Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(C(Cl)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].C(N(CCCC)CCCC)CCC>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:19]([O:18][C:14]([C:15]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1)=[CH2:16])=[O:17])[CH3:20]
Reactant: C=CC(=O)OCC
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccc(C)cc1
Product: C=C(C(=O)OCC)c1cccc2ccccc12

Procedure:
0.2244 g (10-3 mols) of palladium acetate, 15.05 g (0.1 mol) of naphthalene-1-carboxylic acid chloride, 13.54 ml (0.125 mol) of ethyl acrylate and 23.95 ml (0.1 mol) of tri-n-butylamine, in 200 ml of p-xylene, are stirred for 1 hour at 120° C. The crude product is distilled in vacuo. 15.6 g (69% of theory) of a colourless liquid (which distils at 143°-147° C./106 Pa) are obtained. Analysis for C15H14O2 : calculated C 79.62%, H 6.24%, O 14.14%; found C 79.24%, H 6.39%, O 14.27%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)P(=O)(N(C)C)N(C)C.C([N-]C(C)C)(C)C.[Li+].[C:32]([O:36][C:37]([N:39]1[CH2:45][C@H:44]([O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[CH2:43][C@H:40]1[CH:41]=[O:42])=[O:38])([CH3:35])([CH3:34])[CH3:33].[Cl-].[NH4+]>O1CCCC1.O.C(OCC)(=O)C>[C:32]([O:36][C:37]([N:39]1[CH2:45][C@H:44]([O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[CH2:43][C@H:40]1[CH:41]([OH:42])[CH2:10][C:9](=[O:11])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:12])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reactant: CC(=O)N(C)C(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CN(C(=O)CC(O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 37.8 %

Procedure:
Under a nitrogen atmosphere, a solution of N-tert-butoxycarbonyl-N-methylacetamide (289 mg, 1.67 mmol) in tetrahydrofuran (1.0 ml) and then hexamethylphosphoric triamide (290 μl, 1.67 mmol) were dropwise added at -78° C. to a solution comprising a 2.0M lithium diisopropylamide--tetrahydrofuran solution (835 μl, 1.67 mmol) and tetrahydrofuran (10 ml). The mixture was stirred at -78° C. for 20 minutes, and a solution of (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxyprolinal (500 mg, 1.52 mmol) in tetrahydrofuran (2 ml) was dropwise added thereto. The reaction mixture was stirred at the same temperature for 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and then the reaction mixture was poured into a mixture of ethyl acetate--water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained oily residue was subjected to silica gel column chromatography (heptane-ethyl acetate=1:2) to give the title compound (288.8 mg, yield: 37.8%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][N:13]2[CH2:22][C@@H:21]3[CH2:23][O:24][CH2:25][CH2:26][N:20]3[C:19]3[N:18]=[C:17]([Cl:27])[N:16]=[CH:15][C:14]2=3)[CH:3]=1.[C:28]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1.O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:27][C:17]1[N:16]=[CH:15][C:14]2[N:13]([CH2:12][C:4]3[CH:3]=[C:2]([CH3:28])[CH:11]=[CH:10][C:5]=3[C:6]([O:8][CH3:9])=[O:7])[CH2:22][C@@H:21]3[CH2:23][O:24][CH2:25][CH2:26][N:20]3[C:19]=2[N:18]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(Br)cc1CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(C)cc1CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
(R)-methyl 4-bromo-2-((2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)benzoate (PREPARATION x56, 164 mg, 0.361 mmol), K2CO3 (100 mg, 0.723 mmol), PdCl2(dppf) (13.22 mg, 0.018 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.060 mL, 0.434 mmol) were dissolved in dioxane (2 mL) and water (0.4 mL) to give an orange suspension. The reaction mixture was heated to 100° C. and allowed to stir overnight, then quenched with aqueous saturated NH4Cl. The reaction mixture was diluted with ethyl acetate and washed with aqueous saturated NH4Cl (3×15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was then loaded onto an ISCO® silica gel cartridge (12 g) and eluted using an ethyl acetatehexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a white foam (102 mg, 73%). ESI-MS m/z [M+H]+ calc'd for C19H21ClN4O3, 389.14; found 389.2.
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[C:5]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[CH:4]=1.C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=1>>[C:26]1([C:22]2[CH:21]=[C:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([C:5]4[CH:4]=[C:3]([OH:2])[N:7]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=5)[N:6]=4)[CH:15]=3)[CH:25]=[CH:24][CH:23]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2cccc(-c3cccc(-c4ccccc4)c3)c2)nn1-c1ccccn1
Agent: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Product: Oc1cc(-c2cccc(-c3cccc(-c4ccccc4)c3)c2)nn1-c1ccccn1
Yield: 85 %

Procedure:
The title compound was prepared in the same manner as in Example D-1, except that an equimolar amount of Compound 40 of Example C-14 was used in place of Compound 27 of Example C-1.
Reaction SMILES: FC1C(O[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)=[O:10])=C(F)C(F)=C(F)C=1F.[CH3:37][O:38][C:39]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[C:40]=1[CH2:41][NH2:42]>>[CH3:48][O:47][C:43]1[CH:44]=[CH:45][CH:46]=[C:39]([O:38][CH3:37])[C:40]=1[CH2:41][NH:42][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[N:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=1)=[O:10]
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc32)cc1
Reactant: COc1cccc(OC)c1CN
Product: COc1cccc(OC)c1CNC(=O)c1ccc2c(c1)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
The title compound was prepared from 2-oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid pentafluorophenyl ester and 2,6-dimethoxybenzylamine according to Procedure K: mp>250° C.; 1H NMR (DMSO-d6): δ3.76 (s, 6H), 4.43 (d, J=4.2 Hz, 2H), 6.65 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.2 Hz, 1H), 7.23 (s, 2H), 7.25 (d, J=8.2 Hz, 1H), 7.56 (d, J=8.6 Hz, 2H), 7.79 (m, 3H), 8.07 (s, 1H), 8.13 (br s, 1H), 11.27 (s, 1H), 12.76 (s, 1H); APCI−MS m/z 532 (M+Na)+; Anal. Calcd for C24H23N5O6S.1/2H2O: C, 55.59; H, 4.67; N, 13.51; S, 6.18. Found: C, 55.69; H, 4.64; N, 13.61; S, 6.09.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:15][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.BrC1C=C(C=CC=1)N.[S:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1>C1C=CC([P]([Pd]([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)=CC=1>[S:29]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[C:4]([N:8]3[C:12]4[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:15][C:11]=4[N:10]=[CH:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:30]1
Reactant: CCOC(=O)c1cc2c(ncn2-c2cccc(Br)c2)[nH]1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Nc1cccc(Br)c1
Product: CCOC(=O)c1cc2c(ncn2-c2cccc(-c3ccsc3)c2)[nH]1
Temperature: 85 °C
Yield: 97.5 %

Procedure:
A flask containing a mixture of ethyl 1-(3-bromophenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylate (334 mg, 1 mmol, prepared according to the procedure described for example 1 except using 3-bromoaniline in the first step) and 3-thiophene boronic acid (256 mg, 2 mmol) was degassed and placed under a nitrogen atmosphere To this was quickly added tetrakis(triphenylphosphine)palladium(0) (173.3 mg, 0.15 mmol) in one portion followed by degassed solutions of 1,4-dioxane (5 mL) and aqueous sodium carbonate (2 M, 3 mL). The reaction mixture was heated at 85° C. under nitrogen for 24 hours after which time it was cooled, filtered and concentrated in vacuo. The resulting crude material was chromatographed over silica gel eluting with MeOH:CH2Cl2 0%→2%] to afford 329 mg (97.5%) of ethyl 1-(3-thien-3-ylphenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylate. 1H NMR (400 MHz, CDCl3): δ=8.02 (s, 1H), 7.75-7.72 (m, 1H), 7.58-7.53 (m, 3H), 7.48-7.41 (m, 3H), 6.98 (d, J=1.2 Hz, 1H), 4.37 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H). MS (ES+): m/z 338.13 (100) [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:21])[C:12]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:34](=[O:36])[CH3:35])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:21])[C:12]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)Cc3ccccc3)C(=O)[C@@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)Cc3ccccc3)C(=O)[C@@H]2OC(C)=O)cc1

Procedure:
A mixture of 6.22 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 60 ml of acetic anhydride and one ml of pyridine is refluxed for 4 hours. Then, the mixture is evaporated under reduced pressure to remove solvent. Benzene is added to the residue, and the mixture is evaporated under reduced pressure. 7 g of (-)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: [C:1]([C:3]([CH3:10])([CH3:9])[C:4]([O:6]CC)=O)#[N:2].CC(C)C(=O)[CH2:14][C:15]#[N:16]>>[CH3:10][C:3]([CH3:9])([C:4](=[O:6])[CH2:14][C:15]#[N:16])[C:1]#[N:2]
Reactant: CC(C)C(=O)CC#N
Reactant: CCOC(=O)C(C)(C)C#N
Product: CC(C)(C#N)C(=O)CC#N
Yield: 48 %

Procedure:
Prepared from ethyl 2-cyano-2-methylpropanoate (3 g, 21.25 mmol) according to the method described for 4-methyl-3-oxopentanenitrile in Example 122A Step 1, to afford 2,2-dimethyl-3-oxopentanedinitrile as a yellow oil (1.40 g, 48%) which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 3.98 (s, 2H), 1.60 (s, 6H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[O:16]C)[CH2:12][CH:11]=[C:10]2[C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=1.CCOC(C)=O.[Na+].[Cl-]>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[OH:16])[CH2:12][CH:11]=[C:10]2[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1
Reactant: COc1ccc(C2=CCc3cc(OC)c(OC)cc32)cc1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Oc1ccc(C2=CCc3cc(O)c(O)cc32)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 115.7 %

Procedure:
A solution of BBr3 in CH2Cl2 (1.0M, 9.60 ml, 9.60 mmol) is added dropwise to a solution of 5,6-dimethoxy-3-(4-methoxyphenyl)indene (0.60 g, 2.23 mmol) in 2 ml of CH2Cl2, cooled to -70° C. The red solution obtained is heated at room temperature and stirred for 1 h at this temperature. The reaction mixture is poured into a mixture of ice-water and AcOEt. The aqueous phase is saturated with NaCl then extracted twice with AcOEt. The organic phases collected are washed with saturated aqueous NaCl solution, dried over MgSO4 and evaporated to dryness to give a red solid (0.62 g) which is used directly in the following step.
Reaction SMILES: C([O:8][C:9](=[O:33])[C@@H:10]([NH:25][C@H:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:27])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:14][CH:13]=1)C1C=CC=CC=1>CCOC(C)=O.CO.[Pd]>[Cl:24][C:20]1[CH:19]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][C@H:10]([NH:25][C@H:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:27])[C:9]([OH:33])=[O:8])=[CH:17][CH:16]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)[C@H](C)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)[C@H](C)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Temperature: 12.5 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
A suspension of (S)-3-(3′-chloro-biphenyl-4-yl)-2-((S)-1-ethoxycarbonyl-ethylamino)-propionic acid benzyl ester (10.0 g, 21.5 mmol) and 5% Pd on carbon (0.914 g) in EtOAc (200 mL) was treated with H2 (balloon) and stirred at 10-15° C. for 1.5 hour and at room temperature for 0.5 hour. The resulted precipitate was dissolved in methanol and filtered through celite pad. The filtrate was concentrated under reduced pressure and the obtained residue was re-crystallized from EtOAc to give (S)-3-(3′-chloro-biphenyl-4-yl)-2-((S)-1-ethoxycarbonyl-ethylamino)-propionic acid (5.6 g). The mother liquor was concentrated under reduced pressure and purified by silica gel column chromatography to give additional amount of (S)-3-(3′-chloro-biphenyl-4-yl)-2-((S)-1-ethoxycarbonyl-ethylamino)-propionic acid (1.4 g). 1H NMR (400 MHz, DMSO-d6) δ 1.13 (t, 3H, J=7.1 Hz), 1.15 (d, 3H, J=6.8 Hz), 2.85 (dd, 1H, J=7.1, 14.1 Hz), 2.93 (dd, 1H, J=6.3, 13.6 Hz), 3.30-3.37 (m, 1H), 3.48 (dd, 1H, J=6.5, 6.5 Hz), 4.03 (q, 2H, J=7.1 Hz), 7.32 (d, 2H, J=8.3 Hz), 7.38-7.43 (m, 1H), 7.48 (dd, 1H, J=7.8, 7.8 Hz), 7.59-7.65 (m, 3H), 7.70 (dd, 1H, J=2.0, 2.0 Hz); MS: m/z (MH+) 376.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])[CH:7]=1.[CH2:21](O)[CH2:22][CH2:23][OH:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[O:19][CH2:21][CH2:22][CH2:23][OH:24])(=[O:10])=[O:9])[CH:7]=1
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cc(F)ccc2C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cc(F)ccc2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To 458 mg (1.49 mmol) 3-(5-fluoro-2-methylphenylsulfonyloxy)-5-methylphenol, as prepared in the preceding step, 1.08 mL (14.9 mmol) of 1,3-propanediol and 782 mg (2.98 mmol) of triphenylphosphine in 10 mL of anhydrous tetrahydrofuran was added 0.470 mL (2.98 mmol) of diethyl azodicarboxylate dropwise over 15 min. After stirring at ambient temperature for 2 h, the reaction mixture was concentrated to a semisolid. The resulting mixture was flash chromatographed on 50 g of silica gel with 8-10% ethyl acetate-dichloromethane. Impure fractions were re-chromatographed on 40 g of silica gel with 50-100% ethyl acetate-hexane. Material from the two purifications was combined to afford 530 mg (97% yield) of the title compound as a colorless oil: 1H-NMR (300 MHz; CDCl3) δ 7.59 (dd, 1H, J=8.3, 2.8 Hz), 7.38 (dd, 1H, J=8.4, 5.3 Hz), 7.25 (td, 1H, J=8.4, 2.8 Hz), 6.62 (m, 1H), 6.1 (m, 1H), 6.37 (t, 1H, J=2.1 Hz), 4.00 (t, 2H, J=6.0 Hz), 3.83 (dd, 2H, J=11.3, 5.8 Hz), 2.73 (s, 3H), 2.24 (s, 3H) and 1.99 (pentet, 2H, J=6.0 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C17H19FO5S: 377.1 (M+Na). Found: 377.0.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]4)[C:9]=3[C:8]1=2.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:47][Cr](O[Cr]([O-])(=O)=O)(=O)=O>CN(C=O)C>[C:29]([O:28][C:27]([N:26]([CH3:34])[CH:23]1[CH2:22][CH2:21][CH:20]([O:19][C:10]2[C:9]3[C:8]4[C@@H:7]([CH2:6][O:5][CH2:4][CH2:3][C:2]([OH:47])=[O:1])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:25][CH2:24]1)=[O:33])([CH3:31])([CH3:30])[CH3:32]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](COCCCO)CC4)CC1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](COCCC(=O)O)CC4)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 50.1 %

Procedure:
A 50-mL round-bottom flask was charged with a solution of tert-butyl N-(4-[[(3S)-3-[(3-hydroxypropoxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (370 mg, 0.75 mmol, 1.00 equiv) in 5 mL of DMF and PDC (1.656 g, 4.40 mmol, 5.85 equiv) was added at room temperature. The resulting solution was stirred for 14 hrs at 25° C. After completion, the resulting solution was extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2) to give 3-[[(3S)-12-[(4-[[(tert-butoxy)carbonyl](methyl)amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methoxy]propanoic acid (190 mg, 50%) as a colorless oil. MS: m/z 492 (M+H)+.
Reaction SMILES: Cl.Cl.Cl.Cl.[CH3:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C@H:13]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[O:16])[NH2:14])[CH2:8][CH2:7]1.[Cl:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([C:40](O)=[O:41])=[CH:34]2>>[Cl:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([C:40]([NH:14][C@@H:13]([C:15]([N:17]1[CH2:18][CH2:19][N:20]([CH:23]3[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]3)[CH2:21][CH2:22]1)=[O:16])[CH2:12][CH:9]1[CH2:10][CH2:11][N:6]([CH3:5])[CH2:7][CH2:8]1)=[O:41])=[CH:34]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CN1CCC(C[C@@H](N)C(=O)N2CCN(C3CCN(C)CC3)CC2)CC1
Agent: Cl
Product: CN1CCC(C[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)C(=O)N2CCN(C3CCN(C)CC3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the titled compound was prepared from 1-[β-(1-methylpiperidin-4-yl)-D-alanyl]-4-(1-methylpiperidin-4-yl)piperazine tetrahydrochloride and 5-chloroindole-2-carboxylic acid (46%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[O:14])=[C:11]([Cl:24])[CH:10]=1.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]([C:12]1[CH:22]=[CH:23][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:27](=[O:28])[N:26]([CH3:30])[CH3:25])=[CH:10][C:11]=1[Cl:24])=[O:14]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2N)cc1Cl
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)N(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(2-aminophenylamino)-2-chloro-2′-methylbenzophenone (Compound 156, 1.2 g, 3.5 mmol), dimethylcarbamyl chloride (0.32 ml, 3.5 mmol) and potassium carbonate (1.0 g, 7 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 16 hours. The reaction mixture was poured into water (100 ml) and was extracted with ethyl acetate (3×75 ml). The organic phase was dried (MgSO4), filtered and evaporated in vacuo to give the crude product. The crude product was purified by flash chromatography by using ethyl acetate/pentane mixtures from 1:9 to 1:1. Trituration with diethyl ether/pentane 1:1 afforded the pure title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[CH:2]=1.F[C:13](F)(F)C(O)=O>C(OCC)(OCC)OCC>[CH3:13][NH:11][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: Nc1cnc2ccccc2c1
Reactant: O=C(O)C(F)(F)F
Solvent: CCOC(OCC)OCC
Product: CNc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of quinolin-3-ylamine (5.2 g, 36.1 mmol) and trifluoroacetic acid (catalytic) in triethyl orthoformate (30 mL) was heated at reflux for 6 hours. The solvent was evaporated in vacuo, and the residue was dissolved in ethanol (50 mL). Sodium borohydride tablets (2.5 g, 0.203 mol) was added to the solution, and the resultant mixture was stirred at room temperature for 2.5 days. The mixture was partitioned between water and dichloromethane. The organic layer was separated, washed with water and dried over sodium sulfate. The solvent was evaporated in vacuo, to give the product, 5.35 g (94%), an oil, which crystallized on standing. MS: m/z 159 (MH+). 1H NMR (CDCl3): 2.90 (d, 3 H), 4.15 (br s, 1 H), 6.97 (d, 1 H), 7.36-7.47 (m, 2 H), 7.55-7.65 (m, 1 H), 7.91-7.96 (m, 1 H) and 8.42 (d, 1 H).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]2)[CH:2]=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]([NH:12][C:19](=[O:20])[O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:10][C:9]([C:13]([F:15])([F:14])[F:16])=[N:8]2)[CH:2]=1
Reactant: Cc1cccc(-n2nc(C(F)(F)F)cc2N)c1
Reactant: O=C(Cl)Oc1ccccc1
Product: Cc1cccc(-n2nc(C(F)(F)F)cc2NC(=O)Oc2ccccc2)c1
Yield: 57.6 %

Procedure:
Following the procedure in Example 118A, 1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (380 mg, 1.58 mmol) and phenyl chloroformate (0.60 mL, 4.74 mmol) were reacted to give phenyl 1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate (330 mg, 0.91 mmol, 58%). 1H NMR (300 MHz, DMSO-d6) δ 10.4 (br s, 1H), 7.62-6.85 (m, 10H), 2.46 (s, 3H); LC-MS (ESI) m/z 362 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[CH3:25][NH:26][C@H:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][OH:29]>>[CH3:9][O:8][C:6]1[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=[C:2]([N:26]([CH3:25])[C@@H:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][OH:29])[N:7]=1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: CN[C@@H](CO)c1ccccc1
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(N(C)[C@H](CO)c2ccccc2)n1
Yield: 32 %

Procedure:
This compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and (R)-2-methylamino-2-phenyl-ethanol in analogy to example 1c. Purification by chromatography on Si—NH2 gel (Isolute) using ethyl acetate as an eluent gave the title compound as a colorless solid in 32% yield.