Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:29]2[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[CH2:6][CH2:5]2)[C:3]1=[O:33].C[CH2:35][N:36]=[C:37]=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.N(C)C.Cl>C(Cl)Cl>[CH3:35][N:36]([CH3:37])[C:30]([C:26]1[CH:25]=[C:24]2[C:4]3([CH2:5][CH2:6][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:19]([F:22])([F:21])[F:20])[CH2:8][CH2:9]3)[C:3](=[O:33])[N:2]([CH3:1])[C:29]2=[CH:28][CH:27]=1)=[O:31]
Reactant: CCN=C=NCCCN(C)C
Reactant: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(C(=O)O)ccc21
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc2c(c1)C1(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
To a mixture of (E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylic acid (20 mg, 0.508 mmol), EDCI (18 mg, 0.088 mmol), HOBt (12 mg, 0.088 mmol), and DIEA (60 mg, 0.44 mmol) in CH2Cl2 was added NHMe2.HCl (16 mg, 0.176 mmol) at 0° C. The mixture was stirred at rt overnight. The mixture was concentrated to give the crude product, which was purified by preparative TLC to give (E)-N,N,1-trimethyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxamide (6 mg, 14%). 1H NMR (400 MHz, CDCl3): δ=3.05 (m, 6H), 3.25 (m, 3H), 3.60-3.75 (m, 2H), 3.95 (m, 2H), 4.15 (m, 1H), 4.35 (m, 1H), 6.85 (m, 1H), 7.35 (m, 1H), 7.45 (m, 2H), 7.55 (m, 1H) 7.70 (m, 2H), 8.00 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([F:25])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11].[CH3:26][S:27]([NH2:30])(=[O:29])=[O:28]>>[CH3:26][S:27]([NH:30][C:10](=[O:11])[C:9]1[CH:13]=[C:5]([O:4][C:3]2[C:17]([F:25])=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])[CH:6]=[CH:7][C:8]=1[N+:14]([O-:16])=[O:15])(=[O:29])=[O:28]
Reactant: O=C(Cl)c1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Reaction of 5-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2-nitro benzoyl chloride with methanesulphonamide to give the required compound, i.e. N-methanesulphonyl-5-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2-nitro-benzamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:24])=[N:15][CH:16]=[C:17]([C:19]2[CH:20]=[N:21][NH:22][CH:23]=2)[CH:18]=1)[CH3:11].Cl[CH2:26][P:27](=[O:30])([CH3:29])[CH3:28]>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:24])=[N:15][CH:16]=[C:17]([C:19]2[CH:23]=[N:22][N:21]([CH2:26][P:27]([CH3:29])([CH3:28])=[O:30])[CH:20]=2)[CH:18]=1)[CH3:11]
Reactant: CP(C)(=O)CCl
Reactant: CC(Oc1cc(-c2cn[nH]c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Product: CC(Oc1cc(-c2cnn(CP(C)(C)=O)c2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared from 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1H-pyrazol-4-yl)-pyridin-2-ylamine and chloromethyl-dimethyl-phosphine oxide following the same procedure as Example 2. ESMS: m/z 457 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[CH:20](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[F:19][C:17]1[CH:18]=[C:2]2[C:3]([C:4](=[O:5])[N:6]([CH:7]3[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]3=[O:14])[CH:20]=[N:1]2)=[CH:15][CH:16]=1
Reactant: COC(OC)OC
Reactant: Nc1cc(F)ccc1C(=O)NC1CCC(=O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C1CCC(n2cnc3cc(F)ccc3c2=O)C(=O)N1
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-4-fluoro-benzamide (0.9 g, 3.4 mmol) and trimethyl orthoformate (4 mL) and p-toluene sulfonic acid (110 mg) was heated to 160° C. in a microwave oven for 15 minutes. To the mixture, was added methanol (10 mL), and the mixture was stirred for 10 minutes. The suspension was filtered and washed with methanol to give 3-(7-fluoro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (650 mg, 70% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 2.45 min (96.1%); mp: 296-298° C.; 1H NMR (DMSO-d6) δ 2.13-2.19 (m, 1H, CHH), 2.63-2.73 (m, 2H, 2CHH), 2.82-2.93 (m, 1H, CHH), 5.50 (br, 1H, NCH), 7.46 (dt, J=3, 9 Hz, 1H, Ar), 7.53 (dd, J=3, 10 Hz, 1H, Ar), 8.22 (dd, J=6, 9 Hz, 1H, Ar), 8.42 (s, 1H, CH), 11.18 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.45, 30.88, 56.43, 112.3 (d, JC-F=22 Hz), 115.91 (d, JC-F=23 Hz), 118.38, 129.32 (d, JC-F=11 Hz), 148.71, 149.65 (d, JC-F=14 Hz), 159.00, 165.70 (d, JC-F=252 Hz), 169.76, 172.41; LCMS: MH=276; Anal Calcd for C13H10N3O3F: C, 56.73; H, 3.66; N, 15.27. Found: C. 56.39; H, 3.60; N, 15.16.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=1)[NH:7][C:6]1[C:14]([CH2:20][C:21](OCC)=[O:22])([CH2:18][CH3:19])[O:15][CH2:16][CH2:17][C:5]2=1.[Li+].[BH4-].C1COCC1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([CH3:12])[CH3:13])[CH:10]=1)[NH:7][C:6]1[C:14]([CH2:20][CH2:21][OH:22])([CH2:18][CH3:19])[O:15][CH2:16][CH2:17][C:5]2=1
Reactant: CCOC(=O)CC1(CC)OCCc2c1[nH]c1c(C(C)C)cc(Br)cc21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1(CCO)OCCc2c1[nH]c1c(C(C)C)cc(Br)cc21
Yield: 78.3 %

Procedure:
To a stirred solution of ethyl 2-(6-bromo-1-ethyl-1,3,4,9-tetrahydro-8-isopropylpyrano[3,4-b]indol-1-yl)acetate (6.0 g, 0.015 mol) in THF (120 ml), was added 2.0 M solution of LiBH4/THF (20 ml, 0.30 mol) via syringe during 30 min under a nitrogen atmosphere at room temperature. The mixture was refluxed for 10 hr, cooled, quenched with water and 5% HCl, and extracted with EtOAc. The organic phases were combined and washed with brine, dried over MgSO4, and evaporated to give a residue, which was chromatographed on silica gel. Elution with hexane-EtOAc (7:3) gave the product (4.3 g, 80%). 1H NMR (300 MHz, CDCl3) δ 8.18 (b, NH), 0.92 (t, 3H), 1.35 (d, 6H), 1.98 (m, 3H), 2.19 (m, 1H), 2.54 (t, 1H), 2.75 (m, 2H), 3.17 (m, 1H), 3.71 (t, 1H), 4.03 (m, 2H), 7.13 (dd, 1H), 7.45 (d, 1H), 7.96 (b, NH). ESI (+) MS m/e=367 (MH+), ESI (−) MS m/e=365 (MH−).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]1[CH3:13])(=[O:3])[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].COCCOC>CCOCC.[Cl-].[Zn+2].[Cl-]>[C:14]([C:10]1[CH:9]=[C:8]([CH3:13])[N:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:11]=1[CH3:12])(=[O:16])[CH3:15]
Reactant: CC(=O)NCCn1c(C)ccc1C
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: COCCOC
Product: CC(=O)NCCn1c(C)cc(C(C)=O)c1C
Reaction time: 1 h

Procedure:
13.7 g (0.1 mol) of anhydrous zinc chloride are dissolved in 100 ml of ether and the solution is added to 18.0 g (0.1 mol) of 1-(2-acetylaminoethyl)-2,5-dimethylpyrrole and 9.5 ml (0.1 mol) of acetic anhydride in 50 ml of ether. After 1 hour at room temperature, 50 ml of ethylene glycol dimethyl ether are added and stirring is continued for 20 hours. After the hydrolysis, the organic phase is concentrated, the residue is chromatographed and the product is recrystallized from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2([CH3:27])[C:13]3=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]3[CH2:11][CH2:10][N:9]2C(OC(C)(C)C)=O)[CH:5]=[CH:4][C:3]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[ClH:34].CCOC(C)=O>CCOC(C)=O>[ClH:34].[F:1][C:2]1[CH:7]=[C:6]([C:8]2([CH3:27])[C:13]3=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]3[CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:4][C:3]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCN2CCS(=O)(=O)N=C2C1(C)c1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1(c2ccc(-c3ccccc3)c(F)c2)NCCN2CCS(=O)(=O)N=C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of tert-butyl 9-(2-fluorobiphenyl-4-yl)-9-methyl-3,4,6,7-tetrahydropyrazino[2,1-c][1,2,4]thiadiazine-8(9H)-carboxylate 2,2-dioxide (150 mg) and 4 N HCl/EtOAc (5 mL) in EtOAc (5 mL) was stirred at room temperature overnight. After removing solvent, the residue was recrystallized from MeOH to give the title compound (65 mg) as a white solid.
Reaction SMILES: [CH:1]1([C:8]([CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH:12]=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[Na]>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:12][CH2:11][CH:10]([C:8]([CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:9])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:30][CH2:29]1
Reactant: O=CCC(C(=O)C1CCCCCC1)c1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Agent: [Na]
Product: COc1ccccc1N1CCN(CCC(C(=O)C2CCCCCC2)c2ccccc2)CC1
Yield: 70.3 %

Procedure:
Following the procedures described in the Example 1, Step C, the reaction of 3-cycloheptanecarbonyl-3-phenylpropionaldehyde (2.52 mmol) and 1-(2-methoxyphenyl)piperazine (2.52 mmol) with sodium triacetoxyboranehydride (3.28 mmol) gave pure product 1-(2-methoxyphenyl)-4-[3-(cycloheptanecarbonyl)-3-(phenyl)propyl]piperazine (770 mg) in 70% yield. The dihydrochloric acid salt was prepared as described above.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:17])[CH2:15]Cl)([CH3:3])[CH3:2].[SH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].Cl>O.CS(C)=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:17])[CH2:15][S:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Reactant: CCOC(=O)CS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CSCC(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
A mixture of 18.8 g of N-(2,6-diisopropylphenyl)-2-chloroacetamide, 8.9 g of ethyl 2-mercaptoacetate, 20.4 g of potassium carbonate, and 100 ml of dimethyl sulfoxide was stirred at room temperature for 1 hour, and a mixture of 25 ml of concentrated hydrochloric acid and 100 ml of water was added thereto. The reaction mixture was extracted with 300 ml of ethyl acetate, and the extract was washed successively with a 1N hydrochloric acid aqueous solution, a sodium hydrogencarbonate aqueous solution, and a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to yield 22.6 g of N-(2,6-diisopropylphenyl)-2-(ethoxycarbonylmethylthio)acetamide as white needle crystals (m.p.=124.0°-125.0° C.).
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([C:29]#[N:30])[C:22]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:31])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[C:29]([C:21]1[C:22]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]2=[C:17]([CH:20]=1)[C:18](=[O:19])[N:9]([OH:8])[C:10]3=[O:31])#[N:30]
Reactant: [H][H]
Reactant: N#Cc1cc2c3c(cccc3c1N1CCCCC1)C(=O)N(OCc1ccccc1)C2=O
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Product: N#Cc1cc2c3c(cccc3c1N1CCCCC1)C(=O)N(O)C2=O
Yield: 45.9 %

Procedure:
A mixture of 2-benzyloxy-5-cyano-6-(piperidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.16 g, 0.40 mmol, from Example D2) and 5% Pd/BaSO4 (0.05 g) in THF (75 mL) was shaken in an atmosphere of hydrogen at 50 psi at ambient temperature for 86 hours with an additional 0.05 g of 5% Pd/BaSO4 being added after 70 hours. The catalyst was removed by filtration and the filtrate evaporated under reduced pressure. The residue was chromatographed on silica using chloroform/methanol (10:1) to give 0.059 g of the title compound, mp >250° C.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([O:14][C:15]([N:17]1C[CH2:23][CH2:22][C@@H:18]1C(O)=O)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:4][C:2]([C@H:1]1[CH2:23][CH2:22][CH2:18][N:17]1[C:15]([O:14][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:16])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)[C@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 22.5 °C
Reaction time: 0.5 h

Procedure:
A mixture composed of 40 mL of toluene and 40 mL of oxalyl chloride was added—in 30 minutes at room temperature—to a solution of 100 g of 1-[(benzyloxy)carbonyl]-D-proline in 200 mL of toluene and 0.5 mL of DMF. After stirring for 2 hours at 20-25° C. the HPLC showed complete conversion and the reaction mixture was concentrated with oil at about 40° C. under vacuum, redissolved to toluene and reconcentrated obtaining 122.1 g of residue. At 20-25° C. the residue was dissolved in 100.00 mL of THF and this solution was used in example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][NH2:22])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:23])=[C:4]([F:26])[CH:3]=1.CCN(CC)CC.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:8](=[O:23])[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][NH:22][C:34](=[O:36])[CH3:35])=[CH:17][CH:18]=3)=[CH:12]2)=[C:4]([F:26])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: NCCOc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCOc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
According to Scheme 19 Step 3: To a solution of 1-(4-chloro-2-fluorobenzyl)-5-(4-(2-aminoethoxy)phenyl)pyridin-2(1H)-one (1 eq, 0.18 mmol, 0.07 g) in CH2Cl2 (5 mL) at 0° C. were added Et3N (6 eq, 1.10 mmol, 0.15 mL) and 30 min. later acetyl chloride (1.5 eq, 0.27 mmol, 19 μL) and. The reaction mixture was stirred 1 hour at room temperature. The reaction mixture was quenched with water and extracted with CH2Cl2. The organic phase was dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2, CH2Cl2/AcOEt 70/30) to afford N-(2-(4-(1-(4-chloro-2-fluorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)phenoxy)ethyl)acetamide (0.08 mmol, 0.04 g, 47%) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:8]=[C:7]([Cl:22])[N:6]=1)=O.[BH4-].[Li+].C1COCC1>C(COC)OC>[Cl:22][C:7]1[N:6]=[C:5]([CH2:3][OH:2])[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[N:8]=1
Reactant: COC(=O)c1cc(NCCc2ccc(OC)cc2)nc(Cl)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: COc1ccc(CCNc2cc(CO)nc(Cl)n2)cc1
Temperature: 3 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A mixture of 2-chloro-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-4-carboxylic acid methyl ester [7.43 g, 23.09 mmol, Intermediate (55)] in dimethoxyethane (100 mL) is chilled in an ice/water bath to 3° C. and treated dropwise via syringe with a solution of 2 M lithium borohydride in THF (17.3 mL, 34.6 mmol) not allowing the reaction temperature to exceed 7° C. After complete addition stirring is continued at 5° C. for 1 hour. The reaction mixture is poured into ice/water (250 mL) and extracted four times EtOAc (100 mL). The combined organic extracts are washed with water (100 mL), them with brine (100 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporator to afford {2-chloro-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-methanol [6.51 g, 96%, Intermediate (57)].
Reaction SMILES: [O:1]([CH2:8][CH2:9][Br:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1>>[Br:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]([C:15]2[CH:19]=[CH:20][C:12]([OH:11])=[CH:13][CH:14]=2)=[O:17])=[CH:4][CH:3]=1
Reactant: BrCCOc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Product: O=C(c1ccc(O)cc1)c1ccc(OCCBr)cc1

Procedure:
Melting points (mp) were obtained on a capillary melting point apparatus and are uncorrected. Elemental analyses of all compounds prepared were within ±0.4% of calculated theoretical values. Reaction progress and purity of products were checked by analytical TLC using 0.2 mm silica gel plastic backed layers, and viewed under light of 254 nm wavelength. Proton NMR spectra were obtained at 90 mHz and EIMS were obtained using a direct ion probe. 4-(2-Bromoethoxy)-4'-hydroxybenzophenone was prepared by acylation of 2-phenoxyethyl bromide with 4-hydroxybenzoic acid: mp 136°-138° C.
Reaction SMILES: C[O:2][C:3](=[O:9])[CH2:4][C:5](OC)=O.[Na].ClC1[N:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].Cl>O.O1CCOCC1>[Cl:20][C:18]1[N:19]=[C:5]([CH2:4][C:3]([OH:2])=[O:9])[C:13]([C:14]#[N:15])=[CH:16][CH:17]=1
Reactant: N#Cc1ccc(Cl)nc1Cl
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(Cl)nc1CC(=O)O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of malonic acid dimethyl ester, sodium salt (8.067 g, 52.4 mmol), as prepared in the previous step, 2,6-dichloro-nicotinonitrile (4.53 g, 26.2 mmol), as prepared in Example 6b, and dioxane (40 mL) was stirred at 80° C. for 1 h. The resulting easily stirred reddish-brown opaque thin slurry was allowed to cool to rt, 6 M HCl (aq) (80 mL) was added, and the mixture was vigorously stirred at 65-70° C. for 5 h open to air. The resulting clear dark amber solution containing a small amount of dark material was allowed to cool to rt, diluted with water (80 mL), and extracted with DCM (3×100 mL). The organic layers were combined, dried (2×Na2SO4), and concentrated under reduced pressure at 60° C. to provide the crude title compound as a dark brown oil (6.2 g, quantitative yield). A NMR spectrum of the reaction following malonate addition indicated a ˜1:2 mixture of desired/undesired regioisomers.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:7]3[CH:29]=[C:30]([C:34]4[N:35]=[CH:36][N:37]([CH2:39][CH2:40][O:41][CH3:42])[CH:38]=4)[CH:31]=[C:32]([CH3:33])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:7]3[CH:29]=[C:30]([C:34]4[N:35]=[CH:36][N:37]([CH2:39][CH2:40][O:41][CH3:42])[CH:38]=4)[CH:31]=[C:32]([CH3:33])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: COCCn1cnc(-c2cc(C)c3nc(C4CC4)n(Cc4ccc(-c5ccccc5C(=O)OC(C)(C)C)cc4)c3c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCn1cnc(-c2cc(C)c3nc(C4CC4)n(Cc4ccc(-c5ccccc5C(=O)O)cc4)c3c2)c1

Procedure:
Prepared analogously to Example 88 from tert. butyl 4'-[(2-cyclopropyl-4-methyl-6-(1-(2-methoxyethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: Cl[C:2](Cl)([O:4][C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.O[CH2:14][C:15](CO)(C)[C:16](=[O:18])[CH3:17].C1COCC1>C(N(CC)CC)C>[C:16]([C:15]1([CH3:14])[CH2:7][O:6][C:5](=[O:11])[O:4][CH2:2]1)(=[O:18])[CH3:17]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(=O)C(C)(CO)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)C1(C)COC(=O)OC1
Temperature: -78 °C

Procedure:
In a one liter three neck flask equipped with a mechanical stirrer and under nitrogen were added triphosgene (37.0 g), 3,3-dihydroxymethyl-2-butanone (50 g) and THF (300 mL). The resulting mixture was stirred until a homogeneous solution resulted. This homogeneous solution was cooled to -78° C. Triethylamine (75.0 g) was added to the this solution over 30 min. The cold bath was removed and the reaction allowed to warm to room temperature. After stirring for one hour at room temperature the triethylamine/HCl salt was removed by filtration and the filtrate pass through a silica gel plug. The solvent was removed under reduced pressure resulting in an off white product. This product was then washed with hot ether giving a white solid. NMR analysis indicated that the product contained a small amount of triethylamine/HCl salt, thus the material was dissolved in dichloromethane and washed with water affording 15.02 g of material. 1H NMR (CDCl3) ppm: 4.70 (ab doublet, 2H), 4.20 (ab doublet, 2H), 2.3 (S, 3H), 1.25 (S, 3H).
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][CH:5]([CH3:32])[CH2:6][C:7]1([CH:21]([C:29](C)=[CH2:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]1=[O:20].[BH4-].[Na+]>CCO>[OH:1][CH2:30][CH2:29][CH:21]([C:7]1([CH2:6][CH:5]([CH3:4])[CH3:32])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]1=[O:20])[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23]
Reactant: C=C(C)C(C(=O)OC(C)(C)C)C1(CC(C)C)CCN(CCc2ccccc2)C1=O
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)CC1(C(CCO)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Ozone is bubbled through a solution of tert-butyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-α-(propen-2-yl)-3-pyrrolidineacetate (555 mg, 1.39 mmol) and EtOH (12 mL) at -78° C. for 5 minutes. Nitrogen is then bubbled through the solution for 5 minutes. Sodium borohydride (79 mg, 2.1 mmol) is added and the mixture is allowed to warm slowly and to stir at room temperature overnight. The mixture is concentrated to near dryness, and aqueous workup (EtOAc, MgSO4) to give 511 mg (91%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][CH:4](O)[CH3:5])[CH3:2].N1C(C)=CC=CC=1C.[F:15][C:16]([F:29])([F:28])[S:17]([O:20]S(C(F)(F)F)(=O)=O)(=[O:19])=[O:18].[Cl-].[NH4+]>C(Cl)Cl>[O:20]([CH2:2][CH2:1][O:3][CH2:4][CH3:5])[S:17]([C:16]([F:29])([F:28])[F:15])(=[O:19])=[O:18]
Reactant: CCOC(C)O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCOCCOS(=O)(=O)C(F)(F)F
Reaction time: 1 h
Yield: 67.6 %

Procedure:
In a round bottom flask containing a stirring bar was placed 9.0 g (100 mmol) of ethoxyethanol. The atmosphere in the flask was replaced with nitrogen by using a nitrogen bubbler. The flask was given 160 mL of methylene chloride and 23.3 mL (120 mmol) of 2,6-lutidine. The flask cooled with ice was given dropwise 20.2 mL (120 mmol) of trifluoromethanesulfonic acid anhydride over 20 minutes. After stirring for 1 hour, the reaction liquid was mixed with 20 mL of saturated solution of ammonium chloride. The resulting mixture was washed sequentially with 1N hydrochloric acid (100 mL), deionized water (100 mL), saturated solution of sodium hydrogen carbonate (100 mL), and saturated aqueous solution of sodium chloride (100 mL). The organic layer was separated and dried with anhydrous sodium sulfate. With the sodium sulfate filtered off, the solution was concentrated under reduced pressure. The residue underwent silica gel chromatography. Thus there was obtained 15.03 g (67.6% yields) of 2-ethoxyethyl triflate from the fraction in eluate of 20% ethyl acetate-hexane.