Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]([C:16]#[N:17])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].[N-:20]=[N+:21]=[N-:22].[Na+].O>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]([C:16]1[NH:22][N:21]=[N:20][N:17]=1)=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1ccc2[nH]c(=O)c(C#N)cc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc2[nH]c(=O)c(-c3nnn[nH]3)cc2c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
6-tert-Butyl-3-cyano-1,2-dihydroquinolin-2-one (1.74 g, 7.7 mmol) was dissolved in DMF (20 ml), and ammonium chloride (1.65 g, 30.8 mol) and sodium azide (2.00 g, 30.8 mol) were added to the resultant mixture. The mixture was stirred at a bath temperature of 120° C. for 16 hours. Water added to the reaction mixture. After removal of the precipitates by filtration, the reaction mixture was recrystallized from DMF-methanol. The crystals that precipitated were collected, to thereby obtain the title compound as yellow powder (1.08 g, 4.0 mmol, 52%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>COCCOC>[NH2:1][C:2]1[CH:3]=[C:4]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([NH2:23])=[CH:25][CH:26]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)cc(N)nc1-c1ccco1
Reactant: NCc1ccc(N)cc1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc(N)cc2)cc(N)nc1-c1ccco1

Procedure:
From trifluoromethanesulfonic acid 6-amino-3-cyano-2-furan-2-yl-pyridin-4-yl ester and 4-aminobenzylamine in DME. ES-MS m/e (%): 306 (M+H+, 100).
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:32])[NH:11][C@@H:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([OH:24])[CH2:14][NH:15][CH2:16][C:17]([CH3:23])([CH3:22])[CH2:18][CH2:19][C:20]#[N:21])[CH2:2]1.C(N(C(C)C)CC)(C)C.[C:42]([NH:45][C:46]1[CH:51]=[CH:50][C:49]([S:52](Cl)(=[O:54])=[O:53])=[CH:48][CH:47]=1)(=[O:44])[CH3:43]>C(Cl)Cl>[O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:32])[NH:11][C@@H:12]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@H:13]([OH:24])[CH2:14][N:15]([S:52]([C:49]2[CH:48]=[CH:47][C:46]([NH:45][C:42](=[O:44])[CH3:43])=[CH:51][CH:50]=2)(=[O:54])=[O:53])[CH2:16][C:17]([CH3:22])([CH3:23])[CH2:18][CH2:19][C:20]#[N:21])[CH2:2]1
Reactant: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1ccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCC#N)cc1
Yield: 18.7 %

Procedure:
[(1S,2R)-1-Benzyl-3-(4-cyano-2,2-dimethyl-butylamino)-2-hydroxy-propyl]-carbamic acid (3R,3aS,6aR)hexahydro-furo[2,3-b]furan-3-yl ester (0.020 g, 0.05 mmol) was dissolved in CH2Cl2 and treated with diisopropylethylamine (0.016 ml, 0.09 mmol) and 4-acetamidobenzenesulfonyl chloride (0.011 g, 0.05 mmol) at ambient temperature under argon with stirring. After 15 h the reaction mixture was concentrated in vacuo, taken up in EtOAc, washed with sat. aq. NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo. Purification by preparative thin layer chromatography (EtOAc) gave 0.006 g of a white solid. MS (ES): 643 (M+1).
Reaction SMILES: C([C:5]1([C:22]([F:25])([F:24])[F:23])[C:14]2[CH:13]=[C:12](C#N)[CH:11]=[CH:10][C:9]=2[NH:8][C:7]2[C:17](=[O:21])[NH:18]C=[N:20][C:6]1=2)CCC.OO.[OH-].[Na+].CO.C(Cl)[Cl:33]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[NH2:20][C:6]1[C:7]([C:17]([NH2:18])=[O:21])=[N:8][C:9]2[C:14]([C:5]=1[C:22]([F:25])([F:24])[F:23])=[CH:13][C:12]([Cl:33])=[CH:11][CH:10]=2
Reactant: ClCCl
Reactant: CCCCC1(C(F)(F)F)c2cc(C#N)ccc2Nc2c1nc[nH]c2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: OO
Solvent: CO
Product: NC(=O)c1nc2ccc(Cl)cc2c(C(F)(F)F)c1N
Temperature: 0 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
10-Butyl-8-cyano-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one (9, 264 mg, 0.972 mmol) was dissolved in CH3OH—CH2Cl2 (1:2, 6.5 mL) and treated with tetrabutylammonium hydrogen sulfate (109 mg, 0.321 mmol) and 30% aq. H2O2 (1.98 mL). The reaction was cooled to 0° C. and 5N aq. NaOH solution (5.8 mL) was added. After the addition was complete, the reaction mixture had solidified. Additional CH3OH—CH2Cl2 (6 mL) was added to dissolve the solids. The reaction was allow to warm to rt and stir overnight. The reaction mixture was partitioned between EtOAc (25 mL) and H2O (25 mL), and the aqueous layer was extracted with EtOAc (3×15 mL). The combined organic phases were washed with brine, dried (MgSO4) and concetrated. Chromatography (SiO2, 40 g, 30% EtOAc-hexane) afforded the desired product as a yellow crystalline solid (183 mg, 65%). mp 200° C. Rf 0.37 (10% EtOAc-hexane). 1H NMR (CDCl3, 300 MHz) δ 8.20 (br s, NH2), 7.91 (m, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.40 (dd, J=2.2, 9.0 Hz, 1H), 5.63 (br s, NH2); 19F NMR (CDCl3, 300 MHz) δ −54.42; 13C NMR (CDCl3, 75 MHz) δ 168.75, 141.64, 137.05, 136.90, 135.87, 131.96, 128.07, 126.59, 123.84, 121.45, 121.38; IR (KBr) νmax 3515, 3447, 3268, 3204, 1690, 1674, 1597, 1586, 1438, 1357, 1315, 1303, 1226, 1109, 974, 822, 750 cm−1.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[CH:15][N:14]([C:17]4[S:18][C:19]([C:29]([NH2:31])=[O:30])=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=5)[N:21]=4)[C:13]=3[CH:32]=2)[CH2:4][CH2:3]1.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:63][N:64]1[CH2:69][CH2:68][CH:67]([C:70](O)=[O:71])[CH2:66][CH2:65]1>C(OCC)(=O)C.CN(C)C=O>[C:29]([C:19]1[S:18][C:17]([N:14]2[C:13]3[CH:32]=[C:9]([CH2:8][N:5]4[CH2:4][CH2:3][CH:2]([NH:1][C:70]([CH:67]5[CH2:68][CH2:69][N:64]([CH3:63])[CH2:65][CH2:66]5)=[O:71])[CH2:7][CH2:6]4)[CH:10]=[CH:11][C:12]=3[N:16]=[CH:15]2)=[N:21][C:20]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)(=[O:30])[NH2:31]
Reactant: NC(=O)c1sc(-n2cnc3ccc(CN4CCC(N)CC4)cc32)nc1-c1cccc(Cl)c1
Reactant: CN1CCC(C(=O)O)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCC(C(=O)NC2CCN(Cc3ccc4ncn(-c5nc(-c6cccc(Cl)c6)c(C(N)=O)s5)c4c3)CC2)CC1
Reaction time: 0.25 h

Procedure:
A mixture of 0.120 g (0.26 mmole) of 2-[6-(4-amino-piperidin-1-ylmethyl)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.13), 5 mL of dimethylformamide, 0.148 g (0.39 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1), 0.105 g (0.39 mmole) of triethylamine was stirred for 15 minutes, then 0.056 g (0.39 mmole) of 1-methyl-piperidine-4-carboxylic acid was added. After 3 hours, the mixture was taken up in 100 mL of ethyl acetate, washed twice with 100 mL of water, and then once with 100 mL of brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-(methanol-ammonium hydroxide, (92.8:0.3)) (gradient 100:0-0:100) to give 1-methyl-piperidine-4-carboxylic acid (1-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazol-2-yl]3H-benzoimidazol-5-ylmethyl}-piperidin-4-yl)-amide (I.14). This material was taken up in 20 mL of dichloromethane, washed with 20 mL of 1M sodium hydroxide solution. The dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.065 g of 1-methyl-piperidine-4-carboxylic acid (1-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazol-2-yl]-3H-benzoimidazol-5-ylmethyl}-piperidin-4-yl)-amide (I.14) as a solid. MH+/Z=592
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[CH:11]=[CH:10][C:9]=2[F:16])=[O:5])C.Br[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[F:16][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[C:13]2[C:8]=1[N:7]([CH2:18][C:19]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]2
Reactant: CCOC(=O)c1cc2c(C)ccc(F)c2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: Cc1ccc(F)c2c1cc(C(=O)O)n2Cc1cccc2ccccc12

Procedure:
Using general procedure B, 7-fluoro-4-methyl-1H-indole-2-carboxylic acid ethyl ester (Lit. 8) was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 332.0 ([M−H]−).
Reaction SMILES: C([Li])(C)(C)C.CCCCC.BrC1C(C)=CC(C)=CC=1C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.[I:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34](=[O:39])[C:33]2=[O:40].[Cl-].[NH4+]>C1COCC1>[OH:40][C:33]1([C:28]2[C:23]([O:22][CH3:21])=[N:24][CH:25]=[CH:26][CH:27]=2)[C:32]2[C:36](=[CH:37][CH:38]=[C:30]([I:29])[CH:31]=2)[NH:35][C:34]1=[O:39]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: COc1ccccn1
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ncccc1C1(O)C(=O)Nc2ccc(I)cc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
A 1.7 M solution of tert-butyllithium in pentane (35 ml, 60 mmol) was added to THF (100 ml) at −78° C. 2-Bromomesitylene (4.6 ml, 30 mmol) was added dropwise and the mixture stirred at −78° C. for 1 h. 2-Methoxypyridine (3.2 ml, 30 mmol) was added at −78° C. and then the mixture was stirred at 0° C. for 1.5 h. The ice-cold solution of the lithiated 2-methoxypyridine was transferred (via a transfer needle) into an ice-cold suspension of 5-iodoisatin (4.1 g, 15 mmol) in THF (150 ml). The reaction mixture was allowed to warm to room temperature and then saturated ammonium chloride solution was added. The mixture was extracted three times with ethyl acetate, and the collected extracts were washed with saturated brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by crystallization from dichloromethane yielded 2.9 g of the intermediate.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11](O)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1>CC(C)=O>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(O)cc1C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc([Si](C)(C)C(C)(C)C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask is fitted with a stirring bar and charged with 5.0 grams (0.0255 mole) of 2-acetoxy-5-hydroxybenzoic acid [M. Bergmann and P. Dangschat, Berichte, 52, 371 (1919)]. After the flask is flushed with argon and cooled in an ice bath, a solution of t-butyldimethylsilylchloride (9.23 gr., 0.06122 mole) and imidazole (8.5 gr., 0.125 mole) dissolved in 20 ml of anhydrous dimethylformaldehyde (DMF) is added dropwise over a 30 minute period. The reaction mixture is stirred at room temperature overnight. The DMF is removed in vacuo. The residue is taken up in ether (75 ml) transferred to a separatory funnel and extracted with 1 N HCl (3×25 ml), 5% NaOH (3×25 ml), water (2×10 ml) and brine (20 ml). The ether extract is dried over sodium sulfate, filtered and the solvents removed in vacuo to yield 2-acetoxy-5-t-butyldimethylsilylbenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([OH:9])=O.[CH3:20][CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22]1.C(N(CCCC)CCCC)CCC.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH2:30][CH:21]1[CH3:20])=[O:9]
Reactant: CC1CCc2ccccc2N1
Reactant: O=C(O)c1cc(F)ccc1Oc1cc(Cl)ccc1Cl
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: CC1CCc2ccccc2N1C(=O)c1cc(F)ccc1Oc1cc(Cl)ccc1Cl
Temperature: 40 °C
Yield: 15.1 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-5-fluoro-benzoic acid (36.1 mg, 0.12 mmol, 1.0 equiv; Example 113, Step 1) in dichloromethane (1 mL) was added 2-methyl-1,2,3,4-tetrahydro-quinoline (21.2 mg, 0.14 mmol, 1.2 equiv; [CAS RN 1780-19-4]), tri-n-butylamine (111.2 mg, 143 μL, 0.60 mmol, 5.0 equiv; [CAS RN 102-82-9]) and 2-chloro-1-methylpyridinium iodide (36.8 mg, 0.14 mmol, 1.2 equiv; [CAS RN 14338-32-0]). The reaction mixture was heated to 40° C. over night. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μM, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 7.8 mg (15%) of the title compound. MS (ISP): 430.1 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([NH:17][CH2:18][C:19]([OH:21])=O)=[O:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[N:45]1([C:51]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:59]([F:62])([F:61])[F:60])=[O:52])[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>CN(C=O)C.O>[O:21]=[C:19]([N:48]1[CH2:49][CH2:50][N:45]([C:51](=[O:52])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:59]([F:62])([F:60])[F:61])[CH2:46][CH2:47]1)[CH2:18][NH:17][C:15]([C:11]1[S:10][CH:14]=[CH:13][CH:12]=1)=[O:16]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(O)CNC(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
DIPEA (0.130 mL, 0.76 mmol) was added to a stirred solution of [(thiophene-2-carbonyl)-amino]-acetic acid (40 mg, 0.22 mmol) in DMF (1 mL). HOBT (35 mg, 0.26 mmol) and EDCI.HCl (49 mg, 0.26 mmol) were added, followed by the addition of piperazine-1-yl-(2-trifluoromethyl-phenyl)-methanone hydrochloride (70 mg, 0.24 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford thiophene-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazine-1-yl]-ethyl}-amide in 54% yield. LC-MS purity: 98% 1H NMR (CDCL3): δ 7.78-7.44 (m, 5H), 7.34 (t, 1H), 7.10 (d, 2H), 4.40-4.18 (m, 2H), 4.08-3.82 (m, 2H), 3.80-3.50 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:25][C:26](O)=[O:27])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.CC(C)(C)C(Cl)=O.[CH2:43]([C@@H:50]1[CH2:54][O:53][C:52](=[O:55])[NH:51]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[Li]CCCC>C1COCC1>[CH2:43]([CH:50]1[CH2:54][O:53][C:52](=[O:55])[N:51]1[C:26](=[O:27])[CH2:25][C:11]1[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=2)[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: O=C(O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1)N1C(=O)OCC1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a mechanically stirred solution of (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (20 g, 52 mmol) in THF (104 mL) at −78° C. was added N-methyl morpholine (NMM) (6.3 mL, 57 mmol) and trimethylacetyl chloride (7.0 mL, 57 mmol) maintaining the internal temperature below −70° C. This mixture was stirred at −78° C. for 15 minute and 0° C. at 1 h. The white solid was filtered off to receive the anhydride in the filtrate which was cooled back to −78° C. In a separate flask, to a solution of (R)-(+)-4-benzyl-2-oxazolidinone (9.6 g, 54.4 mmol) in THF (109 mL) at −78° C. was added nBuLi (1.6M in hexanes, 34 mL, 54.4 mol), drop-wise, maintaining the internal temperature below −70° C. and stirred at −78° C. for 45 min. This metalated chiral auxiliary was cannulated to the anhydride at −78° C. and warmed to 0° C. over 1.5 h. The resulting mixture was stirred further at 0° C. for 30 minute and quenched by adding excess saturated aqueous NH4Cl solution. The solution was diluted with EtOAc (200 mL) and the organic phase was washed with saturated aqueous NaHCO3 solution (3×100 mL) and brine (2×100 mL). The solution was dried over MgSO4 and the solvent was removed in vacuo. The crude material was purified by ISCO silica gel column chromatography to yield 20.3 g (72%) of 4-benzyl-3-[2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetyl]-oxazolidin-2-one as a white solid.
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:20]1[O:22][CH:21]1[CH2:23][OH:24]>C(O)C>[OH:22][CH:21]([CH2:23][OH:24])[CH2:20][NH:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OCC1CO1
Reactant: CCCCCCCCCCCCCCCCCCN
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCNCC(O)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Octadecylamine (9.09 g, 0.034 mole) was dissolved in absolute ethanol. Glycidol (5.00 g, 0.068 mole) was added to the amine dropwise. The reaction solution was refluxed under nitrogen for 4 hours and then was stirred overnight at room temperature. A white solid was obtained (crude yield=10.8 g). The solid was recrystalized from hot hexane. (Yield=6.9 g).
Reaction SMILES: [ClH:1].[CH3:2][SiH:3]([CH:7]([CH3:9])[CH3:8])[CH:4]([CH3:6])[CH3:5]>>[CH3:2][Si:3]([CH:7]([CH3:9])[CH3:8])([CH:4]([CH3:6])[CH3:5])[Cl:1]
Reactant: Cl
Reactant: CC(C)[SiH](C)C(C)C
Product: CC(C)[Si](C)(Cl)C(C)C
Temperature: 100 °C

Procedure:
A thermometer, hydrogen chloride gas inlet tube, and reflux condenser were fitted to a stirrer-equipped 200 mL four-neck flask, and 100 g methyldiisopropylsilane was then introduced into the flask. This was followed by the addition of 0.01 g platinum/divinyltetramethyldisiloxane complex and heating to 100° C. Hydrogen chloride gas was then introduced into the mixture. The introduction of hydrogen chloride gas was suspended after 4 hours. Distillation at ambient pressure yielded 122 g methyldiisopropylchlorosilane (purity≥99%, bp=146° C.). The methyldiisopropylchlorosilane yield was 97%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:7][N:8]2[CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:4][CH:3]=1.C([O:25][C:26](=[O:37])[C:27]1[CH:32]=[C:31]([CH2:33]Br)[CH:30]=[CH:29][C:28]=1[O:35][CH3:36])C>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:33][C:31]4[CH:30]=[CH:29][C:28]([O:35][CH3:36])=[C:27]([CH:32]=4)[C:26]([OH:37])=[O:25])[CH2:19][CH2:18]3)=[CH:7][N:8]2[CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)cn(Cc3ccsc3)c2c1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Product: COc1ccc(CN2CCC(c3cn(Cc4ccsc4)c4cc(F)ccc34)CC2)cc1C(=O)O

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.12 g (0.34 mmol) of 6-fluoro-3-piperidin-4-yl-1-thiophen-3-ylmethyl-1H-indole and 0.11 g (0.44 mmol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. The crude mixture was purified by HPLC-MS using a C-18 column.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH:18]([N:13]1[C:12]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2c3c(nn2C(C)C)CCNCC3)cc1
Yield: 107.6 %

Procedure:
The title compound (148 mg) was prepared according to Example 189 using 206 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 219 mg of 4-methoxyphenylboronic acid. MS (ESI): exact mass calculated for C17H23N3O, 285.18. found, m/z 286.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.30-7.28 (m, 2H), 7.13-7.11 (m, 2H), 4.68 (m, 1H), 4.47 (m, 1H), 3.87 (s, 3H), 3.47-3.44 (m, 1H), 3.25-3.23 (m, 1H), 2.89-2.81 (m, 2H), 1.43 (d, J=6.6 Hz, 6H).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O>CO>[Cl:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[C:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10]
Reactant: O=C1CCc2ccccc21
Reactant: O=Cc1cccc(OCCCCl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1C(=Cc2cccc(OCCCCl)c2)Cc2ccccc21
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
A solution of indan-1-one (0.4 g, 3.03 mmol) and sodium hydroxide (0.6 g, 15 mmol) in methanol (25 ml) was added to the solution of 3-(3-chloropropoxy)benzaldehyde in methanol (10 ml). The resulting solution was shaken for 30 min and allowed to stand at room temperature with intermittent shaking. The completion of reaction was monitored by TLC. After the completion, excess of methanol was removed; crushed ice was added and allowed to stand overnight. The precipitates obtained were filtered, washed thoroughly with distilled water and dried. The crude product was crystallized from a mixture of acetone and petroleum ether to yield white colored crystals of 2-[3-(3-chloropropoxy)benzylidene]-indan-1-one (1) (0.21 g, 33.5%), mp 73-75° C.