Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[CH:14]=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][C:10]2([CH3:29])[CH3:28])=[CH:5][CH:4]=1)=[O:2].C1COCC1.C(OC(C)C)(C)C>>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:13]3[CH:14]=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][C:10]2([CH3:29])[CH3:28])=[CH:7][CH:8]=1
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2c1ccc(C=O)cc1
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2c1ccc(CO)cc1
Yield: 80 %

Procedure:
Using N-(3-(4-formylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 292, the title compound was synthesized in the same manner as in Example 21. Yield: 80%. Melting point: 162-163° C. (THF-diisopropyl ether).
Reaction SMILES: [CH:1]([F:9])([F:8])[C:2]([F:7])([F:6])[C:3](Cl)=[O:4].N1C=CC=CC=1.[CH:16]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH2:17].O>ClCCl>[CH2:19]([O:18][CH:16]=[CH:17][C:3](=[O:4])[C:2]([F:7])([F:6])[CH:1]([F:9])[F:8])[CH2:20][CH2:21][CH3:22]
Reactant: O=C(Cl)C(F)(F)C(F)F
Reactant: C=COCCCC
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCCOC=CC(=O)C(F)(F)C(F)F
Temperature: 0 °C
Reaction time: 15 h

Procedure:
With stirring and at 0° C., 25.0 g (152 mmol) of 3H-tetrafluoropropionyl chloride—dissolved in 20 ml dichloromethane—were added to a mixture of 14.4 g (182 mmol) of pyridine and 15.2 g (152 mmol) of butyl vinyl ether in 250 ml of dichloromethane. After the addition, stirring was continued at room temperature for another 15 h. 250 ml of water were then added to the mixture, and the organic phase was separated off, dried and concentrated. This gave 12.5 g (36% of theory) of a yellowish oil.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:23][NH:24][C:25](=[O:32])[C:26]([F:31])([CH3:30])[C:27](O)=[O:28]>>[F:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:23][NH:24][C:25](=[O:32])[C:26]([F:31])([CH3:30])[C:27]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:28]
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: CC(F)(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Product: CN1C(=O)C(NC(=O)C(C)(F)C(=O)NCc2cc(F)cc(F)c2)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=482.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2-fluoro-2-methyl-malonamic acid.
Reaction SMILES: [Br:1]CC([O:5][CH2:6][CH3:7])=O.[CH3:8][NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[S:11]>CC(C)=O>[BrH:1].[CH3:8][N:9]1[C:6](=[O:5])[CH2:7][S:11][C:10]1=[N:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CBr
Reactant: CNC(=S)Nc1ccccc1
Solvent: CC(C)=O
Product: Br
Product: CN1C(=O)CSC1=Nc1ccccc1

Procedure:
10 g of ethyl bromoacetate and 9.95 g of 1-methyl-3-phenylthiourea in 150 ml of acetone are boiled for 1 hour under a reflux condenser. The reaction mixture is allowed to cool and the crystals are filtered off and washed with acetone. Melting point 212°-215° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:18]([O:20]C)=[O:19])([C:6]4[C:11]3=[CH:10][CH:9]=[C:8]([Cl:17])[CH:7]=4)[C:4]=2[CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:18]([OH:20])=[O:19])([C:6]4[C:11]3=[CH:10][CH:9]=[C:8]([Cl:17])[CH:7]=4)[C:4]=2[CH:3]=1
Reactant: COC(=O)C12CC(c3ccc(Cl)cc31)c1ccc(Cl)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C12CC(c3ccc(Cl)cc31)c1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 2,7-dichloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylate (described in example 35d) (3.25 g, 10.2 mmol) in tetrahydrofuran/methanol (1:1, 70 mL) was added an aqueous solution (35 mL) of lithium hydroxide monohydrate (4.28 g, 102 mmol, 10 eq). A slight exotherm occurred on addition. The reaction was stirred vigorously for 18 h at room temperature over which time a cloudiness develops. The solvents are removed and replaced with 3N HCl (50 mL) saturated with sodium chloride. The aqueous phase was extracted with ethyl acetate (3×50 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered and reduced to an oil. The procedure yielded 3.11 g (quantitative) of the title compound and did not require addition purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]2[C:7]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[O:16])=[C:8]([C:10]3[CH:11]=[N:12][NH:13][CH:14]=3)[O:9][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][N:13]1[CH:14]=[C:10]([C:8]2[O:9][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:30]=[CH:29][C:6]=3[C:7]=2[C:15](=[O:16])[C:17]2[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=2)[CH:11]=[N:12]1)[CH3:43]
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(-c3cn[nH]c3)oc2c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(-c2oc3cc(OC)ccc3c2C(=O)c2cc(OC)c(OC)c(OC)c2)cn1
Temperature: 70 °C
Yield: 97.8 %

Procedure:
To a stirred solution of [6-Methoxy-2-(1H-pyrazol-4-yl)-benzofuran-3-yl]-(3,4,5-trimethoxyphenyl)-methanone (45 mg, 0.091 mmol) and potassium carbonate (40 mg, 0.29 mmol) in dry DMF (2.5 mL) was added ethyl bromoacetate (30 μL, 0.27 mmol) and the reaction heated to 70° C. for 2 h. After cooling to room temperature the reaction mixture was quenched with 10% NH4Cl(aq) (20 mL) and extracted with ethyl acetate (30 mL). The organic layer was separated and washed with water (3×10 mL) and brine (10 mL), dried over magnesium sulphate and the solvent removed under reduced pressure. The crude residue was purified by flash column chromatography (silica gel, eluent=2:1 hexane:ethyl acetate) to give the title compound as a yellow solid (44 mg, 98%). 1H-NMR (CDCl3) δ 8.28 (s, 1H), 8.06 (s, 1H), 7.13 (s, 2H), 7.10 (d, J=8.7 Hz, 1H), 7.04 (d, J=2.1 Hz, 1H), 6.79 (dd, J=8.7, 2.1 Hz, 1H), 4.91 (s, 2H), 4.23 (q, J=7.1 Hz, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 3.77 (s, 6H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)(=O)C.[OH-].[Li+].Cl>C1COCC1.O>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[CH:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc(C(=Cc2ccc(C)cc2)C(=O)O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C=C(C(=O)O)c2ccc(O)cc2)cc1
Yield: 82.4 %

Procedure:
To a solution of compound 37 (20.16 g, 68.1 mmol) in 100 mL THF was added a solution of lithium hydroxide (5.7 g, 237.5 mmol) in 100 mL water. The reaction was allowed to stir at room temperature for 16 h after which 5% HCl in water was added to pH=1. The yellow solid was filtered and recrystallized out of toluene, washed with hexane and dried under vacuum to yield a white solid (14.27 g, 82.5%). 1H NMR (400 MHz, DMSO-d6) δ 12.46 (br s, 1H), 9.47 (br s, 1H), 7.63 (s, 1H), 7.02 (d, J=8.0 Hz, 2H), 6.97 (d, J=8.4 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.74 (d, J=8.8 Hz, 2H), 2.22 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]3[N:17]=[CH:18][C:19](/[CH:22]=[CH:23]/[C:24]([O:26]C)=[O:25])=[N:20][CH:21]=3)[CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]3[N:17]=[CH:18][C:19](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])=[N:20][CH:21]=3)[CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C/c1cnc(N[C@@H]2CCN(CCc3cccc(F)c3)C2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/c1cnc(N[C@@H]2CCN(CCc3cccc(F)c3)C2)cn1
Temperature: 50 °C
Yield: 100 %

Procedure:
A mixture of methyl (2E)-3-[5-({(3R)-1-[2-(3-fluorophenyl)ethyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]acrylate (235 mg) and 1N—NaOH aq. (1.3 mL) in MeOH (4.7 mL) was heated at 50° C. for 3 hours. After cooling, 1N—HCl (1.37 mL) was added to the solution. The mixture was evaporated and azeotroped with dioxane and toluene to give a crude (2E)-3-[5-({(3R)-1-[2-(3-fluorophenyl)ethyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]acrylic acid (226 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-:6].C[N+](C)=[C:9]1[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][O:10]1>>[Br-:6].[C:14]1([C:13]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:12][CH2:11][O:10][C:9]2=[N+:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C1CCNC1
Reactant: C[N+](C)=C1OCCC1(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: c1ccc(C2(c3ccccc3)CCOC2=[N+]2CCCC2)cc1

Procedure:
Compound (G) 1-(3,3-diphenyl-dihydrofuran-2-ylidene)-pyrrolidinium bromide was prepared with pyrrolidine following the same procedure as the synthesis of compound (F) dimethyl(tetrahydro-3,3-diphenyl-2-furylidene)ammonium bromide.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[OH:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)=[CH:31][CH:32]=1
Reactant: COc1ccc(O)cc1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: COc1ccc(OCc2ccc(-c3nccnc3NS(=O)(=O)c3ccccc3C(F)(F)F)cc2)cc1
Yield: 48 %

Procedure:
Following the general method as outlined in Example 1 (Method 8), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 4-hydroxyanisole, the title compound was isolated as a yellow solid in 48% yield (91% purity by HPLC).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[N:11]1([CH2:17][CH2:18][NH2:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[N:11]1([CH2:17][CH2:18][NH:19][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: NCCN1CCOCC1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Product: O=[N+]([O-])c1cccc(NCCN2CCOCC2)c1

Procedure:
Using 1-bromo-3-nitro-benzene (303 mg) and 2-morpholin-4-yl-ethylamine (315 μl) instead of morpholine, in the same manner as Step A in Example 1-D-105, the desired compound was obtained (374.6 mg, 74%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:22][CH2:21][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:32][C:33]1[N:34]=[CH:35][N:36]([C:38]2[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][C:39]=2[O:45][CH3:46])[CH:37]=1>>[Cl:32][C:33]1[N:34]=[CH:35][N:36]([C:38]2[CH:44]=[CH:43][C:41]([NH:42][C:2]3[N:3]=[C:4]([N:18]4[CH2:22][CH2:21][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH2:19]4)[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=5)[C:6]=4[N:7]=3)=[CH:40][C:39]=2[O:45][CH3:46])[CH:37]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)C1
Product: COc1cc(Nc2nc3c(c(N4CCC(N(C)C(=O)OC(C)(C)C)C4)n2)CCC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Yield: 49.5 %

Procedure:
tert-butyl 1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-yl(methyl)carbamate (Preparation Hm) (148 mg, 0.331 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (74.1 mg, 0.331 mmol) were combined as per Example 26 to give the crude tert-butyl 1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-yl(methyl)carbamate (104 mg, 0.164 mmol, 49.5% yield) which was used without further purification. LC-MS (M+H)+=634.4.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH:30]4[CH2:32][CH2:31]4)=[CH:28][C:27]([C:33]([F:36])([F:35])[F:34])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:37])[CH:11]=1>>[CH:30]1([C:29]2[C:24]([N:21]3[CH2:20][CH2:19][N:18]([C:16]([C:13]4[CH:14]=[CH:15][C:10]([N:4]5[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]5(=[O:8])=[O:7])=[CH:11][C:12]=4[F:37])=[O:17])[CH2:23][CH2:22]3)=[N:25][CH:26]=[C:27]([C:33]([F:35])([F:36])[F:34])[CH:28]=2)[CH2:32][CH2:31]1
Reactant: O=C(c1ccc(Br)cc1F)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Reactant: C[C@H]1CNS(=O)(=O)C1
Product: C[C@H]1CN(c2ccc(C(=O)N3CCN(c4ncc(C(F)(F)F)cc4C4CC4)CC3)c(F)c2)S(=O)(=O)C1
Yield: 57.5 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (110 mg) described in Preparation Example 4 and (4-bromo-2-fluorophenyl)[4-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazin-1-yl]methanone (256 mg) described in Preparation Example 123 and by the reaction and treatment in the same manner as in Example 4, the title compound (164 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)[C:11]([N+:21]([O-])=O)=[CH:10][CH:9]=2)[C:4](=[O:24])[CH2:3]1.[C:25]([C:27]1[O:31][C:30]([C:32](Cl)=[O:33])=[CH:29][CH:28]=1)#[N:26].C(C1OC(C(O)=O)=CC=1)#N>C(Cl)Cl>[CH3:20][CH:17]1[CH2:18][CH2:19][N:14]([C:12]2[C:11]([NH:21][C:32]([C:30]3[O:31][C:27]([C:25]#[N:26])=[CH:28][CH:29]=3)=[O:33])=[CH:10][CH:9]=[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][C:4]3=[O:24])[N:13]=2)[CH2:15][CH2:16]1
Reactant: CC1CCN(c2nc(N3CCN(C)CC3=O)ccc2[N+](=O)[O-])CC1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Agent: N#Cc1ccc(C(=O)O)o1
Solvent: ClCCl
Product: CC1CCN(c2nc(N3CCN(C)CC3=O)ccc2NC(=O)c2ccc(C#N)o2)CC1
Yield: 43 %

Procedure:
4-Methyl-1-(4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazin-2-one (as prepared in the previous step) (99 mg, 0.29 mmol) was converted to corresponding amine according to the procedure in Example 55, step (c) and coupled with 5-cyano-furan-2-carbonyl chloride as prepared in Example 4, step (c) (obtained from 68.5 mg, 0.500 mmol of 5-cyano-furan-2-carboxylic acid as prepared in Example 1) in CH2Cl2 (2 mL) at 0° C. The product was isolated flash chromatography on silica (20% EtOAc/hexane-10% MeOH/EtOAc) to give the title compound (53 mg, 43%). 1H-NMR (CDCl3; 400 MHz): δ 8.98 (br s, 1H), 8.61 (d, 1H, J=8.7 Hz), 7.71 (d, 1H, J=8.7 Hz), 7.28 (d, 1H, J=3.7 Hz), 7.22 (d, 1H, J=3.7 Hz), 3.99 (m, 2H), 3.28 (s, 2H), 3.16 (m, 2H), 2.87-2.77 (m, 4H), 2.38 (s, 3H), 1.83 (m, 2H), 1.62 (m, 1H), 1.44 (m, 2H), 1.04 (d, 3H, J=6.3 Hz). LC-MS (ESI, m/z): Calcd. for C22H26N6O3, 423.2 (M+H), found 423.1
Reaction SMILES: C[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:17])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:18]CCCCCC(O)CCCCCCCCC.CCCCCCCC(O)CCCCCCCC>>[CH3:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:17])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:18]
Reactant: CCCCCCCCCC(O)CCCCCC
Reactant: CCCCCCCCCCC(O)CCCCC
Agent: CCCCCCCCC(O)CCCCCCC
Product: CCCCCCCCCCCC(O)CCCC

Procedure:
6-hexadecanol; 7-hexadecanol; 8-hexadecanol;
Reaction SMILES: C([O:3][C:4]([C:6]1(C(OCC)=O)[CH:10]([CH:11]([CH3:13])[CH3:12])[CH2:9][CH2:8][NH:7]1)=[O:5])C>Cl>[CH:11]([CH:10]1[CH2:9][CH2:8][NH:7][C@@H:6]1[C:4]([OH:5])=[O:3])([CH3:13])[CH3:12]
Reactant: CCOC(=O)C1(C(=O)OCC)NCCC1C(C)C
Agent: Cl
Product: CC(C)C1CCN[C@@H]1C(=O)O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of diethyl-3-isopropylpyrrolidine-2,2-dicarboxylate (Example 39, Step A, 2.27 g, 8.81 mmol) in 6 M HCl (50 mL) was heated to reflux. The solution turned from pale yellow in color to orange with addition of acid, then to brown upon heating. The mixture was stirred overnight at 50° C. Solvent was removed in vacuo to afford the title compound (a mixture of four diastereomers) as a brown oil which was carried on crude. LCMS (M+H): 158.0.
Reaction SMILES: [CH:1]([S:4]([CH2:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[N:11]=[C:10]([C:21]2[CH:26]=[CH:25][C:24]([NH:27]C(=O)OC(C)(C)C)=[CH:23][CH:22]=2)[N:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]([S:4]([CH2:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[N:11]=[C:10]([C:21]2[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=2)[N:9]=1)(=[O:5])=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)S(=O)(=O)Cc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)S(=O)(=O)Cc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(N)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
Tert-butyl (4-{4-[(isopropylsulfonyl)methyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl}phenyl)carbamate (3.2 g, 6.52 mmol) was dissolved in DCM (20 mL) and trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred at room temperature for 2 hours then diluted with DCM (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). Organic phase collected, dried over magnesium sulphate, filtered and concentrated in vacuo to give the desired material as a cream solid (2.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:51][O:52][C:53]1[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=1)[CH:56]([OH:58])[CH3:57]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:58][CH:56]([C:55]2[CH:59]=[CH:60][CH:61]=[C:53]([O:52][CH3:51])[CH:54]=2)[CH3:57])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cccc(C(C)O)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cccc(C(C)OC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C)c2C)c1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (90 mg) was added to toluene/triethylamine=10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (123 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-methoxy-α-methylbenzyl alcohol (64 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (97 mg, yield 70%).
Reaction SMILES: CO[C:3](=O)[NH:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1I.Cl[CH2:15][CH2:16][CH2:17]C#C.[CH2:20](N(CC)CC)C>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Br:11][C:8]1[CH:9]=[CH:10][C:5]2[N:4]3[CH2:15][CH2:16][CH2:17][C:3]3=[CH:20][C:6]=2[CH:7]=1
Reactant: CCN(CC)CC
Reactant: C#CCCCCl
Reactant: COC(=O)Nc1ccc(Br)cc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: Brc1ccc2c(c1)cc1n2CCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 3.350 g (0.0048 mol) bis-(triphenylphosphine)-palladium(II)dichloride and 1.90 g (0.010 mol) copper(I)iodide in 500 mL triethylamine was heated to reflux for 30 min. The mixture was cooled to room temperature and 190 g (0.534 mol) (4-bromo-2-iodo-phenyl)-carbamic acid methyl ester and 66.462 mL 5-chloro-1-pentyne (65 g, 0.634 mol) were added. The mixture was heated to reflux. When a temperature of 70° C. was reached, a strong exothermic reaction was observed leading to vigorous reflux! A thick suspension formed. Refluxing was continued for 15 min. The mixture was cooled to room temperature and diluted with 500 mL ethyl acetate. The solids were removed by filtration and the filter cake was washed with ca. 200 mL ethyl acetate. The filtrate was concentrated under aspirator vacuum, taken up in 500 mL ethyl acetate and washed successively with 10% citric acid solution, 10% sodium thiosulfate solution, 10% sodium bicarbonate solution and brine. The aqueous phases were re-extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate. To the solution was added 200 mL dimethylsulfoxide and the mixture concentrated under aspirator vacuum. Remaining ethyl acetate was removed under high vacuum. The resulting dimethylsulfoxide solution was added to a suspension of 70 g lithium hydroxide monohydrate in 120 mL water and 1000 mL dimethylsulfoxide. The resulting suspension was heated to 80° C. for 2 h. The mixture was cooled to room temperature and 1500 mL of ice water and 600 mL dichloromethane were added. The pH was adjusted to 6 by addition of 25% hydrochloric acid. The phases were separated and the organic phase was washed with half concentrated brine. The aqueous phases were extracted with 200 mL dichloromethane. The combined organic phases were diluted to a volume of 2000 mL with n-hexane. The resulting solution was filtered over 1 kg silica gel with hexane: dichloromethane=2: 1. The product fractions were combined and concentrated under aspirator vacuum, whereby crystallisation occurred to yield 95 g white crystals. (HPLC 100%). The mother liquor was evaporated to afford a second crop [7.2 g, 87% purity by HPLC) which was recrystallised to furnish a further 6 g (100% purity by HPLC) Total yield: 101 g (80%) of the title compound as white crystals, m.p.: 78.7-79.4° C.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31].CN1CCOCC1>C(#N)C>[CH2:12]([O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:25])[CH3:26])[NH:22][C@@H:29]([C:30]([O:32][CH3:33])=[O:31])[CH3:34])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reactant: COC(=O)C(C)Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](C)N[C@@H](CC(C)C)C(=O)OCc1ccccc1

Procedure:
Leucine benzyl ester para-toluene sulphonic acid salt (113 g) in dry acetonitrile (800 ml) was treated with methyl 2-bromopropionate (62.7 ml) and N-methyl morpholine (100 ml) under reflux for 16 h. The reaction mixture was concentrated in vacuo and the residue in ethyl acetate washed with brine, dried (Na2SO4) and evaporated. Chromatography of the resulting oil on silica in 1:4 ethyl acetate-hexane gave N-[1-(R)-methoxycarbonylethyl]-L-leucine benzyl ester (45 g) as the faster running fraction. This material was treated exactly as described above in Example 2 to give the title compound.