Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1.C(N(CC)CC)C>C(Cl)Cl.O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][CH:12]=2)[C:8]([NH:53][C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nccs1
Reactant: O=C(Cc1cccs1)Nc1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1cccs1)Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(2-thiophen-2-yl-acetylamino)-phenyl]-propionic acid (76.6 mg, 0.21 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (142.0 mg, 0.32 mmol) and 2-aminothiazole (32.1 mg, 0.32 mmol) in methylene chloride (1 mL) at 25° C. was treated with triethylamine (0.9 mL, 0.64 mmol). The reaction mixture was stirred at 25° C. for 16 h. This mixture was then poured into water (50 mL) and extracted with methylene chloride (2×25 mL). The combined organic extracts were washed with a 1N aqueous sodium hydroxide solution (1×25 mL), a 1N aqueous hydrochloric acid solution (1×25 mL), water (1×25 mL), and a saturated aqueous sodium chloride solution (3×25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-thiazol-2-yl-2-[4-(2-thiophen-2-yl-acetylamino)-phenyl]-propionamide (82.7 mg, 87.8%) as a tan solid: mp 220-221° C.; EI-HRMS m/e calcd for C23H25N3O2S2 (M+) 4391388, found 439.1379.
Reaction SMILES: Cl[C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.[OH:21][CH2:22][C:23]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:28])[CH2:24][CH:25]([CH3:27])[CH3:26]>>[C:32]([O:31][C:30](=[O:36])[NH:29][C:23]([CH3:28])([CH2:24][CH:25]([CH3:26])[CH3:27])[CH2:22][O:21][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)CC(C)(CO)NC(=O)OC(C)(C)C
Reactant: COc1cc2c3ccnc(C)c3c(=O)n(C)c2cc1Cl
Product: COc1cc2c3ccnc(C)c3c(=O)n(C)c2cc1OCC(C)(CC(C)C)NC(=O)OC(C)(C)C
Yield: 20.9 %

Procedure:
8-Chloro-9-methoxy-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.04 g, 0.139 mmol) was subjected to Buchwald coupling (Example 16, Part H) with tert-butyl (1-hydroxy-2,4-dimethylpentan-2-yl)carbamate (0.048 g, 0.208 mmol) which afforded tert-butyl(1-((9-methoxy-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate as white solid (15 mg, 0.029 mmol, 21% yield). LC/MS (ESI) m/e 484.2 [(M+H)+, calcd for C22H38N3O5, 484.3]; LC/MS retention time (Method C): tR=2.42 min.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]([CH2:11][C:12]([F:14])=[CH2:13])[C:6](=[O:10])[O:7][CH2:8][CH3:9].C(O)=O.[Cl-].[Na+]>O>[F:14][C:12](=[CH2:13])[CH2:11][N:5]([CH2:4][CH:3]=[O:2])[C:6](=[O:10])[O:7][CH2:8][CH3:9]
Reactant: C=C(F)CN(CC(OC)OC)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: C=C(F)CN(CC=O)C(=O)OCC

Procedure:
14.1 g (60 mmol) of ethyl N-(2,2-dimethoxyethyl)-N-(2-fluoroallyl)-carbamate are heated under reflux for three hours with 6.3 ml of formic acid in 120 ml of water. The solution is saturated with sodium chloride and extracted several times with methylene chloride, the organic solutions are washed with saturated sodium hydrogen carbonate solution, dried over magnesium sulphate and concentrated, and the residue is distilled.
Reaction SMILES: C(N1C2C3N(C(C4C=CC=C(OC)C=4)C4C=CC(C(N(CC)CC)=O)=CC=4)C(C1CC2)CC3)C1C=CC=CC=1.C([N:47]1[CH:56]2[CH:51]3[N:52]([CH:57]([C:72]4[CH:77]=[CH:76][CH:75]=[C:74]([O:78][CH3:79])[CH:73]=4)[C:58]4[CH:63]=[CH:62][C:61]([C:64]([N:66]5[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]5)=[O:65])=[CH:60][CH:59]=4)[CH:53]([CH2:54][CH2:55]2)[CH:48]1[CH2:49][CH2:50]3)C1C=CC=CC=1>>[CH:51]12[CH2:50][CH2:49][CH:48]3[CH:53]([CH2:54][CH2:55][CH:56]1[NH:47]3)[N:52]2[CH:57]([C:72]1[CH:77]=[CH:76][CH:75]=[C:74]([O:78][CH3:79])[CH:73]=1)[C:58]1[CH:59]=[CH:60][C:61]([C:64]([N:66]2[CH2:67][CH2:68][CH2:69][CH2:70][CH2:71]2)=[O:65])=[CH:62][CH:63]=1
Reactant: COc1cccc(C(c2ccc(C(=O)N3CCCCC3)cc2)N2C3CCC4C2CCC3N4Cc2ccccc2)c1
Agent: CCN(CC)C(=O)c1ccc(C(c2cccc(OC)c2)N2C3CCC2C2CCC3N2Cc2ccccc2)cc1
Product: COc1cccc(C(c2ccc(C(=O)N3CCCCC3)cc2)N2C3CCC4NC3CCC42)c1

Procedure:
The procedure of Example 5.1 was repeated, but using instead of the compound prepared in Example 4.1 the compound {4-[(7-benzyl-2,7-diazatricyclo[4.4.0.03,8]dec-2-yl)-(3-methoxyphenyl)methyl]phenyl}-piperidin-1-yl-methanone of Example 4.6. The compound {4-[(2,7-diazatricyclo[4.4.0.03,8]dec-2-yl)-(3-methoxyphenyl)methyl]-phenyl}-piperidin-1-yl-methanone was obtained. Yield: quantitative. IR (nujol) (λ=cm−1) 1680 (C═O), 3100 (NH); 1H-NMR (CDCl3) δ 1.40-2.10 (m, 16H); 2.15-2.30 (m, 1H); 2.80-3.00 (m, 2H); 3.15-3.45 (m, 2H); 3.50-3.75 (m, 2H); 3.78 (s, 3H); 5.00-5.25 (m, 3H); 5.70-5.90 (m, 1H); 6.65-7.40 (m, 6H); 7.95-8.15 (m, 2H). Anal. calc. for C28H35N3O2: C, 75.47; H, 7.92; N, 9.43. Found: C, 75.23; H, 7.90; N, 9.41.
Reaction SMILES: C([O:4][C:5]1[C:18]2[CH:17]=[C:16]([O:19][CH3:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[C:8]([CH3:21])=[C:7]([C:22]([O:24][CH3:25])=[O:23])[CH:6]=1)(=O)C.Cl>CO>[OH:4][C:5]1[C:18]2[CH:17]=[C:16]([O:19][CH3:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[C:8]([CH3:21])=[C:7]([C:22]([O:24][CH3:25])=[O:23])[CH:6]=1
Reactant: COC(=O)c1cc(OC(C)=O)c2cc(OC)c3ccccc3c2c1C
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(O)c2cc(OC)c3ccccc3c2c1C
Yield: 21.4 %

Procedure:
The oil from Step 3 containing 1-acetoxy-9-methoxy-3-methoxycarbonyl-4-methylphenanthrene (77.0 grams, 0.236 mole) was added to a reaction flask containing one mL of concentrated hydrochloric acid in 300 mL of methanol. The reaction mixture was refluxed for 3 hours. The methanol was removed under vacuum and the crude product was purified on a silica gel column using a 1:4 ratio of ethyl acetate:hexane as the eluant. The product was crystallized from methanol and collected by vacuum filtration to yield 15.0 grams of 1-hydroxy-9-methoxy-3-methoxycarbonyl-4-methylphenanthrene.
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]C)=[O:28])=[CH:22][CH:21]=3)=[CH:14][C:13]=2[CH2:31][CH3:32])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:24][CH:25]=3)=[CH:14][C:13]=2[CH2:31][CH3:32])[CH2:10][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(C#Cc2ccc(CC(=O)OC)cc2)ccc1C1(OCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1cc(C#Cc2ccc(CC(=O)O)cc2)ccc1C1(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure I; a solution of methyl {4-[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-acetate (Compound 92, 130.0 mg, 0.31 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up and purification by HPLC (Partisil 10-pac, 10% H2O/CH3CN) afforded the title compound.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)=[C:12]([F:28])[CH:11]=1)(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:28][C:12]1[CH:11]=[C:10]([S:7]([NH2:6])(=[O:8])=[O:9])[CH:15]=[CH:14][C:13]=1[O:16][C@H:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(CNS(=O)(=O)c2ccc(O[C@H]3CCC[C@@H]3c3ccnn3C)c(F)c2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(N)(=O)=O)cc1F
Yield: 94 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-3-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide (0.92 g, 1.88 mmol) prepared in Example 16b, triethylsilane (1.5 mL), trifluoroacetic acid (15 mL) and dichloromethane (15 mL), to yield the title compound (0.60 g, 94%) as a colorless solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([NH:15][C:16]2[N:21]=[C:20]([N:22]([CH:32]3[CH2:34][CH2:33]3)[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:19]3=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]3[N:17]=2)=[CH:13][C:12]([C:40]#[N:41])=[CH:11][C:10]=1[N:42]1[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][C:43]1=[O:55]>C(Cl)Cl>[Cl:8][C:9]1[C:10]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][C:43]2=[O:55])=[CH:11][C:12]([C:40]#[N:41])=[CH:13][C:14]=1[NH:15][C:16]1[N:21]=[C:20]([N:22]([CH:32]2[CH2:33][CH2:34]2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:19]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]2[N:17]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C(=O)OC(C)(C)C)CC4=O)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCNCC4=O)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
TFA (2 mL) was added to a solution of tert-butyl 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-oxopiperazine-1-carboxylate (85 mg, 0.127 mmol) in DCM (4 mL) and the reaction mixture was stirred at room temperature for 1 h. Solvent was evaporated and the crude was dried under vacuum for 10 min. The crude was dissolved in MeOH and neutralized with 7N ammonia in methanol. After stirring for 10 min it was concentrated and purification via flash chromatography (0-10% MeOH in DCM, 12 g) gave 2-((2-chloro-5-cyano-3-(2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (50 mg) as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([OH:15])=O.[N:16]1([C:22]2[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[N:16]1([C:22]2[N:27]=[CH:26][C:25]([NH:28][C:13]([C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[O:6][C:2]=3[Br:1])=[O:15])=[CH:24][CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1Br
Product: O=C(Nc1ccc(N2CCOCC2)nc1)c1nc(-c2ccccc2)oc1Br

Procedure:
With a procedure similar to example 1 above, 5-bromo-2-phenyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 5-bromo-2-phenyl-oxazole-4-carboxylic acid and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C19H17BrN4O3 (m/e) 429, obsd 430 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:19]([NH2:21])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)[C@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:19]([NH2:21])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: NC(=O)[C@@H]1CCCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: NC(=O)[C@@H]1CCCCC[C@@H]1N(Cc1ccc(C(F)(F)F)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 58 %

Procedure:
The titled compound (127 mg) was prepared in 58% yield from cis-2-(4-chlorobenzenesulfonylamino)-cycloheptanecarboxylic acid amide (150 mg, 0.45 mmol) and 1-bromomethyl-4-trifluoromethyl-benzene according to the N-alkylation procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.80 (m, 2 H, J=8.0 Hz), 7.62 (m, 4 H), 7.52 (d, 2 H, J=8.0 Hz), 7.35 (s br, 1 H), 6.70 (s br, 1 H), 4.61 (AB2,2 H,Δv=20,Jab=104 Hz), 3.98 (m, 1 H), 2.80 (m, 1 H), 2.29 (m, 1 H), 1.74 (m, 2 H), 1.43 (m, 5 H), 1.22 (m, 2 H); MS m/e 511.05 (M+Na)+.
Reaction SMILES: [CH2:1]([CH:8]([CH:13]=O)[C:9]([O:11]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:22][CH2:23][CH2:24][CH2:25][N:26]([CH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1)[S:27]([C:30]1[CH:31]=[N:32][C:33]([NH:36][NH2:37])=[CH:34][CH:35]=1)(=[O:29])=[O:28])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:1]([C:8]1[C:9](=[O:11])[N:36]([C:33]2[N:32]=[CH:31][C:30]([S:27]([N:26]([CH2:25][CH2:24][CH2:23][O:22][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)(=[O:29])=[O:28])=[CH:35][CH:34]=2)[NH:37][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccc(S(=O)(=O)N(CCCOCc2ccccc2)C2CCCC2)cn1
Reactant: COC(=O)C(C=O)Cc1ccccc1
Product: O=c1c(Cc2ccccc2)c[nH]n1-c1ccc(S(=O)(=O)N(CCCOCc2ccccc2)C2CCCC2)cn1
Yield: 53.7 %

Procedure:
According to the process described in Example 1.3, starting with 0.19 g of methyl 2-benzyl-3-oxopropanoate and 0.4 g of N-[3-(benzyloxy)propyl]-N-cyclopentyl-6-hydrazinylpyridine-3-sulfonamide, 0.29 g of 6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-[3-(benzyloxy)propyl]-N-cyclopentylpyridine-3-sulfonamide is obtained in the form of a beige-coloured solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12](O[Si](C(C)(C)C)(C)C)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:8]=[CH:7]2.C1COCC1.CCCCCC.C([Li])CCC.[C:43](=[O:45])=[O:44]>C(OCC)C>[C:13]1(/[CH:12]=[CH:11]/[N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[C:43]([OH:45])=[O:44])[CH:7]=[CH:8]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)OC(Cn1ccc2cccc(Br)c21)c1ccccc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(O)c1cccc2ccn(/C=C/c3ccccc3)c12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To 7-bromo-1-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-phenylethyl)-1H-indole (0.91 g) was added dehydrated THF (30 mL), and an n-butyl lithium hexane solution (1.6 M, 5.2 mL) was added thereto at −78° C. while replacing with argon. The mixture was warmed from −78° C. to −5° C., followed by stirring for 30 minutes. The reaction mixture was again cooled to −78° C., and dry ice was added thereto, followed by stirring to room temperature. To the mixture was added diethyl ether, followed by washing with a 1 M aqueous sodium hydroxide solution. The obtained aqueous layer was adjusted to pH 3 with a 10% aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to obtain 1-[(E)-2-phenyl vinyl]-1H-indole-7-carboxylic acid (0.34 g).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[N:11]=[C:10](Cl)[C:9]([N:13]([CH3:18])[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:8][N:7]=1.C(N(CC)CC)C>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4].C(Cl)Cl>[Cl:5][C:6]1[N:7]=[C:8]2[C:9]([N:13]([CH3:18])[C:14](=[O:17])[CH2:15][CH2:16][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[CH:10][N:11]=1
Reactant: C=CC(=O)N(C)c1cnc(Cl)nc1Cl
Reactant: NC1CC1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)CCN(C2CC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.5 %

Procedure:
Cyclopropylamine (Aldrich; 150 μL, 2.18 mmol), N-(2,4-dichloropyrimidin-5-yl)-N-methyl-prop-2-enamide (Intermediate 113; 337 mg, 1.45 mmol) Triethylamine (404 μL, 2.9 mmol), Titanium Tetra-ethoxide (152 μL, 0.725 mmol) and DCM (5 mL) were combined and stirred at room temp for 1 hr, heated at 40° C. for 4 hrs then cooled to room temperature. The reaction mixture was washed with water then gravity filtered through a PTFE cup, the aqueous layer containing the titanium emulsion was washed with further DCM (3×10 mL) and the combined organic solutions gravity filtered through a PTFE cup and solvents evaporated. The residue was dissolved in DCM and purified by chromatographic separation on silica eluting with a shallow gradient (25 column volumes) of 10-50% Ethyl Acetate/iso-hexane. Product containing fractions were combined and evaporated to give the title compound as a cream solid (42 mg, 11%)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:28]=[C:29]([OH:31])[CH:30]=1)[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]1)[CH3:4].Cl[CH2:33][C:34]1[N:35]=[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:37][C:38]=1[CH3:39].O>CN(C)C=O>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:28]=[C:29]([O:31][CH2:33][C:34]2[N:35]=[C:36]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[O:37][C:38]=2[CH3:39])[CH:30]=1)[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]1)[CH3:4]
Reactant: CCOC(=O)CCc1cn(Cc2cc(O)cc(OCC)c2)cc1-c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2cc(OCC)cc(OCc3nc(-c4ccccc4)oc3C)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
Sodium hydride (60%, oily, 50.0 mg) was added to a solution of ethyl 3-[1-(3-ethoxy-5-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (492 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-5-methyl-2-phenyloxazole (260 mg) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[3-ethoxy-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (622 mg, yield: 88%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: CC1CCCCC1.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[CH3:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)=[O:19]>Cl>[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=2)=[O:19])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CC1CCCCC1
Product: O=C(C=Cc1ccc(F)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 12.5 °C

Procedure:
8 l of methylcyclohexane are initially charged and 3000 g of 4-fluorobenzaldehyde, 5000 g of 4-trifluoromethylacetophenone and 150 ml of conc. hydrochloric acid are added. The mixture is distilled azeotropically for approximately 8 hours until no more water separates off. After cooling to 10 to 15° C., the precipitated solid is filtered off with suction and washed with cold methylcyclohexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[CH:6]=[C:5]([CH3:17])[CH:4]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:30](O)=[O:31]>>[CH3:1][O:2][C:3]1[C:12]2[C:11]([CH3:13])([CH3:14])[CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[CH:6]=[C:5]([CH3:17])[C:4]=1[CH:30]=[O:31]
Reactant: COc1cc(C)cc2c1C(C)(C)CCC2(C)C
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1c(C=O)c(C)cc2c1C(C)(C)CCC2(C)C
Reaction time: 0.5 h

Procedure:
1-Methoxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (50 g, 0.2155 mol) was added to a stirred mixture of hexamethylenetetramine (31.4 g, 0.224 mol) and trifluoroacetic acid (250 mL) at 35°-40° C., under a nitrogen atmosphere. The stirred reaction mixture was heated to 85°-90° C. and maintained at this temperature for 1.5 h. Trifluoroacetic acid was removed by distillation and the residue was poured onto an ice-water mixture (800 mL). The mixture was then stirred for 0.5 h, neutralized with a 10% sodium carbonate solution and the product extracted with benzene (2×150 mL). The combined extracts were washed with brine (50 mL) and dried (Na2SO4). The solvent was then removed by distillation and the residue crystallized from hexane to provide 1-methoxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-carboxaldehyde (14 g), mp 78° C., GLC purity 100%, exhibiting the expected spectral data.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=3)[CH:14]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[C:33]([C:38](O)=[O:39])[C:32]2=[O:41])=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[CH:21]1([C:19]([NH:18][C:16]2[N:17]=[C:12]3[CH:11]=[CH:10][C:9]([O:8][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:38]([C:33]5[C:32](=[O:41])[N:31]([C:28]6[CH:27]=[CH:26][C:25]([F:24])=[CH:30][CH:29]=6)[C:36]([CH3:37])=[CH:35][CH:34]=5)=[O:39])=[N:7][CH:6]=4)=[CH:14][N:13]3[CH:15]=2)=[O:20])[CH2:22][CH2:23]1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)cn2)c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 89 %

Procedure:
To a solution of N-{6-[(6-aminopyridin-3-yl)oxy]imidazo[1,2-a]pyridin-2-yl}cyclopropanecarboxamide (75 mg, 0.242 mmol) and 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (78 mg, 0.315 mmol) in N,N-dimethylformamide (1 mL) were added N,N-diisopropylethylamine (83 μL, 0.484 mmol) and HATU (120 mg, 0.315 mmol), and the mixture was stirred at room temperature for 17 hr. Ethyl acetate, tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (116 mg, 89%) as a white solid.
Reaction SMILES: C(C1C=CC2NN=NC=2C=1)(O)=[O:2].[CH:13]1([N:19]=[C:20]=[N:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CN(C)C=O>[C:20]([NH:19][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)([NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:2]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 1 h

Procedure:
In 50 ml of dimethylformamide were dissolved 8.1 g of 5-carboxybenzotriazole and 15.3 g of the amino compound obtained in above step 4-(2) and while stirring the solution at 0° C. in a nitrogen gas atmosphere, 5 ml of dimethylformamide solution containing 10.3 g of dicyclohexylcarbodiimide were added dropwise to the solution over a period of 15 minutes. After stirring the mixture for one hour, the mixture-was further stirred for 2 hours at 25° C. Then, dicyclohexylurea formed was removed by filtration and the filtrate thus obtained was added to 1.5 liters of ice water. Crude crystals thus deposited were collected by filtration and dispersed in 100 ml of isopropanol for 15 minutes under heating. The reaction mixture was cooled to room temperature and filtered to provide 12.1 g of desired Compound 201 having a melting point of from 196° C. to 199° C. (decompd.) with the yield of 54%.