Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5](=[O:10])[C:4]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:3]1.CCN(CC)CC.[F:24][C:25]([F:40])([F:39])[C:26]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:27]=1[C:28](Cl)=[O:29].O>ClCCl>[F:24][C:25]([F:39])([F:40])[C:26]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][C:27]=1[C:28]([N:14]1[CH2:13][CH2:12][N:11]([C:4]2[C:5](=[O:10])[N:6]([CH3:9])[C:7](=[O:8])[N:2]([CH3:1])[N:3]=2)[CH2:16][CH2:15]1)=[O:29]
Reactant: Cn1nc(N2CCNCC2)c(=O)n(C)c1=O
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cn1nc(N2CCN(C(=O)c3cc(C(F)(F)F)ccc3C(F)(F)F)CC2)c(=O)n(C)c1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
The compound 40 is prepared according to the synthesis method 2: 0.16 g (0.72 mmol) of derivative 12a is placed in 1 mL of dichloromethane in the presence of 0.15 mL (1.08 mmol) of NEt3 at 0° C. 0.2 g (0.72 mmol) of 2,5-bis-trifluoromethyl-benzoyl chloride is added. This mixture is stirred for 15 min at 0° C., and then for 1 h at room temperature. The medium is taken up with water and extracted with CH2Cl2. After drying on MgSO4, the organic phase is concentrated. The obtained residue is purified by flash chromatography on silica (CH2Cl2-AcOEt: 90-10). 0.24 g of white crystals are isolated (yield: 71%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][C:7]=3[CH:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.[SiH](CC)(CC)[CH2:35]C.B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:35][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][C:7]=3[CH:8]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:17]=3)[O:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc2c(c1)C(c1ccc(OCCN3CCCCC3)cc1)Oc1cc(O)ccc1-2
Reactant: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc2c(c1)OC(c1ccc(OCCN3CCCCC3)cc1)c1cc(C(C)=O)ccc1-2
Temperature: -78 °C

Procedure:
The compound from Step G (1.66 g, 3.2 mmol) was dissolved in CH2Cl2 (90 mL) and cooled to −78° C. Et3SiH (3.1 ml, 19.2 mmol) and BF3-Et2O (2.6 ml, 19.2 mmol) were added slowly under Ar. The mixture was stirred at −78° C., then at room temperature overnight. Saturated NaHCO3 (100 ml) was added and the mixture extracted three times with ethyl acetate (150 ml). The combined organic layer was washed with brine (100 ml) and dried over MgSO4. The solvent was removed and the crude product was chromatographed on silica gel with 7% CH3OH/CH2Cl2 to yield a fraction containing a mixture of the title compound along with side products and a fraction containing 0.52 g (32%) of the title compound. 1H-NMR (400 MHz, CDCl3) δH 1.42 (2H, m, NCH2CH2CH2), 1.59 (4H, m, NCH2CH2CH2), 2.50 (7H, m, NCH2CH2CH2 and COCH3), 2.76 (2H, m, NCH2CH2O), 3.77 (3H, s, OCH3), 4.08 (2H, m, NCH2CH2O), 6.14 (1H, s, Ph2CHO), 6.50 (1H, s, ArH), 6.61 (1H, d, ArH), 6.86 (2H, d, ArH), 7.22 (2H, d, ArH), 7.45 (1H, s, ArH), 7.66 (1H, d, ArH), 7.72 (1H, d, ArH), 7.93 (1H, d, ArH).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C.O>C(#N)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([S:22](=[O:24])(=[O:23])[NH2:25])=[CH:20][CH:21]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(CNC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 85.5 %

Procedure:
A solution of 4-nitrobenzoylchloride (1.85 g, 1 eq.) in acetonitrile (20 ml) was added to a solution of 4-aminomethyl-benzenesulfonamide hydrochloride (4.44 g, 2 eq.) and triethylamine (2.78 ml, 2 eq.) in acetonitrile (40 ml) at 0° C. under inert atmosphere. After the addition was completed, the mixture was warmed to rt and stirred for 3 d. Water was added and the mixture was concentrated under reduced pressure. The resulting precipitate was filtered off and washed with water and methanol to yield 2.86 g (85%) of 4-nitro-N-(4-sulfamoylbenzyl)-benzamide.
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)[CH:3]=1.C(S[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:22]=[CH:23][C:24]2[N:25]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=2)[CH:26]=1)C.[S:34]([O-:38])([O-])(=[O:36])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:34]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:22]=[CH:23][C:24]2[N:25]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=2)[CH:26]=1)(=[O:38])=[O:36])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1ccccc1-c1ccc2nc(C(F)(F)F)cn2c1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1ccccc1-c1ccc2nc(C(F)(F)F)cn2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
220 mg of 3-chloroperbenzoic acid (purity of 65% or more) was added to a mixture of 134 mg of 6-(2-ethylsulfanylphenyl)-2-trifluoromethylimidazo[1,2-a]pyridine and 4 ml of chloroform, under ice cooling, and the mixture was stirred at room temperature for 4 hours. A 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. 93 mg of 6-(2-ethylsulfonylphenyl)-2-trifluoromethylimidazo[1,2-a]pyridine (Compound of Present Invention 27) was obtained.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)[N:9]=2)[N:6]=[CH:5][C:4]=1[C:38]([O:40]CC)=[O:39].[OH-:45].[Li+].Cl.[O:48]1CCOCC1>>[C:3]([OH:48])([C:2]([F:44])([F:43])[F:1])=[O:45].[F:44][C:2]([F:1])([F:43])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=4)=[CH:26][CH:27]=3)[N:9]=2)[N:6]=[CH:5][C:4]=1[C:38]([OH:40])=[O:39]
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(-c4ccc(C(F)(F)F)cc4)cc3)n2)c1C(F)(F)F
Reactant: [OH-]
Reactant: C1COCCO1
Agent: Cl
Agent: [Li+]
Product: O=C(O)C(F)(F)F
Product: O=C(O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(-c4ccc(C(F)(F)F)cc4)cc3)n2)c1C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of the title compound from Example 2 Step B (ca. 0.073 mmol) in 1,4-dioxane (0.5 mL) was added lithium hydroxide (0.50 mL, 2.0 M in water, 1.00 mmol), and the resulting mixture was stirred at 50° C. After 2 h, the reaction mixture was rendered acidic by addition of aqueous hydrochloric acid, then was diluted with 1,4-dioxane and passed through a 0.45 micron syringe filter. Purification by reverse phase HPLC (50 to 100% acetonitrile in water, each with 0.1% v/v TFA) provided the title compound: LCMS m/z 584.1 [M+H]+; 1H NMR (500 MHz, d6-DMSO) δ 8.30 (s, 1H), 8.18 (d, J=8.0 Hz, 1H), 8.14 (t, J=8.0 Hz, 1H), 7.88 (d, J=8.0 Hz, 2H), 7.80 (d, J=8.0 Hz, 2H), 7.75-7.71 (m, 4H), 7.56 (d, J=8.0 Hz, 2H), 7.46-7.43 (m, 1H), 7.30 (d, J=7.5 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 5.32 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:24])=[C:8]2[CH:14]=[CH:13][N:12](CC3C=CC(OC)=CC=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]>C(O)(C(F)(F)F)=O.OS(O)(=O)=O.C1(OC)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:24])=[C:8]2[CH:14]=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(ccn2Cc2ccc(OC)cc2)c1Cl
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCOC(=O)c1cnc2[nH]ccc2c1Cl
Reaction time: 3 h
Yield: 46.3 %

Procedure:
To a solution of 4-chloro-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (prepared as described in J. Heterocycl. Chem. 1972, 235 and Bioorg. Med. Chem. Lett. 2003, 2405) (3.48 g, 10 mmol) in TFA (20 mL), conc. H2SO4 (1.5 mL) and anisole (3 mL) were added at room temperature. The resulting solution was stirred at this temperature for 3 hours and then basified slowly by addition of ice-cold aqueous NaHCO3. The aqueous solution was extracted with ethyl acetate and the combined organic layers were dried (Na2SO4) and concentrated. The residue was filtered and washed with n-hexanes to give a yellow solid (1.04 g, 46%). LC-MS (LCT2) m/z 226 [M+H+], Rt 6.22 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([OH:17])=O)[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:60]1([C:66]([NH2:69])([CH3:68])[CH3:67])[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:69][C:66]([CH3:68])([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[CH3:67])=[O:17])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CC[C@H](C(=O)NC(C)(C)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the resulting mixture was stirred at room temperature for 15 minutes. 2-Phenyl-2-propanamine (71 mg, 0.53 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic layer solution was concentrated, and the formed solid was recrystallized from CH3CN to afford the title compound (222 mg) as a light yellow solid. LC-MS (ES) m/z=473 [M+H]+.
Reaction SMILES: [Li+].C[CH:3]([N-:5]C(C)C)C.CCCCCCC.C1COCC1.[CH2:21]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:32]1[C:44](O)=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CI>C1COCC1>[C:3]([C:32]1([CH3:44])[CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:38])[CH2:35][CH2:36][N:31]1[C:29]([O:28][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:30])#[N:5]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)O)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C)(C#N)C1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
To a cooled (−75° C.) solution of LDA 2M in heptane/THF (1.5 eq) in THF, a solution of 1-[(benzyloxy)carbonyl]-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (Bigge et al, Tetrahedron Lett. 1989, 30: 5193) in THF was added dropwise at −75° C. After being stirred for 1 hour at −75° C., MeI (1.5 eq) was added. After 2 hours at −75° C. the reaction mixture was left warming to r.t., evaporated, diluted with AcOEt, washed with NaHCO3, water, brine and dried over Na2SO4. The crude was purified by flash chromatography on silica gel (petroleum ether/AcOEt, 85:15) to obtain the title compound.
Reaction SMILES: [CH2:1]([Li])CCC.[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:9]=2[O:8][CH2:7]1.CI.[OH-].[Na+]>O1CCCC1.O>[CH3:1][C:14]1[C:9]2[O:8][CH2:7][O:6][C:10]=2[CH:11]=[CH:12][C:13]=1[C:15]([OH:17])=[O:16]
Reactant: [Li]CCCC
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)ccc2c1OCO2
Temperature: -78 °C
Reaction time: 7 h

Procedure:
A solution of n-butyllithium (5.1 ml of a 2.5M solution in hexanes) was added to a stirred suspension of 1,3-benzodioxole-5-carboxylic acid (1.0 g) in anhydrous tetrahydrofuran under an inert atmosphere keeping the temperature-below -60° C. The mixture was then stirred at -78° C. for 7 hours and methyl iodide (0.50 g) added and the mixture stirred at room temperature for 18 hours. The mixture was then treated with water and 2N sodium hydroxide. The aqueous phase was washed with ether, acidified and filtered. The solid was washed with hexane and dried to give 4-methyl-1,3-benzodioxole-5-carboxylic acid as a cream solid (0.91 g), m.p. 217°-219° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)[CH3:21]>>[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]3[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[O:6][C:7]=3[CH3:19])=[CH:13][CH:14]=2)=[CH:25][CH:24]=1)[CH3:21]
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Reactant: CCOc1ccc(B(O)O)cc1
Product: CCOc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)cc1

Procedure:
Compound (98) was prepared from compound (20) and (4-ethoxyphenyl)-boronic acid by an adapting the procedure of Example 24A. LC/MS System B; Rt=1.86 mins, m/z (ES−) 351 (M−H for C21H20O5).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:4][N:3]=1.[O:13]1[C:21]2[CH:20]=[C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])[N:18]=[CH:17][C:16]=2[N:15]=[CH:14]1>>[CH:10]1([CH2:9][O:8][C:5]2[CH:4]=[N:3][C:2]([C:14]3[O:13][C:21]4[CH:20]=[C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH3:25])[N:18]=[CH:17][C:16]=4[N:15]=3)=[N:7][CH:6]=2)[CH2:12][CH2:11]1
Reactant: C[C@@H](COc1cc2ocnc2cn1)NC(=O)OC(C)(C)C
Reactant: Clc1ncc(OCC2CC2)cn1
Product: C[C@@H](COc1cc2oc(-c3ncc(OCC4CC4)cn3)nc2cn1)NC(=O)OC(C)(C)C

Procedure:
Using 2-chloro-5-(cyclopropylmethoxy)pyrimidine and tert-butyl ((2S)-1-([1,3]oxazolo[4,5-c]pyridin-6-yloxy)propan-2-yl)carbamate, and in the same manner as in Step B of Example 22, the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14]C(C)(C)C)=[O:13])=[CH:10][N:9]=1.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:20]=[CH:19][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2F)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(-c2ccccc2F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To tert-butyl 6-(2-fluorophenyl)nicotinate (479 mg, 1.75 mmol) in DCM (12 mL) at 0° C. was added TFA (2.5 mL). After stirring at rt overnight, toluene was added (10 mL) and the solvent removed to give a white solid (375 mg, 98%), 6-(2-fluorophenyl)nicotinic acid. LC/MS (M+H)=218.0 observed, 218.06 expected.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7]C(O)=O)=[CH:3][CH:2]=1.[Cl:17][C:18]1[C:23]2[N:24]=[C:25]([CH3:27])[S:26][C:22]=2[CH:21]=[CH:20][C:19]=1[NH2:28].C(N(CC)CC)C.S(Cl)(Cl)=[O:37]>C1COCC1>[Cl:17][C:18]1[C:23]2[N:24]=[C:25]([CH3:27])[S:26][C:22]=2[CH:21]=[CH:20][C:19]=1[NH:28][C:7]([C:4]1[CH:3]=[CH:2][C:1]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=1)=[O:37]
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc2c(Cl)c(NC(=O)c3ccc(-c4ccccc4)cc3)ccc2s1
Yield: 60 %

Procedure:
Reaction of 4-biphenylacetic acid (160 mg, 0.76 mmol) in thionyl chloride (1 mL) then with 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in presence of triethylamine (0.5 mL) in THF (2 mL) according to method B gave biphenyl-4-carboxylic acid (4-chloro-2-methyl-benzothiazol-5-yl)-amide (60 mg, 0.15 mmol, 60% yield) as a pink powder after purification by chromatography on silica gel (eluent: DCM).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:28][C@@H:29]1[CH2:38][CH2:37][C:36]2[C:31](=[C:32]([N:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]3)[CH:33]=[CH:34][C:35]=2[CH2:39][CH3:40])[CH2:30]1>CN(C)C=O>[NH3:4].[CH2:39]([C:35]1[CH:34]=[CH:33][C:32]([N:41]2[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]2)=[C:31]2[C:36]=1[CH2:37][CH2:38][C@@H:29]([NH:28][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:15][CH:14]=1)[CH2:30]2)[CH3:40]
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: CCc1ccc(N2CCN(C)CC2)c2c1CC[C@@H](N)C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCc1ccc(N2CCN(C)CC2)c2c1CC[C@@H](NC(=O)c1ccc(N3CCOCC3)cc1)C2
Product: N
Temperature: 75 °C
Reaction time: 1 h
Yield: 118.5 %

Procedure:
4-Morpholinobenzoic acid (64 mg, 0.31 mmol) was dissolved in dry N,N-dimethylformarnide (1 mL) and 1,1′-carbonyldiimidazole (52 mg, 0.32 mmol) was added. The reaction mixture was stirred at 75° C. for 1 h and cooled to room temperature. A solution of (R)-2-amino-5-ethyl-8-(4-metylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (80 mg, 0.29 mmol) in dry N,N-dimethylformamide (3 mL) was added and the reaction mixture was stirred at room temperature for 14 h. The solvent was evaporated and the residue was dried in vacuo. The crude product was purified by preparative TLC on silica using chloroform/methanol/conc. NH3 (95:5:0.5) as the eluent which gave 85 mg (59% yield) of the title compound as a white solid: mp 234° C. (dec); EIMS (70 eV) m/z (relative intensity) 462 (27, M+); [α]21D−48° (c 0.09, chloroform).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)[CH2:6]1)=[O:4].Cl>C1COCC1.[Li+].[OH-]>[O:10]=[C:8]1[N:7]([CH2:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:9]1
Reactant: COC(=O)C1CC(=O)N(CCCn2cccc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C1CC(=O)N(CCCn2cccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cooled solution (0° C.) of 5-Oxo-1-(3-pyrrol-1-yl-propyl)-pyrrolidine-3-carboxylic acid methyl ester in THF, 0.2M LiOH is added and RM is stirred for 3 hours gradually warming to room temperature. Reaction mixture is acidified with 1N HCl and product extracted into ethyl acetate. The organic phase is washed with brine, dried over magnesium sulphate and the solvent evaporated in vacuo to yield 5-Oxo-1-(3-pyrrol-1-yl-propyl)-pyrrolidine-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:13]([NH2:15])[CH3:14]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:15][CH2:13][CH3:14])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: CCN
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Product: CCNc1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
In DMF was dissolved 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then an aqueous solution of 338 mg (7.5 mmol) of ethylamine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/6) to give 524 mg (yield: 72.0%) of the title compound.
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([OH:24])=O.[NH2:25][C@H:26]([C:30]([NH:32][CH:33]([CH:42]([OH:45])[CH2:43][F:44])[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:31])[CH:27]([CH3:29])[CH3:28]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([NH:25][C@H:26]([C:30]([NH:32][CH:33]([CH:42]([OH:45])[CH2:43][F:44])[CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[O:31])[CH:27]([CH3:28])[CH3:29])=[O:24]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF

Procedure:
DMAP (95 mg, 0.78 mmol) and EDAC (200 mg, 1.04 mmol) were added as solid to a solution of 1-methylindole-2-carboxylic acid (130 mg, 0.74 mmol) and N-(valinyl)-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (227 mg, 0.74 mmol) in methylene chloride (5 mL), and the resultant solution was stirred for 1 hour under a nitrogen atmosphere at 0° C. and then 4 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous solution was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×) and brine, dried over sodium sulfate, and concentrated to give a foam. The foam was triturated with ether to yield the title product as a slightly brown solid (224 mg, 65%). TLC(methanol/methylene chloride, 1:9): Rf =0.46.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([CH:18]2[CH2:20][CH2:19]2)=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([Br:17])[CH:10]=2)=[O:5])C.C[Al](C)C.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1.CCOC(C)=O.C1CCCCC1>C1(C)C=CC=CC=1>[Br:17][C:11]1[CH:10]=[C:9]2[C:14]([C:15]([CH3:16])=[C:6]([C:4]([NH:31][CH2:30][C:29]3[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=3)=[O:5])[C:7]([CH:18]3[CH2:19][CH2:20]3)=[N:8]2)=[CH:13][CH:12]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1c(C2CC2)nc2cc(Br)ccc2c1C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)NCc2ccc(F)cc2)c(C2CC2)nc2cc(Br)ccc12
Temperature: 120 °C
Yield: 73.6 %

Procedure:
To a stirred solution of 1.0 g (2.99 mmol) 7-bromo-2-cyclopropyl-4-methylquinoline-3-carboxylic acid ethyl ester in toluene (10 ml) were added 10.5 ml (2M solution in toluene, 20.9 mmol) Me3Al at RT followed by the addition of 3.74 g (29.9 mmol) 4-fluorobenzylamine. The reaction mixture was heated at 120° C. for 16 h. Then the reaction was quenched with water (15 ml) and extracted with EtOAc (3×30 ml). The combined organic layers were washed with 2N aq. HCl and brine, dried over MgSO4 and concentrated in vacuum. After CC (EtOAc/cyclohexane 1:2) of the residue, 900 mg (2.2 mmol, 73%) 7-Bromo-2-cyclopropyl-N-[(4-fluorophenyl)-methyl]-4-methyl-quinoline-3-carboxylic acid amide (example 28) were obtained. MS: m/z 413.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.I[CH3:23]>>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH3:23])=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Reactant: CI
Product: COC(=O)c1nc2n(c1C)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
Methyl 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (1 g) was reacted with iodomethane similar to as described in example 8 with non-critical modifications to produce methyl 10-bromo-9-fluoro-3-methyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. This crude intermediate (0.3 g) was reacted via General Procedure L to provide