Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([NH:12][C@H:13]1[C@H:18](OS(C)(=O)=O)[CH2:17][CH2:16][C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O.C(OCC)(=O)C>[Cl-].C[N+](C)(C)C.CN1CCCC1=O>[N:1]([C@H:18]1[CH2:17][CH2:16][C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14][C@H:13]1[NH:12][C:10]([O:9][C:5]([CH3:6])([CH3:8])[CH3:7])=[O:11])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OC(C)(C)C)C1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CC[C@H](N=[N+]=[N-])[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 74 h

Procedure:
Sodium azide (357.6 mg) and tetramethylammonium chloride (91.0 mg) were added at room temperature to a solution (2 mL) of ethyl (1S,3R,4R)-3-[(t-butoxycarbonyl)amino]-4-methanesulfonyloxycyclohexanecarboxylate (1.01 g) in N-methyl-2-pyrrolidone, followed by stirred at 60° C. for 74 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was washed with aqueous saturated sodium bicarbonate solution and water, followed by drying over magnesium sulfate anhydrate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 648.3 mg of the title compound. Spectral data of this compound were found to be identical with those of the compound of Example 5.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=[N:3]1.[H-].[Na+].Cl[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1.O>C1COCC1>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([O:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][C:5]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:19][CH:20]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cn1nnc(-c2ccccc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccccc3)nnn2C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
A solution of (3-methyl-5-phenyl-3H-[1,2,3]triazol-4-yl)-methanol (189 mg, 1.0 mmol) in THF (3 mL) was added dropwise at 0° C. to a suspension of NaH (55% in oil, 48 mg, 1.1 mmol) in THF (1.5 mL) and the reaction mixture was then stirred at room temperature for 30 min. Then a solution of methyl 6-chloronicotinate (189 mg, 1.1 mmol) in THF (3 mL) was added dropwise at 0° C. and the reaction mixture stirred at room temperature for 20 h. The mixture was then poured into water extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (203 mg, 63%) as an off white solid. MS: m/e=325.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH:7]=O)[CH3:2].[S:15]1[CH2:21][C:19](=[O:20])[NH:18][C:16]1=[S:17].C(O)(=O)C>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH:7]=[C:21]1[S:15][C:16](=[S:17])[NH:18][C:19]1=[O:20])[CH3:2]
Reactant: O=C1CSC(=S)N1
Reactant: CCOc1ccc(C=O)cc1OCC
Solvent: O
Solvent: CC(=O)O
Product: CCOc1ccc(C=C2SC(=S)NC2=O)cc1OCC

Procedure:
A solution of 10.0 g. of 3,4-diethoxybenzaldehyde, 6.86 g. of rhodanine, and 14.5 g. of fused sodium acetate in 70 ml. of acetic acid was heated to reflux for one hour. The hot mixture was poured into one liter of water with stirring. The resulting precipitate was col-lected by filtration and dried. Recrystallization from ethanol provided 10.22 g. of the subtitle intermediate.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:25]2[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])=[C:27]([CH3:38])[CH:26]=2)([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][C:15]=1[CH3:39])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:25]2[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([OH:35])([CH:1]([CH3:3])[CH3:2])[CH:32]([CH3:33])[CH3:34])=[C:27]([CH3:38])[CH:26]=2)([CH2:21][CH3:22])[CH2:23][CH3:24])=[CH:16][C:15]=1[CH3:39])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)C)c(C)c1)c1ccc(OCc2ccccc2)c(C)c1
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCc2ccccc2)c(C)c1)c1ccc(OCC(O)(C(C)C)C(C)C)c(C)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Anhydrous CeCl3 (0.82 g) is suspended in THF (30 mL) with stirring overnight. It is cooled to 0° C., treated with 2.0 M iPrMgCl (1.3 mL) and stirred at 0° C. for 1 h. A solution of 1-{4-[1-(4-benzyloxy-3-methyl-phenyl)-1-ethyl-propyl]-2-methyl-phenoxy}-3-methyl-butan-2-one (1.01 g, 2.21 mmol) in THF (10 mL) is added. The mixture is stirred at 0° C. for 1 h, before it is quenched with 0.1 M HCl (20 mL). It is extracted with EtOAc (200 mL), washed with 0.1 M HCl (3×50 mL); MgSO4 dried and concentrated to give the title compound (1.10 g, 2.19 mmol, 99%). 1H NMR (CDCl3), δ 0.62 (t, J=7.0 Hz, 6H), 1.01 (d, J=7.1 Hz, 6H), 1.04 (d, J=7.1 Hz, 6H), 1.57 (b, 2H), 2.04 (q, J=7.0 Hz, 4H), 2.17 (s, 3H), 2.24 (s, 3H), 3.88 (s, 2H), 5.04 (s, 2H), 6.70 (d, J=8.3 Hz, 1H), 6.77 (d, J=9.2 Hz, 1H), 6.90 (d, J=2.2 Hz, 1H), 6.93-6.98 (m, 3H), 7.29-7.47 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:18])([C:16]#[CH:17])[CH3:15])[CH2:10][CH2:9]2)[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.Br[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1>>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:18])([C:16]#[C:17][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=3)[CH3:15])[CH2:10][CH2:9]2)[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1
Reactant: C#CC(C)(O)C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Reactant: Cc1cccc(Br)n1
Product: Cc1cccc(C#CC(C)(O)C2CCN(c3nc(C)ccc3[N+](=O)[O-])CC2)n1
Yield: 41 %

Procedure:
According to the Method B detailed for Examples 218-226 starting from Compound 312c and using 2-bromo-6-methylpyridine the title compound was prepared. After the work-up, the residue was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with PE-EtOAc 1:1 affording the title product as a yellow oil. Yield: 41%.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[N:19]=[C:18]([Cl:20])[CH:17]=[C:16](Cl)[N:15]=2)=[CH:9][CH:8]=1)=[O:5].[CH3:26][C:27]1[CH:28]=[C:29]([NH2:32])[NH:30][N:31]=1.[I-].[Na+].C(N(CC)C(C)C)(C)C>O.CN(C)C=O>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[N:19]=[C:18]([Cl:20])[CH:17]=[C:16]([NH:32][C:29]3[NH:30][N:31]=[C:27]([CH3:26])[CH:28]=3)[N:15]=2)=[CH:9][CH:8]=1)=[O:5]
Reactant: O=C(Nc1ccc(Sc2nc(Cl)cc(Cl)n2)cc1)c1ccccc1Cl
Reactant: Cc1cc(N)[nH]n1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Nc2cc(Cl)nc(Sc3ccc(NC(=O)c4ccccc4Cl)cc3)n2)[nH]n1
Temperature: 90 °C
Reaction time: 5 h
Yield: 82.1 %

Procedure:
A 250 mL round bottom flask was charged with 2-chloro-N-[4-(4,6-dichloro-pyrimidin-2-ylsulfanyl)-phenyl]-benzamide (12.5 g, 30.4 mmol), 5-methyl-2H-pyrazol-3-ylamine (3.55 g, 36.5 mmol), sodium iodide (4.56 g, 30.4 mmol), N,N-diisopropylethylamine (6.9 mL, 40.0 mmol) and N,N-dimethylformamide (125 mL) under nitrogen. The reaction mixture was stirred at 90° C. for 5 h, then allowed to cool to room temperature. Water (600 mL) was added and the resulting suspension stirred at room temperature for 2 h and the solid collected by filtration and dried. The resulting white solid was triturated with hot ethyl acetate (50 mL), filtered and washed with ethyl acetate (1×20 mL) to give the title compound as a white solid (11.76 g, 82%). 1H NMR (DMSO): 2.16 (3H, s), 5.30 (1H, s), 6.48 (1H, s), 7.49-7.62 (6H, m), 7.89 (2H, m), 10.28 (1H, s), 10.84 (1H, s), 11.93 (1H, s); MS (ES+): 471.
Reaction SMILES: C(OC([C:6]1[N:7]([C@H:18]([CH3:28])[CH2:19][NH:20][C:21]([O:23]C(C)(C)C)=O)[C:8]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]1[C:9]=2[CH2:10][CH2:11][CH2:12]1)=O)C.FC(F)(F)C(O)=O>ClCCl>[CH3:28][C@@H:18]1[CH2:19][NH:20][C:21](=[O:23])[C:6]2[N:7]1[C:8]1[C:9]3[CH2:10][CH2:11][CH2:12][C:13]=3[CH:14]=[CH:15][C:16]=1[CH:17]=2
Reactant: CCOC(=O)c1cc2ccc3c(c2n1[C@H](C)CNC(=O)OC(C)(C)C)CCC3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CNC(=O)c2cc3ccc4c(c3n21)CCC4
Reaction time: 1 h
Yield: 63.6 %

Procedure:
(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-1,6,7,8-tetrahydro-1-aza-as-indacene-2-carboxylic acid ethyl ester (7.2 g, ˜17 mmol) was dissolved in dichloromethane (110 mL) and treated with trifluoroacetic acid (29 mL) at 0° C. After removal of the ice bath, the solution was stirred for 1 h, and evaporated under reduced pressure. The residue was dissolved in methanol (120 mL); after addition of saturated sodium bicarbonate solution (110 mL) and 2.6 g potassium carbonate the mixture was stirred for 20 h at room temperature. Water (100 mL) was added and the mixture was extracted with dichloromethane (2×100 mL). The organic layer was separated, washed with brine, dried (MgSO4), and evaporated. Crystallization from diethyl ether yielded the title compound as a colorless solid (2.6 g, 57%). EI-MS: m/e 240.2 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([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:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[C:29]([CH3:35])[CH:28]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][C:29]=3[CH3:35])[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:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CCl)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCN(C(=O)OC(C)(C)C)CC3)c(C)c1
Temperature: 110 °C

Procedure:
To a solution of 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; 0.4 mmol) in toluene (3 mL) was added 4-methoxy-2-methyl-benzyl chloride (0.9 mmol) and cyanomethylene-tri-n-butylphosphorane (1 mmol). The mixture was heated at 110° C. for 16 h. After concentration and purification (SiO2, EtOAc/hexanes), 3-(4-chloro-phenyl)-1-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester was obtained (54 mg). The other regioisomer, 3-(4-chloro-phenyl)-2-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester, was also obtained (86 mg). 3-(4-Chloro-phenyl)-1-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (20 mg) was treated with TFA (1 mL) in CH2Cl2 (10 mL) for 4 h. After concentration of the reaction mixture, the title compound was obtained (0.02 g). MS (ESI): exact mass calculated for C22H24ClN3O, 381.16; found, m/z 382.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.37 (m, 2H), 7.34-7.32 (m, 2H), 6.68-6.66 (br m, 1H), 6.54-6.52 (br m, 1H), 6.37 (d, J=8.3 Hz, 1H), 5.21 (s, 2H), 2.81-2.79 (m, 4H), 2.71-2.69 (m, 4H).
Reaction SMILES: CS([O:5][CH2:6][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:9])[CH3:8])(=O)=O.CC(NC(=O)OC(C)(C)C)(C)COC1C=CC=CC=1.[C:37]1([CH2:43]O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH3:8][C:7]([NH:10][C:11](=[O:12])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:9])[CH2:6][O:5][CH2:43][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: OCc1ccccc1
Agent: CC(C)(COc1ccccc1)NC(=O)OC(C)(C)C
Product: CC(C)(COCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
1,1-Dimethylethyl {1,1-dimethyl-2-[(phenylmethyl)oxy]ethyl}carbamate (D275) was prepared from 2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylpropyl methanesulfonate (D273) in an analogous manner to 1,1-dimethylethyl [1,1-dimethyl-2-(phenyloxy)ethyl]carbamate (D274) using phenylmethanol instead of phenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH2:12].C1C(=O)N([Br:20])C(=O)C1>CC#N>[Br:20][C:5]1[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[NH2:12]
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])cc(Br)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 2 L round bottom flask with a stir bar was added 2-methoxy-4-nitro-phenylamine (50.0 g, 297.4 mmol), CH3CN (1 L), and NBS (53.5 g, 297.4 mmol). The reaction was stirred at room temperature for 2 hours while protected from light. The reaction was concentrated and then 500 mL water was added. The product was extracted with ethyl acetate and concentrated. The solid which precipitated from the aqueous washes was combined with the solid which resulted from the organic concentration to give I-229 (59.6 g) which was used without further purification.
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[CH2:11](Br)[C:12]#[CH:13]>CN(C)C=O.C1(C)C=CC=CC=1>[C:11]([O:1][C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4])#[C:12][CH3:13]
Reactant: COC(=O)C(C)(C)O
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC#COC(C)(C)C(=O)OC
Temperature: 20 °C
Reaction time: 3 h
Yield: 40.9 %

Procedure:
55 g (0.47 mol) of methyl 2-hydroxy-2-methylpropionate in 400 ml of dry dimethylformamide were added dropwise while stirring during 0.75 hour to 14 g (0.47 mol, 80% oil dispersion) of sodium hydride in 200 ml of dry dimethylformamide. After 3 hours at 20° C. 62.5 g (0.42 mol) of propargyl bromide (as a 80% solution in toluene) in 200 ml of dimethylformamide was added during 0.5 hour while cooling to maintain the temperature below 25° C. After stirring at 20° C. for 17 hours the mixture was poured on to ice and extracted with toluene. The toluene phase was evaporated carefully and the residue was distilled at 80° C./15 mmHg to give 26.8 g (41%) of methyl 2-propynyloxy-2-methylpropionate.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl.[Br:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41].[C:48]1([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:53]=[CH:52][C:51]([NH:54][C:55](=[O:61])[CH:56]([CH3:60])[C:57](O)=[O:58])=[CH:50][CH:49]=1>CN(C=O)C.O>[C:48]1([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:53]=[CH:52][C:51]([NH:54][C:55](=[O:61])[CH:56]([CH3:60])[C:57]([N:45]2[CH2:44][CH2:43][N:42]([C:40](=[O:41])[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[Br:33])[CH2:47][CH2:46]2)=[O:58])=[CH:50][CH:49]=1
Reactant: CC(C(=O)O)C(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: O=C(c1ccccc1Br)N1CCNCC1
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: CC(C(=O)Nc1ccc(-c2ccccc2)cc1)C(=O)N1CCN(C(=O)c2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
HOBt (60 mg, 0.44 mmol), DIPEA (140 mg, 1.1 mmol), EDCI.HCl (85 mg, 0.44 mmol) followed by (2-bromo-phenyl)-piperazin-1-yl-methanone hydrochloride (136 mg, 0.44 mmol), were added to a stirred solution of N-biphenyl-4-yl-2-methyl-malonamic acid (100 mg, 0.37 mmol) in DMF (2.0 mL). The resulting mixture was stirred at ambient temperature overnight then diluted with water. The product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and concentrated under reduced pressure to afford 140 mg (73%) of N-biphenyl-4-yl-3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-2-methyl-3-oxo-propionamide. LCMS: 520.12 (M+1)+, 97.32%, 1H NMR (DMSO-d6): δ 10.2 (d, 1H), 7.8-7.3 (m, 13H), 4.0-3.4 (m, 7H), 3.2-3.0 (m, 2H), 1.3 (m, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2>C1COCC1>[NH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][C:10]=1[CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20]1
Reactant: Nc1cc(C(F)(F)F)ccc1-c1cc2ccccc2[nH]1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(C(F)(F)F)ccc1C1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
Borane-tetrahydrofuran complex (1.0M, 130 ml) was added dropwise to a solution of 90 ml THF and 90 ml TFA (trifluoroacetic acid) at -5° C., and then 17.93 g 2-(2-amino-4-trifluoromethylphenyl)-1H-indole was added. The resulting solution was stirred at room temperature overnight. The reaction mixture was quenched with water and basified with 50% NaOH. The solution was extracted with Et2O. This organic layer was washed with water and saturated NaCl solution, dried (MgSO4), and concentrated to yield 3.65 g solid. Purification by HPLC and recrystallization from MeOH/water yielded 1.93 g solid, m.p. 152°-154° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([CH3:15])[CH:3]=1.[CH3:16][N:17]([CH3:30])[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O)(=[O:20])=[O:19]>>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:22]3[C:21]([S:18]([N:17]([CH3:30])[CH3:16])(=[O:19])=[O:20])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:3][C:4]=2[CH3:15])=[N:9][CH:10]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1B(O)O
Reactant: Cc1cc(Br)ccc1-c1cnc(N)cn1
Product: Cc1cc(-c2ccccc2S(=O)(=O)N(C)C)ccc1-c1cnc(N)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 589 using 5-(4-bromo-2-methylphenyl)pyrazin-2-amine and (2-(N,N-dimethylsulfamoyl)phenyl)boronic acid. MS (ESI): mass calcd. for C19H20N4O2S, 368.46; m/z found, 369.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J=1.5, 1H), 8.12 (dd, J=8.0, 1.3, 1H), 8.10 (d, J=1.5, 1H), 7.60-7.55 (m, 1H), 7.52-7.47 (m, 1H), 7.43 (d, J=7.8, 1H), 7.35-7.29 (m, 3H), 4.77 (s, 2H), 2.44 (s, 3H), 2.42 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C@H:10]2[CH2:12][C@H:11]2[CH2:13][CH2:14][OH:15])[CH2:6][CH2:5]1.[H-].[Na+].F[C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>CN(C=O)C>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([O:15][CH2:14][CH2:13][C@@H:11]2[CH2:12][C@@H:10]2[CH:7]2[CH2:8][CH2:9][N:4]([CH2:3][C:2]([F:1])([F:16])[F:17])[CH2:5][CH2:6]2)=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(CC(F)(F)F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(CC(F)(F)F)CC2)cc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-((1S,2R)-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]cyclopropyl)ethanol (30 mg, 0.119 mmol) in DMF (1 mL) was added NaH (60%, 7.2 mg, 0.179 mmol) at RT. The mixture was stirred for 15 min. 1-fluoro-4-(methylsulfonyl)benzene (20.8 mg, 0.119 mmol) was added to the reaction mixture. It was heated at 50° C. for 3 hours. The reaction was quenched with water, extracted with EtOAc. The organic layer was dried by sodium sulfate and concentrated. The residue was purified by Mass directed RPHPLC. The product fraction was basified with 1 M sodium bicarbonate aq. solution, extracted with EtOAc. Solvent was removed under vacuum to yield the Example 4. LCMS calc: 405.47; obs: 406.04 (M+1); Human GPR119 EC50: 175.6 nM. 1H NMR (CDCl3, 500 MHz) 7.90 (d, 2H), 7.02 (d, 2H), 4.15 (m, 2H), 3.05 (s, 3H), 2.97 (m, 4), 2.34 (m, 2H), 2.18 (m, 1H), 1.78 (m, 2H), 1.45-1.58 (m, 3H), 0.96 (m, 1H), 0.82 (m, 1H), 0.65 (m, 2H), −0.88 (m, 1H)
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[C:11]3[C:15]([CH:16]=[C:17](B4OC(C)(C)CC(C)(C)O4)[CH:18]=2)=[N:14][N:13](C2CCCCO2)[CH:12]=3)=[O:8])[N:6]=1.Br[C:36]1[CH:44]=[C:43]([C:45]#[N:46])[CH:42]=[C:41]2[C:37]=1[CH:38]=[CH:39][NH:40]2.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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]>[C:45]([C:43]1[CH:42]=[C:41]2[C:37]([CH:38]=[CH:39][NH:40]2)=[C:36]([C:17]2[CH:16]=[C:15]3[C:11]([CH:12]=[N:13][NH:14]3)=[C:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[O:8])[CH:18]=2)[CH:44]=1)#[N:46]
Reactant: Cc1nc(C(=O)Nc2cc(B3OC(C)(C)CC(C)(C)O3)cc3nn(C4CCCCO4)cc23)cs1
Reactant: N#Cc1cc(Br)c2cc[nH]c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(C(=O)Nc2cc(-c3cc(C#N)cc4[nH]ccc34)cc3[nH]ncc23)cs1
Temperature: 140 °C
Yield: 53.1 %

Procedure:
2-Methyl-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg, 0.104 mmol), 4-bromo-1H-indole-6-carbonitrile (252 mg, 0.114 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol) and sodium carbonate (44 mg, 0.415 mmol) were added to a 0.5-2 ml microwave vial and suspended in 1,4-dioxane (0.5 mL) and water (0.5 mL). The mixture was heated in the microwave at 140° C. for 20 min, then cooled and passed through a 1 g silica cartridge which was washed with methanol. The solvent was evaporated by blow down. The residue was dissolved in 1.6 ml DMSO:methanol (1:1, v/v) and purified by Mass Directed Auto Preparative HPLC (Method F). To the sample-containing fractions 2M HCl (aq) (ca. 1 ml) was added and the fractions were blown down. The residue was dissolved in DCM:methanol (ca. 50:50, v/v) and passed through a 1 g PS—NH2 cartridge, washing with DCM:methanol. Solvent was removed by blow down then the residue was suspended in 2 ml dioxane:water (1:1, v/v) and freeze dried to afford the title compound as a white solid (22 mg).
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=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.C(O)C>[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[C:39]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:16]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2cccc(C(F)(F)F)c2)cc1
Yield: 59.9 %

Procedure:
Prepared according to the method described in Example 33a) from toluene (5 ml), aqueous sodium carbonate (2 M, 1 ml), (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.25 g), ethanol (1 ml), 3-trifluoromethylbenzeneboronic acid (0.161 g) and tetrakis(triphenylphosphine)palladium(0) (22 mg) with heating at reflux for 6 hours. The residue obtained after work-up was purified by column chromatography over silica eluting with ethyl acetate to give (2R)-1-(3'-trifluoromethylbiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol as a colourless oil (0.180 g). Conversion to the oxalate salt upon treatment with excess saturated ethereal oxalic acid gave the title compound as a hygroscopic gum. (0.150 g)