Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[O:15][P:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC(CC(C1C(O)=CC(O)=C(CC=C(C)C)C=1[O-])=O)C>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([P:16](=[O:15])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COP(c1ccccc1)c1ccccc1
Agent: CC(C)=CCc1c(O)cc(O)c(C(=O)CC(C)C)c1[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(=O)P(=O)(c2ccccc2)c2ccccc2)cc1

Procedure:
41.3 parts of p-tert.-butylbenzoyl chloride are reacted with 45.4 parts of methoxydiphenylphosphine, dissolved in 20 parts of toluene, in 90 minutes at 50° C., by a method similar to that described for compound X. After evaporating off the solvent on a rotary evaporator, the product is recrystallized from cyclohexane.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C@@H:27]1[CH2:38][CH2:37][C@@H:36]([O:39][Si](C(C)C)(C(C)C)C(C)C)[C:30]2=[N+:31]([O-:35])[CH:32]=[CH:33][CH:34]=[C:29]2[CH2:28]1>C1COCC1>[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C@@H:27]1[CH2:38][CH2:37][C@@H:36]([OH:39])[C:30]2=[N+:31]([O-:35])[CH:32]=[CH:33][CH:34]=[C:29]2[CH2:28]1
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)Cc2ccc[n+]([O-])c21)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: [O-][n+]1cccc2c1[C@H](O)CC[C@@H](c1cccc(F)c1F)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
TBAF (4.18 mL, 4.18 mmol) was added to the THF (10 mL) solution of (6R,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine 1-oxide (1.56 g, 3.48 mmol) at rt. The reaction was stirred at room temperature for 2 hours and LCMS showed that the reaction was completed. The solvent was removed via vacuum and the crude was load to flash column and eluted with methanol in CH2Cl2 from 0 to 10% to afford the desired product (0.7662 g, 75%) as a yellow solid. MS (ESI)[M+H+]=292.10; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.16-8.26 (m, 1H) 7.14-7.20 (m, 1H) 6.98-7.12 (m, 3H) 6.90 (td, J=7.55, 1.76 Hz, 1H) 5.38-5.48 (m, 1H) 3.24-3.47 (m, 2 H) 3.02 (dd, J=14.60, 1.76 Hz, 1H) 2.27-2.44 (m, 3H) 1.79-1.94 (m, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:18]2[O:17][C:16]3[C:19]([CH:25]=O)=[C:20]([OH:24])[CH:21]=[C:22]([CH3:23])[C:15]=3[C:14](=[O:27])[O:13][C:12]=2[C:11]([CH3:28])=[C:10]([O:29][CH3:30])[CH:9]=1)=[O:7])[CH2:2][CH2:3]C.[N:31]1([CH2:37][CH2:38][NH2:39])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH2:1]([O:5][C:6]([C:8]1[C:18]2[O:17][C:16]3[C:19]([CH2:25][NH:39][CH2:38][CH2:37][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[C:20]([OH:24])[CH:21]=[C:22]([CH3:23])[C:15]=3[C:14](=[O:27])[O:13][C:12]=2[C:11]([CH3:28])=[C:10]([O:29][CH3:30])[CH:9]=1)=[O:7])[CH2:2][CH3:3]
Reactant: CCCCOC(=O)c1cc(OC)c(C)c2c1Oc1c(C=O)c(O)cc(C)c1C(=O)O2
Reactant: NCCN1CCOCC1
Product: CCCOC(=O)c1cc(OC)c(C)c2c1Oc1c(CNCCN3CCOCC3)c(O)cc(C)c1C(=O)O2

Procedure:
This compound was prepared from the compound from Example 8 by means of a procedure similar to that used for Example 18 except replacing ethanolamine with 2-morpholin-4-yl-ethylamine.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH:14]1([C@H:17]([NH2:39])[C:18]([N:20]2[CH2:24][C:23]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])=[CH:22][C@H:21]2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:19])[CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>ClCCl>[CH:14]1([C@H:17]([NH:39][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[C:18]([N:20]2[CH2:24][C:23]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])=[CH:22][C@H:21]2[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:19])[CH2:16][CH2:15]1
Reactant: N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
4-nitrophenyl chloroformate (171 mg, 0.85 mmol, 1.5 equiv) was added to a solution of (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethanamine (16-7, 200 mg, 0.564 mmol, 1 equiv) and N,N-diisopropylethylamine (172 μL, 0.988 mmol, 1.75 equiv) in dichloromethane (5 mL) at 0° C., and the resulting mixture was stirred for 15 minutes, then warmed to 23° C. and stirred for an additional 30 minutes. Additional 4-nitrophenyl chloroformate (1.0 equiv) and N,N-diisopropylethylamine (1.0 equiv) were added and the mixture was stirred for 2.5 hours, then partitioned between water (55 mL) and dichloromethane (2×45 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide 4-nitrophenyl(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethylcarbamate (26-1) as a light yellow oil. LRMS m/z (M+H) 520.4 found, 520.2 required.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:15][CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)[C:4]=2[C:5]([N:8]=CN(C)C)=[N:6][CH:7]=1.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[NH2:8][C:5]1[C:4]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)=[CH:14][S:15][C:3]=2[C:2]([NH:1][S:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:45])=[O:44])=[CH:7][N:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cc(-c2csc3c(N)cnc(N=CN(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: COc1cc(-c2csc3c(NS(=O)(=O)c4ccccc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-[4-(7-amino-4-{[(dimethylamino)methylene]amino}thieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide and phenylsulfonyl chloride using General Procedure G followed by General Procedure M. 1H NMR (DMSO-d6, 400 MHz) δ 9.80 (br, 1H), 9.49 (s, 1H), 7.97 (d, 1H), 7.75 (d, 2H), 7.70 (d, 1H), 7.64 (d, 1H), 7.58 (m, 3H), 7.51 (s, 1H), 7.34 (m, 2H), 7.17 (m, 2H), 7.15 (s, 1H), 7.05 (d, 1H), 5.50 (br, 2H), 4.03 (s, 3H), 3.90 (s, 3H); MS: (MH)+ 584.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH2:19][CH3:20])[C:10]([NH:12][C:13]([CH3:18])([CH3:17])[C:14]#[C:15][CH3:16])=[O:11])[CH:5]=[N:6][CH:7]=1.[CH2:21](C([Sn])=C(CCCC)CCCC)[CH2:22]CC.C(OCC)C>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:21]([C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH2:19][CH3:20])[C:10]([NH:12][C:13]([CH3:18])([CH3:17])[C:14]#[C:15][CH3:16])=[O:11])[CH:5]=[N:6][CH:7]=1)=[CH2:22]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: CC#CC(C)(C)NC(=O)C(CC)Oc1cncc(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=Cc1cncc(OC(CC)C(=O)NC(C)(C)C#CC)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-(5-Bromo-3-pyridyloxy)-N-(4-methylpent-2-yn-4-yl)butyramide (0.34 g), tetrakis(triphenylphosphine) palladium (0) (0.0.02 g) and tributylvinyl tin(0.38 g) in dry toluene (5 ml) were stirred and heated to reflux for 9 hours under an atmosphere of nitrogen. The mixture was cooled to ambient temperature, stored for 72 hours then evaporated under reduced pressure to give a gum that was fractionated by chromatography (silica; diethyl ether) to give the required product, 0.16 g, as a colourless gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.CN(C)C1N=CC(B(O)O)=CC=1.Br[C:25]1[CH:26]=[CH:27][C:28]2[O:49][CH2:48][C:31]3([C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH2:40][C:41]4[S:42][C:43]([Cl:46])=[CH:44][CH:45]=4)[C:32]3=[O:47])[C:29]=2[CH:30]=1.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2CC1SC(Cl)=CC=1>>[Cl:46][C:43]1[S:42][C:41]([CH2:40][N:33]2[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:31]3([C:29]4[CH:30]=[C:25]([C:6]5[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[CH:26]=[CH:27][C:28]=4[O:49][CH2:48]3)[C:32]2=[O:47])=[CH:45][CH:44]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C1N(Cc2ccc(Cl)s2)c2ccccc2C12COc1ccc(Br)cc12
Agent: CN(C)c1ccc(B(O)O)cn1
Agent: O=C1N(Cc2ccc(Cl)s2)c2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Product: COc1ccc(-c2ccc3c(c2)C2(CO3)C(=O)N(Cc3ccc(Cl)s3)c3ccccc32)cn1

Procedure:
Following the procedure as described in EXAMPLE 16.12 and making non-critical variations using (6-methoxypyridin-3-yl)boronic acid to replace 6-(dimethylamino)pyridin-3-ylboronic acid, and 5-bromo-1′-[(5-chloro-2-thienyl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-[(5-chloro-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, 1′-[(5-chloro-2-thienyl)methyl]-5-(6-methoxypyridin-3-yl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (20%) as a colorless solid: mp 60-62° C.; 1H NMR (300 MHz, CDCl3) 8.16 (d, J=2.5 Hz, 1H), 7.54 (dd, J=8.6, 2.2 Hz, 1H), 7.35 (dd, J=8.4, 1.6 Hz, 1H), 7.27 (t, J=7.7 Hz, 1H), 7.17 (d, J=7.3 Hz, 1H), 7.07-6.98 (m, 2H), 6.95 (d, J=7.8 Hz, 1H), 6.88 (d, J=2.2 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H), 5.12 (d, J=15.8 Hz, 1H), 5.00 (d, J=9.2 Hz, 1H), 4.91 (d, J=15.8 Hz, 1H), 4.73 (d, J=9.2 Hz, 1H), 3.89 (s, 3H); 13C NMR (75 MHz, CDCl3) 176.9, 163.2, 160.3, 144.5, 141.3, 137.2, 136.9, 132.2, 131.7, 130.1, 129.8, 129.6, 129.1, 128.5, 126.4, 126.0, 124.1, 123.9, 121.7, 110.9, 110.6, 109.0, 79.7, 60.4, 58.0, 53.5, 39.2; MS (ES+) 475.5 (M+1) 477.5 (M+1).
Reaction SMILES: [Cl:1][C:2]1C=[CH:9][C:8]([N:11]([CH3:28])[C:12]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=2[C:24]([F:27])([F:26])[F:25])=[O:13])=[CH:7][C:3]=1C(O)=O.CN(C)C=O.[C:34](Cl)(=O)[C:35]([Cl:37])=[O:36]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:7][C:8]([N:11]([CH3:28])[C:12]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=2[C:24]([F:25])([F:26])[F:27])=[O:13])=[CH:9][C:34]=1[C:35]([Cl:37])=[O:36]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C(=O)c1c(C(F)(F)F)c(C(F)(F)F)nn1C)c1ccc(Cl)c(C(=O)O)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C(=O)c1c(C(F)(F)F)c(C(F)(F)F)nn1C)c1ccc(Cl)c(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
150.0 mg (0.29 mmol) of 2-chloro-5-(methyl{[1-methyl-3,4-bis(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)benzoic acid are suspended in 5.0 ml of dichlormethane p.a. 0.02 ml of N,N-dimethylformamide p.a. and 0.075 ml (0.86 mmol) oxalyl chloride are then added successively to the suspension. The reaction mixture is stirred at room temperature for 0.5 h and then heated under reflux for 40 minutes. The solvent is removed under reduced pressure on a rotary evaporator. The 2-chloro-5-(methyl{[1-methyl-3,4-bis(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)benzoyl chloride formed is used for the subsequent synthesis step without further purification.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([OH:7])=O)#[N:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:50][C:51]1[CH:52]=[C:53]([C:58]2([C:71]([F:74])([F:73])[F:72])[O:62][N:61]=[C:60]([C:63]3[S:67][C:66]([CH3:68])=[C:65]([CH2:69][NH2:70])[CH:64]=3)[CH2:59]2)[CH:54]=[C:55]([Cl:57])[CH:56]=1>ClCCl>[C:1]([CH2:3][CH2:4][C:5]([NH:70][CH2:69][C:65]1[CH:64]=[C:63]([C:60]2[CH2:59][C:58]([C:53]3[CH:54]=[C:55]([Cl:57])[CH:56]=[C:51]([Cl:50])[CH:52]=3)([C:71]([F:73])([F:74])[F:72])[O:62][N:61]=2)[S:67][C:66]=1[CH3:68])=[O:7])#[N:2]
Reactant: N#CCCC(=O)O
Reactant: Cc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1CNC(=O)CCC#N
Reaction time: 4 h
Yield: 19.6 %

Procedure:
3-Cyanopropionic acid (104 mg) and PyBOP (400 mg) are added to a solution of DIPEA (0.36 ml) and C-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-thiophen-3-yl}-methylamine (286 mg, Example 1, step F) in dichloromethane (5 ml). After 4 hours at RT, the reaction is quenched with water. The aqueous phase is separated and further extracted two times with dichloromethane. The organic phases are combined, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 3-cyano-N-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-thiophen-3-ylmethyl}-propionamide (compound 1.39, 67 mg) as a beige resin. MS (HPLC/MS): 491 (MH+). Retention time: 1.90 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1.[C:21]([O:25][C:26]([NH:28][C@H:29]([CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1)[CH2:30][C:31](O)=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:31](=[O:32])[CH2:30][C@H:29]([NH:28][C:26](=[O:27])[O:25][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)[CH2:16]1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Yield: 92.8 %

Procedure:
(R)-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (7D) (0.387 mmol, 0.120 g) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. DMF (3 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (0.387 mmol, 0.127 g) and N-methylmorpholine (1.55 mmol, 0.170 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.426 mmol, 0.162 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (25-95% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (R)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (7E) as a clear oil (0.359 mmol, 0.210 g, 93% yield). ESI-MS: m/z 585.5 (M+Hr.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])=[N+:2]=[N-:3].[CH2:15](O)[CH2:16][OH:17].O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:15]1[CH2:16][O:17][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[O:8]1
Reactant: [N-]=[N+]=NCCCC(=O)c1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCCCC1(c2ccccc2)OCCO1
Temperature: 25 °C
Yield: 107.6 %

Procedure:
4-Azidobutyrophenone (100.0 mg, 0.53 mmol) was dissolved in toluene (5 ml) at room temperature, and thereto were added ethylene glycol (0.06 ml, 1.06 mmol) and p-toluene sulfonic acid mono hydrate (10.1 mg, 0.05 mmol) in sequential order at the same temperature, and thereafter, the mixture was refluxed using a Dean Stark tube for 24 hours. The reaction solution was cooled to room temperature and added to water thereafter, followed by the extraction using ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The target compound was thus obtained as a colorless oil (133 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[F:19])[N:3]=1.[IH:20].[Na+].[I-]>O>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([F:19])=[C:12]([C:4]2[N:3]=[C:2]([I:20])[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[N:5]=2)[CH:17]=1
Reactant: I
Reactant: Fc1ccc(Cl)cc1-c1nc(Cl)c2c(n1)CCCC2
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: Fc1ccc(Cl)cc1-c1nc(I)c2c(n1)CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-chloro-2-(5-chloro-2-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (534 mg, 1.89 mmol, 1 eq) in a 57% HI solution in water (10 ml) at r.t. was added NaI (1.42 g, 9.47 mmol, 5 eq). The reaction mixture was stirred at r.t. overnight and then poured onto ice. The product was extracted with chloroform and the aqueous layer was neutralized with NaHCO3 and extracted further with more chloroform. The organic layers were combined washed with brine, dried (MgSO4), filtered and evaporated in vacuo to provide a crude white solid 2-(5-Chloro-2-fluorophenyl)-4-iodo-5,6,7,8-tetrahydroquinazoline which was not further purified.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:11][N:12]([C:15]3[C:16]([O:23][CH3:24])=[N:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[C:34]([CH3:40])[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:31][C:32]2[CH:33]=[C:34]([CH3:40])[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=2)[C:9]2[C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:11][N:12]([C:15]3[C:16]([O:23][CH3:24])=[N:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C)c1C(O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C)c1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-methyl-1H-pyrazole-3-carboxylate (Step 55.3) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.59 min (HPLC 1); tR: 1.06 min (LC-MS 2); ESI-MS: 553 [M+H]+ (LC-MS 2); Rf=0.40 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=2)=[CH:23][C:20]=1[CH2:21]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:9]([O:8][P:1]([CH2:21][C:20]1[CH:23]=[C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=2)[CH:25]=[CH:26][C:19]=1[O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:2])[O:5][CH2:6][CH3:7])[CH3:10]
Reactant: CCc1ccc(Cc2ccc(OCc3ccccc3)c(CCl)c2)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cc(Cc2ccc(CC)cc2)ccc1OCc1ccccc1)OCC
Temperature: 155 °C
Reaction time: 4 h

Procedure:
Triethyl phosphite (0.6 mL) was added to 2-benzyloxy-5-(4-ethylbenzyl)benzylchloride (1.00 g), and the mixture was stirred for 4 hr at 150-160° C. The mixture was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/2) to give the title compound (1.09 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(OC(F)(F)F)cc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(OC(F)(F)F)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 2-methoxy-5-trifluoromethoxybenzoic acid (0.6 g, 2.53 mmol) and dichloromethane (10 mL). Cool in an ice bath. Add dropwise oxalyl chloride (0.64 mL, 5.0 mmol) followed by dimethylformamide (1 drop). Warm to ambient temperature. After 3 hours, evaporate in vacuo and dry to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:13].[C:15]1(N)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>O.N>[CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([C:11]3[NH:21][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:12]=3)=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:13]
Reactant: CC1(C)C(=O)Nc2cc(C#N)ccc21
Reactant: Nc1ccccc1N
Agent: N
Solvent: O
Product: CC1(C)C(=O)Nc2cc(-c3nc4ccccc4[nH]3)ccc21
Yield: 10.3 %

Procedure:
One heated 3,3-dimethyl-2,3-dihydro-2-oxo-(1H)-6-indolecarbonitrile (2.6 g, preparation described in DE-A-3,818,830) and ortho-phenylenediamine (2.6 g) in polyphosphoric acid for 6 h at 160° C. One allowed to cool to 80°-90° C., added ice thereto, diluted with water to a volume of 1.2 l and neutralised with conc. ammonia. One extracted with a mixture of dichloromethane:methanol=10:1, removed the solvent in a vacuum and purified the residue column chromatographically (silica gel 60, dichloromethane:methanol. ammonia=20:1). One obtained 0.4 g of grey crystals which one recrystallised from ethanol/water. One obtained 195 mg of the title compound with the m.p. 326°-330° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.[H-].[Na+].Cl[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[N:9]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=2)[N:7]=1
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Reactant: CCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1nc2ccc(Cl)nn2c1=O
Temperature: 90 °C

Procedure:
To a solution of 6-chloro-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-one [P. Francavilla and F. Lauria, J. Het. Chem., 8, 415 (1971)] (1, 1.00 g., 5.9 m.mole) in dry DMF (30 ml.) was added sodium hydride (50% in paraffin, 0.3 g., 6.3 m.mole) under stirring with formation of yellow crystals. To the mixture was added ethyl chloroacetate (1.4 ml., 13 m.mole) and the mixture was heated at 90° C. for 8 hours with stirring. After cooling, the reaction mixture was poured into water (50 ml.) and extracted with toluene (5 × 40 ml.). The organic extracts were combined, dried over anhydrous sodium sulfate and evaporated at reduced pressure. The residue was crystallized with benzene-n-hexane to give yellow needles of 2 (1.16 g., 77%), m.p. 114°-115° C. (lit. 110° C.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].CCN(C(C)C)C(C)C.C(OC1C=CC(/C=C2/C(=O)N(CCNC(=O)C)C(=O)S/2)=CC=1)C>>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11](/[CH:10]=[C:7]2/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][C:22](=[O:23])[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:5](=[O:20])[S:6]/2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CCOc1ccc(/C=C2\SC(=O)N(CCNC(C)=O)C2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(/C=C2\SC(=O)N(CCNC(=O)OCc3ccccc3)C2=O)cc1

Procedure:
The title compound 26d was prepared from compound 76 (70 mg, 0.17 mmol), benzyl chloroformate (27 μL, 0.19 mmol) and DIPEA (75 μL, 0.43 mmol) in a manner similar to that described for 25a in 95.5% (70 mg) yield as a light-yellow solid.