Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>ClC(Cl)C.CN(C)C=O>[ClH:16].[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([Cl:1])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCc1ccncc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: O=C(Cl)CCCc1ccncc1

Procedure:
4-(Pyrid-4-yl)butyric acid hydrochloride (ca. 35 g) in dichloroethane (250 ml) and dimethylformamide (0.5 ml) was treated with thionyl chloride (100 ml). The vigorous exothermic reaction was allowed to subside and then the mixture was heated under reflux for 10 minutes, followed by evaporation to dryness in vacuo to give crude 4-(pyrid-4-yl)butyroyl chloride hydrochloride.
Reaction SMILES: [NH2:1][CH:2]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[CH:25](=[O:27])[CH3:26]>C1COCC1.C(OCC)(=O)C>[C:25]([NH:1][CH:2]([CH2:13][O:14][CH:15]([F:16])[F:17])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])(=[O:27])[CH3:26]
Reactant: NC(COC(F)F)C(=O)NCc1ccccc1
Reactant: CC=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NC(COC(F)F)C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a solution of 2-amino-N-benzyl-3-(difluoromethoxy)propanamide (195 mg, 0.798 mmol) and triethylamine (322 mg, 3.19 mmol) in THF (5 mL), acetic hydride (98.5 mg, 0.958 mmol) was added. The reaction mixture was stirred at room temperature for an hour, diluted with ethyl acetate and washed with water. The organic layer was concentrated with silica gel and purified by column chromatography, eluting with 50-100% ethyl acetate in hexanes. The product was triturated with diethyl ether to give 2-(acetylamino)-N-benzyl-3-(difluoromethoxy)propanamide (135 mg, 59%) as a white solid, MP: 173.3° C. 1H NMR (300 MHz, CDCl3): (ppm) 7.25-7.39 (m, 5H), 6.68 (w, 1H), 6.42 (d, 1H), 6.24 (wt, 1H), 4.73 (m, 1H), 4.48 (d, 2H), 4.24 (dd, 1H), 4.01 (dd, 1H) and 2.05 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[O:7])[CH2:5][CH3:6].[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=O>C1COCC1>[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:15])[CH2:3][C:4](=[O:7])[CH2:5][CH3:6]
Reactant: COC(=O)CCCCCl
Reactant: CCC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=O)CC(=O)CCCCCl
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a suspension of NaH (60% dispersion in mineral oil: 8.88 g) in THF (250 mL) was added a mixture of 2-butanone (7.98 g) and methyl 5-chlorovalerate (50.0 g) in THF (100 mL) dropwise via cannula at 0° C. The mixture was stirred at 0° C. for 10 min and at rt for 24 h. After the reaction was quenched with 2 N HCl (200 mL), aqueous layer was extracted with EtOAc (3×). Concentration of the combined organic phase gave a brown colored oil, which was purified by fractional vacuum distillation. The title compound was collected in the temperature range between 95° C. and 110° C. at 10 mmHg. 1H NMR (500 MHz, CDCl3) δ 1.14 (t, 3H, J=7.4 Hz), 1.65–1.90 (m, 4H), 2.30–2.60 (m, 4H), 3.50–3.60 (m, 2H), 5.51 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([N+:14]([O-])=O)[CH:8]=1)(=[O:5])=[O:4].C(OCC)(=O)C>C(O)(=O)C.[Fe]>[NH2:14][C:9]1[CH:8]=[C:7]([NH:6][S:3]([CH2:2][Cl:1])(=[O:4])=[O:5])[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: O=[N+]([O-])c1cc(NS(=O)(=O)CCl)ccc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc(NS(=O)(=O)CCl)ccc1F
Temperature: 80 °C
Yield: 93.9 %

Procedure:
A mixture of 12.5 g of iron powder (223 mmol) and 16 mL of an aqueous solution of acetic acid (8%) was heated to 80° C., and a solution of 6 g of I -chloro-N-(4-fluoro-3-nitrophenyl)methanesulfonamide (22.3 mmol) in 20 mL of glacial acetic acid and 22 mL ethyl acetate was added dropwise to the mixture. After heating for 1.5 h the reaction mixture was filtered through a pad of Celite® and washed with 200 mL of ethyl acetate and water (twice with 25 mL). The organic phase was separated, dried (MgSO4), filtered and concentrated under reduced pressure to yield 5 g (94%) of the title compound as a solid melting at 128-129° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:36][CH2:35][C:34]1[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=1[O:32][CH3:31])=[O:29]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(C[C@@H]2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNC(=O)CN1CCc2cc(OC)c(OC)cc2[C@@H]1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of (1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-methoxy-benzylamine
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]([CH2:21][CH2:22][CH:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[OH:24])[C:10]2=[O:32])[CH:6]=[CH:7][CH:8]=1.[C:33]([O:36][CH:37]([CH:53]([O:57][C:58](=[O:60])[CH3:59])[C:54](Cl)=[O:55])[CH:38]([O:49][C:50](=[O:52])[CH3:51])[CH:39]([O:45][C:46](=[O:48])[CH3:47])[CH2:40][O:41][C:42](=[O:44])[CH3:43])(=[O:35])[CH3:34]>C(Cl)Cl.C(N(CC)CC)C.C(OCC)(=O)C>[C:58]([O:57][CH:53]([C:54](=[O:55])[NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[C:10](=[O:32])[CH:11]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:12]2[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH:4]=1)[CH:37]([O:36][C:33](=[O:35])[CH3:34])[CH:38]([O:49][C:50](=[O:52])[CH3:51])[CH:39]([O:45][C:46](=[O:48])[CH3:47])[CH2:40][O:41][C:42](=[O:44])[CH3:43])(=[O:60])[CH3:59]
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2cccc(CN)c2)cc1
Reactant: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2cccc(CNC(=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(COC(C)=O)OC(C)=O)c2)cc1
Reaction time: 0.5 h

Procedure:
112 mg (0.24 mmol) of 1-(3-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)azetidin-2-one are dissolved in 5 ml of methylene chloride and 0.5 ml of triethylamine. At 0° C., 0.5 g of 2,3,4-triacetoxy-1-(acetoxychlorocarbonylmethyl)butyl acetate are added, and the mixture is allowed to thaw to room temperature. After 30 minutes, the mixture is diluted with ethyl acetate and then filtered through silica gel. The solvent is distilled off and the residue is purified by flash chromatography. The product is obtained as an amorphous solid:
Reaction SMILES: C([O:8][C:9](=[O:25])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH:17][S:18]([CH2:21][CH2:22][CH3:23])(=[O:20])=[O:19])[C:11]=1[F:24])C1C=CC=CC=1.[OH-].[K+].O.Cl>O1CCCC1>[Cl:16][C:15]1[C:10]([C:9]([OH:25])=[O:8])=[C:11]([F:24])[C:12]([NH:17][S:18]([CH2:21][CH2:22][CH3:23])(=[O:19])=[O:20])=[CH:13][CH:14]=1
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)OCc2ccccc2)c1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1F
Yield: 85.6 %

Procedure:
To 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid benzyl ester (49, 6.00 g, 15.6 mmol) in tetrahydrofuran (100 mL) was added 1.0 M aqueous potassium hydroxide (100 mL). The reaction was heated to reflux overnight. The reaction was poured into water, acidified to pH 2 with 1 N hydrochloric acid and extracted with ethyl acetate. The organic portion was dried over anhydrous sodium sulfate, filtered and concentrated to give a white solid 115 (3.95 g, 85.8%).
Reaction SMILES: [CH2:1]([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@H:9]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])/[CH:10]=[CH:11]/[C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([NH2:40])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([NH:40][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[N:20][C:12]=1/[CH:11]=[CH:10]/[C@H:9]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1cccnc1/C=C/[C@@H](Cc1ccccc1F)N(Cc1ccccc1)Cc1ccccc1
Product: CC(C)(C)NC(=O)c1cccnc1/C=C/[C@@H](Cc1ccccc1F)N(Cc1ccccc1)Cc1ccccc1

Procedure:
Using general procedure 5 with 2-[(E)-(R)-3-dibenzylamino-4-(2-fluoro-phenyl)-but-1-enyl]-nicotinic acid (0.64 g, 1.4 mmol) and tert-butylamine (0.73 mL, 1.5 mmol) gives the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][NH2:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:40][CH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=1)=[O:31]
Reactant: NCc1ccccn1
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3c2cc(OC)c(OC)c3OC)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)c(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-picolylamine
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]([SH:15])=[N:13][N:12]=[C:11]3[C:16]3[C:21]([OH:22])=[CH:20][CH:19]=[C:18]([CH:23]([CH3:25])[CH3:24])[C:17]=3O)=[CH:7][CH:8]=2)[CH2:3][C:2]21[O:30]CCO2.O.CC1C=CC(S(O)(=O)=[O:40])=CC=1>CC(C)=O>[OH:22][C:21]1[CH:20]=[C:19]([OH:40])[C:18]([CH:23]([CH3:24])[CH3:25])=[CH:17][C:16]=1[C:11]1[N:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][C:2](=[O:30])[CH2:3]3)[C:14]([SH:15])=[N:13][N:12]=1
Reactant: CC(C)c1ccc(O)c(-c2nnc(S)n2-c2ccc3c(c2)CC2(C3)OCCO2)c1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)c1cc(-c2nnc(S)n2-c2ccc3c(c2)CC(=O)C3)c(O)cc1O
Temperature: 25 °C
Yield: 902.9 %

Procedure:
Compound 10 (160 mg, 0.38 mmol) was stirred in acetone (7 mL) and water (2 mL) at 63° C. in the presence of p-TsOH (5 mg, cat. amount) for 2 h. After cooled to room temperature, water was added and the reaction mixture was extracted with EtOAc. Combined organic layers were washed with water and brine and dried over Na2SO4. Purification of the concentrated crude product by column chromatography (EtOAc:Hexane=1:1) afforded the title product as a white solid (100 mg, 69%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[O:4][C:5]1([CH2:13][OH:14])[CH2:10][CH2:9][CH2:8][N:7]([N:11]=O)[CH2:6]1>C(O)(=O)C.O.[Zn]>[NH2:11][N:7]1[CH2:8][CH2:9][CH2:10][C:5]([CH2:13][OH:14])([O:4][C:3]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:2]=2[F:1])[CH2:6]1
Reactant: O=NN1CCCC(CO)(Oc2cc(F)ccc2F)C1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: NN1CCCC(CO)(Oc2cc(F)ccc2F)C1
Temperature: 25 °C

Procedure:
To the suspension of zinc dust (10 mmol, 0.65 g) in a mixture of acetic acid (5 mL) and water (5 mL) was added a solution of (3-(2,5-difluorophenoxy)-1-nitrosopiperidin-3-yl)methanol in acetic acid. The reaction mixture was stirred at room temperature for an hour. The mixture was filtered. The filtrate was basified with sodium hydroxide aqueous solution. The organics were extracted with EtOAc. The product, (1-amino-3-(2,5-difluorophenoxy)piperidin-3-yl)methanol, was obtained after removal of the solvent.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][S:6]([C:9]2[CH:26]=[CH:25][C:12]3[N:13]([CH2:21][CH:22]4[CH2:24][CH2:23]4)[C:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:15][C:11]=3[CH:10]=2)(=[O:8])=[O:7])[CH2:2]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH:22]1([CH2:21][N:13]2[C:12]3[CH:25]=[CH:26][C:9]([S:6]([CH2:5][CH:3]4[CH2:2][N:1]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:4]4)(=[O:8])=[O:7])=[CH:10][C:11]=3[N:15]=[C:14]2[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CNC3)ccc2n1CC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CN(S(C)(=O)=O)C3)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
To a solution of 5-(azetidin-3-ylmethylsulfonyl)-1-(cyclopropylmethyl)-2-neopentyl-1H-benzo[d]imidazole (STEP F of Example 3, 350 mg, 0.780 mmol) and triethylamine (395 microL, 2.81 mmol) in dichloromethane (10 mL) was added methanesulfonyl chloride (67.0 microL, 0.819 mmol) and stirred for 3 h at room temperature. The reaction mixture was concentrated in vacuo, extracted with ethyl acetate (15 mL) and water (30 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by silica gel column chromatography (dichloromethane-methanol=100:0 to 100:6). T he resulting product was recrystallized with ethanol (6 mL)-ethyl acetate (1 mL) to give the title compound (212 mg) as pale yellow solid.
Reaction SMILES: [C:1]([C:3]1([C:6]([OH:8])=O)[CH2:5][CH2:4]1)#[N:2].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:45][N:46]1[CH:50]=[C:49]([C:51]2[N:52]=[C:53]3[C:58]([NH:59][C@H:60]4[C@@H:64]([CH3:65])[CH2:63][NH:62][CH2:61]4)=[C:57]([C:66]([NH2:68])=[O:67])[CH:56]=[N:55][N:54]3[CH:69]=2)[CH:48]=[N:47]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1([C:6]([N:62]2[CH2:63][C@H:64]([CH3:65])[C@H:60]([NH:59][C:58]3[C:53]4[N:54]([CH:69]=[C:51]([C:49]5[CH:48]=[N:47][N:46]([CH3:45])[CH:50]=5)[N:52]=4)[N:55]=[CH:56][C:57]=3[C:66]([NH2:68])=[O:67])[CH2:61]2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: C[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(C)c3)nc12
Reactant: N#CC1(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(C)c3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
To a solution of cyanocyclopropanecarboxylic acid (3.67 mg, 0.033 mmol) in DCM (330 μl) were added DIEA (14.41 μl, 0.083 mmol) and BOP (17.52 mg, 0.040 mmol). The solution was stirred at room temperature for 10 minutes. 2-(1-Methyl-1H-pyrazol-4-yl)-8-(((3S,4S)-4-methylpyrrolidin-3-yl)amino)imidazo[1,2-b]pyridazine-7-carboxamide, TFA (15 mg, 0.033 mmol) was added. The reaction mixture was stirred at room temperature for another 30 min and concentrated to give an orange oil. The oil was partitioned between ethyl acetate and water. The organic layer was washed with (sat.) sodium chloride, dried with sodium sulfate, filtered and concentrated. The crude product was purified via preparative LCMS (prep. LCMS Method A) to afford 8-(((3S,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methylpyrrolidin-3-yl)amino)-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-7-carboxamide (8.5 mg, 0.020 mmol, 59.4% yield) as an off-white solid. 1H NMR (500 MHz, DMSO-d6, 2 rotamers) δ 10.74 (d, J=8.4 Hz, 1H), 10.69 (d, J=8.9 Hz, 1H), 8.48 (br. s., 1H), 8.47 (br. s., 1H), 8.28 (s, 1H), 8.27 (s, 1H), 8.12 (s, 2H), 8.01 (br. s., 2H), 7.88 (s, 1H), 7.87 (s, 1H), 7.41 (br. s., 2H), 6.00-5.88 (m, 1H), 5.82 (d, J=5.9 Hz, 1H), 4.25 (dd, J=10.9, 5.0 Hz, 1H), 4.13 (dd, J=10.2, 7.7 Hz, 2H), 3.92 (d, J=3.5 Hz, 1H), 3.88 (s, 6H), 3.79 (dd, J=12.6, 5.2 Hz, 1H), 3.69 (dd, J=12.1, 7.7 Hz, 1H), 3.58 (s, 1H), 3.54-3.50 (m, 1H), 2.80-2.74 (m, 1H), 2.72-2.65 (m, 1H), 1.64-1.52 (m, 6H), 1.50-1.45 (m, 1H), 1.39-1.34 (m, 1H), 1.08 (d, J=6.9 Hz, 3H), 1.04 (d, J=6.9 Hz, 3H). HPLC/LCMS (Method F): m/z 434.10 ([M+H]+), Rt. 1.066 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[N:20]1C=CC=CC=1>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH2:3][CH2:2]1.[NH3:20]
Reactant: c1ccncc1
Reactant: OCC1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Product: N

Procedure:
Tetrahydro-2-H-pyran-4-ylmethanol (Combi-Blocks, 2.0 g, 17 mmol) and p-toluenesulfonyl chloride (3.5 g, 18 mmol) in 10 mL of CH2Cl2 and 10 mL of pyridine were processed as in Example 160A to afford the title compound MS (DCI/NH3) m/z 288 (M+NH4)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([N:10]2[C:15](C)=[CH:14][C:13]([O:17]CC3C=CC(OC)=CC=3)=[CH:12][C:11]2=[O:27])[C:7]([CH3:28])=[CH:6][N:5]=1)(=[O:3])[CH3:2].[Cl:29]N1C(=O)CCC1=O>CC(O)C.ClC(Cl)C(O)=O>[C:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH:15]=[CH:14][C:13]([OH:17])=[C:12]([Cl:29])[C:11]2=[O:27])[C:7]([CH3:28])=[CH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(COc2cc(C)n(-c3cc(C(C)=O)ncc3C)c(=O)c2)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CC(C)O
Product: CC(=O)c1cc(-n2ccc(O)c(Cl)c2=O)c(C)cn1
Temperature: 60 °C

Procedure:
To a solution of 2′-acetyl-4-((4-methoxybenzyl)oxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one of part C (3.3 g, 8.7 mmol) in 2-propanol (100 mL) was added N-chlorosuccinimide (1.27 g, 9.6 mmol) and 10 drops of dichloroacetic acid. The slurry was heated at 60° C. for 3 h. The resulting slurry was concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The solution was concentrated in vacuo. The residue was suspended into dichloromethane and the resulting white solid was collected by vacuum filtration to provide the chlorinated deprotected product (1.16 g): MS (ES) m/e 293 (M+H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH:30]=[O:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][C:38]([Si:41]([CH3:55])([CH3:54])[O:42][CH2:43][C@@H:44]1[CH2:53][N:52]2[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]2)[CH2:46][NH:45]1)([CH3:40])[CH3:39].[Cl-].[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:45]3[C@H:44]([CH2:43][O:42][Si:41]([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:54])[CH3:55])[CH2:53][N:52]4[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]4)[CH2:46]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH:30]=[O:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCOC[C@@H]2CN1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1C=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)cc1-c1ccccc1C=O
Temperature: 90 °C
Yield: 18 %

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(2-formyl phenyl)-3-pyridinyl]-N,2-dimethylpropanamide (D59, 106 mg, 0.201 mmol),), (7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)octahydropyrazino[2,1-c][1,4]oxazine (D51, 72 mg, 0.251 mmol) were dissolved in toluene (2 mL). Bis tritertbutylphosphine palladium (27 mg, 0.052 mmol), followed by hexadecyltrimethylammoium chloride (30 μL, 25% aq sol), and finally sodium hydroxide solution (0.25 mL, 50% aq sol) were added. The mixture was degassed for 5 minutes before heating at 90° C. for 2 hours. Reaction cooled to R.T., diluted with EtOAc, washed with sat NaHCO3 solution, dried (MgSO4). Filtered. Solvent evaporated. Residue purified eluting with 0-50% EtOAc/Pent. Solvent evaporated under reduced pressure to afford a pale yellow solid in 18% yield.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:20]I.[H-].[Na+]>C1COCC1.CCOC(C)=O.O>[CH3:20][N:11]([C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])[C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CI
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Yield: 97.1 %

Procedure:
To a solution of N-Cbz-leucine (1.38 g, 5.2 mmol) in THF (15 mL) at 0° C. was added methyl iodide (2.5 mL, 40.1 mmol). Sodium hydride (60% dispersion in oil, 0.6 g, 15 mmol) was added cautiously, and the resultant mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with EtOAc (25 mL) and water (2 mL) was added dropwise. The mixture was concentrated to dryness, and the residue was partitioned between ether (15 mL) and water (50 mL). The organic layer was extracted with saturated aqueous NaHCO3 (25 mL), and the combined aqueous extracts were acidified to pH 2 with 3N HCl. The product was extracted with EtOAc (3×25 mL), dried over MgSO4, filtered, and concentrated to afford the title compound (1.41 g) as a yellow solid.
Reaction SMILES: CC([O:4][C@@H:5]1[C@@H:14]2[O:15][C:16]3=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:11]4=[C:12]3[C@:13]32[CH2:22][CH2:23][N:24](C)[C@H:9]([CH2:10]4)[C@@H:8]3[CH:7]=[CH:6]1)=O.[Cl:26]C(OC(Cl)C)=O.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C>C(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:11]2[CH2:10][C@H:9]3[NH:24][CH2:23][CH2:22][C@:13]45[C@H:14]([C@@H:5]([OH:4])[CH:6]=[CH:7][C@@H:8]34)[O:15][C:16]=1[C:12]=25.[ClH:26]
Reactant: CC(Cl)OC(=O)Cl
Reactant: COc1ccc2c3c1O[C@H]1[C@@H](OC(C)=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCl
Product: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)NCC[C@@]341
Product: Cl
Yield: 93.3 %

Procedure:
A solution of 6-acetylcodeine (10.0 g, 29.3 mmol), 1-chloroethyl chloroformate (5.56 g, 38.1 mmol), and proton sponge (1.0 g) in methylene chloride (50 ml) was heated at reflux for 50 min. The reaction mixture was evaporated in vacuo to about 30 ml. Methanol (25 ml) and concentrated HCl (2 ml) were added. The solution was heated at reflux for 40 min. and evaporated in vacuo to almost dryness. The residue was added hexane and filtered to give norcodeine hydrochloride (8.8 g, 93% yield). IR (KBr), (ν, cm-1): 3540 (NH), 3380 (6--OH), 2800-2600 (broad) and 2480 (sharp) (NH·HCl); NMR (δH)(DMSO-d6): 9.66 (2, s (broad), 17-N+H2Cl-), 6.72 (1, d, J, 8.2, 2-H), 6.57 (1, d, J, 8.2, 1-H), 5.66 (1, dt, J, 9.9 & 3.0, 7-H), 5.28 (1, dt, J, 9.8 & 3.0, 8-H), 5.10 (1, s (broad), 6-OH), 4.82 (1, dd, J, 6.1 & 1.2, 5-H), 4.15 (2, m, 6-H & 9-H), 3.77 (3, s, 3-OCH3), 3.22 (1, d, J, 19.1, 10-Hβ), 3.21 (1, td, J, 13.2 & 4.1, 16-He), 3.06 (1, m, 14-H), 2.91 (1, dd, J, 18.5 & 6.3, 10-Hα), 2.79 (1, dd, J, 13.0 & 3.9, 16-Ha), 2.22 (1, td, J, 13.4 & 4.9, 15-He) and 1.89 (1, dd, J, 13.6 & 2.7, 15-He).
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[O:16])[NH:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([N:20]=[C:21]=[O:22])[CH:18]=[CH2:19].N12CCN(CC1)CC2>C1C=CC=CC=1>[CH2:17]([NH:20][C:21]([N:14]1[C:15](=[O:16])[C:6]2([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]2)[NH:7][C:8]21[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:22])[CH:18]=[CH2:19]
Reactant: O=C1NC2(CCCCC2)NC12CCCCC2
Reactant: C=CCN=C=O
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: C=CCNC(=O)N1C(=O)C2(CCCCC2)NC12CCCCC2
Reaction time: 12 h

Procedure:
4.4 Parts of 7,14-diazadispiro[5.1.5.2]pentadecan-15-one, 20 parts of allyl isocyanate and a trace of 1,4-diazabicyclo[2.2.2]octane in 100 parts of dry benzene were heated at reflux for 18 hours. The solvent was evaporated in vacuo and the residue was stirred in 100 parts of water for 12 hours. This phase was extracted with chloroform and the extracts washed with brine and dried over magnesium sulphate. Evaporation of the solvent in vacuo afforded an oil which was chromatographed on an alumina column to give 14-allylcarbamoyl-7,14-diazadispiro[5.1.5.2]pentadecan-15-one which gave the following elemental analysis by weight: