Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.[CH3:16][N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH2:22][CH2:23][NH2:24].[Cl-].[NH4+]>>[CH3:15][C:5]1[N:4]=[N:3][C:2]([NH:24][CH2:23][CH2:22][CH:18]2[CH2:19][CH2:20][CH2:21][N:17]2[CH3:16])=[C:7]2[C:6]=1[N:14]1[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]1)=[CH:8]2
Reactant: CN1CCCC1CCN
Reactant: Cc1nnc(Cl)c2cc3ccccn3c12
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1nnc(NCCC2CCCN2C)c2cc3ccccn3c12

Procedure:
Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine, ten equivalents of 2-(1-methyl-2-pyrrolidinyl)ethylamine and one equivalent of ammonium chloride under reflux in a nitrogen atmosphere for 3 to 4 hours gave the title compound as the free base after removal of excess amine in vacuo and treatment of the residue with boiling ethyl acetate. The solid collected upon filtration was converted to the hydrochloride salt (methanol/ethereal HCl/ether), mp 169° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]([N:35]3[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]3)=[N:33][CH:34]=2)O1>>[C:44]([O:43][C:41]([N:38]1[CH2:39][CH2:40][N:35]([C:32]2[N:33]=[CH:34][C:29]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]4=[O:20])=[CH:30][CH:31]=2)[CH2:36][CH2:37]1)=[O:42])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)ccn2c1=O

Procedure:
Methyl 8-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (159.9 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded quantitatively the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[C:12]2[C:28]1[CH:33]=[N:32][CH:31]=[C:30](Cl)[N:29]=1.[NH:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=1)(=[O:19])=[O:20])[CH:13]=[C:12]2[C:28]1[N:29]=[C:30]([N:35]2[CH2:36][CH2:37][CH:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:39][CH2:40]2)[CH:31]=[N:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(Cl)n3)c3cc(-c4c(F)cccc4Cl)ccc32)cc1
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(N4CCC(NC(=O)OC(C)(C)C)CC4)n3)c3cc(-c4c(F)cccc4Cl)ccc32)cc1
Reaction time: 1 h
Yield: 70.5 %

Procedure:
A slurry of 5-(2-chloro-6-fluorophenyl)-3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indole (Ref, 0.200 g, 0.390 mmol) and tert-butyl piperidin-4-ylcarbamate (Combi-blocks Inc., 0.313 g, 1.561 mmol) in 2 mL DMSO in a sealed tube was heated to 130° C. The solids dissolved and the reaction became a yellow solution. After 1 h, reaction was complete by LCMS. The reaction was cooled and partitioned between water and EtOAc. The organic layer was washed with water once, satd NaHCO3 once, satd NaCl once, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was suspended in MeOH and filtered, rinsing 1×1 mL MeOH. The solid was collected and dried in vacuo to give tert-butyl 1-(6-(5-(2-chloro-6-fluorophenyl)-1-tosyl-1H-indol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (0.186 g, 0.275 mmol, 70.5% yield) as a light yellow solid. MS (ESI, pos. ion) m/z: 676 (M+1).
Reaction SMILES: CS[C:3](=[NH:17])[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[CH3:18][NH:19][CH3:20]>C(N(CC)CC)C>[CH3:18][N:19]([CH3:20])[C:3]([NH2:17])=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Reactant: CNC
Solvent: CCN(CC)CC
Product: CN(C)C(N)=Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroidide (3.8 g), a 33% ethanolic solution of dimethylamine (5 ml) and triethylamine (25 ml) was heated at 80° C. for 8 hours. Triethylamine was removed by evaporation under reduced pressure and the residue treated with a mixture of ice and water to give 1,1-dimethyl-2-(2-morpholinophenyl)guanidine (m.p. 141°-143° C.) which was recrystallised from hexane.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[NH2:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.[Cl-].[Na+]>CN(C)C=O>[Si:6]([O:21][C:17]1[CH:16]=[C:15]([NH2:14])[CH:20]=[CH:19][CH:18]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1cccc(O)c1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(N)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
6.81 g (100 mmol) of imidazole and 9.04 g (60 mmol) of tert-butyl-dimethylsilyl chloride are added to a solution of 5.46 g (50 mmol) of 3-aminophenol in 13.5 ml of N,N-dimethylformamide. The resulting reaction mixture is stirred at room temperature for 12 h. After addition of a saturated aqueous sodium chloride solution, the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulphate. The crude product obtained after removal of the solvent by distillation is purified by flash chromatography. 7.62 g (34 mmol, 68%) of the desired product are obtained.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:7]1
Reactant: C[C@H]1CN(c2ccccn2)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CN(c2ccccn2)CCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of (S)-tert-butyl 2-methyl-4-(pyridin-2-yl)piperazine-1-carboxylate (5.2 g, 18.75 mmol,) in dichloromethane (30 ml) was added trifluoroacetic acid (5 ml). After stirring overnight at room temperature, the pH was adjusted to 8 with an aqueous sodium carbonate solution, extracted with dichloromethane (3×150 ml), dried over anhydrous magnesium sulfate and concentrated under vacuum to afford (S)-3-methyl-1-(pyridin-2-yl)piperazine as yellow oil (3.1 g, 93%).
Reaction SMILES: C([O:5][C:6](=[O:45])[CH:7]([NH:20][C:21]([C:23]1[CH:24]=[N:25][N:26]2[C:31]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[C:30]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH:29]=[N:28][C:27]=12)=[O:22])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C(C)(C)C)=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>O>[CH:32]1([C:31]2[N:26]3[N:25]=[CH:24][C:23]([C:21]([NH:20][CH:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=4)[C:6]([OH:45])=[O:5])=[O:22])=[C:27]3[N:28]=[CH:29][C:30]=2[C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)c1cnn2c(C3CCCCC3)c(-c3ccc(F)cc3)cnc12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(NC(Cc1ccc(O)cc1)C(=O)O)c1cnn2c(C3CCCCC3)c(-c3ccc(F)cc3)cnc12
Yield: 45 %

Procedure:
A sample of crude 3-(4-tert-butoxy-phenyl)-2-{[7-cyclohexyl-6-(4-fluoro-phenyl)-pyrazolo[1,5-α]pyrimidine-3-carbonyl]-amino}-propionic acid tert-butyl ester was treated with 1 mL of 95:5 trifluoroacetic acid (TFA): H2O and the resulting solution was stirred at rt for 1 h. Then the reaction mixture was quenched with 2 mL of 1:1 acetonitrile:water, concentrated, and the residue was purified via reverse-phase chromatography to afford (after lyophilization)10 mg (45% yield over two steps) of desired 2-{[7-cyclohexyl-6-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonyl]-amino}-3-(4-hydroxy-phenyl)-propionic acid (505) as a solid as indicated by 1H NMR; LC-MS calcd. for C28H27FN4O4 [M++H]+: 503.2; found: 503.2.
Reaction SMILES: C(OC(O[CH2:8][CH3:9])CBr)C.COCCOC.C(=O)([O-])O.[Na+].[N:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[N:22]=1>Br.O>[N:21]1[N:22]2[CH:9]=[CH:8][N:27]=[C:23]2[N:24]=[CH:25][CH:26]=1
Reactant: CCOC(CBr)OCC
Reactant: Nc1nccnn1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: c1cnn2ccnc2n1
Temperature: 80 °C
Reaction time: 20 h
Yield: 4.7 %

Procedure:
A stirred mixture of bromoacetaldehyde diethyl acetal (8.88 ml, 57.24 mmol) in concentrated hydrobromic acid (1.7 ml) and water (1.7 ml) was heated at reflux for 20 min, then poured into 1,2-dimethoxyethane (12.5 ml). The solution was neutralised to pH 7 with solid sodium hydrogencarbonate, then filtered. To the filtrate was added [1,2,4]triazin-3-ylamine (5.00 g, 52.03 mmol) and neutralised again with solid sodium hydrogencarbonate. The mixture was stirred at 80° C. for 20 h. After allowing to cool, silica gel was added to the mixture, the solvent was removed in vacuo and the residue was purified by chromatography (silica gel 5% MeOH/CH2Cl2) to give 0.292 g (5%) of the title compound: 1H NMR (360 MHz, DMSO-d6) δ 8.01 (1H, d, J 1.4 Hz), 8.38 (1H, d, J 1.4 Hz), 8.59 (1H, d, J 2.1 Hz), 8.68 (1H, d, J 1.8 Hz); MS (ES+) m/z 121 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH:15]1[CH2:18][CH2:17][CH2:16]1)[C:12](=[O:14])[CH3:13])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:50][C:51]1[CH:62]=[CH:61][C:54]2[N:55]=[C:56]([CH:58]([NH2:60])[CH3:59])[NH:57][C:53]=2[CH:52]=1.ClCl>O1CCCC1.C(Cl)Cl.C(O)C>[Cl:50][C:51]1[CH:62]=[CH:61][C:54]2[NH:55][C:56]([CH:58]([NH:60][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]([CH:15]4[CH2:18][CH2:17][CH2:16]4)[C:12](=[O:14])[CH3:13])=[C:2]([CH3:1])[CH:3]=3)[CH3:59])=[N:57][C:53]=2[CH:52]=1
Reactant: CC(N)c1nc2ccc(Cl)cc2[nH]1
Reactant: CC(=O)N(c1ccc(C(=O)O)cc1C)C1CCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(c1ccc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)cc1C)C1CCC1

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(N-cyclobutyl-N-acetylamino)benzoic acid, TBTU, diisopropylethylamine, and 1-(5-chlorobenzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: quantitative; Rf value: 0.50 (silica gel; methylene chloride/ethanol=9:1); C23H25ClN4O2 (424.93); mass spectrum: (M+H)+=425/427 (chlorine isotope).
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH2:8]O)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29]C(Br)(Br)Br>C1COCC1>[Br:29][CH2:8][C:7]1[CH:6]=[CH:5][S:4][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1sccc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1sccc1CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 110.7 %

Procedure:
11.7 g (84.07 mmol) of 2-cyano-3-hydroxymethylthiophene were dissolved together with 24.1 g (91.87 mmol) of triphenylphosphine in 100 ml of THF at room temperature and, while cooling (ice bath), 30.47 g (91.87 mmol) of tetrabromomethane were added in portions. Stirring at room temperature for 3 hours was followed by concentration under reduced pressure and purification by chromatography on silica gel (methylene chloride/petroleum ether) to result in 18.8 g of pale yellow crystalline product still containing petroleum ether.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1.[CH3:18][C:19]12[CH2:26][C:23]([CH3:27])([CH2:24][CH2:25]1)[C:22](=[O:28])[O:21][C:20]2=O>>[N:17]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]2[C:22](=[O:28])[C:23]3([CH3:27])[CH2:26][C:19]([CH3:18])([CH2:25][CH2:24]3)[C:20]2=[O:21])[CH2:11][CH2:10]1
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Reactant: CC12CCC(C)(C1)C(=O)OC2=O
Product: CC12CCC(C)(C1)C(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O
Yield: 20.4 %

Procedure:
Following substantially the procedure of Example 1, 4.2 g (17.8 mmol) of 1-(4-aminobutyl)-4-(2-pyrimidinyl) piperazine was reacted with 2.99 g (17.8 mmol) of 1,5-dimethyl-3-oxabicyclo[3.2.1]octan-2,4-dione. The product was chromatographed on silica gel, eluting with dichloromethane/methanol (96:4), to give 1.4 g (21% yield) of the title compound.
Reaction SMILES: ClC1C=CC(N(CC)C([C@@H]2C3C(=CC=CC=3)N([C:21]([C:23]3[O:27][N:26]=[C:25]([CH3:28])[CH:24]=3)=[O:22])[C@@H](C)C2)=O)=CC=1.FC(F)(F)C1C=CC(C([Cl:40])=O)=CC=1.CC1C=C(C(O)=O)ON=1.C(Cl)(=O)C(Cl)=O.[OH-].[Li+].C(OC(C1ON=C(C)C=1)=O)C>C(Cl)Cl.CN(C)C=O>[CH3:28][C:25]1[CH:24]=[C:23]([C:21]([Cl:40])=[O:22])[O:27][N:26]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CCN(C(=O)[C@H]1C[C@H](C)N(C(=O)c2cc(C)no2)c2ccccc21)c1ccc(Cl)cc1
Agent: CCOC(=O)c1cc(C)no1
Agent: Cc1cc(C(=O)O)on1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(=O)Cl)on1

Procedure:
(±)-trans-2-Methyl-1-(3-methyl-isoxazole-5-carbonyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide was made following general procedure A, substituting 3-methyl-isoxazole-5-carbonyl chloride for 4-trifluoromethyl-benzoyl chloride. 3-Methyl-isoxazole-5-carbonyl chloride was prepared by reaction of the preformed 3-methyl-isoxazole-5-carboxylic acid with oxalyl chloride and dimethylformamide in methylene chloride. In addition, only 1.2 equivalents of lithium hydroxide were used in the ester hydrolysis step. The crude 2-methyl-1-(3-methyl-isoxazole-5-carbonyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide was isolated as a mixture of cis and trans isomers. Purification by silica gel chromatography (dichloromethane/methanol gradient: 99.5/0.5->99/1) yielded (±)-trans-methyl-1-(3-methyl-isoxazole-5-carbonyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide (24%). 1H-NMR (CDCl3) δ: 1.02 (t, 3H), 1.13 (d, 3H), 1.40-1.50 (m, 1H), 2.25 (s, 3H), 2.70-2.80 (m, 1H), 3.40-3.52 (m, 1H), 3.80 (q, 2H), 4.95-5.10 (m, 1H), 6.35 (d, 1H), 6.42 (s, 1H), 6.70 (d, 1H), 6.90 (t, 1H), 7.00 (t, 1H), 7.10 (d, 2H), 7.40 (d, 2H). MS m/z: 438/440 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:37][CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:37][CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3coc(-c4ccccc4)n3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3coc(-c4ccccc4)n3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(2-phenyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.O[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2
Reactant: OCc1cccnc1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCc1cccnc1
Yield: 20.7 %

Procedure:
Using an analogous procedure to that described in Example 20, 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g, 0.5 mol), (prepared as described in Example 4), was reacted with 3-(hydroxymethyl)pyridine (60 μl, 0.9 mmol) to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyridylmethoxy)cinnoline (80 mg, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:28]=[CH:27][C:22]([C:23](OC)=[O:24])=[CH:21][C:20]=3[O:29][CH3:30])=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C[AlH]CC(C)C)C.[NH4+].[Cl-].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:28]=[CH:27][C:22]([CH2:23][OH:24])=[CH:21][C:20]=3[O:29][CH3:30])=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1ccc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)c(OC)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CO)ccc1NC(=O)c1nnn(Cc2ccc(Cl)c(Cl)c2)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-3-(methyloxy)benzoate (Example 17) (0.1 g, 0.2 mmol) in THF was added a 1M solution of DIBAL-H in THF (800 μL, 4 eq) and the reaction was stirred to room temperature for 2 hours. Solid NH4Cl was added followed by water and a 1N HCl solution. The aqueous phase was extracted with ether and AcOEt, dried over sodium sulphate and evaporated. After recrystallisation from acetonitrile, the title compound was obtained as a white solid (30 mg, 35%). HRMS calculated for C19H18Cl2N4O3 (M+H)+421.0834, found: 421.0834, Rt: 2.94 min. MP: 136° C.
Reaction SMILES: C([O:4][CH2:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[O:14])=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>O.CO>[OH:4][CH2:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[O:14])=[O:7]
Reactant: CC(=O)OCC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(CO)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
(S)-2-[[(S)-2-(Acetoxyacetyl)-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)-1-pyrrolidinecarboxamide (3.0 g) obtained in Example 1 was dissolved in water-methanol (1:1, 30 ml) and anhydrous potassium carbonate (1.14 g) were added under ice-cooling. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was concentrated. Methylene chloride was added and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in ethyl acetate, added with active charcoal, stirred at room temperature for 30 minutes, filtered and concentrated to give the title compound (0.81 g) (see Table 1).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]([C:31](=[O:47])[NH:32][CH2:33][CH2:34][N:35]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[CH3:36])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>>[C:27]([O:26][C:24](=[O:25])[NH:23][CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]([NH2:17])[C:31](=[O:47])[NH:32][CH2:33][CH2:34][N:35]([C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[CH3:36])([CH3:30])([CH3:28])[CH3:29]
Reactant: CN(CCNC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Solvent: C1CCNCC1
Product: CN(CCNC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.9 %

Procedure:
To a solution of compound G (2.3 g, 3.49 mmol) in EtOAC (50 ml) was added piperidine (0.34 mL, 3.49 mmol). The reaction mixture was stirred for 18 h at room temperature and then the solvents were removed in vacuo. The residue was dissolved in a minimum amount of EtOAc, and then was precipitated with Et2O. Precipitate was filtered off and washed with Et2O and dried to afford compound H (1.4 g, 94%). LC-MS [M+H] 437.6 (C22H36N4O5+H, calc: 437.5).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:23]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([OH:30])[CH2:25]2)=[C:22]2[C:17]([CH:18]=[CH:19][CH:20]=[N:21]2)=[C:16]([Cl:31])[CH:15]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)C>[Cl:31][C:16]1[CH:15]=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[C:23]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([OH:30])[CH2:25]2)=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1cc(Cl)c2cccnc2c1N1CCC[C@H](O)C1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cccnc2c1N1CCC[C@H](O)C1

Procedure:
A mixture of 6-bromo-9H-purine (0.0234 g, 0.118 mmol), (3S)-1-[7-(1-aminoethyl)-5-chloroquinolin-8-yl]piperidin-3-ol (0.018 g, 0.059 mmol), and N,N-diisopropylethylamine (0.0205 mL, 0.118 mmol) in ethanol (0.2 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the products. First peak retention time 1.482 minutes, LCMS calculated for C21H23ClN7O (M+H)+: m/z=424.2; Found: 424.0. Second peak retention time 1.583 minutes, LCMS calculated for C21H23ClN7O (M+H)+: m/z=424.2; Found: 424.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][NH:12][C:11](=O)[CH2:10][O:9]2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:9][CH2:10][CH2:11][NH:12][CH2:13]2)=[CH:4][C:3]=1[C:15]([F:18])([F:16])[F:17]
Reactant: O=C1CO[C@H](c2ccc(F)c(C(F)(F)F)c2)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1ccc([C@@H]2CNCCO2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
(R)-6-(4-Fluoro-3-(trifluoromethyl)phenyl)morpholin-3-one (486 mg, 1.85 mmol) was dissolved in 2 mL of THF and 10 mL of ether. To this solution under ice bath was added powder LiAlH4 (72 mg, 1.85 mmol). The mixture was stirred at 0° C. for 1 h and then at room temperature overnight. LC/MS indicated only the starting material. To this mixture was added LiAlH4 (1M) in THF (2 mL, 2 mmol) under ice bath. The mixture was stirred at room temperature for 15 h. LC/MS indicated complete consumption of the starting material and the formation of the desired MW (250, M+1). Under ice bath, 2.5 mL of water was added and the mixture was stirred for 30 min. The top solution was decanted and concentrated. The slurry residue was treated with methylene chloride and water. The organic layer was combined with the dichloromethane solution from the decanted top solution, washed and dried. Solvents were evaporated to give (R)-2-(4-fluoro-3-(trifluoromethyl)phenyl)morpholine as a pale green oil (460 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.74 (dd, J=12.13, 10.36 Hz, 1H) 2.86-2.96 (m, 1H) 2.96-3.03 (m, 1H) 3.08 (dd, J=12.38, 2.53 Hz, 1H) 3.80 (td, J=11.37, 3.03 Hz, 1H) 4.06 (dd, J=11.37, 3.03 Hz, 1H) 4.52 (dd, J=10.36, 2.53 Hz, 1H) 7.14-7.23 (m, 1H) 7.50-7.58 (m, 1H) 7.64 (dd, J=6.69, 2.15 Hz, 1H).