Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:5]([N:7]1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9](O)=[O:10])=[O:6]>O1CCCC1>[CH3:1][N:2]1[C:3]2[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=2[C:5](=[O:6])[N:7]2[CH2:14][CH2:13][CH2:12][CH:8]2[C:9]1=[O:10]
Reactant: CNc1ccccc1C(=O)N1CCC[C@H]1C(=O)O
Solvent: C1CCOC1
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21

Procedure:
A mixture of 24.8 g. of (-)-1-(N-methylanthraniloyl)proline and 18.0 g. of N,N'-carbonyldiimidazole in 300 ml. of dry tetrahydrofuran is stirred for 2 hours at room temperature and then heated at reflux temperature for 3 hours. The reaction mixture is concentrated to remove the solvent and the residue is extracted into benzene. The benzene solution is washed twice with water and concentrated to recover the desired product.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([O:18][CH3:19])=[C:12]([Cl:20])[C:11]=1[C:21]1[N:26]=[C:25]2[NH:27][N:28]=[CH:29][C:24]2=[CH:23][N:22]=1>CN(C)C=O.O>[Cl:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([O:18][CH3:19])=[C:12]([Cl:20])[C:11]=1[C:21]1[N:26]=[C:25]2[NH:27][N:28]=[C:29]([I:1])[C:24]2=[CH:23][N:22]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3cn[nH]c3n2)c1Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Temperature: 40 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
N-Iodosuccinimide (0.23 g, 1.0 mmol) was added to a solution of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (0.30 g) in N,N-dimethylformamide (5.0 mL). The reaction mixture was stirred at 40° C. overnight. The reaction mixture was diluted with water and quenched with aqueous Na2S2O3. The precipitates formed were filtered, washed with water, ether, and dried in vacuum to afford the desired product (0.33 g). LCMS (M+H)+=450.8/452.8.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26][CH2:25][C:24]1([CH3:32])[CH3:31].C(OCC)(=O)C>CN(C)C=O.O>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([S:1][CH2:21][CH2:22][N:23]3[C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26][CH2:25][C:24]3([CH3:31])[CH3:32])[NH:3][C:4]=2[CH:10]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: CC1(C)CCCC(C)(C)N1CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2nc(SCCN3C(C)(C)CCCC3(C)C)[nH]c2c1
Reaction time: 4.5 h
Yield: 80 %

Procedure:
In 15 ml of N,N-dimethylformamide was dissolved 810 mg of 2-mercapto-5-methoxybenzimidazole, and 933 mg of potassium carbonate and 1.62 g of 1-(2-chloroethyl)-2,2,6,6-tetramethylpiperidine hydrochloride were added to the solution, followed by stirring at 65° to 70° C. for 4.5 hours. After completion of the reaction, 200 ml of ethyl acetate and 70 ml of water were added to the reaction mixture, and the thus extracted ethyl acetate layer was washed successively with a diluted sodium hydrogencarbonate aqueous solution and a diluted sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The extracting solution was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=50:1 to 25:1 by volume) to obtain 1.25 g (80%) of the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:24]([CH3:26])[CH3:25])[C:10]([N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH2:14][CH:13]1[C:21](O)=[O:22])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[F:51][C:52]1[CH:58]=[CH:57][CH:56]=[C:55]([F:59])[C:53]=1[NH2:54].OS([O-])(=O)=O.[K+]>C(Cl)Cl>[F:51][C:52]1[CH:58]=[CH:57][CH:56]=[C:55]([F:59])[C:53]=1[NH:54][C:21]([C@H:13]1[N:12]([C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:24]([CH3:25])[CH3:26])[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH2:14]1)=[O:22].[F:51][C:52]1[CH:58]=[CH:57][CH:56]=[C:55]([F:59])[C:53]=1[NH:54][C:21]([C@H:13]1[N:12]([C:10](=[O:11])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:24]([CH3:25])[CH3:26])[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH2:14]1)=[O:22]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ncccc2CC1C(=O)O
Reactant: Nc1c(F)cccc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Reaction time: 0.08 h

Procedure:
To a solution of 1-((S)-2-(tert-butoxycarbonylamino)-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (260 mg, 715 μmol, Eq: 1.00) and diisopropylethylamine (375 μL, 2.15 mmol, Eq: 3) in DCM (7.8 mL) was added diphenylphosphinic chloride (372 mg, 300 μL, 1.57 mmol, Eq: 2.2). After stirring for 5 min, 2,6-difluoroaniline (109 μL, 1.07 mmol, Eq: 1.5) was added and the resulting solution was stirred at rt overnight. The reaction mixture was poured into 0.1 M aqueous KHSO4 (20 mL) and the resulting mixture was extracted with EtOAc. The organic layers were concentrated in vacuo and the crude material was purified by flash chromatography (silica gel, 40 g, 0% to 30% EtOAc in hexanes) to give tert-butyl (S)-1-((S)-2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (100 mg) and tert-butyl (R)-1-((S)-2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate white solid (80 mg), m/z=497 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:16](N(CC)CC)[CH3:17].ICC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC1(c2cc(F)cc(Cl)c2)CCNC1
Reactant: CCN(CC)CC
Solvent: CCI
Solvent: C1CCOC1
Product: CCN1CCC(OC)(c2cc(F)cc(Cl)c2)C1

Procedure:
Preparation according to Example 22. (−)-3-(3-chloro-5-fluorophenyl)-3-methoxypyrrolidine (0.01 g, 0.043 mmol), triethylamine (12.1 μL, 0.086 mmol), tetrahydrofuran (2 ml) and iodoethane (5.2 μL, 0.065 mmol). The crude product analyzed by GCMS. Analysis showed 83% conversion. MS m/z (relative intensity, 70 eV) 257 (M+, 8), 242 (78), 227 (31), 157 (36), 71 (bp).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11].O>C(O)C>[Cl:1][C:2]1[C:7]([NH:10][NH2:11])=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccnc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1nccnc1Cl
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2,3-Dichloropyrazine A-1 (15 g; 100.68 mmol) and hydrazine hydrate 65% (15.509 ml; 201.37 mmol) are dissolved in 45 ml ethanol and stirred for 1 h at 80° C. While cooling down, a precipitate is formed. It is slurred up with a small amount of water and filtered off. It is washed with water and then dried to afford the product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])=[N:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH:28]4[CH2:31]OC4)=[O:26])=[CH:20][CH:19]=3)=[N:6][C:5]=2[CH:4]=[N:3]1.Cl.[CH3:33][S:34](CCN)(=[O:36])=[O:35]>>[CH3:1][N:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])=[N:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH2:28][CH2:31][S:34]([CH3:33])(=[O:36])=[O:35])=[O:26])=[CH:20][CH:19]=3)=[N:6][C:5]=2[CH:4]=[N:3]1
Reactant: CS(=O)(=O)CCN
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3COC3)cc2)nc2cnn(C)c12
Agent: Cl
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCS(C)(=O)=O)cc2)nc2cnn(C)c12

Procedure:
This compound was prepared in an analogous fashion to (S)-1-(4-(1-methyl-7-(3-methylmorpholino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-3-(oxetan-3-yl)urea, using 2-(methylsulfonyl)ethanamine hydrochloride as the starting material. 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.96 (s, 1H), 8.25 (d, J=8.8 Hz, 2H), 8.21 (s, 1H), 7.51 (d, J=8.8 Hz, 2H), 6.42 (t, J=5.9 Hz, 1H), 4.25 to 4.13 (m, 4H), 3.96 to 3.83 (m, 2H), 3.78 to 3.79 (m, 1H), 3.79 to 3.60 (m, 2H), 3.60 to 3.47 (m, 3H), 3.37 to 3.30 (m, 5H), 1.27 (d, J=6.5 Hz, 3H); LC-MS m/z (method C1)=474.2 [M+H]+, RT=3.13 min
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH3:18])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:22][C:23]1[CH:28]=[C:27](Cl)[N:26]=[CH:25][N:24]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:27]2[CH:28]=[C:23]([Cl:22])[N:24]=[CH:25][N:26]=2)=[C:13]([CH3:18])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(NC(=O)OCc2ccccc2)ccc1O
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)OCc2ccccc2)ccc1Oc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(4-Hydroxy-3-methyl-phenyl)-carbamic acid benzyl ester (278 mg, 1.08 mmol) and NaH (29 mg, 1.2 mmol) dissolved in DMF (5 mL) are stirred at rt for 15 min. 4,6-Dichloro-pyrimidine (177 mg, 1.19 mmol) dissolved in DMF (5 mL) is added and the reaction solution is stirred for 1 h, concentrated under reduced pressure and flash chromatographed (silica gel, 2.5×60 cm, AcOEt/hexane=1:6): M+H=370.8; Rf (AcOEt/hexane=1:6): 0.31.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1)[NH2:5].Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]3[O:30][C:31]([CH3:34])=[N:32][N:33]=3)[CH:27]=2)[N:22]=[CH:21][N:20]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]4[O:30][C:31]([CH3:34])=[N:32][N:33]=4)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1
Reactant: Cc1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Product: Cc1nnc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Product: Cl

Procedure:
The title compound was prepared according to Procedure A from 3-chloro-4-(3-fluoro-benzyloxy)aniline and 4-chloro-6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.73(1H,bs), 9.38(1H,s), 8.94(1H,s), 8.57(1H,d), 8.10(1H,d), 7.90(1H,d), 7.65(1H,dd), 7.45(1H,m), 7.30(3H,m), 7.16(1H,m), 5.30(2H,s), 2.65(3H,s); m/z (M+1+) 462.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([O:65][C:66]([C@H:68]1[CH2:72][CH2:71][CH2:70][NH:69]1)=[O:67])[CH3:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:69]1[CH2:70][CH2:71][CH2:72][C@@H:68]1[C:66]([O:65][CH2:63][CH3:64])=[O:67])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CCOC(=O)[C@H]1CCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1CCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (R)-2-ethyloxycarbonyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH:14]([C:17](O)=[O:18])[CH:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:12]4[C:26](=[O:28])[NH:27][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:29])[O:4][N:3]=1.[CH3:30][CH2:31][N:32](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C1COCC1>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH:14]([C:17]([NH:32][CH2:31][CH3:30])=[O:18])[CH:13]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:12]4[C:26](=[O:28])[NH:27][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OC(C(=O)O)C3c1ccccc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNC(=O)C1Oc2c(-c3c(C)noc3C)ccc3[nH]c(=O)n(c23)C1c1ccccc1
Temperature: 25 °C

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxylic acid (0.04 g, 0.1 mmol) was dissolved in DMF (2.0 mL) with DIPEA (0.036 mL, 0.20 mmol) at room temperature. HATU (0.054 g, 0.14 mmol) was added and then the 2.0 Methylamine in THF (0.20 mL, 0.41 mmol) was added. The reaction mixture was stirred at room temperature for an hour and was diluted with EtOAc. The organic layer was washed with 1 N HCl, brine, dried over magnesium sulfate and concentrated to give a solid. The product was purified by preparative HPLC on a C-18 column eluting with a water:MeCN gradient buffered pH 2 to give the title compound as two separated diastereoisomers.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])/[C:5](/Br)=[CH:6]/[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2].[CH3:15][S:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:14])/[C:5](/[C:20]1[CH:21]=[CH:22][C:17]([S:16][CH3:15])=[CH:18][CH:19]=1)=[CH:6]/[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CCOC(=O)/C(Br)=C/C1CCCCC1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(=C/C1CCCCC1)c1ccc(SC)cc1
Yield: 87.6 %

Procedure:
Dissolve (Z)-2-bromo-3-cyclohexyl-acrylic acid ethyl ester (76.4 g, 300 mmol) and 4-(methylthio)benzene boronic acid (60.5 g, 360 mmol) in a mixture of 1500 mL toluene, 500 mL ethanol and 2M aqueous sodium carbonate solution (500 mL). Add tetrakis(triphenylphosphino)palladium(0) (10.4 g, 3mol %) and heat the mixture at reflux for 5 h. Cool and remove the ethanol under vacuum. Partition the residue between water (250 mL) and dichloromethane (4×250 mL). Combine the extracts and dry over magnesium sulfate, filter and concentrate. Pass through a silica gel pad with a mix of iso-hexane:dichloromethane:diethyl ether (92:4:4) to give the title compound as a hazy oil (80 g). GC-MS (m/e): 304 (M+).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].CN([CH:9]=[O:10])C.[C:11]1([C:17]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>O>[Cl:3][C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:9]=[O:10]
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=CC(=C(Cl)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.25 mol (23 mL) of POCl3 was added at 0° C. to a 0.3 mol (23.5 mL) of DMF. At the end of the addition, the mixture was allowed to warm to room temperature and stirred for 1 h. Then it was cooled again to 0° C. and treated with 0.1 mol (19.6 g) of deoxybenzoin. The resulting reaction mixture was allowed to reach room temperature, stirred for 12 h at the same temperature and subsequently heated at 100° C. for 2 h. Finally it was poured into a mixture of ice and 10% solution of sodium acetate in water. The oily precipitate was filtered and washed with cold methanol and hexane. The residue was crystallized. Yield 18.5 g (76%).
Reaction SMILES: [C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[C:24]([Cl:25])=[CH:23][C:22]([OH:26])=[CH:21][C:20]=3[Cl:27])[C:14]2=[O:28])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[C:31]([O-])([O-])=O.[Cs+].[Cs+].FC[C:39]1[CH:47]=[CH:46][C:42]([C:43]([O-:45])=[O:44])=[CH:41][CH:40]=1>CN(C=O)C.O.CCOC(C)=O>[CH3:31][O:45][C:43](=[O:44])[C:42]1[CH:46]=[CH:47][C:39]([O:26][C:22]2[CH:21]=[C:20]([Cl:27])[C:19]([CH2:18][CH:15]3[CH2:16][CH2:17][N:13]([C@H:10]4[CH2:11][CH2:12][C@@H:7]([O:6][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:30])[CH3:29])[CH2:8][CH2:9]4)[C:14]3=[O:28])=[C:24]([Cl:25])[CH:23]=2)=[CH:40][CH:41]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(O)cc3Cl)C2=O)CC1
Reactant: O=C([O-])c1ccc(CF)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Oc2cc(Cl)c(CC3CCN([C@H]4CC[C@@H](O[Si](C)(C)C(C)(C)C)CC4)C3=O)c(Cl)c2)cc1

Procedure:
Combine 0.5 g (1 mmol) of 1-[cis-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-3-(2,6-dichloro-4-hydroxy-benzyl)-pyrrolidin-2-one (Preparation 72) 0.7 g (2 mmol) Cs2CO3 and 0.49 g (3 mmol) p-fluoromethylbenzoate in 10 mL dry DMF and heat at 100° C. for 4 hours. Dilute the mixture with 25 mL H2O and 50 mL EtOAc. Separate the layers and extract the aqueous with 50 mL EtOAc. Combine the organic layers, wash with brine, dry over MgSO4 and concentrate under vacuum. Purify via chromatography using 30% EtOAc in hexanes to recover 0.47 g of an oil.
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.Br[CH2:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29].C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC(CC)CC)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CCC(CC)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CCC(CC)Cn1nc2c(c1-c1ccc(Cl)cc1)CCN(C(=O)OC(C)(C)C)CC2
Product: CCC(CC)Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 15.1 %

Procedure:
The title compound (0.010 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 103, Step B; 0.2 mmol) using 1-bromo-2-ethyl-butane (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(2-ethyl-butyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C19H26ClN3, 331.18. found, m/z 332.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.50-7.48 (br m, 4H), 4.11-4.09 (br m, 2H), 3.71-3.69 (br m, 2H), 3.33-3.31 (br m, 2H), 3.26-3.24 (br m, 2H), 3.06-3.04 (br m, 2H), 1.91-1.89 (m, 1H), 1.36-1.34 (m, 4H), 0.93 (t, J=7.3 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].C(N(CC)CC)C.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: NCc1ccccc1Cl
Reactant: COc1cccc(CC(=O)O)c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cccc(CC(=O)NCc2ccccc2Cl)c1

Procedure:
A mixture of 12.5 g of 3-methoxyphenylacetic acid, 21.2 g of 2-chlorobenzylamine, 15.1 g of triethylamine, 19.3 ml of borontrifluoride etherate, and 500 ml of toluene was stirred under reflux for 18 hours using a Dean-Stark moisture trap and allowed, to cool. The mixture was extracted with aqueous sodium hydroxide, dilute hydrochloric acid, and water. The remaining organic solution was then evaporated and the residue crystallized from hexane to yield N-(2-chlorobenzyl)-3-methoxyphenylacetamide as a yellow solid, m.p. 89°-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:15]1[NH:20][CH2:19][CH2:18][N:17]2[CH2:21][CH2:22][CH2:23][C@H:16]12.C(=O)([O-])[O-].[Na+].[Na+].[F:30][C:31]([F:40])([F:39])[C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1>ClCCl.CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([NH:36][C:35]2[CH:37]=[CH:38][C:32]([C:31]([F:30])([F:39])[F:40])=[CH:33][CH:34]=2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([N:20]1[CH2:19][CH2:18][N:17]2[CH2:21][CH2:22][CH2:23][C@@H:16]2[CH2:15]1)=[O:5]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: C1C[C@@H]2CNCCN2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(c1cc(S(=O)(=O)Nc2ccc(C(F)(F)F)cc2)ccc1Cl)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To crude 2-chloro-5-(chlorosulfonyl)benzoyl chloride (2 mmol) in anhydrous dichloromethane (50 mL) was added (R)-octahydropyrrolo[1,2-α]pyrazine (0.252 g, 2 mmol) in dichloromethane (4 mL) slowly over 10 minutes at room temperature. Then sodium carbonate (0.46 g, 4.4 mmol) was added. The mixture was stirred at room temperature overnight. Then dichloromethane was removed by concentration, and 4-(trifluoromethyl)aniline (3.22 g, 20 mmol) was added. The mixture was stirred at 70° C. overnight. Then sodium carbonate (0.21 g, 2 mmol) and methanol (5 mL) were added at room temperature. The mixture was stirred for 30 minutes, then filtered, and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate, then methanol/ethyl acetate=1:10) to give the titled compound: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.30 (m, 1H), 1.55 (m, 1H), 1.70-2.00 (m, 4H), 2.60 (m, 2H), 2.80-3.50 (m, 4H), 4.40-4.60 (m, 1H), 7.30 (m, 2H), 7.62 (m, 2H), 7.82 (m, 3H), 11.00 (br s, 1H); MS (ESI) m/z 488 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:16][C:17](O)=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1.O.CCOC(C)=O>CCOCC>[CH:7]1([CH2:16][CH2:17][OH:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1
Reactant: O=C(O)CC1CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: OCCC1CCc2ccccc21
Temperature: 25 °C
Yield: 92.5 %

Procedure:
Lithium aluminum hydride (1 M in Et2O, 14 mL, 14 mmol) was slowly added to a solution of 2-indanylacetic acid (2.5 g, 14 mmol) in Et2O. The reaction mixture was heated at reflux for 2 h and was cooled to room temperature. Water and EtOAc were added and the organic solution was washed with water (2×) and brine (1×), dried over MgSO4, filtered, and concentrated to afford 2-indanylethanol (2.1 g) which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.08–7.24 (m, 4H), 3.75 (t, 2H), 3.07 (m, 2H), 2.61 (m, 3H), 1.80 (m, 2H); MS 180 (M+18).