Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([C:14]3[S:18][C:17]([CH:19]4[CH2:23][CH2:22][NH:21][CH2:20]4)=[N:16][CH:15]=3)=[O:13])=[CH:6][C:5]=12.C(N(CC)CC)C.[CH3:31][CH:32]([CH3:38])[CH2:33][S:34](Cl)(=[O:36])=[O:35]>CN(C)C=O.O>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([C:14]3[S:18][C:17]([CH:19]4[CH2:23][CH2:22][N:21]([S:34]([CH2:33][CH:32]([CH3:38])[CH3:31])(=[O:36])=[O:35])[CH2:20]4)=[N:16][CH:15]=3)=[O:13])=[CH:6][C:5]=12
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: O=C(NCc1ccn2ccnc2c1)c1cnc(C2CCNC2)s1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CS(=O)(=O)N1CCC(c2ncc(C(=O)NCc3ccn4ccnc4c3)s2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(imidazo[1,2-a]pyridin-7-ylmethyl)-2-(pyrrolidin-3-yl)thiazole-5-carboxamide, 2.7-trifluoroacetic acid (150 mg, 0.236 mmol) was dissolved in N,N-dimethylformamide (0.7 mL). Triethylamine (0.3 mL, 2.152 mmol) was added, followed by 2-methylpropane-1-sulfonyl chloride (74.0 mg, 0.472 mmol) and the reaction was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were dried with sodium sulfate, filtered, and concentrated and purified by normal phase chromatography to give the title compound. 1H NMR (300 MHz, DMSO-d6). δ ppm 9.24 (t, J=5.9 Hz, 1H), 8.49 (d, J=7.0 Hz, 1H), 8.35 (s, 1H), 7.89 (s, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.41 (s, 1H), 6.83 (dd, J=7.0, 1.7 Hz, 1H), 4.48 (d, J=5.9 Hz, 2H), 3.91 (p, J=7.2 Hz, 1H), 3.74 (dd, J=9.8, 7.3 Hz, 1H), 3.51-3.35 (m, 3H), 2.99 (d, J=6.6 Hz, 2H), 2.46-2.33 (m, 1H), 2.24-2.03 (m, 2H), 1.03 (d, J=6.7 Hz, 6H); MS (ESI(+)) m/e 448 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.CCN(CC)CC.[C:26]1([C:32]#[C:33][C:34]2[O:38][C:37]([C:39](ON3C(=O)CCC3=O)=[O:40])=[CH:36][CH:35]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][C:2]1([NH:1][C:39]([C:37]2[O:38][C:34]([C:33]#[C:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:35][CH:36]=2)=[O:40])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])[CH2:3]1)[CH3:18]
Reactant: CCOC(=O)CC1(N)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(C#Cc2ccccc2)o1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(NC(=O)c2ccc(C#Cc3ccccc3)o2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A stirred solution of tert-butyl 3-amino-3-(2-ethoxy-2-oxoethyl)azetidine-1-carboxylate (130 mg, 0.503 mmol) in DMF (3 mL) was treated with NEt3 (0.19 mL, 1.37 mmol), and 2,5-dioxopyrrolidin-1-yl 5-(phenylethynyl)furan-2-carboxylate, prepared as described in Preparation 5 (141 mg, 0.457 mmol). The reaction was stirred overnight, at room temperature, then the solvent removed in vacuo and the crude product purified by column chromatography to obtain the title compound (168 mg, 81%). 1H NMR (400 MHz, CDCl3) δ 7.57 (m, 2H), 7.40 (m, 3H), 7.12 (s, 1H), 7.04 (s, 1H), 6.70 (s, 1H), 4.17 (m, 4H), 4.03 (d, 2H, J=9.6 Hz), 3.17 (s, 2H), 1.45 (s, 9H), 1.26 (t, 3H, J=7.2 Hz); MS ESI 453.2 [M+H]+, calcd for [C25H28N2O6+H]+ 453.51.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1.[CH:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]2[N:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:33]=[C:34]([C:35]([O:37][CH3:38])=[O:36])[C:27]=12)=O>C(Cl)Cl>[C:42]([O:41][C:39]([N:32]1[C:28]2=[N:29][CH:30]=[CH:31][C:26]([CH2:24][NH:15][C:16]3([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:27]2[C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33]1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Reactant: NC1(C(=O)O)CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CNC3(C(=O)O)CCCC3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 10 mL round bottom flask was added sodium triacetoxyborohydride (104 mg, 0.493 mmol) and 1-aminocyclopentanecarboxylic acid (42.4 mg, 0.329 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 30 min after which was added 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (50 mg, 0.164 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 2 h and then quenched with MeOH (3 drops). The mixture was concentrated to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C21H27N3O6, 418; found, 418.3.
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]1[CH:10]=[C:11]([C:15]#[C:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=2)[CH:12]=[N:13][CH:14]=1.CC(O)=O>CO>[CH3:3][N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]1[CH:10]=[C:11]([C:15]#[C:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=2)[CH:12]=[N:13][CH:14]=1
Reactant: COC(=O)c1ccc(C#Cc2cncc(C3CCCN3C)c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCCC1c1cncc(C#Cc2ccc(C(=O)O)cc2)c1
Temperature: 25 °C

Procedure:
KOH (168 mg, 3 mmol) was added to YH19 (0.32 g, 1 mmol) in MeOH (5 mL). The stirred mixture was refluxed for 2 h and then cooled to room temperature. HOAc was added to pH8 and the volatiles were evaporated. The residue was chromatographed [SiO2, CHCl3/MeOH (5:1)] to give 0.19 g (62%) of YH20; 1H NMR (270 MHz, CDCl3) δ 11.00 (br s, OH), 8.75 (br s, 1H), 8.44 (m, 2H), 8.10 (d, J=8 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 3.94-3.84 (m, 1H), 3.63-3.52 (m, 1H), 2.69-2.58 (m, 1H), 2.42 (s, 3H), 2.42-1.98 (m, 4H); 13C NMR (270 MHz, CDCl3) δ 169.5, 151.6, 148.9, 139.0, 133.8, 132.9, 131.5, 129.6, 125.3, 120.8, 93.0, 87.4, 69.0, 55.5, 38.8, 33.2, 21.7;
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][C:26]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:27]=1[CH2:28][C:29]1([NH2:32])[CH2:31][CH2:30]1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:32][C:29]2([CH2:28][C:27]3[C:33]([CH3:38])=[CH:34][C:35]([CH3:37])=[CH:36][C:26]=3[CH3:25])[CH2:31][CH2:30]2)=[CH:11][CH:10]=1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: Cc1cc(C)c(CC2(N)CC2)c(C)c1
Agent: O=C([O-])C(F)(F)F
Product: Cc1cc(C)c(CC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)c(C)c1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 189 mg (1 mmol) 1-(2,4,6-trimethyl-benzyl)-cyclopropylamine. Yield: 26 mg (5%, trifluoroacetate); mass spectroscopy: [M+H]+=397.
Reaction SMILES: [CH3:1][N:2]([C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([NH2:14])=O)=[N:10][N:11]=2)[N:8]=1.C([O-])(O)=O.[Na+].C(Cl)Cl>CN(C=O)C.O=S(Cl)Cl>[CH3:1][N:2]([C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]#[N:14])=[N:10][N:11]=2)[N:8]=1
Reactant: C[C@@H](c1ccccc1)N(C)c1ccc2nnc(C(N)=O)n2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: C[C@@H](c1ccccc1)N(C)c1ccc2nnc(C#N)n2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of compound (S)-6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxamide (0.1 g, 0.34 mmol) in 2 mL of DMF, 1 mL of SOCl2 was added dropwise at 0-5° C., the reaction mixture was stirred for 5 h at room temperature. The mixture was poured onto ice (20 mL) and the mixture was neutralized with NaHCO3. DCM (50 mL) was added; the separated organic layer was dried over anhydrous Na2SO4, and concentrated in vacuum. The residue was purified by flash chromatography eluting with PE/EA=5:1 to give product (S)-6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-3-carbonitrile as a yellow solid (Compound 9) (60 mg, 64%). LRMS (M+H+) m/z: calcd 279.43; found 279. 1H NMR (300 MHz, CDCl3): δ 7.98-7.94 (d, J=12 Hz, 1H), 7.35-7.30 (m, 5H), 7.11-7.08 (d, J=9 Hz, 1H), 5.77-5.75 (q, 1H), 2.94 (s, 3H), 1.69-1.66 (d, 3H).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:20](Cl)(=[O:22])[CH3:21].CCN(CC)CC.CO>C(Cl)Cl>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]3[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][C:20](=[O:22])[CH3:21])[C:11]=3[CH:10]=[N:9][CH:8]=2)=[CH:19][CH:18]=1)#[N:17]
Reactant: CC(=O)Cl
Reactant: N#Cc1ccc(-c2cncc3c2CCCC3N)cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCCc2c(-c3ccc(C#N)cc3)cncc21
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
A cooled (−20° C.) solution of (rac)-4-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)benzonitrile (example 1) (62.3 mg, 250 μmol) in CH2Cl2 (3.6 ml) was treated with acetyl chloride (21.3 μL, 275 μmol) and Et3N (41.8 μL, 300 μmol). After ½ h, an additional drop of acetyl chloride was added and after 5 min. the mixture was treated with MeOH (0.2 mL) and extracted with water/AcOEt (3×). The organic phases were dried over Na2SO4, filtered and evaporated under reduced pressure. Purification by flash chromatography (50 g SiO2, Telos-cartridge, CH2Cl2/MeOH (2 to 3%)) and precipitation from CH2Cl2 with n-pentane gave the title compound (32 mg, 44%) as off-white powder. MS: 292.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13].[NH2:18][C:19]1[C:23]([C:24]#[N:25])=[CH:22][NH:21][N:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]2[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:19]2[N:18]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)cc1F
Reactant: N#Cc1c[nH]nc1N
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(F)cc3F)nc12
Yield: 22.2 %

Procedure:
Reaction of 1-(2,4-difluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (252 mg, 1.0 mmol), prepared from commercially available 2,4-difluoro-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (72 mg, 22%). MS (ISP) 325.0 [(M+H)+]; mp 149° C.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][S:6][C:7]1[NH:11][C:10]2[C:12]([CH:18]=[O:19])=[C:13]([O:16]C)[CH:14]=[CH:15][C:9]=2[N:8]=1)C.B(Br)(Br)Br>ClCCl>[CH:18]([C:12]1[C:10]2[NH:11][C:7]([S:6][CH2:5][C:4]([OH:20])=[O:3])=[N:8][C:9]=2[CH:15]=[CH:14][C:13]=1[OH:16])=[O:19]
Reactant: CCOC(=O)CSc1nc2ccc(OC)c(C=O)c2[nH]1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1c(O)ccc2nc(SCC(=O)O)[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
To a solution of (7-Formyl-6-methoxy-1H-benzoimidazol-2-ylsulfanyl)-acetic acid ethyl ester (500 mg, 1.88 mmol) in abs. dichloromethane (40 mL) stirred under argon at −78° C., boron tribromide (723 μl, 1.88 g, 7.52 mmol) was added dropwise and the mixture was warmed to room temperature and stirred for 2 h. An additional portion of boron tribromide (723 μl, 1.88 g, 7.52 mmol) was added at −78° C. and stirred for 2 h at room temperature. The mixture was quenched by slow addition of 120 mL. of water. The mixture was evaporated to dryness, suspended in boiling ethyl acetate, and the solid was filtered off. The filtrate was evaporated and triturated with diethyl ether. The title compound (220 mg, 0.87 mmol, 46%) was obtained as a light orange powder.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH:20][C:21](=[O:24])[CH:22]=[CH2:23])[N:19]=[C:15]4[CH:14]=[CH:13][CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C[N:26]1[CH2:31]C[NH:29][CH2:28][CH2:27]1>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH:20][C:21](=[O:24])[CH2:22][CH2:23][N:26]5[CH:27]=[CH:28][N:29]=[CH:31]5)[N:19]=[C:15]4[CH:14]=[CH:13][CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: C=CC(=O)Nc1nc2cccc(-c3ccc4c(c3)OCCO4)n2n1
Solvent: CCO
Product: O=C(CCn1ccnc1)Nc1nc2cccc(-c3ccc4c(c3)OCCO4)n2n1
Reaction time: 8 h

Procedure:
To a solution of N-[5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-acrylamide (0.05 g, 0.155 mmol) in ethanol (2 mL) was added N-methylpiperazine (0.13 g, 1.86 mmol) and the solution was stirred overnight. The reaction mixture was purified by prep LCMS. LCMS Method: 2, RT: 2.09 min, MI: 423 [M+1].
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH:4]=[CH2:5].[CH3:8][C:9]1[CH:18]=[C:17]([CH2:19][O:20][C:21]2[CH:29]=[CH:28][C:24]([CH:25]=[N:26][OH:27])=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1>>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH:4]1[O:27][N:26]=[C:25]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:17]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=[C:9]([CH3:8])[CH:18]=3)=[CH:29][CH:28]=2)[CH2:5]1
Reactant: Cc1cc(COc2ccc(C=NO)cc2)c2ccccc2n1
Reactant: C=CC(OC)OC
Product: COC(OC)C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Yield: 100 %

Procedure:
Following a procedure analogous to that used in Example step 1c, but using 3,3-dimethoxy-propene and 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde oxime from step 1b, the crude reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give 4-[4-(5-dimethoxymethyl-4,5-dihydro-isoxazol-3-yl)-phenoxymethyl]-2-methyl-quinoline (0.4 g, 100%) as a crude oil. MS found: (M+H)+=393.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1[Cl:27])/[C:20](=[N:22]/O)/[NH2:21].CC(C)N=C=NC(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.N1C=CC=CC=1.CCOC(C)=O>[Cl:16][C:17]1[CH:18]=[C:19]([C:20]2[N:22]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[O:15][N:21]=2)[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Reactant: N/C(=N\O)c1ccc(Cl)c(Cl)c1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCCc1nc(-c2ccc(Cl)c(Cl)c2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
The 5-(tert-butoxycarbonylamino)pentanoic acid (424 mg, 1.95 mmol) was introduced into a microwave vial charged with DMAP (238 mg, 1.95 mmol) and Intermediate 20A (400 mg, 1.95 mmol). The reactants were dissolved in DMF (5 mL) and the DIC (0.304 mL, 1.95 mmol) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with 3 mL of pyridine. The vial was capped and the reaction was heated in the microwave at 145° C. for 20 min. The reaction mixture was allowed to cool to rt. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic portion was concentrated under reduced pressure and purified by silica gel chromatography with EtOAc/Hexane to give Intermediate 20B as a white solid (230 mg, 0.595 mmol, 30.5% yield). HPLC/MS (Method D) RT=2.40 min [M+H]+ 385.9.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:15]([C:31](=[O:33])[CH3:32])[CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C:10]2[CH:34]=[C:35]([CH3:42])[C:36]([C:38]([F:41])([F:40])[F:39])=[CH:37][C:9]1=2)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:30][C:27]([F:28])([F:29])[C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:20]=1)[CH2:16][N:15]([CH:11]1[CH2:12][CH2:13][CH2:14][NH:8][C:9]2[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[C:35]([CH3:42])=[CH:34][C:10]1=2)[C:31](=[O:33])[CH3:32]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1CCCN(C(=O)OC(C)(C)C)c2cc(C(F)(F)F)c(C)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2cc(C(F)(F)F)c(C)cc21
Yield: 95.8 %

Procedure:
A solution of (S)-5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (0.920 g, 1.50 mmol) (Example 110) in 1:1 TFA/DCM (10.0 ml) was stirred at room temperature for 2 hours. The solvents were evaporated on a (rotary evaporation). Purification by silica gel chromatography (gradient eluent, 0-30% ethyl acetate in hexane) provided the titled compound (0.736 g, 96%) as white solid. MS (ES+): 513 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH2:15][OH:16].N1C=CC=CC=1>C(O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]([CH:12]=[N:15][OH:16])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: NO
Reactant: O=Cc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: ON=Cc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-chloro-5-(trifluoromethyl)picolinaldehyde (1.0 eq.), hydroxylamine hydrochloride (5.0 eq.), and pyridine (4.0 eq.) in ethanol was heated to 95° C. and stirred for 1 hour. The reaction was cooled to room temperature and diluted with ethyl acetate and water. The organic layer was washed with brine, water, dried over anhydrous MgSO4, and concentrated en vacuo to give a solid that was carried onto the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[NH:14][C:13]2=[O:27])=[C:4]([F:28])[CH:3]=1.[C:29](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([C:20]([F:25])([F:26])[C:21]([F:24])([F:23])[F:22])[N:14]=[C:13]2[O:27][CH3:29])=[C:4]([F:28])[CH:3]=1
Reactant: CC(C)Oc1cc(-n2c(=O)[nH]c(C(F)(F)C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1nc(C(F)(F)C(F)(F)F)c(F)c(=O)n1-c1cc(OC(C)C)c(Cl)cc1F

Procedure:
using 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-6-pentafluoroethyl-2,4(1H,3H)-pyrimidinedione with sodium bicarbonate and dimethyl sulphate in acetone there is obtained 1-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-2-methoxy-4-pentafluoroethyl-6(1H) -pyrimidinone, m.p. 69°-71° C.;
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[OH:13].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)C>ClCCl>[C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:13]
Reactant: Cc1ccccc1C1CCCCC1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccccc1C1CCCCC1=O
Yield: 54.6 %

Procedure:
To (cis/trans) 2-o-tolyl-cyclohexanol (1 g) in dichloromethane (30 ml) was added Dess-Martin periodinane (Aldrich 27,462-3) at room temperature. The reaction mixture was allowed to stir at room temperature for 16 hours before diethyl ether was added. The volume of solvent was reduced in vacuo to about one quarter of the initial amount. More diethylether (87 ml) was added and the solution was washed with a 10% solution of sodium thiosulfate (87 ml), a solution of saturated sodium bicarbonate (87 ml), brine (100 mL) and water (100 ml). The organic phase was then dried over sodium sulfate and concentrated in vacuo. The residue was then purified by column chromatography to give 0.54 g of 2-o-tolyl-cyclohexanone MS (EI) 188.2 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=3)[N:16]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC1C=CC(N2C3C(=CC([C:48]4N[N:51]=[N:50][N:49]=4)=CC=3)C(C3CCN(C(OC(C)(C)C)=O)CC3)=C2)=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]4[N:51]=[N:50][N:49]([CH3:48])[N:24]=4)[CH:21]=3)[N:16]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cn(-c3ccc(F)cc3)c3ccc(-c4nnn[nH]4)cc23)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cn(-c3ccc(F)cc3)c3ccc(C#N)cc23)CC1
Product: Cn1nnc(-c2ccc3c(c2)c(C2CCN(C(=O)OC(C)(C)C)CC2)cn3-c2ccc(F)cc2)n1

Procedure:
Following the procedure in Example 8, the cyanoderivative 12a was converted to the corresponding 5-[1-(4-fluorophenyl)-3-(1-t-butyloxycarbonyl-4-piperidinyl)-5-(5-tetra-zolyl)-1H-indole which was methylated according to the procedure in Example 9 to give the title compound 13a.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][C:12]2[NH:13][C:14](=[O:22])[C:15]3[CH2:21][O:20][CH2:19][CH2:18][C:16]=3[N:17]=2)[CH3:9])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:41]=[CH:40][C:27]([C:28]([CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][C:37](O)=[O:38])[CH2:32][CH2:31]2)=[O:29])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([CH:30]2[CH2:31][CH2:32][N:33]([CH2:36][C:37]([N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH3:9])[CH2:11][C:12]3[NH:13][C:14](=[O:22])[C:15]4[CH2:21][O:20][CH2:19][CH2:18][C:16]=4[N:17]=3)=[O:38])[CH2:34][CH2:35]2)=[O:29])=[CH:40][CH:41]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: C[C@H](NCc1nc2c(c(=O)[nH]1)COCC2)c1ccc(F)cc1
Product: C[C@@H](c1ccc(F)cc1)N(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (40.7 mg) from (S)-2-((1-(4-fluorophenyl)ethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C30H32FN4O4 550.6. found 551.4 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.97 (dd, J=8.84, 5.31 Hz, 2H) 7.31 (dd, J=8.59, 5.05 Hz, 1H) 7.13-7.27 (m, 3H) 6.88 (t, J=7.83 Hz, 1H) 6.03 (q, J=7.07 Hz, 1H) 4.27-4.57 (m, 5H) 4.11 (br. s., 2H) 3.85-4.03 (m, 4H) 3.36 (br. s., 1H) 3.30 (br. s., 2H) 2.97 (s, 1H) 2.70 (br. s., 2H) 2.59 (d, J=4.04 Hz, 1H) 2.12 (s, 4H) 1.68 (d, J=7.07 Hz, 1H) 1.49 (d, J=7.07 Hz, 2H).