Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]1=[O:21].[CH2:22]([O:24][C:25](=[O:48])[C@H:26](OS(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH3:23].CN1CCOCC1>C(OCC)(=O)C.CCCCCC>[CH2:22]([O:24][C:25]([C@@H:26]([NH:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[C:3]1=[O:21])[CH2:27][CH2:28][CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)=[O:48])[CH3:23]
Reactant: Cc1ccc(CN2C(=O)C(N)CCc3ccccc32)cc1
Reactant: CCOC(=O)[C@@H](CCC1CCCCC1)OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CN1CCOCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCC1CCCCC1)N[C@@H]1CCc2ccccc2N(Cc2ccc(C)cc2)C1=O

Procedure:
The reaction of 5.4 g of 3-amino-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one with 8.84 g of (R)-alpha-[[(4-nitrophenyl)sulfonyl]oxy]-4-cyclohexylbutyric acid ethyl ester and 2.6 ml of N-methylmorpholine yields the two diastereoisomeric esters 3-(S)-[(1-(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-amino]-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one and 3-(R)-[(1-(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-amino]-1-(p-methylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one, Rf values (eluant ethyl acetate/hexane 1:2) non-polar component 0.58, polar component 0.39.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13](=NN)[CH3:14])([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[I:24]I>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]([I:24])=[CH2:14])([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=NN)C1(C)CN(C(=O)OC(C)(C)C)C1
Reactant: II
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(I)C1(C)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
To a solution of 3-(1-hydrazono-ethyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.076 g, 0.33 mmol) and triethylamine (0.169 g, 1.67 mmol) in THF (3 mL) was added dropwise a solution of iodine (0.127 g, 0.50 mmol) in THF (1 mL). The reaction mixture was stirred for 1 h at ambient temperature then concentrated in vacuo. The residue was dissolved in DCM (10 mL) and washed with aqueous Na2S2O3 (5%, 2 mL). The organic phase was separated and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 20% EtOAc in petroleum ether) to give 3-(1-iodo-vinyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.060 g, 55%), which was unstable and used without further purification. TLC: Rf=0.30 (eluting with 10% EtOAc in petroleum ether).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:26]1([CH2:32][CH2:33][NH2:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][NH:34][CH2:33][CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: NCCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.277 g, 0.79 mmol) and 2-phenylethylamine (0.15 mL, 1.18 mmol) in CH2Cl2 (4 mL) was added sodium triacetoxyborohydride (0.251 g, 1.18 mmol), and the reaction was stirred at room temperature for 2 hours. Analytical LCMS indicated that some starting material was still present, so additional 2-phenylethylamine (0.15 mL, 1.18 mmol) was added, along with acetic acid (1 drop), and the reaction was stirred overnight at room temperature. Analytical LCMS showed that starting material still remained, so additional sodium triacetoxyborohydride (0.260 g, 1.23 mmol) was added, and the reaction was stirred for 2.5 hours. Additional sodium triacetoxyborohydride (0.500 g, 2.36 mmol) was added, and the reaction was stirred for 1.5 hours, until no starting material was seen by analytical LCMS. The mixture was worked-up, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [O-2].[O-2].[Ti+4:3].P(=O)(O)(O)O.[O:9]=[P:10]12[O:21]P3([O:22][P:12]([O:14]P(O3)([O:17]1)=O)(=[O:13])[O:11]2)=O>>[O-:17][P:10]([O:11][P:12]([O-:22])([O-:14])=[O:13])(=[O:9])[O-:21].[Ti+4:3]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Ti+4]
Agent: O=P(O)(O)O
Agent: [O-2]
Product: O=P([O-])([O-])OP(=O)([O-])[O-]

Procedure:
The method of the present invention generally involves the mixture of titanium dioxide and hot concentrated phosphoric acid in a reaction vessel. The reaction mixture has a phosphorus pentoxide to titanium dioxide mole ratio greater than one. Preferably, the phosphorus pentoxide to titanium dioxide mole ratio is about 1.06 or more, and most preferably about 1.20 to about 1.25. The reactants are thoroughly mixed and heated at temperatures of about 400° C. to about 500° C. to produce a fine titanium pyrophosphate powder having a significantly higher fines yield over conventional titanium pyrophosphate processes. The fines yield is greater than 90% when using a phosphorus pentoxide to titanium dioxide mole ratio of about 1.20 to about 1.25.
Reaction SMILES: [Li].[F:2][C:3]1[CH:4]=[N:5][C:6]2[N:7]([N:9]=[CH:10][C:11]=2[C:12]([O-:14])=O)[CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:48][C@@H:49]1[NH:54][CH2:53][CH2:52][N:51]([S:55]([C:58]2[CH:63]=[CH:62][C:61]([C:64]([F:67])([F:66])[F:65])=[CH:60][CH:59]=2)(=[O:57])=[O:56])[CH2:50]1>CN(C=O)C>[F:2][C:3]1[CH:4]=[N:5][C:6]2[N:7]([N:9]=[CH:10][C:11]=2[C:12]([N:54]2[CH2:53][CH2:52][N:51]([S:55]([C:58]3[CH:59]=[CH:60][C:61]([C:64]([F:67])([F:65])[F:66])=[CH:62][CH:63]=3)(=[O:56])=[O:57])[CH2:50][C@@H:49]2[CH3:48])=[O:14])[CH:8]=1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Reactant: O=C([O-])c1cnn2cc(F)cnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cnn2cc(F)cnc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
The lithium salt of 6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate (117 mg, 0.63 mmol) (may be prepared as described in Description 16) was weighed into a vial with HATU (247 mg, 0.65 mmol), suspended in DMF (2 ml) and treated with DIPEA (0.170 ml, 0.97 mmol). This mixture was stirred about 15 min at ambient temperature. (3S)-3-Methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (100 mg, 0.32 mmol) was added and stirring was continued for 3 h at ambient temperature. The reaction mixture was partitioned between DCM and sat. aq. NaHCO3 solution (10 ml each). The layers were separated (hydrophobic frit) and the aqueous layer was washed with further DCM (2×5 ml). The combined organic layers were concentrated to leave an orange gum. Purification by MDAP gave the title compound (112 mg, 0.24 mmol, 73% yield) as an orange solid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:18]C)(=[O:17])[CH:14]([CH3:16])[CH3:15].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27].[NH4+].[Cl-]>C1COCC1.CN1C(=O)N(C)CCC1>[CH3:15][C:14]([CH3:16])([CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27])[C:13]([OH:18])=[O:17]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: COC(=O)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CC(C)(C)C(=O)O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.6M in hexane, 5.05 ml) was added dropwise to a solution of diisopropylamine (1.16 ml) in THF (30 ml) at 0° C. under argon. The resulting mixture was stirred for another 15 minutes before it was cooled to −78° C. and a solution of methyl isobutyrate (0.84 ml) in THF (3 ml) was added dropwise. After the addition was completed, the reaction mixture was allowed to warm to 0° C. and than again cooled to −78° C. At this temperature a solution of 4-chloromethyl-5-methyl-2-phenyl-oxazole [CAS 103788-61-0, commercially available] (1.17 g) in THF (6 ml) and DMPU (7.7 ml) was added. Stirring was continued for another 30 minutes before a saturated NH4Cl solution (1 ml) was added. Then the THF was removed in vacuo and water was added to the remaining residue. This mixture was extracted with ether and the combined organic extracts were washed with water and brine and dried (MgSO4). After evaporation of the solvent the crude alkylation product (1.46 g) was dissolved in THF (20 ml) and LiOH solution (1M, 14.5 ml) was added. The reaction mixture was stirred overnight, concentrated and washed with ether. Then the pH was adjusted to 1 by addition of 3N HCl and the resulting suspension was extracted with ether. Finally the combined extracts were washed with water and brine, dried (MgSO4) and the solvent was removed in vacuo. The product was obtained as a white solid (1.33 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:12]1(N=C=NC2CCCCC2)CCCC[CH2:13]1.N1C=CC=CC=1.C(O)C>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3-Hydroxyphenylacetic acid (10 g, 65.7 mmol) and 1,3-dicyclohexylcarbodiimide (DCC, 16.27 g, 78.8 mmol) in DMF (30 ml) was added pyridine (2.5 ml) followed by absolute ethanol (15 ml, 255.5 mmol). The reaction mixture was stirred at room temperature for 16 hours, filtered, concentrated and purified by flash chromatography on a silica gel column (hex: ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Br.[CH3:13][NH:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:13][N:14]([CH3:15])[CH2:5][C:4]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(CBr)ccc1[N+](=O)[O-]
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CN(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 3-methyl-4-nitrobenzyl bromide (1.0 g, 4.3 mmol), anhydrous dimethylamine (0.34 mL, 5.1 mmol) and potassium carbonate (1.5 g, 0.011 mol) in N,N-dimethylformamide (4.5 mL) was stirred at 70° C. for 12 h. Cooled to ambient temperature, the reaction mixture was poured into ice water, extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to afford N,N-dimethyl-1-(3-methyl-4-nitrophenyl)methanamine as oil (0.80 g, y. 95%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8](COCC[Si](C)(C)C)[N:9]=2)[CH:5]=[C:4]([CH2:19][CH:20]([NH:33][C:34](=O)[O:35]C(C)(C)C)[C:21]2[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:23]=[CH:24][N:25]=2)[CH:3]=1.Cl.C(C1NC=CN=1)(C1NC=CN=1)=O.C(N(C(C)C)CC)(C)C.[NH:63]1[CH2:68][CH2:67][CH:66]([N:69]2[CH2:78][C:77]3[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=3)[NH:71][C:70]2=[O:79])[CH2:65][CH2:64]1>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:19][CH:20]([NH:33][C:34]([N:63]2[CH2:64][CH2:65][CH:66]([N:69]3[CH2:78][C:77]4[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=4)[NH:71][C:70]3=[O:79])[CH2:67][CH2:68]2)=[O:35])[C:21]2[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:23]=[CH:24][N:25]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2ccccn2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nccn2Cc2ccccn2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-(1-(pyridin-2-ylmethyl)-1H-imidazol-2-yl)ethylcarbamate (35.2 mg, 0.063 mmol) was dissolved in a minimum amount of ethyl acetate, and treated with hydrochloric acid (4 N in dioxane, 1.0 mL). The mixture was stirred under nitrogen overnight. After removal of the solvents, the crude mixture was treated with diethyl ether to give a precipitate which was filtered. The resulting solid was dissolved in dimethylformamide (1.0 mL), cooled to 0° C., and treated with carbonyl diimidazole (11.0 mg, 0.066 mmol, 1.05 equiv) and diisopropylethylamine (44.0 μL, 4.0 equiv). The reaction was stirred for 5 min at 0° C., warmed to room temperature, stirred for 10 min, and treated with 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (17.6 mg, 0.066 mmol, 1.05 equiv). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to afford 4.6 mg (12%, 2 steps). 1H-NMR (CD3OD, 500 MHz) δ 1.48-1.65 (m, 4H), 2.03 (s, 1H), 2.45 (s, 3H), 2.69-2.82 (m, 2H), 3.99-4.16 (m, 2H), 4.19 (s, 2H), 5.24 (d, J=16.5, 1H), 6.67 (d, J=7.6, 1H), 6.80 (d, J=7.9, 1H), 6.89 (s, 1H), 6.97 (dd, J=8.2, 7.6, 1H), 7.10-7.23 (m, 5H), 7.30 (s, 1H), 7.37-7.42 (m, 1H), 7.94 (s, 1H). Mass spec.: 590.3 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@@H:20]3[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]3[C@@H:18]([CH2:26][OH:27])[O:17]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[S:38]([NH2:41])(=[O:40])=[O:39].C(#N)C>CN(C)C=O>[S:38](=[O:40])(=[O:39])([O:27][CH2:26][C@@H:18]1[C@@H:19]2[C@@H:20]([O:21][C:22]([CH3:25])([CH3:24])[O:23]2)[C@H:16]([N:11]2[CH:10]=[N:9][C:8]3[C:12]2=[N:13][CH:14]=[N:15][C:7]=3[CH2:6][C:5]2[CH:28]=[CH:29][C:2]([F:1])=[CH:3][CH:4]=2)[O:17]1)[NH2:41]
Reactant: NS(=O)(=O)Cl
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(Cc3ccc(F)cc3)ncnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(N)(=O)=O)O[C@H]2n1cnc2c(Cc3ccc(F)cc3)ncnc21
Reaction time: 1.5 h
Yield: 88 %

Procedure:
{(3aR,4R,6R,6aR)-6-[6-(4-Fluorobenzyl)-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}methanol (249 mg, 0.000622 mol) and triethylamine (173.4 μL, 0.001244 mol) were dissolved in dry N,N-dimethylformamide (10 mL) under nitrogen and the solution was cooled in a water/ice bath. A 2M solution of chlorosulfonamide in acetonitrile (0.0012 mol, 600 μL) was added dropwise. After 1.5 h, the reaction was quenched with methanol, concentrated in vacuo and the residue was purified by flash chromatography (DCM/EtOAc 30% to 80%) to obtain the product as an oil (262 mg, 88%).
Reaction SMILES: C(OC([NH:8][N:9]([C:13]([C:15]1[N:24]=[C:23]2[N:17]([CH2:18][CH2:19][O:20][C:21]3[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:22]=32)[CH:16]=1)=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[ClH:30].O1CCOCC1>CO>[ClH:30].[ClH:30].[CH:10]([N:9]([C:13]([C:15]1[N:24]=[C:23]2[N:17]([CH2:18][CH2:19][O:20][C:21]3[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:22]=32)[CH:16]=1)=[O:14])[NH2:8])([CH3:12])[CH3:11]
Reactant: CC(C)N(NC(=O)OC(C)(C)C)C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)N(N)C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of N′-(8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonyl)-N′-isopropyl-hydrazinecarboxylic acid tert-butyl ester (2.71 g, 5.83 mmol) in methanol (52 mL) was treated with 4N HCl in dioxane (5.83 mL, 23.3 mmol). The reaction mixture was stirred at 50° C. overnight before the reaction was concentrated in vacuo and the resultant residue triturated with diethyl ether to give 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid N-isopropyl-hydrazide dihydrochloride as a pale yellow foam (2.69 g, quantitative yield). LCMS RT=4.17 min, [M+H]+=365/367
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[S:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH:13]=[N:14][C:15]([C:16]([OH:18])=O)=[C:4]2[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.Cl.[CH3:35][O:36][C:37](=[O:42])[C@H:38]([CH2:40][OH:41])[NH2:39].C(N(CC)CC)C>CN(C)C=O>[OH:41][CH2:40][C@H:38]([NH:39][C:16]([C:15]1[N:14]=[CH:13][N:5]2[C:6]3[CH:12]=[CH:11][S:10][C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12)=[O:18])[C:37]([O:36][CH3:35])=[O:42]
Reactant: COC(=O)[C@@H](N)CO
Reactant: CN1Cc2c(C(=O)O)ncn2-c2ccsc2C1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(=O)c1ncn2c1CN(C)C(=O)c1sccc1-2
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
A suspension of 15.5 g (0.0493 mol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylic acid in 200 ml of dimethylformamide was treated portionwise with 8.07 g (0.0498 mol) of carbonyldiimidazole while gassing with argon. After completion of the CO2 evolution the mixture was stirred at 650 for 1 hr. After cooling to 0°-5° the clear solution obtained was treated with 8.62 g (0.0554 mol) of L-serine methyl ester hydrochloride and with 12.3 ml (0.0554 mol) of triethylamine and stirred at room temperature for 16 hrs. The suspension was completely freed from the solvents. The residue was partitioned between water and ethyl acetate and extracted. The yellow oily residue was chromatographed over silica gel with ethyl acetate as the eluent. There were obtained 17.09 g (95%) of methyl (S)-3-hydroxy-2-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]-diazepin-3-ylcarbonylamino)-propionate as a yellowish oil. An analytical sample was recrystallized from ethyl acetate and gave white crystals; m.p. 158°-160°. [α]D20 =+3.9° (CHCl3, c=1%).
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](B3OC(C)(C)C(C)(C)O3)=[CH:10]2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][N:31]2[CH:35]=[CH:34][N:33]=[C:32]2[CH3:36])[N:27]=[N:28][CH:29]=1>>[ClH:23].[F:22][CH:2]([F:1])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:24]3[CH:25]=[C:26]([CH2:30][N:31]4[CH:35]=[CH:34][N:33]=[C:32]4[CH3:36])[N:27]=[N:28][CH:29]=3)=[CH:10]2)=[CH:5][CH:4]=1
Reactant: CC1(C)OB(c2ccc3ccc(C(F)F)cc3c2)OC1(C)C
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1nccn1Cc1cc(-c2ccc3ccc(C(F)F)cc3c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=351.3 (M+H+), was prepared from 2-(7-difluoromethyl-naphthalen-2-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH2:9][C:8]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[CH:7]2
Reactant: O=C1CCc2cccc(Br)c2C1
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: Brc1cccc2c1CCC(N1CCCC1)=C2

Procedure:
To a solution of 8-bromo-2-tetralone (10 gm, 44.4 mMol) in toluene (175 ml) was added pyrrolidine (6.6 ml), and the solution was stirred at reflux for three hours. The volatiles were removed in vacuo to give 8-bromo-3-pyrrolidino-1,2-dihydronaphthalene as a brown oil. To this oil in p-dioxane (60 mL) was added methyl iodide (20 mL, 322 mMol), and the resulting solution was stirred at reflux for eighteen hours. The reaction mixture was diluted with water (60 mL) and acetic acid (3.2 mL), and heating was continued for an additonal three hours. After this time the solution was cooled to room temperature and the volatiles removed in vacuo. The residue was suspended in water and extracted well with diethyl ether. The organic phases were combined, washed with saturated aqueous NaHCO3, dried with Na2SO4 and concentrated in vacuo to give an orange oil. Purification by flash chromatography (33% diethyl ether in hexane) gave the title compound as a light orange oil (6.88 gm, 65%).
Reaction SMILES: [N+:1]1([O-:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C([O-])(C)(C)C.[K+].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=2[O-:8])=[CH:18][CH:17]=1
Reactant: Cc1cccc[n+]1[O-]
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: [O-][n+]1ccccc1C=Cc1ccc(Cl)cc1

Procedure:
Following the general method described in example 2a, 2-picoline-1-oxide was reacted with potassium tert.-butanolate and 4-chloro-benzaldehyde. After extraction and chromatography the title compound was obtained as a yellow solid material. MS: m/e=231 (M+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C@@:8]([CH3:16])([C:12]([F:15])([F:14])[F:13])[C:9](O)=[O:10].[Cl:17][C:18]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:19]=1[NH2:20].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>C(Cl)Cl.CN(C=O)C>[Cl:17][C:18]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:19]=1[NH:20][C:9](=[O:10])[C@:8]([OH:7])([CH3:16])[C:12]([F:15])([F:14])[F:13]
Reactant: C[C@@](O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(I)cc1Cl
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@](O)(C(=O)Nc1ccc(I)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
Oxalyl chloride (1.07 ml) was added dropwise to a stirred suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 9) (1.95 g) in DCM (42 ml) and DMF (0.8 ml). The mixture was stirred at ambient temperature for 2 hours and was then added over 35 minutes to a solution of 2-chloro-4-iodoaniline (2.5 g) and 2,6-di-t-butylpyridine (2.94 ml) in DCM (40 ml) and stirred a further 18 hours. Volatile material was removed by evaporation and the residue was purified by flash chromatography on silica gel eluting with DCM to give the title compound (2.85 g) as a solid. NMR: 1.6 (s, 3H), 7.7 (m, 2H), 7.8 (d, 1H), 7.9 (brs, 1H); MS (ESP−): 392.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH3:20])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:21]=[CH:22][C:2]([NH:1][C:30]([NH:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:31])=[CH:3][CH:4]=1)#[N:18]
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)c2cc1C#N

Procedure:
4-(4-Aminophenoxy)-6-cyano-7-methoxyquinoline (148 mg) was added to 5.5 ml of toluene, and the mixture was heated to reflux. After then adding phenyl isocyanate (0.08 ml), the mixture was further heated to reflux for 1 hour. After cooling, the precipitated solid was filtered out and washed with ethyl acetate/toluene=1/1 to obtain 150 mg of the title compound as light brown crystals. 1H-NMR Spectrum (DMSO-d6) δ (ppm): 4.05 (3H, s), 6.50-6.54 (1H, m), 6.96 (t, 1H, 7.2 Hz), 7.23 (2H, d, J=9.2 Hz), 7.27 (2H, d, J=7.2 Hz), 7.44 (2H, d, J=7.2 Hz), 7.56-7.62 (3H, m), 8.68-8.77 (3H, m), 8.83 (1H, brs).