Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]([C:14]2[N:18]([CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[N:17]=[C:16]([C:29]3[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=3)[CH:15]=2)=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C([O:61][C:62](=[O:66])[CH2:63][CH2:64][NH2:65])(C)(C)C.C(Cl)CCl>CN(C=O)C.C(OCC)(=O)C>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([NH:11][C:12]([C:14]2[N:18]([CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH:65][CH2:64][CH2:63][C:62]([OH:61])=[O:66])=[O:25])=[CH:22][CH:21]=3)[N:17]=[C:16]([C:29]3[CH:30]=[C:31]([F:37])[C:32]([F:36])=[C:33]([F:35])[CH:34]=3)[CH:15]=2)=[O:13])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1CC[C@H](NC(=O)c2cc(-c3cc(F)c(F)c(F)c3)nn2Cc2ccc(C(=O)O)cc2)CC1
Reactant: CC(C)(C)OC(=O)CCN
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)[C@H]1CC[C@H](NC(=O)c2cc(-c3cc(F)c(F)c(F)c3)nn2Cc2ccc(C(=O)NCCC(=O)O)cc2)CC1

Procedure:
To a solution of the intermediate from example 1 step F (90 mg, 0.175 mmol) in DMF was added HOAt (36 mg, 0.26 mmol), DIEA (92 μL, 0.52 mmol), β-alanine-tert-butyl ester(48 mg, 0.26 mmol) and EDC (50 mg, 0.26 mmol). After stirring the reaction at room temperature for 18 hours it was diluted with ethyl acetate (20 mL), washed with 1N HCl, saturated NaHCO3, and saturated NaCl. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified on the Biotage quad 3 using 30% ethyl acetate-hexanes to give the title compound. 1H NMR (CDCl3, 500 MHz): 7.72 (d, J=8.3 Hz, 2H), 7.45 (t, J=6.9 Hz, 2H), 7.40 (d, J=8.2 Hz, 2H), 6.87 (bt, J=5.5 Hz, 1H), 6.73 (s, 1H), 5.83 (s, 2H), 3.9 (m, 1H), 3.7 (q, J=6.0 Hz, 2H), 2.57 (t, J=6.0 Hz, 2H), 2.1 (bm, 2H), 1.9 (bm, 2H), 1.47 (s, 9H), 1.2-1.4 (m, 4H), 0.88 (s, 9H). LC-MS: 4.55 min; (M+H)=641.5.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:32])[C:18]=1[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)=[O:21]>>[Cl:32][C:17]1[CH:16]=[N:15][CH:14]=[C:13]([Cl:12])[C:18]=1/[CH:19]=[C:20](\[O:21][C:3](=[O:4])[N:2]([CH3:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)/[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC
Reactant: CN(C(=O)Cl)c1ccccc1
Product: COc1ccc(/C(=C/c2c(Cl)cncc2Cl)OC(=O)N(C)c2ccccc2)cc1OC

Procedure:
The compound was obtained starting from methyl-phenyl-carbamoyl chloride and 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethanone, following the procedure of Example 28.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Li]CCCC.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:38]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)=[O:39])[CH:27]=2)[N:22]=1>C1COCC1.O>[Cl:20][C:21]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:38]([C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)([C:40]3[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=3)[OH:39])[CH:27]=2)[N:22]=1
Reactant: Cn1ccnc1
Reactant: Cc1ccc(C(=O)c2ccc3nc(Cl)nc(-c4cccc(Cl)c4)c3c2)cc1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(O)(c2ccc3nc(Cl)nc(-c4cccc(Cl)c4)c3c2)c2cncn2C)cc1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
1-Methyl-1H-imidazole (0.0507 mol) was added at −70° C. to THF (90 ml) under N2 flow. nBuLi (31.5 ml) was added dropwise. The mixture was stirred at −70° C. for 15 minutes. Chlorotriethyl-silane (0.0522 mol) was added dropwise. The mixture was stirred at −70° C. for 15 minutes. nBuLi (28 ml) was added. The mixture was stirred at −70° C. for 15 minutes. A mixture of intermediate 23 (0.029 mol) in THF (115 ml) was added dropwise. The mixture was stirred at −70° C. for 1 hour, poured out into water and extracted with DCM. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (15-35 μm) (eluent: DCM/MeOH/NH4OH; 96/4/0.1). The pure fractions were collected and the solvent was evaporated, yielding 9 g (65%). A sample (0.3 g) was crystallized from 2-propanone, The precipitate was filtered off and dried, yielding 2-chloro-4-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-α-(4-methylphenyl)-6-quinazolinemethanol (intermediate 24), mp. 220° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])NC(=O)[NH:12]3)[CH2:10][CH2:9][O:8][C:5]2=[CH:6][CH:7]=1.[OH2:18].O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>O>[NH2:12][C:11]1([C:15]([OH:16])=[O:18])[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[O:8][CH2:9][CH2:10]1
Reactant: O
Reactant: O=C1NC(=O)C2(CCOc3ccc(F)cc32)N1
Agent: [Ba+2]
Agent: [OH-]
Product: NC1(C(=O)O)CCOc2ccc(F)cc21
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A stirred slurry of 78 g (0.33 mole) of (RS)-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione and 208.3 g (0.66 mole) of barium hydroxide octahydrate in 585 ml of water was slowly heated to reflux over 3 hours and refluxed 16 hours. The slurry was cooled to 80° C. and powdered NH4CO3 (78 g) added portionwise over 5 minutes. Moderate foaming was noted. After stirring 1.5 hours at 80° C., the mixture was cooled to 60° C., and filtered over diatomaceous earth with 2×100 ml hot water for wash. The combined filtrate and washes were stripped to 200 ml and allowed to stand overnight. 2-Propanol (600 ml) was added and the mixture heated to 70° C. to dissolve precipitated solids. The hot solution was treated with activated carbon, filtered over diatomaceous earth and washed with hot 1:1 water:2-propanol. The combined filtrate and washes were stripped to 200 ml, and water chased with 3×300 ml fresh 2-propanol. The resulting thick slurry was diluted with 200 ml additional 2-propanol, cooled to 5° C., granulated for 0.5 hour, filtered and air dried to yield title product, 63.5 g, 91.2%, mp 252°-253° C. (dec).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:14][C:7]1[C:6]2[CH:15]=[C:2]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:3]=[CH:4][C:5]=2[O:9][C:8]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1oc2ccc(Br)cc2c1C
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1oc2ccc(N3CCOCC3)cc2c1C
Temperature: 25 °C
Yield: 13 %

Procedure:
To a solution (100 mL) of methyl 5-bromo-3-methyl-1-benzofuran-2-carboxylate (5.4 g) synthesized in the above-mentioned (1) in toluene were added morpholine (5.2 mL), cesium carbonate (13.0 g), tris(dibenzylideneacetone)dipalladium (0) (0.92 g) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (1.1 g), and the mixture was heated under reflux under argon atmosphere for 20 hr. The reaction mixture was cooled to room temperature, and filtered through celite. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.69 g, 13%) as a yellow oil.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH:11][C:12](=[O:14])[CH3:13].[O:15]=[C:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([F:29])([F:28])[F:27])[C:20]=2[N:19]=[C:18]([CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[O:17]1.Cl>CCCCCC.O1CCCC1.O>[O:15]=[C:16]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([F:29])([F:28])[F:27])[C:20]=1[NH:19][C:18](=[O:17])[CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36])[CH2:13][C:12](=[O:14])[NH:11][C:7]1[S:6][CH:10]=[CH:9][N:8]=1
Reactant: CC(=O)Nc1nccs1
Reactant: CC(C)(C)OC(=O)NCc1nc2c(C(F)(F)F)cccc2c(=O)o1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Temperature: -75 °C
Yield: 52.8 %

Procedure:
A solution of 85.6 ml of n-butyllithium in hexane was introduced into 8.5 g of N-2-thiazolyl acetamide suspended in 260 ml of tetrahydrofuran. After cooling to -75° C., a solution of 10.33 g of the product of Step A in 75 ml of tetrahydrofuran was added at this temperature. The reaction mixture was poured into 400 ml of water and 100 ml of 2N hydrochloric acid, and was extracted with ether. The organic phase was washed with N hydrochloric acid, then with water, dried, and concentrated to dryness under reduced pressure. The orange oil residue crystallized and the residue was triturated in ether, separated, washed with ether, and dried under reduced pressure to obtain 7.7 g of 1,1-dimethylethyl N-[2-[[2-[1,3-dioxo-3-(2-thiazolylamino)-propyl]-6-trifluoromethylphenyl]-amino]-2-oxo-ethyl]-carbamate melting at 166° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:23][C:22]1[CH:24]=[CH:25][C:19]([S:16]([O:15][CH2:14][C@H:10]2[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: OC[C@@H]1CN(Cc2ccccc2)CCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
(S)-(4-benzylmorpholin-2-yl)methanol 36 g (173.68 mmnol) was dissolved in CH2Cl2 (400 ml), and TsCl (49.6 g, 260.52 mmol), DMAP (2.12 g, 17.36 mmol), and Et3N (36.31 ml, 260.52 mmol) were added, followed by stirring at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was extracted with H2O and EA, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and then the residue was purified by column chromatography (EA:Hex=1:4), to give (S)-(4-benzylmorpholin-2-yl)methyl 4-methylbenzene sulfonate as a white solid (62.15 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][N:18]=1>>[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]3[CH3:11])=[CH:4][CH:3]=2)=[O:22])=[CH:19][N:18]=1
Reactant: COc1ccc(C(=O)O)cn1
Reactant: CN1C(=O)C(C)(C)c2ccc(N)cc21
Product: COc1ccc(C(=O)Nc2ccc3c(c2)N(C)C(=O)C3(C)C)cn1

Procedure:
Prepared in analogy to example 1b from 6-amino-1,3,3-trimethylindolin-2-one and 6-methoxynicotinic acid. The title compound was obtained as light yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29].[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:37][CH2:36][C:35]3[CH:38]=[CH:39][C:32]([O:31][CH3:30])=[CH:33][CH:34]=3)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29]
Reactant: COc1ccc(CN)cc1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1ccccc1)C(=O)N(c1c(Cl)cccc1Cl)C2
Product: COc1ccc(CNc2ncc3c(n2)N(c2ccccc2)C(=O)N(c2c(Cl)cccc2Cl)C3)cc1
Temperature: 100 °C
Yield: 100 %

Procedure:
A mixture of 56 mg (0.13 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one and 1 ml of 4-methoxybenzylamine was heated at 100° C. for 30 minutes, then cooled and partitioned between 30 ml of dichloromethane and 30 ml of 2M hydrochloric acid. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 68 mg (100%) of 3-(2,6-dichlorophenyl)-3,4-dihydro-7-(4-methoxybenzyl)amino-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one as a yellow solid of melting point 56° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]3[CH2:18][O:17][CH2:16]3)[CH:10]=2)=[CH:7][C:6]([C:19](O)=[O:20])=[CH:5][CH:4]=1.[CH3:22][O:23][C:24]([C:26]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25]>>[CH3:22][O:23][C:24]([C:26]1([NH:33][C:19]([C:6]2[CH:7]=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]4[CH2:18][O:17][CH2:16]4)[CH:10]=3)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:20])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)=[O:25]
Reactant: COC(=O)C1(N)CCCCCC1
Reactant: COc1ccc(C(=O)O)cc1-c1cccc(C2COC2)c1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(-c3cccc(C4COC4)c3)c2)CCCCCC1

Procedure:
The title compound was synthesized from 6-Methoxy-3′-oxetan-3-yl-biphenyl-3-carboxylic acid and 1-amino-cycloheptanecarboxylic acid methyl ester in analogy to example 126, step 4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9].S(Cl)([Cl:15])(=O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:11])[CH:4]([Cl:15])[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(=O)CC(=O)OC
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCCCC(=O)C(Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-oxo-heptanoic acid methyl ester (5.0 g, 31.6 mmol) in dry dichloromethane (80 mL) add sulfurylchloride (2.82 mL). Stir the reaction mixture at room temperature for 30 minutes then add water (20 mL) and the reaction mixture extracted five times with portions of 30 mL of dichloromethane. Wash the combined organic extracts with water, saturated aqueous solution of NaHCO3 and brine and then dry over MgSO4. Remove the solvent under reduced pressure to give 2-chloro-3-oxo-heptanoic acid methyl ester (6.0 g), which was used in the next step without further purification. To a solution of 2-chloro-3-oxo-heptanoic acid methyl ester (6.0 g, 31.1 mmol) in ethanol (50 mL) add 4-(trifluoromethyl) thiobenzamide (6.4 g, 31.2 mmol). Heat the reaction mixture to reflux overnight. Remove the solvent under reduced pressure and purify the residue by chromatography on silica gel (eluting with a gradient of n-heptane:ethyl acetate (100:1 to 60:1)) to give 4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-carboxylic acid methyl ester (7.4 g) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16])[C:5]([OH:7])=O)[CH3:2].[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH2:18][NH:17][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[F:16])=[C:20]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=1)#[N:24]
Reactant: N#Cc1ccc(CN)c(Oc2ccccc2)c1
Reactant: CCOC(C(=O)O)c1ccc(OC)cc1F
Product: CCOC(C(=O)NCc1ccc(C#N)cc1Oc1ccccc1)c1ccc(OC)cc1F

Procedure:
(RS)-Ethoxy-(2-fluoro-4-methoxy-phenyl)-acetic acid, described in example 63.1 was coupled with 4-aminomethyl-3-phenoxy-benzonitrile according to general procedure B to give (RS)-N-(4-cyano-2-phenoxy-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide. Colorless oil. MS 435.2 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[C:9]([Br:12])[C:5]2=[N:6][S:7][N:8]=[C:4]2[C:3]=1[Br:13].[CH3:14][CH:15]([CH2:17][CH2:18][CH2:19][CH:20]([CH3:37])[CH2:21][CH2:22][C:23](=O)[C:24](=O)[CH2:25][CH2:26][CH:27]([CH3:34])[CH2:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH3:16]>C(O)(=O)C>[Br:13][C:3]1[C:4]2[C:5](=[N:6][S:7][N:8]=2)[C:9]([Br:12])=[C:10]2[C:2]=1[N:1]=[C:24]([CH2:25][CH2:26][CH:27]([CH3:34])[CH2:28][CH2:29][CH2:30][CH:31]([CH3:32])[CH3:33])[C:23]([CH2:22][CH2:21][CH:20]([CH3:37])[CH2:19][CH2:18][CH2:17][CH:15]([CH3:16])[CH3:14])=[N:11]2
Reactant: CC(C)CCCC(C)CCC(=O)C(=O)CCC(C)CCCC(C)C
Reactant: Nc1c(N)c(Br)c2nsnc2c1Br
Solvent: CC(=O)O
Product: CC(C)CCCC(C)CCc1nc2c(Br)c3nsnc3c(Br)c2nc1CCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 71 h

Procedure:
5,6-Diamino-4,7-dibromobenzo[c][1,2,5]thiadiazole (0.224 g, 6.91×10−4 mol) was dissolved in acetic acid (40 ml). 2,6,13,17-Tetramethyloctadecane-9,10-dione (0.261 g, 7.71×10−4 mol) was added, and the reaction mixture was stirred for 71 h at room temperature under N2. After the solvent was evaporated, water was added, and the mixture was extracted with CHCl3. The combined organic layers were washed with water, aq. NaHCO3 and dried over Na2SO4. After the solvent was evaporated, the residue was chromatographed on silica gel with CHCl3 and further purified by size exclusion column chromatography (BioRad Bio-Beads SX-1 packed in THF, gravity flow). Yield=0.360 g (83% based on 0.224 g of 5,6-diamino-4,7-dibromobenzo[c][1,2,5]thiadiazole). 1H NMR (250 MHz, CDCl3): δ 3.01-3.22 (m, 4H, Ar—CH2), 1.11-2.09 (m, 20H, (CH3)2CHCH2 CH2CH2CH(CH3)CH2CH2Ar), 1.03 (d, 6H, J=6.5 Hz, —CH3), 0.88 (d, 12H, J=6.6 Hz, —CH3). CI MS m/z: 625.157 ((M+H)+) (calcd 625.158).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:17])[C:5]([C@H:8]([NH:10][S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9])=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].ClC1C=C(C=CC=1)C(OO)=O.[Cl:52][C:53]1[CH:62]=[C:61]([Cl:63])[CH:60]=[C:59](OS(C(F)(F)F)(=O)=O)[C:54]=1[C:55]([O:57][CH3:58])=[O:56].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:13]([S:11]([NH:10][C@@H:8]([C:5]1[N:6]=[CH:7][C:2]([C:59]2[CH:60]=[C:61]([Cl:63])[CH:62]=[C:53]([Cl:52])[C:54]=2[C:55]([O:57][CH3:58])=[O:56])=[CH:3][C:4]=1[F:17])[CH3:9])=[O:12])([CH3:16])([CH3:15])[CH3:14]
Reactant: C[C@@H](NS(=O)C(C)(C)C)c1ncc(Br)cc1F
Reactant: COC(=O)c1c(Cl)cc(Cl)cc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)cc(Cl)cc1-c1cnc([C@@H](C)NS(=O)C(C)(C)C)c(F)c1
Temperature: 90 °C

Procedure:
A mixture of N-[(1R)-1-(5-bromo-3-fluoropyridin-2-yl)ethyl]-2-methylpropane-2-sulfinamide (0.500 g, 1.55 mmol), bis(pinacolato)diboron (0.412 g, 1.62 mmol), potassium acetate (0.456 g, 4.64 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.030 g, 0.041 mmol) in 5 mL DMF was heated to 90° C. under N2 for 4 hours. Additional bis(pinacolato)diboron (0.295 g, 1.16 mmol) and 3-chloroperoxybenzoic acid (861 mg, 4.99 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.030 g, 0.041 mmol) were added to drive the reaction to completion. The reaction mixture was cooled to room temperature, and methyl 2,4-dichloro-6-{[(trifluoromethyl)sulfonyl]oxy}benzoate (0.546 g, 1.55 mmol), sodium carbonate (2M, 2.32 mL, 4.64 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]palladium (II) dichloride (0.003 g, 0.041 mmol) were added. The reaction mixture was heated to 90° C. 1.5 hours, then cooled to room temperature and partitioned between ethyl acetate and water. The organic extract was washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0–30% ethyl acetate in hexanes to provide methyl 2-(6-{(1R)-1-[(tert-butylsulfinyl)amino]-ethyl}-5-fluoropyridin-3-yl)-4,6-dichlorobenzoate that gave proton NMR spectra consistent with theory.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[O:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11](Cl)=[O:12]>C(Cl)(Cl)Cl>[N:1]1([C:11]([C@H:7]2[CH2:8][CH2:9][CH2:10][O:6]2)=[O:12])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(Cl)[C@H]1CCCO1
Reactant: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Product: O=C([C@H]1CCCO1)n1ccnc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
21.8 g (32 mmol) imidazole are placed in 400 ml chloroform and cooled to 0° C. 21.3 g (15.0 mol) (R)-tetrahydrofuran-2-carbonyl chloride are added dropwise, then the mixture is stirred for 1.5 hours at ambient temperature. After cooling again to 0° C. the reaction mixture is extracted with semisaturated sodium chloride solution. The organic phase is dried and evaporated to dryness. Yield: 24.0 g
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([C:13]2[N:14]=[CH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=O)[C:5]=1[NH2:23].C([O-])(C)=O.[NH4+]>CC(O)=O>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[C:13]([C:11]2[NH:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]=3[N:23]=2)[N:14]=1
Reactant: COC(=O)c1cccc(NC(=O)c2cc3ccccc3cn2)c1N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=C(O)c1cccc2[nH]c(-c3cc4ccccc4cn3)nc12
Yield: 55 %

Procedure:
To a solution of the above crude product 2-amino-3-[(isoquinoline-3-carbonyl)-amino]-benzoic acid methyl ester in AcOH (25 mL) was added AcONH4 (16 g). The reaction mixture was refluxed for 3 h. After removal of AcOH under vacuum, the reaction mixture was washed with water (150 mL) The crude solid product 2-isoquinolin-3-yl-1H-benzoimidazole-4-carboxylic acid methyl ester was collected after filtration. LCMS: 304 (M+1)+. This product was hydrolyzed according to the general procedure C to provide 2-isoquinolin-3-yl-1H-benzoimidazole-4-carboxylic acid (1.6 g, 55% yield over three steps). LCMS: 290 (M+1)+.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]2[C:11]([OH:12])=[C:10]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[C:9](=[O:20])[N:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=3)[C:7]2=[O:30])[CH2:3][CH2:2]1.C1(CCN2C(=O)CC(=O)N(C3C=CC=C([N+]([O-])=O)C=3)C2=O)CC1.C(N(C(C)C)CC)(C)C.N(CC(OCC)=O)=C=O>ClCCl>[CH:1]1([CH2:4][CH2:5][N:6]2[C:11](=[O:12])[C:10]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])=[C:9]([OH:20])[N:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=3)[C:7]2=[O:30])[CH2:3][CH2:2]1
Reactant: O=C(O)CNC(=O)c1c(O)n(CCC2CC2)c(=O)n(-c2cccc([N+](=O)[O-])c2)c1=O
Agent: CCOC(=O)CN=C=O
Agent: O=C1CC(=O)N(c2cccc([N+](=O)[O-])c2)C(=O)N1CCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1c(O)n(-c2cccc([N+](=O)[O-])c2)c(=O)n(CCC2CC2)c1=O
Reaction time: 8 h
Yield: 37 %

Procedure:
N-{[1-(2-Cyclopropylethyl)-6-hydroxy-3-(3-nitrophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine. A mixture 1-(2-cyclopropylethyl)-3-(3-nitrophenyl)-2,4,6(1H,3H,5H)-pyrimidinetrione (1.66 g, 5.23 mmole) and diisopropylethylamine (1.80 mL, 10.5 mmoles) in dichloromethane (80 mL) was treated with ethyl isocyanatoacetate (704 uL, 6.27 mmoles) and stirred overnight. The mixture was washed with 1 molar hydrochloric acid (×2), dried and evaporated. The residue was dissolved in ethanol (6 mL) and treated with 6 molar sodium hydroxide (5.0 mL). The mixture was stirred for 1 hour, acidified and extracted with ethyl acetate (×2), dried and evaporated. A solid was obtained from acetic acid-water, which was purified by trituration in boiling chloroform to give the title compound (800 mg, 37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.12 (br. s, 1 H), 10.03 (s, 1 H), 8.35 (s, 1 H), 8.32 (ddd, J=8.40, 1.64, 1.33 Hz, 1 H), 7.82-7.88 (m, 1 H), 7.79 (t, J=8.08 Hz, 1 H), 4.14 (d, J=5.81 Hz, 2 H), 3.88-3.97 (m, 2 H), 1.50 (q, J=7.16 Hz, 2 H), 0.66-0.76 (m, 1 H), 0.42 (ddd, J=7.96, 5.68, 4.04 Hz, 2 H), 0.05 (td, J=5.18, 4.29 Hz, 2 H).