H, d, J=9.00 Hz, ArH); EI-MS m/e (%): 296.1 (M, 100), 219.0 (19); HREI-MS Calcd. for C17H16N2OS: 296.0983. found: 296.0978. Anal. Calcd. for C17H16N2OS: C, 68.89; H, 5.44; N, 9.45. found: C, 69.08; H, 5.32; N, 9.57.