Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:8]2[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=1[CH2:18]Br>>[Cl:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=1[CH2:18][N:9]1[C:10]([CH3:14])([CH3:13])[C:11](=[O:12])[N:8]1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: CC1(C)NN(C2CCCCCC2)C1=O
Product: CC1(C)C(=O)N(C2CCCCCC2)N1Cc1ccc(F)cc1Cl

Procedure:
2-Cycloheptyl-4,4-dimethyl-1,2-diazetidin-3-one and 2-chloro-4-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]#[C:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1.[CH:22]([C:24]1[C:25]([OH:38])=[CH:26][C:27]2[C:28]([CH3:37])([CH3:36])[CH2:29][CH2:30][C:31]([CH3:35])([CH3:34])[C:32]=2[CH:33]=1)=[O:23].O>CN(C)C=O>[CH:22]([C:24]1[C:25]([O:38][CH2:8][C:9]#[C:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)=[CH:26][C:27]2[C:28]([CH3:37])([CH3:36])[CH2:29][CH2:30][C:31]([CH3:34])([CH3:35])[C:32]=2[CH:33]=1)=[O:23]
Reactant: CCOC(=O)c1ccc(C#CCBr)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)c(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C#CCOc2cc3c(cc2C=O)C(C)(C)CCC3(C)C)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
0.71 g of potassium carbonate and 1.0 g of ethyl 4-(3-bromo-1-propynyl)benzoate were added to 20 ml of a solution of 0.80 g of 3-formyl-5,6,7,8-tetrahydro-2-hydroxy-5,5,8,8-tetramethylnaphthalene in anhydrous N,N-dimethyl formamide at room temperature. The obtained mixture was stirred at 50° C. for 30 minutes, followed by the addition thereto of 20 ml of water. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography (developer: 20% diethyl ether/n-hexane) to give 0.87 g of the title compound as a pale-yellow solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]([O:9][CH2:10][C@@H:11]1[CH2:15][O:14]C2(CCCCC2)[O:12]1)=[O:8])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]([O:9][CH2:10][C@@H:11]([OH:12])[CH2:15][OH:14])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)OC[C@@H]1COC2(CCCCC2)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Oc1ccccc1C(=O)OC[C@@H](O)CO
Reaction time: 2 h

Procedure:
The solution from [2S]-1,4-dioxa-spiro[4,5]dec-2-yl-methyl 2-acetoxybenzoate (527 mg, 1.58 mmol) in dichloromethane (10 ml) is treated with trifluoroacetic acid (2 ml). After 2 h at room temperature, the mixture is concentrated, the residue is taken up in toluene (10 ml) and the solution is concentrated. The residue is purified by column chromatography (dichloromethane/methanol=30/1). Yield: 161 mg.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](O)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].C(Cl)(=O)C([Cl:23])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([Cl:23])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCN1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Yield: 92.9 %

Procedure:
2-Butyl-4-hydroxy-5-phenylisothiazol-3(2H)-one 1,1-dioxide (444 mg, 1.58 mmol) was dissolved in dry DCM (15 mL) at rt and under an atmosphere of nitrogen. Oxalyl chloride (0.15 mL, 1.73 mmol) was added dropwise and the reaction mixture was refluxed for 1.5 h. DMF (0.08 mL) was added followed by oxalyl chloride (0.15 mL, 1.73 mmol) in 2 portions and the reaction mixture was refluxed for another 6 h. The solvents were evaporated and the residue was partitioned between water and DCM. The combined organic layers were washed with water and the two phases were separated using a phase separator. Evaporation of the organic phase gave the title compound (440 mg, 88%) as a brown oil with approximately 95% purity according to 1H-NMR and was used without further purification; 1H-NMR (400 MHz, CDCl3): δ 7.96-8.00 (m, 2H), 7.53-7.62 (m, 3H), 3.74-3.80 (t, 2H), 1.78-1.87 (m, 2H), 1.39-1-50 (m, 2H), 0.98 (t, 3H); 13C-NMR (100 MHz, CDCl3): δ 156.3, 137.1, 132.7, 129.6, 129.2, 127.6, 123.7, 40.9, 30.1, 20.1, 13.7.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH:23]1([S:29]([NH2:32])(=[O:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:32][S:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)(=[O:31])=[O:30])=[O:21])=[CH:19][CH:18]=1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: NS(=O)(=O)C1CCCCC1
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)C1CCCCC1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with cyclohexanesulfonic acid amide as described in the preparation of compound 1 to yield the title compound. LCMS (M+H) calcd for C18H24FN2O6S: 415.1; found: 415.0. 1H NMR (500 MHz, CDCl3) δ: 1.19 (overlapping m, 30,1.63 (overlapping m, 3), 1.90 (br m, 2), 2.17 (m, 2), 3.51 (m, 1), 3.69 (s, 3), 4.78 (s, 2), 6.53 (s, 1), 7.00 (m, 2), 7.26 (m, 2).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[C:11]1[N:15]=[C:14]([NH:16][C:17]2[N:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25]C(OC)=O)=[CH:19][C:18]=2[O:30][C:31]2[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=2)[S:13][N:12]=1.C[C:39]([O-:42])(C)C.[K+].BrCCOC>C1COCC1>[CH3:39][O:42][CH2:25][CH2:24][S:23][C:20]1[CH:19]=[C:18]([O:30][C:31]2[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=2)[C:17]([NH:16][C:14]2[S:13][N:12]=[C:11]([C@H:2]3[CH2:3][O:4][C:5]4([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]4)[O:1]3)[N:15]=2)=[N:22][CH:21]=1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)CCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Agent: COCCBr
Agent: [K+]
Solvent: C1CCOC1
Product: COCCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 100 %

Procedure:
(S)-Methyl 3-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)propanoate (2.0 g, 3.68 mmol) was dissolved in THF (20 mL) and nitrogen was bubbled through the solution for 5 minutes. Potassium 2-methylpropan-2-olate (1M in THF, 11.0 ml, 11.0 mmol) was added and the reaction was stirred at ambient temperature for 1 minute. 1-Bromo-2-methoxyethane (0.518 ml, 5.52 mmol) was added and the reaction was stirred at ambient temperature for 20 minutes. The reaction was partitioned between EtOAc and aqueous NH4Cl, dried, filtered and concentrated. The residue was purified over silica gel (100% EtOAc) to afford (S)-N-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (1.9 g, 3.68 mmol, 100% yield).
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@H:20]([F:22])[CH2:21][N:15]3[C:14]2=[O:23])[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])(=[O:5])=[O:4].N1C=CC=CC=1.Cl[C:33]([O:35][CH3:36])=[O:34]>ClCCl>[Cl:25][C:8]1[CH:9]=[C:10]([F:24])[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@H:20]([F:22])[CH2:21][N:15]3[C:14]2=[O:23])=[CH:12][C:7]=1[N:6]([S:3]([CH2:2][Cl:1])(=[O:5])=[O:4])[C:33](=[O:34])[O:35][CH3:36]
Reactant: COC(=O)Cl
Reactant: O=C1[C@H]2C[C@H](F)CN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N(c1cc(N2C(=O)[C@H]3C[C@H](F)CN3C2=O)c(F)cc1Cl)S(=O)(=O)CCl

Procedure:
To a mixture of the title compound of Example 1, Step H (0.32 g, 0.7 mmol) and pyridine (0.5 mL) in dichloromethane (5 mL) was added a solution of methyl chloroformate (0.09 g, 0.95 mmol) in dichloromethane (1 mL) at room temperature. After completion of the reaction (2 h), the solvents were removed in vacuo and the title compound of Step A, a compound of this invention, was isolated by flash chromatography (0.31 g, 95%) as a white solid melting at 108-115° C. 1H NMR (CDCl3) δ 7.40 (m, 2H), 5.42 (m, 1H), 5.36 (dd, 1H), 4.92 (dd, 1H), 4.60 (m, 1H), 4.04 (m, 1H), 3.82 (s, 3H), 3.60 (dd, 1H), 2.64 (m, 1H), 2.02 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH:16]=[C:15]([CH:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)O)[C:14]([CH3:25])=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[C:3]([N:12]2[CH:16]=[C:15]([CH:17]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:31][CH:32]=3)[CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:14]([CH3:25])=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Cc1nn(-c2ncc(C(F)(F)F)cc2Cl)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: Cc1nn(-c2ncc(C(F)(F)F)cc2Cl)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 4.8 %

Procedure:
Using {1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-3-methyl-1H-pyrazol-4-yl}(cyclohexyl)methanol (0.74 g) synthesized in Example 31(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.60 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (54.4 mg, 5%) was obtained as an amorphous pale-yellow solid.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.CCCCCC.C([Li])CCC.[C:17]1([CH2:23][C:24](=O)[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:25]([C:24]([CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:2]1[CH:1]=[CH:5][CH:4]=[CH:3]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C1=CCC=C1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C1=CC(=C(Cc2ccccc2)Cc2ccccc2)C=C1

Procedure:
In an atmosphere of nitrogen, 8.0 g (121.0 mmol) of cyclopentadiene and 100 ml of dehydrated THF were placed in a 500 ml three-necked flask, and they were stirred. This mixed solution was cooled in an ice bath, and to the mixed solution was added 80 ml (125.6 mmol) of a hexane solution of n-butyllithium having a concentration of 15.7 mol/liter. Thereafter, the mixture was stirred at room temperature for 3 hours, and the resulting white slurry was cooled in an ice bath, followed by adding a solution obtained by dissolving 25.0 g (118.0 mmol) of 1,3-diphenyl-2-propanone in 50 ml of dehydrated THF. Thereafter, the mixture was stirred at room temperature for 12 hours, and the resulting yellow solution was quenched with a saturated NH4Cl aqueous solution. Then, 100 ml of hexane was added to extract a soluble matter, and this organic phase was washed with water and a saturated saline solution, followed by drying using magnesium sulfate. Then, the solvent was distilled off, and the residue was purified by column chromatography to obtain a desired product of a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]([N:22]([CH2:30][CH2:31][C:32]3[CH:37]=[C:36]([O:38][CH3:39])[C:35]([NH2:40])=[CH:34][C:33]=3[Cl:41])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:42]([C:44]1[N:45]=[CH:46][C:47]([NH:50][C:51](=O)[O:52]C2C=CC=CC=2)=[N:48][CH:49]=1)#[N:43]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]([N:22]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:30][CH2:31][C:32]3[CH:37]=[C:36]([O:38][CH3:39])[C:35]([NH:40][C:51]([NH:50][C:47]4[CH:46]=[N:45][C:44]([C:42]#[N:43])=[CH:49][N:48]=4)=[O:52])=[CH:34][C:33]=3[Cl:41])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1cnc(NC(=O)Oc2ccccc2)cn1
Reactant: COc1cc(CCN(C(=O)OC(C)(C)C)[C@@H](C)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c(Cl)cc1N
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CCN(C(=O)OC(C)(C)C)[C@@H](C)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
A stirred solution of 4-[4-((S)-1-{[2-(4-amino-2-chloro-5-methoxy-phenyl)-ethyl]-tert-butoxycarbonyl-amino}ethyl)-phenyl]piperazine-1-carboxylic acid tert-butyl ester (0.28 g, 0.475 mmol) and phenyl 5-cyanopyrazin-2-ylcarbamate (0.091 g, 0.38 mmol) in DMF (18 mL) was heated to 100° C. for 1 hour. The mixture was allowed to cool to room temperature, diluted with water (50 mL) and extracted with EtOAc (2×40 mL). The combined organic extracts were washed with water (3×40 mL), brine (40 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified with column chromatography on neutral silica gel using 25% EtOAc in hexane to give the title compound (0.16 g, 46%).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:13]([OH:15])=O)=[CH:8]2)#[N:2].C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:13]([Cl:19])=[O:15])=[CH:8]2)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cccc2cc(C(=O)O)ccc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cccc2cc(C(=O)Cl)ccc12

Procedure:
To a suspension of 5-cyano-naphthalene-2-carboxylic acid, 2, (0.084 g, 0.426 mmol) in CH2Cl2 (2 mL) at room temperature containing 1 drop of DMF is added oxalyl chloride (0.074 mL). Once the solution is homogeneous, the solution is concentrated in vacuo and the crude product is used without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH:18](=O)[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.O>C(COC)OC>[CH:23]([C:22]1[CH:25]=[CH:26][C:19]([CH:18]=[C:8]([CH3:9])[C:6]([O:5][CH2:4][CH3:3])=[O:7])=[CH:20][CH:21]=1)=[O:24]
Reactant: O=Cc1ccc(C=O)cc1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(C)=Cc1ccc(C=O)cc1

Procedure:
To a suspension of 10.0 g of 50% sodium hydride (dispersion in mineral oil) in freshly distilled dimethoxyethane (DME, 350 ml) stirred under nitrogen at 10° is added 53.6 ml of triethyl 2-phosphonopropionate in ca. 40 minutes. The mixture is stirred for 0.5 hour at 10° and for an additional 1.5 hours during which time the temperature is allowed to rise to room temperature. This solution is transferred under nitrogen by cannula to a 500 ml addition funnel and is added dropwise to a solution of terephthalaldehyde (33.53 g) in dry DME (475 ml) over a period of 1 hour at 22°-34°. After addition is complete the reaction mixture is stirred mechanically at room temperature for 2 hours, poured into 1 L of water and extracted with 4×500 ml of ether. The ether extract is washed with a saturated sodium chloride solution (700 ml), dried over magnesium sulfate, filtered, and concentrated in vacuo to give a yellow oil which partially crystallizes on standing. This crude mixture is purified by suspending in petroleum ether and ethyl acetate (93:7). The filtrate, after removal of unreacted dialdehyde, is concentrated in vacuo to give a mixture which is further purified by high pressure liquid chromatography (using petroleum ether/ethyl acetate 93:7). There is obtained pure ethyl 4-formyl-α-methylcinnamate. A solution of the aldehyde (34.80 g) in 820 ml of absolute ethanol is treated with 12.11 g of granular sodium borohydride at room temperature under nitrogen. The resulting mixture is stirred at room temperature for 3 hours (or until all borohydride has dissolved) and then concentrated to ca. 200 ml volume, diluted with 400 ml of water, and extracted with 3×200 ml of ether. The ether extract is washed with 100 ml of water and brine (100 ml), is dried over magnesium sulfate, filtered, and the filtrate concentrated in vacuo to give ethyl 3-(p-hydroxymethylphenyl)-2-methylacrylate. To a solution of this product in 350 ml of methylene chloride is added at room temperature 11.53 ml of thionyl chloride dropwise over 25 minutes. The clear, colorless solution is stirred for 2 hours. The solution is washed with 100 ml of water, 200 ml of saturated sodium bicarbonate, 100 ml of water, and 100 ml of brine. The organic layer after drying and removal of solvent yields ethyl 3-(p-chloromethylphenyl)-2-methylacrylate.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@@H:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].CN1[C@@H]2CC3=CC=C(O)C4[O:34][C@H]5C(CC[C@@H]2[C@]5(C=43)CC1)=O.C1C2C[C@H]3N(CC[C@@]45[C@H]3C=C[C@H](O)[C@@H]4OC(C=25)=C(O)C=1)C>>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:34])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Agent: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314

Procedure:
To a 150 mL beaker was charged 10.0 g oxycodone hydrochloride and 100 mL water. Concentrated ammonium hydroxide (2.6 grams) was then added to bring the pH to approximately 9. The product was collected by vacuum filtration, washed with cold water and dried for about 5 hours under vacuum to provide 8.3 g (93% yield) of a white solid consistent in structure with oxycodone free base. This procedure was used to prepare hydrocodone, hydromorphone and morphine free base as needed.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.N1(C=O)CC[O:13][CH2:12]C1.Cl.CCOCC>C1COCC1>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([CH:12]=[O:13])=[CH:7][N:6]=1
Reactant: O=CN1CCOCC1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1cnc(Cl)nc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
A solution of isopropyl magnesium chloride lithium chloride complex in THF (2M, 184 mL, 368 mmol) was added drop-wise over about 30 min to a 2 L round-bottomed flask charged with a solution of 5-bromo-2,4-dichloropyrimidine (49.6 g, 218 mmol) in THF (1000 mL) at about −78° C. The reaction was allowed to stir at about −78° C. for about 30 min. Morpholine-4-carbaldehyde (75.0 g, 653 mmol) was then added drop-wise at about −78° C. over about 30 min. The reaction was allowed to stir for about 30 min at about −78° C. then allowed to warm to about −35° C. and stirred for about 30 min. Aqueous HCl (1N, 250 mL) and Et2O (500 mL) were added and the reaction mixture was allowed to warm to ambient temperature. The organic layer was separated and the aqueous layer was further extracted with Et2O (200 mL). The combined organic layers were dried over anhydrous MgSO4, filtered through a silica gel pad on a fritted funnel, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using DCM (100%) as the eluent to provide 2,4-dichloropyrimidine-5-carbaldehyde (27.3 g, 71%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 9.30 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][C@H:12]([OH:24])[CH2:13][N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:9])[CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]1.CCN(CC)CC>CC(O)C>[C:32]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][C@H:12]([OH:24])[CH2:13][N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15]3)=[O:9])[CH:3]=2)[CH2:27][CH2:28]1)(=[O:34])[CH3:33]
Reactant: CC(=O)N1CCC(N)CC1
Reactant: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1cc(Cl)ncn1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(Nc2cc(C(=O)NC[C@H](O)CN3CCc4ccccc4C3)ncn2)CC1
Yield: 130573.4 %

Procedure:
The solution of (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide (190 g, 0.55 mmol) and 1-(4-aminopiperidin-1-yl)ethanone (78 g), Et3N (100 g, 1 mol) in i-PrOH (2000 mL) was stirred at 60° C. for 16 h, at which time LCMS showed completed conversion. The mixture was concentrated and the residue was purified by flash chromatography to give the crude product. Four batches were run in parallel and produced a combined crude product weight of 482 g. This crude was further purified on preparative HPLC to give the title compound (325 g, >98% purity, free base form). 1H NMR (400 MHz, MeOD-d4) 8.26 (s, 1H), 7.15-7.02 (m, 5H), 4.46 (m, 1H), 4.15-4.07 (m, 2H), 3.88 (m, 1H), 3.74 (s, 2H), 3.53 (m, 2H), 3.33 (m, 1H), 2.95-2.86 (m, 5H), 2.68 (m, 2H), 2.14-2.01 (m, 5H), 1.48-1.42 (m, 2H); LCMS (m/z): 453.3 [M+H]+
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)cc2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(N2CCCNCC2)c(Cl)c1
Yield: 96.6 %

Procedure:
To a solution of 4-(2,4-dichloro-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.13 g, 0.38 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred until complete (as monitored by LC-MS) and the volatiles were removed in vacuo. The residue was partitioned between ethyl acetate (5 mL) and saturated aqueous sodium bicarbonate (5 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a gum (0.09 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[Br:14]Br>C(O)(=O)C.O>[Br:14][C:8]1[CH:7]=[C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(CCC(=O)O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CCC(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of 3-(4-methoxyphenyl)propionic acid (4.0 g, 22.2 mmol) in acetic acid (20 ml) was added bromine (3.9 g, 24.4 mmol) gradually dropwise at 10° C. and the mixture was stirred at room temperature for 30 minutes. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed serially with saturated saline and water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane to provide the title compound (yield 5.0 g, 87%).
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4](OC)[CH:3]=1.[F:40]C1C=CC=CC=1B(O)O>C(Cl)Cl.CO>[F:40][C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35]
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: OB(O)c1ccccc1F
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)CCNc1cnccc1-c1ccccc1F

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2-methanesulfonyl-ethyl)-amine (example 158, intermediate b) and 2-fluorophenylboronic acid (CAS RN 1193-03-9) and using a gradient of CH2Cl2:methanol (100:0 to 70:30) for the chromatographic purification. Light brown solid (85%). MS (ESI): m/z=295.09 [M+H]+.