Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13]([C:14]2[C:18]([Cl:19])=[C:17]([O:20][CH:21]([F:23])[F:22])[N:16]([CH3:24])[N:15]=2)=[C:12]([F:25])[CH:11]=[C:10]([Cl:26])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>C(Cl)Cl>[CH2:1]([N:8]1[C:13]([C:14]2[C:18]([Cl:19])=[C:17]([O:20][CH:21]([F:23])[F:22])[N:16]([CH3:24])[N:15]=2)=[C:12]([F:25])[CH:11]=[C:10]([Cl:26])[C:9]1=[S:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2c(F)cc(Cl)c(=O)n2Cc2ccccc2)c(Cl)c1OC(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cn1nc(-c2c(F)cc(Cl)c(=S)n2Cc2ccccc2)c(Cl)c1OC(F)F
Temperature: 120 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
0.50 g of 1-benzyl-3-chloro-6-(4-chloro-5-difluoromethoxy-1-methyl-[1H]-pyrazol-3-yl)-5-fluoro-[1H]-pyridin-2-one is introduced into 5 ml of toluene, 0.63 g of Lawesson's reagent is added and the resulting yellow suspension is stirred overnight at 120° C. The next day, the mixture is cooled to 22° C., diluted with methylene chloride and, after the addition of 3 g of silica gel, concentrated to dryness in vacuo. The silica gel is applied to a flash chromatography column and eluted first with toluene/ethyl acetate 30/1 (v/v) and then with n-hexane/ethyl acetate 2/1 (v/v). 0.32 g of the desired title compound is obtained in the form of a yellow solid having a melting point of 135-138° C.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([O:16][C:17](=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=1)[CH3:15].[Br:28][C:29]1[CH:34]=[CH:33][C:32](/[C:35](/[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:36]/[CH2:37]O)=[CH:31][CH:30]=1>C1COCC1>[CH2:14]([O:16][C:17](=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:37]/[CH:36]=[C:35](/[C:32]2[CH:31]=[CH:30][C:29]([Br:28])=[CH:34][CH:33]=2)\[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[C:21]([Cl:26])[CH:20]=1)[CH3:15]
Reactant: OC/C=C(\c1ccccc1)c1ccc(Br)cc1
Reactant: CCOC(=O)Cc1ccc(O)c(Cl)c1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(OC/C=C(\c2ccccc2)c2ccc(Br)cc2)c(Cl)c1
Reaction time: 2 h
Yield: 65.9 %

Procedure:
Under a atmosphere of nitrogen, azodicarboxylic dipiperidide (756 mg, 3.0 mmol) was added at 0-5° C. to a stirred solution of tributylphosphine (786 mg, 3.0 mmol), 3-chloro-4-hydroxyphenyl-acetic acid ethyl ester (537 mg, 2.5 mmol) and (E)-3-(4-bromo-phenyl)-3-phenyl-prop-2-en-1-ol (578 mg, 2.0 mmol) in dry THF (15 ml), the mixture was stirred for 2 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluent: toluen) to give 640 mg (66%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](=[O:11])[O:8][C:9](=O)[C:2]=12.[C:12]1([NH2:19])[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=1>CN(C)C=O>[NH:18]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:19]=[C:9]1[C:2]1[N:1]=[CH:6][CH:5]=[CH:4][C:3]=1[C:7]([OH:8])=[O:11]
Reactant: O=C1OC(=O)c2ncccc21
Reactant: Nc1ccccc1N
Solvent: CN(C)C=O
Product: O=C(O)c1cccnc1-c1nc2ccccc2[nH]1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
A mixture of furo[3,4-b]pyridine-5,7-dione (2.0 g, 13.41 mmol) and benzene-1,2-diamine (1.45 g, 13.41 mmol) in 20 ml of N,N-dimethylformamide (DMF) was heated to 100° C. for 3 hours. The reaction mixture was evaporated to dryness, the obtained residue taken up in 15 mL of dichloromethane and stirred for 30 minutes at 5° C. Filtration with suction and drying gave 1.0 g of a red solid, which was used further without additional purification.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[C:18]1[N:19]=[CH:20][N:21]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[CH:22]=1>>[CH:1]1([NH:5][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([N:21]3[CH:22]=[C:18]([C:8]4[C:9]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[N:10][O:11][C:7]=4[CH3:6])[N:19]=[CH:20]3)[CH:24]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(=O)O)c2)cn1
Reactant: NC1CCC1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(=O)NC3CCC3)c2)cn1
Yield: 45 %

Procedure:
As described for Example 71, cyclobutylamine was converted, using 3-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (52 mg, 45%) which was obtained as an off-white solid. MS: m/e=399.1 [M+H]+.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:6][O:5]1)[CH:2]=[CH2:3].[C:7](=[O:17])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:8].[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O>CC(OC)(C)C>[CH2:10]([O:9][C:7](=[O:17])[NH:8][CH2:6][C@H:4]([OH:5])[CH2:1][CH:2]=[CH2:3])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)OCc1ccccc1
Reactant: C=CCC1CO1
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: COC(C)(C)C
Product: C=CC[C@@H](O)CNC(=O)OCc1ccccc1
Yield: 59.5 %

Procedure:
To a solution of 2-allyl-oxirane (Synthesis 1986, 309; 918 mg, 10.9 mmol) in TBME (12 mL) were added benzyl carbamate (750 mg, 4.96 mmol), 4-nitrobenzoic acid (146 mg, 0.87 mmol) and (1S,2S)-(+)-N—N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) 264 mg, 0.44 mmol) at RT, then after 72 h the reaction mixture was partitioned between TBME and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane-EtOAc gradient) produced the title compound (694 mg, 48%). Brown oil, MS: 236.2 (M+H)+.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)[CH3:6].[OH-].[Na+].Cl>CO.O>[CH2:5]([O:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:10]([CH2:11][CH2:4][N+:1]([O-:3])=[O:2])[CH:9]=1)[CH3:6]
Reactant: C[N+](=O)[O-]
Reactant: CCOc1cccc(C=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOc1cccc(CC[N+](=O)[O-])c1
Temperature: -10 °C
Yield: 37.5 %

Procedure:
A mixture of nitromethane (0.36 mL, 6.7 mmol) and 3-ethoxy-benzaldehyde (1 g, 6.7 mmol) in methanol (1.4 mL) was cooled to −10° C. To this mixture sodium hydroxide (0.28 g in 1 mL water) was added dropwise. The temperature during addition was maintained around 10° C. After 1 hour a yellow precipitate formed and water (5 mL) was added. The resulting solution was added to HCl (4M, 3 mL). The precipitate that formed was filtered off and washed with water. Purification by chromatography on silica, eluting with 1 to 15% ethyl acetate in hexane, gave the subtitled compound as a yellow solid (0.49 g). 1H NMR δ (CDCl3) 1.40-1.48 (3H, t), 4.014.13 (2H, q), 6.97-7.06 (2H, m), 7.09-7.15 (1H, d), 7.30-7.40 (1H, t), 7.53-7.62 (1H, d), 7.91-8.00 (1H, d).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C@H:16]([C:32]([N:34]1[C@H:39]([C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[CH:38]2[CH2:50][CH2:51][CH:35]1[CH2:36][CH2:37]2)=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=O)(C)(C)C>C(Cl)Cl>[CH2:25]([O:24][C:22]([NH:21][CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]([C:32]([N:34]1[C@H:39]([C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[CH:38]2[CH2:50][CH2:51][CH:35]1[CH2:36][CH2:37]2)=[O:33])[NH2:15])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1C2CCC(CC2)[C@H]1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1C2CCC(CC2)[C@H]1C(=O)OCc1ccccc1

Procedure:
Using the method of deprotection with trifluoroacetic acid in anhydrous methylene chloride, described by B. GUTTE and K. B. MERRIFIELD (J. Am. Chem. Soc. 1969, 91, 501), a quantitative yield of (3S)-2-[(S)-Nε -benzyloxycarbonyllysyl]-3-benzyloxycarbonyl-2-azabicyclo[2.2.2]octane is obtained from the (3S)-2-[(S)-Nα -tert-butoxycarbonyl-Nε -benzyloxycarbonyllysyl]-3-benzyloxycarbonyl-2-azabicyclo[2.2.2]octane prepared in the preceding stage.
Reaction SMILES: N=C=N.[CH:4]1(/[CH:9]=[C:10](\[C:14]2[CH:15]=[N:16][C:17]([S:20][CH3:21])=[CH:18][CH:19]=2)/[C:11]([OH:13])=O)[CH2:8][CH2:7][CH2:6][CH2:5]1.C1C=CC2N(O)N=NC=2C=1.[S:32]1[CH:36]=[CH:35][N:34]=[C:33]1[NH2:37]>CN(C=O)C>[CH:4]1(/[CH:9]=[C:10](\[C:14]2[CH:15]=[N:16][C:17]([S:20][CH3:21])=[CH:18][CH:19]=2)/[C:11]([NH:37][C:33]2[S:32][CH:36]=[CH:35][N:34]=2)=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CSc1ccc(/C(=C\C2CCCC2)C(=O)O)cn1
Reactant: Nc1nccs1
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CSc1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cn1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A suspension of PS-carbodiimide (1.08 g, loading 1.32 mmol g−1, 1.42 mmol), (E)-3-cyclopentyl-2-(6-methylsulfanylpyridin-3-yl)acrylic acid (Preparation 3, 125 mg, 475 μmol), and HOBt (128 mg, 949 μmol) in anhydrous DMF (8 mL) was stirred for 15 min at 20° C. Thiazol-2-ylamine (48 mg, 475 μmol) was added, then the mixture was stirred for 14 h at 20° C. LCMS indicated that the reaction had not gone to completion, so more thiazol-2-ylamine (95 mg, 950 μmol) was added. The mixture was stirred for an additional 64 h, before being filtered. The resin collected was washed with CH2Cl2, then the combined filtrate and washings were concentrated under reduced pressure. Column chromatography (2:11H-EtOAc) provided the title compound: RTA=3.85 min; m/z (ES+)=346.1 [M+H]+.
Reaction SMILES: C([O-])=O.[NH4+].[CH:5]([N:18]1[CH2:21][CH:20]([O:22][Si](C(C)(C)C)(C)C)[CH2:19]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14]C=1)C1C=CC=CC=1.FC1C=CC([N+:37]([O-:39])=[O:38])=CC=1>CO.N1C=CC=CC=1.[Pd]>[N+:37]([C:16]1[CH:17]=[CH:12][C:5]([N:18]2[CH2:19][CH:20]([OH:22])[CH2:21]2)=[CH:14][CH:15]=1)([O-:39])=[O:38]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)[Si](C)(C)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: CO
Product: O=[N+]([O-])c1ccc(N2CC(O)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
Ammonium formate (15.1 g, 246 mmol) was added to a solution of 1-benzhydryl-3-(tert-butyl-dimethyl-silanyloxy)-azetidine (which was obtained in Example 395) (8.7 g, 24.6 mmol) and 10%Pd/C (1 g) in methanol (100 mL). The reaction was stirred for 3 hours at room temperature. The solution was passed through celite and concentrated to afford a crude solid. The crude solid was taken up in pyridine (75 mL) and the salts were removed by filtration. 4-Fluoronitrobenzene (2.9 mL, 27.1 mmol) was added to the above solution and the reaction was stirred at reflux overnight. Pyridine was removed by vacuum distillation and the resultant crude was treated with water (100 mL), followed by extraction with ethyl acetate (3×25 mL). The organic layers were combined, dried (Na2SO4), filtered, and passed through a plug of silica. The solvent was evaporated and triturated with hexanes to give 3.91 g of the desired product as red solid; 1H NMR (300 MHz, CDCl3) δ 1.62 (s, 1H), 3.89(m, 2H), 4.31 (m, 2H), 4.87 (m, 1H), 6.31 (d, 2H, J=7.14), 8.09 (d, 2H, J=7.14 Hz); MS (ES) m/z: 194.8 (MH+); Anal. Calcd. for C9H10N2O3: C, 55.67; H, 5.19; N, 14.43. Found: C, 55.67; H, 5.05; N, 14.59.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH2:22]Br>>[F:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH2:22][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:2][CH2:3]1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: Fc1ccc(CBr)c(F)c1
Product: Nc1nc(N)c2c(N3CCN(Cc4ccc(F)cc4F)CC3)cccc2n1
Yield: 88 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2,4-Difluorobenzyl bromide (76.6 mg; 0.37 mmol) to obtain 65 mg. (88% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.87 (s, 1H), 7.67 (m, 3H), 7.48 (m, 1H), 7.24 (m, 3H), 7.09 (m, 1H), 3.61 (s, 2H), 3.02 (br d, J=10.8 Hz, 2H), 2.89 (m, 4H), 2.33 (m, 2H). ESIMS+371.5 m/z
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[CH:8]=[O:9].[Na+].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([S:17]([C:2]2[CH:6]=[C:5]([CH3:7])[S:4][C:3]=2[CH:8]=[O:9])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S([O-])c1ccccc1
Reactant: Cc1cc(Br)c(C=O)s1
Agent: [Na+]
Product: Cc1cc(S(=O)(=O)c2ccccc2)c(C=O)s1

Procedure:
The title compound was prepared by the method of Preparation 7a using 3-bromo-5-methylthiophene-2-carbaldehyde and phenylsulfinic acid sodium salt.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[CH2:17]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
To a stirred solution of 2-nitrophenol (10.0 g, 72.0 mmol) and K2CO3 (9.96 g, 72.0 mmol) in DMF (150 mL) was added dropwise benzyl bromide (9.40 mL, 79.2 mmol) at 0° C. After being stirred at room temperature for 3 hr, the reaction mixture was diluted with water, which was extracted with Et2O. The extracts were washed with brine, dried over Na2SO4, and concentrated to dryness. Chromatography of the residue with hexane-EtOAc (2:1, v/v) as eluent gave 2-benzyloxy nitrobenzene (14.7 g, 89%) as a yellow oil. 1H-NMR (CDCl3) δ 5.24 (s, 2H), 7.04 (t, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 7.31–7.50 (m, 5H), 7.51 (d, J=1.5 Hz, 1H), 7.86 (dd, J=7.8, 1.5 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]2[O:19][CH2:20][O:21][C:3]=12.C([Li])CCC.CN([CH:35]=[O:36])C1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[CH:35]([C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]2[O:19][CH2:20][O:21][C:3]=12)=[O:36]
Reactant: Brc1c2c(cc3c1OCO3)C(c1ccccc1)CNCC2
Reactant: CN(C=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=Cc1c2c(cc3c1OCO3)C(c1ccccc1)CNCC2
Reaction time: 1 h

Procedure:
A mixture of 7.8 g (0.0225 mole) of 6-bromo-7,8-methylenedioxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine in toluene was added to a mixture of 2.2 ml (6.07 mole) of butyl lithium diluted with 100 ml of ethyl ether at -78°. Then, 10 ml of N-methylformanilide was added. After stirring for 1 hour at -78°, the cooling bath was removed and 100 ml of 10% hydrochloric acid was added. After stirring for 15 minutes, the layers were separated. The ether layer was dried and evaporated. The residue was dissolved in ethyl acetate then extracted by aqueous sodium bisulfite. The aqueous layer was removed, washed with ether and made basic with solid carbonate. After extraction with ethyl ether the extracts were evaporated. The residue was heated in 6 N hydrochloric acid for 1 hour. The solution was made basic and the product extracted into chloroform. After purification over silica with 5% methanol-chloroform, 6-formyl-7,8-methylenedioxy-1-phenyl-2,3,4,5-tetrahydro- 1H-3-benzazepine was obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].O.[NH2:15][NH2:16]>N1C=CC=CC=1>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([C:10]([F:13])([F:12])[F:11])[CH:4]=[CH:5][C:6]=1[NH:15][NH2:16]
Reactant: NN
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1Cl
Solvent: O
Solvent: c1ccncc1
Product: NNc1ccc(C(F)(F)F)c(Cl)c1Cl
Yield: 79.4 %

Procedure:
100 g of 2,3,4-trichlorobenzotrifluoride are initially introduced, 200 ml of pyridine are added, followed by 100 g of hydrazine hydrate and the mixture is then heated to the reflux temperture for 12 hours. Thereafter, 90% of the pyridine is distilled off and the remaining residue is stirred into 250 ml of water. The crystalline product is filtered off under suction, washed with a little water and dried. 78 g of 2,3-dichloro-4-trifluoromethyl-phenylhydrazine having a melting point of 79° to 80° C. are obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[F:32][C:33]1[CH:57]=[CH:56][CH:55]=[CH:54][C:34]=1[O:35][C:36]1[N:37]=[CH:38][C:39]2[N:44]=[C:43]([C:45]3[CH:50]=[C:49]([CH3:51])[C:48]([OH:52])=[C:47]([CH3:53])[CH:46]=3)[O:42][C:40]=2[N:41]=1.O[CH:59]1[CH2:62][CH:61]([C:63]([O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)=[O:64])[CH2:60]1>O1CCCC1.C(N(CC)CC)C>[F:32][C:33]1[CH:57]=[CH:56][CH:55]=[CH:54][C:34]=1[O:35][C:36]1[N:37]=[CH:38][C:39]2[N:44]=[C:43]([C:45]3[CH:46]=[C:47]([CH3:53])[C:48]([O:52][CH:59]4[CH2:62][CH:61]([C:63]([O:65][CH2:66][C:67]5[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=5)=[O:64])[CH2:60]4)=[C:49]([CH3:51])[CH:50]=3)[O:42][C:40]=2[N:41]=1
Reactant: O=C(OCc1ccccc1)C1CC(O)C1
Reactant: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1OC1CC(C(=O)OCc2ccccc2)C1
Reaction time: 0.25 h

Procedure:
At 0° C., 179 mg of triphenylphosphine and 107 μl of diethyl azodicarboxylate were initially charged in 4.5 ml of tetrahydrofuran, and the mixture was stirred for 15 min. 200 mg of 4-[5-(2-fluorophenoxy)oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenol, 95 μl of triethylamine and 141 mg of benzyl 3-hydroxycyclobutanecarboxylate were then added to the reaction, and the reaction was stirred under argon, initially at room temperature for 3 h. Another 179 mg of triphenylphosphine and 107 μl of diethyl azodicarboxylate were then added, and the reaction was stirred for 12 h. For work-up, the reaction was concentrated and the resulting residue was purified by flash chromatography (silica gel, heptane/ethyl acetate). This gave 216 mg (70%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31].C(OC(N1CCC2N(CCCCC(OC)=O)N=C(C3C=CC(Cl)=CC=3)C=2CC1)=O)(C)(C)C>>[CH3:33][O:32][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][N:13]1[C:12]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1
Reactant: COC(=O)CCCCCl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: COC(=O)CCCCn1nc(-c2ccc(Cl)cc2)c2c1CCN(C(=O)OC(C)(C)C)CC2
Product: COC(=O)CCCCn1nc2c(c1-c1ccc(Cl)cc1)CCNCC2

Procedure:
The title compound (0.0042 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.15 g) using methyl 5-chlorovalerate (0.90 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-1-(4-methoxycarbonyl-butyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C19H24ClN3O2, 361.16. found, m/z 362.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.54-7.51 (m, 2H), 7.31-7.29 (m, 2H), 3.95 (t, J=7.0 Hz, 2H), 3.60 (s, 3H), 3.03-3.01 (m, 2H), 2.93-2.91 (m, 4H), 2.56-2.53 (m, 2H), 2.16 (t, J=7.4 Hz, 2H), 1.67-1.62 (m, 2H), 1.41-1.38 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].[CH2:13]([N:15]1[CH2:19][CH:18]2[O:20][CH:17]2[CH2:16]1)[CH3:14].[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].C(O)(C)C>O>[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].[CH2:13]([N:15]1[CH2:16][C@@H:17]([OH:20])[C@H:18]([O:10][C:9]2[CH:11]=[CH:12][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=2[O:7][CH3:8])[CH2:19]1)[CH3:14].[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].[CH2:13]([N:15]1[CH2:16][C@@H:17]([OH:20])[C@H:18]([O:10][C:9]2[CH:11]=[CH:12][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=2[O:7][CH3:8])[CH2:19]1)[CH3:14]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: CCN1CC2OC2C1
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CC(C)O
Product: CCN1C[C@@H](O)[C@H](Oc2ccc(C(C)=O)cc2OC)C1

Procedure:
A mixture of 17.0 g. (0.15 mole) of acetovanillone and 1-ethyl-3,4-epoxypyrrolidine and 3 drops of water was heated on a steam bath overnight. The mixture was dissolved in 250 ml. of methylene chloride and extracted with three 150-ml. portions of 5% sodium hydroxide and one 100-ml. portion of water. The methylene chloride layer was dried over anhydrous sodium sulfate and concentrated to give 19.0 g. crude oil. This oil was chromatographed on 400 g. of silica gel. The desired product was eluted with acetone. The fractions were concentrated to give 14.0 g. of oil which was treated with oxalic acid in isopropyl alcohol. The resulting white solid was recrystallized twice from isopropyl alcohol to yield 13.4 g. (24%) of sesquioxalate, m.p. 121-3° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[CH:3]=[N:2]1.[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22].C(N(CC)CC)C>C(#N)C>[CH2:21]([S:23]([N:1]1[CH:5]=[C:4]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:19][CH2:20]4)=[O:17])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[CH:3]=[N:2]1)(=[O:25])=[O:24])[CH3:22]
Reactant: O=C(Nc1nc2cccc(-c3cn[nH]c3)n2n1)C1CC1
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCS(=O)(=O)n1cc(-c2cccc3nc(NC(=O)C4CC4)nn23)cn1
Reaction time: 8 h

Procedure:
To a solution of cyclopropanecarboxylic acid [5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (WW-060) (0.05 g, 0.186 mmol) in acetonitrile (2 mL), ethanesulfonyl chloride (0.022 ml, 0.224 mmol) and triethylamine (0.052 mL, 0.373 mmol) were added successively and the mixture was stirred overnight. After concentration under reduced pressure water was added and extracted with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by preparatory HPLC. LCMS method: 1, RT: 3.87 min; MI: 361 [M+1]; NMR 1H (DMSO): 0.81-0.95 (m, 4H), 1.15 (t, 3H), 1.94 (brs, 1H), 3.82 (q, 2H), 7.66 (d, 1H), 7.73 (t, 1H), 7.81 (dd, 1H), 8.99 (s, 1H), 9.46 (s, 1H).
Reaction SMILES: C1(S([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=2)[N:25]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[N:24]=[CH:23]4)=[N:16][CH:15]=[N:14]3)=O)C=CC=CC=1.[NH:37]1[CH2:43][CH:42]([OH:44])[CH2:41][NH:40][CH2:39][CH2:38]1>CS(C)=O.C(Cl)Cl>[F:36][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][N:25]1[C:26]2[C:22](=[CH:21][C:20]([NH:19][C:17]3[C:18]4=[C:10]([CH2:9][N:37]5[CH2:43][CH:42]([OH:44])[CH2:41][NH:40][CH2:39][CH2:38]5)[CH:11]=[CH:12][N:13]4[N:14]=[CH:15][N:16]=3)=[CH:28][CH:27]=2)[CH:23]=[N:24]1
Reactant: O=S(Cc1ccn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)c1ccccc1
Reactant: OC1CNCCNC1
Solvent: CS(C)=O
Solvent: ClCCl
Product: OC1CNCCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)C1
Temperature: 140 °C
Yield: 62.2 %

Procedure:
A mixture of (5-benzenesulfinylmethyl-pyrrolo[2,1-f][1,2,4]triazin-4-yl)-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (397 mg, 0.8 mmole) and [1,4]diazepan-6-ol (417 mg, 4.5 equiv, Saari et al., J. Org. Chem., 1971, 36, 1711) in dry DMSO (1.5 mL) in a sealed tube was heated at 140° C. for 11 hr. This was diluted with DCM (150 ml), washed with water and dried (Na2SO4). Removal of the solvent followed by radial chromatography (4 mm silica gel plate; gradient elution with DCM containing 0 to 3% of a 2N NH3 solution in MeOH) gave the title compound as a solid (242 mg, 62%), MS: 487 (M+H)+; HPLC Ret Time: 0.96 min (Xterra S7 3.0×50 mm S7 C18 column, 2 min gradient, 5 ml/min). The racemic material could be separated on a Chiralpak AD 4.6×250 mm column, eluting with 0.05% diethylamine in EtOH for 25 min with a flow rate of 0.7 mL/min) The S and R enantiomers had retention times of 16.20 and 18.90 min respectively. The R enantiomer was synthesized as outlined below.