Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:3]=1[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][C:3]=1[CH2:4][N:5]([CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[C:9]([C:17]([F:18])([F:19])[F:20])[CH:8]=1)[C:29](=[O:31])[CH3:30]
Reactant: Nc1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of [2-amino-5-(trifluoromethyl)benzyl][3,5-bis(trifluoromethyl)benzyl]amine (Example 3) (270 mg, 0.65 mmol) in methylene chloride at 0° C., acetic anhydride (0.061 mL, 0.65 mmol) in methylene chloride and then triethylamine were added (0.018 mL, 0.13 mmol). The solution was stirred for 0.5 hours at 0° C. This solution was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was purified by column chromatography using 40% EtOAC/hexane. 1H NMR (CDCl3, 500 MHz) δ 7.80 (s, 1H), 7.56 (s, 2H), 7.30 (d, J=8.5 Hz, 1H), 7.04 (s, 1H), 6.65 (d, J=8.5 Hz, 1H), 4.67 (s, 2H), 4.65 (s, 2H), 2.22 (s, 3H).
Reaction SMILES: N[C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.N([O-])=O.[Na+].[ClH:29]>S(=O)(=O)(O)O.CC(O)=O.O.C(Cl)Cl.[Cu]Cl>[Cl:29][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(N)cnc21
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(Cl)cnc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43 %

Procedure:
A solution of 3-amino-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (45.4 mg, 0.134 mmol) in 2M aqueous sulfuric acid (2.0 mL) and AcOH (1.0 mL) was cooled to 0° C. and treated with a solution of sodium nitrite (10.2 mg, 0.147 mmol) in water (0.30 mL). After 20 min, the solution of the diazonium salt was added slowly to a cooled (0° C.) solution of copper (I) chloride (29.1 mg, 0.294 mmol) in 1M hydrochloric acid (0.60 mL). The reaction mixture was allowed to warm to ambient temperature then diluted with DCM and water. The layers were separated, the aqueous phase extracted further with DCM, and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The resultant residue was dissolved in ethyl acetate and pre-absorbed onto silica gel and purified by flash chromatography (silica, 4 g column, Biotage, 1-50% EtOAc in heptane) to afford the title compound as a yellow-orange solid (20 mg, 43%). LCMS (Method D): RT=3.61 min, M+H+=359/361.
Reaction SMILES: [OH:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:10][C:5]=2[O:4][C:3]=1[C:15]#[N:16].N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:15]([C:3]1[O:4][C:5]2[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=2[C:2]=1[O:1][S:24]([CH3:23])(=[O:26])=[O:25])#[N:16]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1ccc2c(O)c(C#N)oc2c1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1c(C#N)oc2cc(S(C)(=O)=O)ccc12
Temperature: 25 °C

Procedure:
A suspension of 13 (3.9 g) in CH2Cl2 (200 mL) was treated with pyridine (10 mL), methanesulfonyl chloride (4 mL), and a catalytic amount of dimethylaminopyridine at 0° C., under an N2 atmosphere, for 2 h. The reaction was allowed to warm to ambient temperature overnight. The reaction was partitioned between 1:1 Et2O/hexanes and brine. The organic layer was dried (MgSO4), filtered, and evaporated. The residue was purified by chromatography (silica gel, 1:1 EtOAc/hexanes) giving 1.05 g of methanesulfonic acid 2-cyano-6-methanesulfonyl-benzofuran-3-yl ester 14.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]2[CH2:8][S:9][C@@H:10]3[C@H:21]([NH:22][C:23](=[O:71])/[C:24](/[C:46]4[N:47]=[C:48]([NH:51]C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[S:49][CH:50]=4)=[N:25]\[O:26]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:20](=[O:72])[N:11]3[C:12]=2[C:13]([O:15]C(C)(C)C)=[O:14])[O:3]1>Cl.C(O)=O>[NH2:51][C:48]1[S:49][CH:50]=[C:46](/[C:24](=[N:25]/[OH:26])/[C:23]([NH:22][C@@H:21]2[C:20](=[O:72])[N:11]3[C:12]([C:13]([OH:15])=[O:14])=[C:7]([CH:4]4[O:3][C:2](=[O:1])[CH2:6][CH2:5]4)[CH2:8][S:9][C@H:10]23)=[O:71])[N:47]=1
Reactant: CC(C)(C)OC(=O)C1=C([C@@H]2CCC(=O)O2)CS[C@@H]2[C@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Agent: Cl
Solvent: O=CO
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(C4CCC(=O)O4)CS[C@H]23)cs1
Reaction time: 1 h

Procedure:
t-Butyl (6R,7R)-3-[(5S)-2-oxotetrahydrofuran-5-yl]-7-[2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityloxyiminoacetamido]ceph-3-em-4-carboxylate (0.22 g) was dissolved in 0.1M hydrochloric acid in 90% formic acid (2.5 ml) and stirred for 1 h. Concentrated hydrochloric acid (0.1 ml) was added and stirring was continued for a further 0.5 h. The precipitate was filtered off, washed with 90% formic acid, and the filtrate was evaporated to dryness. The residue in water was adjusted to pH3 with solid potassium carbonate, washed with ether and freeze dried. The crude product (0.153 g) was chromatographed on HP20SS, eluting with 0,2,4,6% THF in water. Fractions containing the title compound were combined, concentrated and freeze dried (41 mg, 40%), νmax (KBr) 1764, 1664, 1609, 1529, 1389 and 1184 cm-1 ; δH (D2O) 2.1-2.8 (4H,m , 3.37 and 3.63, 3.39 and 3.53 (2H,2ABq,J17.5,17.8 Hz), 5.21, 5.23 (1H,2d, J4.6 Hz), 5.5-5.65 (1H,m), 5.82 (1H,d,J4.6 Hz), 6.95 (1H,s); [mass spectrum: + ve ion (thioglyerol) MH+, 454].
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1C(=O)CCC1>[C-]#N.[Zn+2].[C-]#N.O>[Cl:8][C:7]1[C:2]([C:9]#[N:10])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: CN1CCCC1=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ncccc1Cl
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 29.6 g of 2,3-dichloropyridine, 46.97 g of zinc cyanide, 11.56 g of tetratris(triphenylphosphine)palladium(0) and 150 mL of NMP was stirred at 100° C. for 2 hours. Water was added to the reaction mixture cooled to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 9.08 g of 3-chloropyridine-2-carbonitrile.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].N[C@H](C([O-])=O)CCC([O-])=O.[Na+].[Na+].[O-]P(OP(OP([O-])([O-])=O)([O-])=O)([O-])=O.[Na+].[Na+].[Na+].[Na+].[Na+]>>[OH:8][CH2:6][C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:23])[OH:7])[OH:22])[OH:21])[OH:20]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Agent: [Na+]
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Temperature: 0 °C

Procedure:
Four thousand parts of a thawed raw meat paste of Alaska pollack was mixed with 80 parts of maltose, 80 parts of sodium glutamate, 200 parts of potato starch, 300 parts of ice water, 12 parts of sodium tripolyphosphate, 120 parts of salt, and 100 parts of an aqueous solution containing 10 parts of a polyol-type ganoderan obtained by the method in Example 3, and 1 part of sorbitol, after which about 120 g aliquots of the mixture were shaped, and placed on pieces of wood. The resultant was heated with steam so that the product temperature increased to about 80° C. in 30 minutes, cooled at room temperature, and allowed to stand at 4° C. for 24 hours to obtain a fish meat product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:15][CH:16]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17]1>>[CH2:21]([N:18]1[CH2:19][CH2:20][CH:16]([NH:15][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[C:3]([NH:13][CH3:14])=[CH:4][C:5]=2[O:11][CH3:12])[CH2:17]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: CNc1cc(OC)c(C(=O)O)cc1Cl
Product: CNc1cc(OC)c(C(=O)NC2CCN(Cc3ccccc3)C2)cc1Cl

Procedure:
Following the procedure set forth in general method A supra using 1.08 g. of 5-chloro-2-methoxy-4-methylaminobenzoic acid and 0.97 g. of 3-amino-1-benzylpyrrolidine, 1.07 g. of N-(1-benzyl-3-pyrrolidinyl)-5-chloro-2-methoxy-4-methylaminobenzamide was obtained.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][C:28]#[N:29].O>CN(C)C=O>[C:28]([CH2:27][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:13][CH2:12][CH2:11]1)#[N:29]
Reactant: N#CCCl
Reactant: c1ccc(C2(c3ccccc3)CCNCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCN1CCOC(c2ccccc2)(c2ccccc2)CC1

Procedure:
To the solution of 2.5 g of 7,7-diphenyl-hexahydro-1,4-oxazepine in 5 ml of dimethylformamide, 1.5 g of anhydrous potassium carbonate are added while stirring, followed by the dropwise addition of the solution of 0.85 g of chloroacetonitrile in 2 ml of dimethylformamide and the suspension is stirred for 5 hours at room temperature. It is poured onto a mixture of ice and water, the aqueous phase extracted twice with 20 ml of diethyl ether each, the extract dried, filtered and evaporated. The residue is recrystallized from ethanol, to yield the 4-cyanomethyl-7,7-diphenyl-hexahydro-1,4-oxazepine melting at 119°-121° (its hydrochloride melts at 178°-180° with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C(=O)C(C)(C)C)=[CH:4][C:3]=1[C:15]([NH:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)=[O:16].C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:15]([NH:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=1)=[O:16]
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(OC(=O)C(C)(C)C)ccc2Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(CNC(=O)c2cc(O)ccc2Cl)cc1

Procedure:
A solution of methyl 4-{[({2-chloro-5-[(2,2-dimethylpropanoyl)oxy]phenyl}carbonyl)amino]methyl}benzoate (590 mg, 1.46 mmol) and sodium methoxide (1.2 eq, 95 mg, 1.76 mmol) in methanol (10 ml) was heated at 65° C. overnight. On cooling the solvent was evaporated in vacuo to give the title compound as a white solid. MS (ES+) m/z 320 [M+H]+ (C16H1435ClNO4). 1H-NMR (400 MHz, d6-DMSO) δ 3.84 (3H, s), 4.45 (2H, d, J 6), 6.55 (2H, m), 6.99 (1H, d, J 8.8), 7.46 (2H, d, J 8.4), 7.92 (2H, m), 8.82 (1H, t).
Reaction SMILES: O[CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[OH2:7]>>[CH3:2][CH:3]([O:4][C:3]([CH2:5][OH:6])=[O:4])[C:5]([OH:6])=[O:7]
Reactant: O
Reactant: OCC(O)CO
Product: CC(OC(=O)CO)C(=O)O

Procedure:
The insulin-loaded PLGA/HP55 nanoparticles are prepared as follows: Insulin (5 mg) is dissolved into 0.1% PVA (1.0 mL, pH=2) or glycerin as an internal stabilizer to form internal water phase (W1), poly (lactic acid-co-glycolic acid) (PLGA) (100 mg) and HP55 (50 mg) are dissolved into 5 mL of an organic solvent (volume ratio of dichloromethane and acetone is 4:1 or 3:1) to form an oil phase (O), respectively. Optionally, a hydrophobic carrier is added to the oil phase (O) before pouring W1 into O. At 25° C., 1 mL W1 is poured into O, and the mixture is ultrasonic for 0.5 min at 60 W to obtain an initial W1/O emulsion. The initial emulsion is poured into an external water phase with 1.0% PVA (10 mL) (W2) quickly, and the mixture is ultrasonic for 4 min at 60 W to obtain a double W1/O/W2 emulsion. The acetone and dichloromethane in the double emulsion are eliminated totally by rotary evaporation (45° C., 451 mbar, 15 min). The residue is centrifuged (10° C., 20,000 rpm, 10 min). Finally, the pH-sensitive nanoparticles are obtained from the precipitate after at least twice of washing by distilled water and freeze drying. The molecular weight of the PVA used in the present invention is from 31,000 to 50,000 daltons. The molecular weight of the hydrophobic polymer or carrier used in the present invention is from 20,000 to 40,000 daltons.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1.C(N(CC)CC)C.[Cl:15][C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:17].Cl>C(OCC)(=O)C>[ClH:15].[N+:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][C:16]([O:1][CH2:2][C:3]2[S:7][CH:6]=[N:5][CH:4]=2)=[O:17])=[CH:24][CH:23]=1)([O-:27])=[O:26]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCc1cncs1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Temperature: -1 °C
Reaction time: 0.75 h
Yield: 74.6 %

Procedure:
Distilled 5-(hydroxymethyl)thiazole (14.1 g, 123 mmol) and triethylamine (17.9 mL, 129 mmol) were dissolved in ethyl acetate (141 mL) and cooled to -1° C. (ice/salt bath). A solution of 4-nitrophenyl chloroformate (26.0 g, 129 mmol) dissolved in ethyl acetate (106 mL) was added dropwise over 50 minutes at an internal temperature of 0°-4° C. An ethyl acetate flask rinse (20 mL) was also added. Salts precipitated from solution throughout the addition. The yellow mixture was stirred another 1 hour 45 minutes at 0°-2° C., then a solution of dilute HCl (3.1 g, 31 mmol of conc. HCl in 103 mL water) was added at once. The mixture was stirred for 0.5 hours while warming to 15° C., then stirring was stopped. The organic layer was washed twice with aqueous 5% K2CO3 solution (2×70 mL), then dried with Na2SO4 (30 g). After filtration the solution was concentrated under vacuum on a rotary evaporater (bath temperature of 41° C.) to a brown oil (38 g). The crude 5-(p-nitrophenyoxycarbonyloxymethyl)-thiazole was dissolved in ethyl acetate (282 mL), then cooled in an ice bath to 2° C. Dry HCl gas (7.1 g, 195 mmol) was bubbled in slowly over 50 minutes (temperature 2°-4° C.). After stirring for another 1 hour 45 minutes at 2°-4° C., the solid precipitate was collected on a sintered glass funnel under a nitrogen blanket and the flask was washed out with 50 mL cold ethyl acetate which was used to rinse the filter cake. The cake was dried on the funnel under strong nitrogen purge for 15 minutes then dried in a vacuum oven at 50° C. with a nitrogen purge to provide 29.05 g of the title compound as tan powder, m.p. 131°-135° C. (dec). 1H NMR (DMSO-d6) δ9.21 (d, 1H), 8.27 (m, 2H), 8.06 (d, 1H), 7.52 (m, 2H), 5.54 (s, 2H). 13C NMR (DMSO-d6) δ157.3, 155.2, 151.8, 145.3, 143.7, 131.9, 125.5, 122.7, 62.1.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23]/[CH:24]=[CH:25]/[CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23]/[CH:24]=[CH:25]/[CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: BrC/C=C/COc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OC/C=C/COc3ccccc3)cc2)C(O)C1

Procedure:
In an analogous manner to that described in Example 44 (e), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate [Example 46 (b)] with (E)-(4-bromo-but-2-enyloxy)-benzene there was obtained tert-butyl (E)-(3RS,4RS)-3-hydroxy-4-[4-(4-phenoxy-but-2-enyloxy)-phenyl]-piperidine-1-carboxylate. Subsequent hydrogenation with palladium/charcoal analogously to Example 73 (c) yielded tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(4-phenoxy-butoxy)-phenyl]-piperidine-1-carboxylate, alkylation of which with 2-bromomethyl-naphthalene analogously to Example 1 (g) gave tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(4-phenoxy-butoxy)-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 582 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][NH:3]1.S(Cl)(Cl)=O.[CH3:19]O>>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:19])=[O:13])[CH:10]=2)[N:5]=[CH:4][NH:3]1
Reactant: CO
Reactant: O=C(O)c1ccc2nc[nH]c(=O)c2c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2nc[nH]c(=O)c2c1
Temperature: 80 °C

Procedure:
To a mixture of 4-oxo-3,4-dihydroquinazoline-6-carboxylic acid (2.5 g, 13.15 mmol) in methanol (80 mL) was added thionyl chloride (2.5 mL) at 5° C. The mixture was refluxed at 80° C. over night. The reaction mixture was concentrated under vacuum and crude taken in ethyl acetate. The organic layer was washed with 10% aqueous NaHCO3, water, brine and dried. The solvent was removed to give methyl 4-oxo-3,4-dihydroquinazoline-6-carboxylate in 55% as solid.
Reaction SMILES: CCC([O-])(C)C.[K+].[C:8]1([CH2:14][C:15]#[N:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O:19][C:20](=O)[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=1)C>C1COCC1>[CH3:27][C:23]1[CH:22]=[C:21]([C:20](=[O:19])[CH:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:15]#[N:16])[CH:26]=[CH:25][N:24]=1
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)c1ccnc(C)c1
Agent: CCC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)C(C#N)c2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Potassium tert-pentylate (25% in toluene, 11.3 mL, 20 mmol) was added dropwise to a solution of phenylacteonitrile (590 mg, 5.0 mmol, [CAS Reg. No. 140-29-4]) in THF (8 mL). After 45 min, 2-methyl-isonicotinic acid ethyl ester (998 mg, 6.0 mmol, [CAS Reg. No. 25635-17-0]) was added drop wise, and the mixture was stirred for 3 h at r.t. The solvent was evaporated, and the residue was taken up in ethyl acetate, and washed with 1N aqueous HCl. The combined water layers were saturated with NaCl, and the crude title compound (as an orange precipitate) was collected by filtration. Evaporation of the organic layer gave an additional small crop of crude product. The combined material (1.02 g, 85%) was used in the next step without further purification. 1H NMR (300 MHz, DMSO-D6) 8.81 (1H, d), 7.94 (1H, s), 7.86 (1H, d), 7.78 (2H, d), 7.44 (2H, dd), 7.33 (1H, d), 2.71 (3H, s); MS (m/e)=237.1 [MH+].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:20](=O)[C:19]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)=[N:25][C:18]=2[O:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].[Cl-].[NH4+]>C1COCC1.C(OCC)C.O>[CH2:7]([N:14]1[CH2:20][C:19]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)=[N:25][C:18]=2[O:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1c2ccc(Oc3cccc(Cl)c3)nc2OCCN1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Clc1cccc(Oc2ccc3c(n2)OCCN(Cc2ccccc2)C3)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
To a mixture of lithium aluminum hydride (0.079 g) and THF-diethyl ether solution (2.5 mL-2.5 mL) was added a solution of the compound obtained in step 1 (0.51 g) in THF-diethyl ether (2.5 mL-2.5 mL), and the resulting mixture was stirred at room temperature for 2 hr under a nitrogen atmosphere. 1N Aqueous sodium hydroxide solution (0.079 mL), saturated aqueous ammonium chloride (0.079 mL) and water (0.079 mL) were added, and the resulting mixture was stirred at room temperature for 3 hr. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give 4-benzyl-8-(3-chlorophenoxy)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.25 g, 49%) as a white powder.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:40]=[CH:39][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[C:23]([C:35]([F:38])([F:37])[F:36])[CH:22]=2)=[O:19])=[CH:16][C:15]=1I>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[C:23]([C:35]([F:37])([F:36])[F:38])[CH:22]=2)=[O:19])=[CH:39][C:40]=1[C:12]#[C:11][C:8]1[N:7]=[N:6][C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[CH:10][CH:9]=1
Reactant: CN1CCN(Cc2ccc(NC(=O)c3ccc(Cl)c(I)c3)cc2C(F)(F)F)CC1
Reactant: C#Cc1ccc(NC2CC2)nn1
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC5CC5)nn4)c3)cc2C(F)(F)F)CC1

Procedure:
The title compound was synthesized from N-cyclopropyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl) benzamide in a manner similar to that described for in Example 1. The intermediate compound 4-chloro-3-iodo-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide was made as for Example 12 (Step 1 to 4) with the spectra below: 1H NMR (300 MHz, DMSO-d6) δ: 10.66 (1 H, s), 8.53 (1 H, s), 8.19 (1 H, s), 8.02-8.05 (1 H, d, J=6.0 Hz), 7.98-8.01 (1 H, d, J=6.0 Hz), 7.77 (1 H, s), 7.70-7.73 (1 H, d, J=6.0 Hz), 3.62 (2 H, s), 3.33 (2 H, m), 2.82 (2 H, m), 2.54 (4 H, m), 2.50 (3 H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:22][C@@H:14]4[CH2:15][N:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:17][C@@H:13]4[C@H:12]3[CH3:23])=[C:8]([C:24]([NH2:26])=[O:25])[CH:7]=[N:6][N:5]2[CH:27]=1.[Cu][C:29]#[N:30]>CN1CCCC1=O.C(OCC)(=O)C>[C:29]([C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:22][C@@H:14]4[CH2:15][N:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:17][C@@H:13]4[C@H:12]3[CH3:23])=[C:8]([C:24]([NH2:26])=[O:25])[CH:7]=[N:6][N:5]2[CH:27]=1)#[N:30]
Reactant: N#C[Cu]
Reactant: C[C@@H]1[C@H]2CN(S(C)(=O)=O)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C[C@@H]1[C@H]2CN(S(C)(=O)=O)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(C#N)cc12
Temperature: 220 °C
Yield: 56.8 %

Procedure:
A mixture of 6-bromo-4-(((3aS,4R,5R,6aS)-4-methyl-2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide from Step 3 of Example 59 (70 mg, 0.153 mmol) and copper(I) cyanide (27.5 mg, 0.307 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was heated to 220° C. under microwave for 2 h. The resulting mixture was diluted with ethyl acetate (80 mL), washed with saturated NH4Cl, water, brine, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography, eluting with 60-100% ethyl acetate in hexanes, to give 6-cyano-4-(((3aS,4R,5R,6aS)-4-methyl-2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (35 mg, 56% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (d, J=1.8 Hz, 1H), 8.37 (s, 1H), 7.61 (d, J=1.5 Hz, 1H), 4.24-4.01 (m, 1H), 3.26-3.11 (m, 2H), 3.05 (m, 1H), 2.93 (s, 3H), 2.93-2.83 (m, 1H), 2.61-2.54 (m, 1H), 2.36-2.17 (m, 1H), 1.93-1.82 (m, 1H), 1.70-1.55 (m, 1H), 1.36-1.25 (m, 1H), 1.10-1.02 (m, 3H).