Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:23])([CH3:22])[CH:14]1[C:24](O)=[O:25])=[O:12])([CH3:9])([CH3:8])[CH3:7].[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:29]=1[NH2:30]>N1C=CC=CC=1.O>[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:29]=1[NH:30][C:24]([CH:14]1[C:15]([CH3:22])([CH3:23])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]1[C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:12])=[O:25]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C(C)(C)C1C(=O)O
Reactant: Nc1c(F)cccc1F
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N1c2ccccc2C(C)(C)C1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
Phosphorus oxychloride (74.0 mg, 0.045 mL, 483 μmol, Eq: 2.2) was added dropwise to a solution of 1-(tert-butoxycarbonyl)-3,3-dimethylindoline-2-carboxylic acid (64 mg, 220 μmol, Eq: 1.00) and 2,6-difluoroaniline (54.0 mg, 0.045 mL, 418 μmol, Eq: 1.9) in pyridine (1 mL) and the resulting dark yellow suspension stirred at rt overnight. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (10 mL), 0.1 M aqueous HCl (10 mL) and brine (5 mL) and concentrated in vacuo to give tert-butyl 2-(2,6-difluorophenylcarbamoyl)-3,3-dimethylindoline-1-carboxylate as a white solid (42 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:31])[C:23](=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1>O1CCOCC1>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:31])[C:23](=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1
Reactant: CCCCCCC(=O)N(C)Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Solvent: C1COCCO1
Product: CCCCCCC(=O)N(C)Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Yield: 65.6 %

Procedure:
In a manner similar to that of Example 1(g), starting with 360 mg (0.8 mmol) of N-[4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-methylheptanamide in 15 ml of dioxane, under 3 atm, 230 mg (66%) of the desired product are obtained in the form of a colorless film.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:15][CH:16]=[CH:17][C:10]=23)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].CN(C)C=O.C(O)C>[Fe].O>[NH:15]1[C:11]2=[N:12][CH:13]=[CH:14][C:9]([O:8][C:7]3[CH:18]=[CH:19][C:4]([NH2:1])=[CH:5][CH:6]=3)=[C:10]2[CH:17]=[CH:16]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3[nH]ccc23)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccnc3[nH]ccc23)cc1

Procedure:
4-(4-Nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine (84 mg), iron powder (160 mg), ammonium chloride (320 ml), dimethylformamide (4 ml), ethanol (2 ml) and water (2 ml) were stirred at 100° C. for 15 minutes. The mixture was filtered with celite, and then water and ethyl acetate were added for extraction. The organic layer was washed 5 times with ammonium chloride water and then dried over magnesium sulfate. The drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 230 mg of the target substance as a brown oil.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20]3[N:25]=[CH:24][C:23]([C:26]#[C:27][Si](C)(C)C)=[CH:22][N:21]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:26]([C:23]1[CH:24]=[N:25][C:20]([NH:19][CH2:18][CH:15]2[CH2:16][CH2:17][N:12]([C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:11])[CH2:13][CH2:14]2)=[N:21][CH:22]=1)#[CH:27]
Reactant: C[Si](C)(C)C#Cc1cnc(NCC2CCN(C(=O)[C@@H]3C[C@H]3c3ccccc3)CC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc(NCC2CCN(C(=O)[C@@H]3C[C@H]3c3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-[(1-{[(1R,2R)-2-phenylcyclopropyl]carbonyl}piperidin-4-yl)methyl]-5-[(trimethylsilyl)ethynyl]pyrimidin-2-amine (EXAMPLE 154) (0.200 g, 0.462 mmol) and potassium carbonate (0.128 g, 0.924 mmol) in methanol (3 mL) was stirred at RT for 0.5 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate (50 mL), washed with water (20 mL), and brine (10 mL), then dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60 (35 g), eluting with 10:1-20:89-70 CH2Cl2:2-propanol:hexane to give the title compound. M.S. (M+1): 361.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.Cl[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1>CN(C)C1C=CN=CC=1.CN(C)C=O>[N+:26]([C:25]1[C:20]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[CH:12]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]3)=[CH:4][CH:3]=2)=[N:21][CH:22]=[CH:23][CH:24]=1)([O-:28])=[O:27]
Reactant: CN1CCC(c2cccc3ccc(N)cc23)CC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CN1CCC(c2cccc3ccc(Nc4ncccc4[N+](=O)[O-])cc23)CC1
Yield: 33.5 %

Procedure:
A mixture of the product from Example 57 (0.338 g, 1.4 mmol), 2-chloro-3-nitropyridine (0.446 g, 2.81 mmol), and 4-dimethylaminopyridine (0.172 g, 1.4 mmol) in dimethylformamide (6 mL) was refluxed 5 hours. The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The organic phase was washed with 1N sodium hydroxide and brine, then it was concentrated onto silica gel and flash chromatographed (1×4 inches silica gel). The elution proceeded as follows: 75% methylene chloride/hexane (175 mL) nil; methylene chloride (250 mL) unweighed excess 2-chloro-3-nitropyridine; 2% methanol/methylene chloride (200 mL) nil, (550 mL) 0.373 g of crude product contaminated with 4-dimethylamino-pyridine. This material was triturated with ether and filtered to give 0.17 g of title product as orange crystals. 1H NMR δ 10.34 (br s, 1 H), 8.59 (dd, J=2, 8.5 Hz, 1 H), 8.54-8.50 (m, 2 H), 7.88 (d, J=9 Hz, 1 H), 7.72-7.70 (m, 1 H), 7.66 (dd, J=2, 9 Hz, 1H), 7.45-7.41 (m, 2 H), 6.89 (dd, J=4.5, 8.5 Hz, 1 H), 3.27 (tt, J=4, 11.5 Hz, 1 H), 3.11 (long range coupled d, J=11.5 Hz, 1 H), 2.41 (s, 3 H), 2.27 (dt, J=2.5, 11.5 Hz, 2 H), 2.09-1.89 (m, 4 H).
Reaction SMILES: O.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4:18].C(NCCO)CCC.[CH3:27][CH:28]([O:32][C:33]([CH3:35])=[O:34])[CH2:29][O:30][CH3:31]>C(O)(C)C>[CH3:27][CH:28]([O:32][C:33]([CH3:35])=[O:34])[CH2:29][O:30][CH3:31].[Ti:18]
Reactant: [Ti+4]
Agent: CC(C)[O-]
Agent: CCCCNCCO
Solvent: CC(C)O
Solvent: COCC(C)OC(C)=O
Solvent: O
Product: [Ti]
Reaction time: 2 h

Procedure:
A mixture of purified water (2.7 g) and isopropyl alcohol (50 g) was dropped to a mixture of titanium tetraisopropoxide (28.4 g), isopropyl alcohol (50 g) and 2-(butylamino)ethanol (11.8 g). After completion of dropping, the mixture was agitated for 2 hours, subjected to hydrolytic condensation and heated to reflux for 2 hours. PGMEA (100 g) was added thereto and was concentrated under reduced pressure to obtain a PGMEA solution of a titanium-containing condensate (B-I) (130 g). The solid content concentration of the titanium-containing condensate was 13.5%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:15]=3)[CH2:10][CH2:9]2)=[C:4]([F:27])[CH:3]=1.[N+:28]([C:31]1[O:35][C:34]([CH:36]=O)=[CH:33][CH:32]=1)([O-:30])=[O:29]>CC(O)=O.CO>[CH2:20]([N:16]1[N:15]=[C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:5]3[CH:6]=[CH:7][C:2](/[N:1]=[CH:36]/[C:34]4[O:35][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=4)=[CH:3][C:4]=3[F:27])[CH2:13][CH2:12]2)[O:18][C:17]1=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccc(N2CCC(c3nn(Cc4ccccc4)c(=O)o3)CC2)c(F)c1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Solvent: CO
Solvent: CC(=O)O
Product: O=c1oc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3F)CC2)nn1Cc1ccccc1
Yield: 88 %

Procedure:
5-[1-(4-Amino-2-fluorophenyl)-4-piperidyl]-3-benzyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7 h, 0.36 g, 1 mmol) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and recrystallized in ethanol to obtain product 3-benzyl-5-[1-(2-fluoro-4-[(E)-1-(5-nitro-2-furyl)methylidene]amino phenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9 h, 432 mg, 88%).
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:32])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[CH2:43][CH2:44][CH2:45][NH2:46])[CH:36]=[CH:35][N:34]=1>O1CCCC1>[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[CH2:43][CH2:44][CH2:45][NH:46][C:11](=[O:32])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:36]=[CH:35][N:34]=1
Reactant: NCCCc1cccc2ccncc12
Reactant: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=C/C=C/C(=O)NCCCc2cccc3ccncc23)c2ccc(OC)cc2)cc1
Yield: 68.4 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(4-methoxyphenyl) -2,4-pentadienoic acid 4-nitrophenyl ester (0.24 g) and 8-isoquinolinepropanamine (0.103 g) in tetrahydrofuran (5 mL) was stirred for 17 hours at room temperature and was worked up in the usual manner. The crude amide was purified by HPLC (ethyl acetate) and then was crystallized from ethyl acetatehexane to afford 0.181 g of (E)-N-[3-(8-isoquinolinyl) propyl]-5,5-bis(4-methoxyphenyl)-2,4-pentadienamide, mp 115°-118° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:25]([C:26](=[O:29])[NH:27][CH3:28])=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.Cl.[C:31]1([C:37]2([NH2:41])[CH2:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:25]([C:26]([NH:27][CH3:28])=[O:29])=[C:11]3[CH:12]=[C:13]([C:16]4[CH:24]=[CH:23][CH:22]=[C:18]([C:19](=[O:20])[NH:41][C:37]5([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH2:38][CH2:39][CH2:40]5)[CH:17]=4)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: NC1(c2ccccc2)CCC1
Agent: Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cccc(C(=O)NC4(c5ccccc5)CCC4)c3)cc12

Procedure:
2-(4-fluorophenyl)-N-methyl-5-(3-(1-phenylcyclobutylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide was prepared from 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl)benzoic acid (0.070 g, 0.14 mmol) and 1-phenylcyclobutanamine hydrochloride (0.040 g, 0.20 mmol). 1H NMR (500 MHz, DMSO-D6) δ ppm 9.21 (s, 1H), 8.90 (d, J=7.02 Hz, 1H), 8.30 (s, 1H), 8.09 (s, 1H), 7.96-8.03 (m, 2H), 7.88-7.96 (m, 3H), 7.63 (t, J=7.63 Hz, 1H), 7.53 (d, J=7.63 Hz, 2H), 7.48 (dd, J=7.32, 1.83 Hz, 1H), 7.30-7.37 (m, 4H), 7.21 (t, J=7.32 Hz, 1H), 2.82 (d, J=4.58 Hz, 3H), 2.63-2.71 (m, 2H), 2.58 (ddd, J=12.13, 8.62, 6.10 Hz, 2H), 2.03-2.11 (m, 1H), 1.84-1.93 (m, 1H). LCMS: retention time: 3.225 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10u, C18, 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 519 (MH+).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2].[CH:58](OC)=[O:59]>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][CH:58]=[O:59])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: COC=O
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1N
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1NC=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 17-ethyl-1-hydroxy-12-[2'-(4"-amino-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (30 mg) is mixed with methyl formate (0.5 ml) and is stirred at 0° C. for 1 hr. The reaction mixture is allowed to warm to room temperature and then is stirred overnight. The excess methylformate is removed with nitrogen flow and the crude mixture is purified by preparative tlc on silica gel to give the title compound.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:54])[C@H:14]([NH:34][C:35]([N:37]3[CH2:42][CH2:41][CH:40]([N:43]4[CH2:52][C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[NH:45][C:44]4=[O:53])[CH2:39][CH2:38]3)=[O:36])[CH2:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21](S(CC[Si](C)(C)C)(=O)=O)[N:20]=[CH:19]4)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].[Cs+]>C(#N)C>[N:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:54])[C@H:14]([NH:34][C:35]([N:37]3[CH2:38][CH2:39][CH:40]([N:43]4[CH2:52][C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[NH:45][C:44]4=[O:53])[CH2:41][CH2:42]3)=[O:36])[CH2:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][N:20]=[CH:19]4)[CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCS(=O)(=O)n1ncc2cc(C[C@@H](NC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)C(=O)N3CCC(N4CCCCC4)CC3)ccc21
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: O=C(N[C@H](Cc1ccc2[nH]ncc2c1)C(=O)N1CCC(N2CCCCC2)CC1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Yield: 62.6 %

Procedure:
A solution of (R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4′]bipiperidinyl-1′-yl-2-oxo-1-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol-5-ylmethyl]-ethyl}-amide (568 mg, 0.73 mmol) and cesium fluoride (1.11 g, 7.31 mmol) was heated at 80° C. in acetonitrile (50 mL) for 4.5 h. The reaction mixture was concentrated and the residue was subjected to flash column chromatography (methylene chloride/methanol/triethylamine, 94:5:1) to give 280 mg (63% yield) of the title compound as a white solid with 98.2% ee as determined by HPLC analysis using a Chirocel OD column with 20% B (A=ethanol, B=0.05% diethylamine in hexanes) as eluent (Retention times: 9.51 min for title compound and 15.9 min for S-enantiomer). 1H-NMR (CD3OD, 500 MHz) δ 8.04 (s, 0.75H), 8.03 (s, 0.25H), 7.67 (s, 0.75H), 7.65 (s, 0.25H), 7.56 (d, J=8.5 Hz, 0.75H), 7.51 (d, J=8.5 Hz, 0.25H), 7.41 (d, J=8.5 Hz, 0.75H), 7.31 (d, J=8.5 Hz, 0.25H), 7.19–7.12 (m, 2H), 6.97–6.94 (m, 1H), 6.80 (d, J=7.9 Hz, 1H), 5.08–5.05 (m, 1H), 4.60–4.53 (m, 1H), 4.48–4.40 (m, 1H), 4.37 (s, 1.5H), 4.26 (s, 0.5H), 4.24–4.14 (m, 2H), 4.06–3.97 (m, 1H), 3.15 (d, J=7.9 Hz, 1.5H), 3.12–3.05 (m, 0.5H), 2.94–2.86 (m, 3H), 2.57–2.51 (m, 1.5H), 2.47–2.42 (m, 1H), 2.37–2.33 (m, 0.75H), 2.03–2.02 (m, 1.5H), 1.87–1.75 (m, 3.75H), 1.73–1.68 (m, 2H), 1.67–1.54 (m, 3H), 1.53–1.44 (m, 4H), 1.43–1.34 (m, 2H), 1.30–1.26 (m, 1H), 0.83–0.77 (m, 0.75H), −0.16 to −0.24 (m, 0.75H). Mass spec.: 613 (MH)+.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@H:7]1[CH2:11][CH2:10][CH:9]([CH3:12])[N:8]1C(OCC=C)=O)=[O:6])([CH3:3])[CH3:2].[BH4-].[Na+]>C(#N)C.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>[CH:1]([NH:4][C:5]([C@H:7]1[CH2:11][CH2:10][CH:9]([CH3:12])[NH:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)N1C(C)CC[C@@H]1C(=O)NC(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)NC(=O)[C@H]1CCC(C)N1
Temperature: 50 °C

Procedure:
(R)-allyl 2-(isopropylcarbamoyl)-5-methylpyrrolidine-1-carboxylate (450 mg, 1769 μmol) was dissolved in acetonitrile (13 mL) before sodium borohydride (268 mg, 7078 μmol) and tetrakis(triphenylphosphine)palladium(0) (102 mg, 88 μmol) were added at ambient. The reaction mixture was heated to 50° C. for 4 h then filtered through a pad of silica gel and washed with chloroform to remove impurities. The silica was washed again with methanol to obtain the title compound as a mixture of diastereomers (˜60:40). MS (ES+): 171(M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1.[CH:11]([B-](F)(F)F)=[CH2:12].[K+]>CCO.CCOC(C)=O.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]>[CH:11]([C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1)=[CH2:12]
Reactant: Brc1ccc2nonc2c1
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C=Cc1ccc2nonc2c1
Temperature: 80 °C

Procedure:
5-bromo-2,1,3-benzoxadiazole (4.0 g, 20 mmol), potassium vinyltrifluoroborate (5.40 g, 40.2 mmol) and Pd(dppf)Cl2 (1.6 g, 2 mmol) in TEA (5.2 mL) and EtOH (15 mL) were added to a flask containing a stir bar, and the flask was then heated at 80° C. for 12 h. The organic residue was dissolved in EtOAc (500 mL) and the solution was washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting organic residue was subjected to purification over silica gel to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.C(N(CC)CC)C.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>CCOCC>[CH3:8][C:6]1[N:5]=[C:4]([C:9]([Cl:12])([Cl:10])[Cl:11])[N:3]=[C:2]([O:1][C:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:22])[CH:7]=1
Reactant: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1cc(OC(=O)Oc2ccccc2)nc(C(Cl)(Cl)Cl)n1
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To 5.6 g (0.02 mole) 4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 2.0 g (0.02 moles) triethylamine, and 100 ml ether was added 3.2 g (0.07 mole) phenyl chloroformate. The solution refluxed on addition and a precipitate formed. This was stirred 0.5 hour, filtered, and the filtrate rotary evaporated to give 6.6 g (76% yield) thick oily residue. Extraction with ligroin gave, on cooling of the extract, 3.7 g pure product as a viscous oil. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:11]([O:13][C:14](=[O:25])[CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH3:12].Br[CH2:27][C:28]1[C:29]([F:40])=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[C:35]([O:38][CH3:39])[CH:34]=[CH:33]2.O>C1COCC1.CC(=O)OCC>[CH2:11]([O:13][C:14](=[O:25])[CH:15]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:27][C:28]1[C:29]([F:40])=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[C:35]([O:38][CH3:39])[CH:34]=[CH:33]2)[CH3:12]
Reactant: CCOC(=O)CCNC(=O)OC(C)(C)C
Reactant: COc1ccc2ccc(F)c(CBr)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CNC(=O)OC(C)(C)C)Cc1c(F)ccc2ccc(OC)nc12
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To a solution of LiHMDS (1M, 20 mL), cooled to −78° C., was added dropwise a solution of 3-tert-butoxycarbonylamino-propionic acid ethyl ester (2.01 g, 9.26 mmol; prepared as in Tetrahedron Lett. (2003), 44(14), 2807) in THF (20 mL). The solution was stirred at the same temperature for 90 min. A solution of 8-bromomethyl-7-fluoro-2-methoxy-quinoline (2.5 g; prepared as in WO 2007/081597) in THF (10 mL) was quickly added and the reaction proceeded for 2 h, keeping the internal temperature below −50° C. Water (100 mL) and EA (200 mL) were added. The two layers were separated and the aq. layer was extracted with EA. The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA 2:1) to afford the title intermediate as a pale yellow oil, which solidified (2.83 g, 75% yield) after standing at rt for one day.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8](Cl)=[O:9])[CH2:3][CH2:2]1.[NH4+:11].[OH-]>C1COCC1>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([NH2:11])=[O:9])[CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: O=C(Cl)CC1CCOCC1
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 116 %

Procedure:
A 0° C. solution of tetrahydropyran-4-ylacetyl chloride (0.500 g, 3.07 mmol) in THF (25 mL) was treated drop-wise with NH4OH (˜15M, 2.05 mL, ˜30.7 mmol), allowed to warm to RT and stirred overnight. The mixture was concentrated to dryness, co-evaporated with IPA (2×), then suspended in IPA and the solids removed via filtration. The filtrate was concentrated to dryness to afford 2-(tetrahydro-2H-pyran-4-yl)acetamide (510 mg, 116%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.25 (s, 1H), 6.73 (s, 1H), 3.78 (dd, J=11.4, 4.1 Hz, 2H), 3.29-3.19 (m, 2H), 2.15-1.92 (m, 2H), 1.91-1.78 (m, 1H), 1.58-1.48 (m, 2H), 1.23-1.06 (m, 2H); MS (ESI) m/z: 144.1 (M+H+).
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][C:35]=5[CH3:44])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22]([C:45]([CH3:47])=[CH2:46])[N:21]=3)[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H][H]>[Pd].CO>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][C:35]=5[CH3:44])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22]([CH:45]([CH3:47])[CH3:46])[N:21]=3)[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: C=C(C)c1ccc(-c2cc(-c3ccc(C(=O)OC)cc3C)ccc2OC)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(C)C)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1

Procedure:
Methyl 3′-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-isopropenylpyridin-3-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (131 mg, 0.189 mmol) and a catalytic amount of palladium on carbon and CH3OH (5 mL) were stirred vigorously under a balloon atmosphere of hydrogen for 1 h and 20 min at 20° C. The reaction mixture was filtered then the filtrate was concentrated in vacuo to afford methyl 3′-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-isopropylpyridin-3-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate, as a light yellow glass. LCMS calc.=700.24; found=701.29 (M+1).