Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:36])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:16]([CH3:24])([CH3:23])[C:17]([CH3:22])([CH3:21])[CH:18]([CH3:20])[CH3:19])[C:7]=1[CH2:25][S:26][CH2:27][C@H:28]([NH2:35])[C:29]1[O:33][N:32]=[C:31]([CH3:34])[N:30]=1)[CH:2]=[CH2:3].[C:37]([O:56][CH2:57][C:58](O)=[O:59])([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl.CN(CCCN=C=NCC)C>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:4][C:5](=[O:36])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:16]([CH3:24])([CH3:23])[C:17]([CH3:21])([CH3:22])[CH:18]([CH3:19])[CH3:20])[C:7]=1[CH2:25][S:26][CH2:27][C@@H:28]([C:29]1[O:33][N:32]=[C:31]([CH3:34])[N:30]=1)[NH:35][C:58](=[O:59])[CH2:57][O:56][C:37]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CSC[C@H](N)c1nc(C)no1
Reactant: O=C(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CSC[C@H](NC(=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nc(C)no1
Temperature: 0 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a suspension of 1.07 g of (R)-2-[2-amino-2-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylsulfanylmethyl]-3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-5-methoxy-6-methylbenzoic acid allyl ester and 0.96 g of trityloxy-acetic acid in 15 ml of acetonitrile, cooled to 0° C., were added 0.58 g of N-(dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride. The mixture was stirred at 0° C. for 4 h, then diluted with 30 ml of ethyl acetate, and washed successively with 0.5N hydrochloric acid, water, 5% sodium bicarbonate solution, and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using ethyl acetate/hexane (1:1, v/v) as eluent to yield 1.42 g of (R)-3-[dimethyl-(1,1,2-trimethyl-propyl)silanyloxy]-5-methoxy-6-methyl-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-trityloxy-acetylamino]-ethylsulfanylmethyl]-benzoic acid allyl ester as a foam.
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[C:25]12([CH2:35][O:36][C:37]3[C:45]([CH:46]4[CH2:48][C:47]4([F:50])[F:49])=[CH:44][C:40]([C:41](O)=[O:42])=[C:39]([F:51])[CH:38]=3)[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2.COCCS(N)(=O)=O.[CH:60]1([S:63]([NH2:66])(=[O:65])=[O:64])[CH2:62][CH2:61]1>>[C:25]12([CH2:35][O:36][C:37]3[C:45]([CH:46]4[CH2:48][C:47]4([F:50])[F:49])=[CH:44][C:40]([C:41]([NH:66][S:63]([CH:60]4[CH2:62][CH2:61]4)(=[O:65])=[O:64])=[O:42])=[C:39]([F:51])[CH:38]=3)[CH2:32][CH:31]3[CH2:33][CH:27]([CH2:28][CH:29]([CH2:30]3)[CH2:34]1)[CH2:26]2
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)c1cc(C2CC2(F)F)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: COCCS(N)(=O)=O
Agent: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2(F)F)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Yield: 43 %

Procedure:
Following the procedure as described in Example 271 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 4-(adamantan-1-ylmethoxy)-5-(2,2-difluorocyclopropyl)-2-fluorobenzoic acid and to replace 2-methoxyethanesulfonamide with cyclopropylsulfonamide. Purification by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compound as a colorless solid (0.055 g, 43%): 1H NMR (300 MHz, DMSO-d6) δ 11.86 (br s, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.00 (d, J=13.0 Hz, 1H), 3.70-3.56 (m, 2H), 3.10-2.99 (m, 1H), 2.84-2.71 (m, 1H), 2.04-1.85 (m, 5H), 1.76-1.55 (m, 12H), 1.14-1.02 (m, 4H); MS (ES+) m/z 484.1 (M+1).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[C:4]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:3]=1[C:21]#[N:22].[CH3:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)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:16]1([C:4]2[C:3]([C:21]#[N:22])=[C:2]([C:28]3[CH:27]=[CH:26][N:25]=[C:24]([CH3:23])[CH:29]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=3)[N:5]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: N#Cc1c(C2CCCC2)nc2ccc(C(F)(F)F)cc2c1Br
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: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2c(C#N)c(C3CCCC3)nc3ccc(C(F)(F)F)cc23)ccn1
Temperature: 90 °C
Yield: 14.9 %

Procedure:
A suspension of 4-bromo-2-cyclopentyl-6-trifluoromethyl-quinoline-3-carbonitrile (130 mg, 352 μmol), 2-methylpyridine-4-boronic acid pinacol ester (92.6 mg, 423 μmol), cesium carbonate (103 mg, 317 μmol) and tetrakis(triphenylphosphine)palladium (0) (40.7 mg, 35.2 μmol) in DMF (5.2 ml) was heated to 90° C. for 16 h. The reaction mixture was poured on water and extracted with EtOAc. The combined extracts were washed with water and brine, dried with Na2SO4 and evaporated. The remaining solid was purified by column chromatography (silica gel, n-heptane/EtOAc 4:1) to afford the title compound (20 mg, 15%) as off-white solid. MS (ESI): 382.6 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.O>CN1C(=O)CCC1>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=2)[CH2:15][CH2:14]1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5-fluoro-2-nitroaniline (1 g), 1-methylpiperazine (0.752 mL) and TEA (1.86 mL) in NMP (1.5 mL) was heated at 100° C. in a microwave oven for 20 h. After cooling down, H2O (50 mL) was added, the resulting suspension was stirred for 20 min and filtrated off. The yellow solid was washed with water and dried under high vacuo (1.45 g). LC-MS (B): tR=0.47 min; [M+H]+: 237.19.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[O:34][N:33]=2)=[CH:28][CH:27]=1)=O.C([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C.CC(O)=O>[N:1]1([CH2:24][C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[O:34][N:33]=3)=[CH:30][CH:31]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: NC(=O)c1cc(-c2ccc(C=O)cc2)no1
Reactant: c1ccc2c(c1)CCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: NC(=O)c1cc(-c2ccc(CN3CCc4ccccc43)cc2)no1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.8 %

Procedure:
To a solution of indoline (13 μL, 0.116 mmol) in dichloroethane (1 mL) was added Na(OAc)3BH (74 mg, 0.35 mmol). The mixture was stirred at room temperature under argon for 20 min. A slurry of 3-(4-formyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 20; 25 mg, 0.116 mmol) in dichloroethane (1 mL) was added, followed by AcOH (20 μL). The reaction mixture was stirred at room temperature overnight. 1 M Na2CO3 solution was added and the mixture was extracted with EtOAc (3×25 mL). The organic layer was washed with brine, dried (Na2SO4), evaporated, and purified by chromatography (12.5-20% acetone/CH2Cl2) to give 3-[4-(2,3-dihydro-indol-1-ylmethyl)-phenyl]-isoxazole-5-carboxylic acid amide (24 mg, 65%), as an off-white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.27 (br. s., 1H), 7.90 (br. s., 1H), 7.79 (d, J=8.2 Hz, 2H), 7.48 (s, 1H), 7.41 (d, J=8.2 Hz, 2H), 6.95 (d, J=6.9 Hz, 1H), 6.88 (t, J=7.7 Hz, 1H), 6.42-6.55 (m, 2H), 4.23 (s, 2H), 3.14-3.21 (m, 2H), 2.75-2.87 (m, 2H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[CH:7]=[CH:6][N:5]=1.[CH:20]1([NH:23][C:24](=O)[O:25]C2C=CC=CC=2)[CH2:22][CH2:21]1.O>CN(C)C=O>[CH:20]1([NH:23][C:24]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][C:8]4[CH:7]=[CH:6][N:5]=[C:4]([NH2:3])[CH:9]=4)=[CH:19][CH:18]=3)[CH:14]=[CH:15]2)=[O:25])[CH2:22][CH2:21]1
Reactant: O=C(NC1CC1)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 1168.8 %

Procedure:
After adding 28 mg of sodium hydride (60% in oil) to a solution of 150 mg of 5-[(2-amino-4-pyridyl)oxy]-1H-indole in dimethylformamide at room temperature and stirring for 5 minutes, the mixture was cooled to 0° C., 124 mg of phenyl N-cyclopropylcarbamate was added and the mixture was further stirred for 30 minutes. Water was added, extraction was performed with ethyl acetate, the organic layer was washed 3 times with water and once with aqueous ammonium chloride solution, and then silica gel was added and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel and purification was performed by column chromatography (hexane:ethyl acetate=1:1, followed by ethyl acetate), to obtain 2.4 g of a colorless powder.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[Br:23][CH2:24][C:25](Br)=[O:26]>ClCCl>[Br:23][CH2:24][C:25]([C:4]1[CH:5]=[CH:6][C:1]([C@H:7]2[CH2:8][CH2:9][C@H:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:12]2)=[CH:2][CH:3]=1)=[O:26]
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccccc2)CC1
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)CBr)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution containing the product from Example 1B (1.5 g, 6.1 mmol) and AlCl3 (2.4 g, 18 mmol) in 10 mL of dichloromethane at 0° C. was added bromoacetyl bromide (0.55 mL, 6.2 mmol). The mixture was stirred at room temperature for 30 min, to one hour. Upon completion of the reaction as monitored by thin layer chromatography, the reaction mixture was poured into ice-cold water (100 mL), and extracted with dichloromethane (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure, and the resulting oil was purified by flash chromatography (ethyl acetate/hexane, 1/8) to afford the title compound as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (m, 2H), 1.19 (t, J=7.06 Hz, 3H), 1.50 (m, 2H), 1.70-1.85 (m, 5H), 2.22 (d, J=6.75 Hz, 2H), 2.56 (m, 1H), 4.07 (q, J=7.06 Hz, 3H), 4.88 (s, 2H), 7.41 (d J=8.28 Hz, 2H), 8.92 (d, J=8.28 Hz, 2H); MS (ESI) m/z 367.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1O[C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:19])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:19][C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1
Reactant: Cc1cc(=O)cc(C)o1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(=O)cc(C)s1
Temperature: 100 °C
Yield: 181.6 %

Procedure:
2,6-Dimethyl-4-pyranone (0.25 g, 2.0 mmol) in toluene (10 ml) was treated with Lawesson's reagent (0.22 g, 1.1 mmol) and heated at 100° C. for 3h. A further quantity of Lawesson's reagent (0.22 g, 1.1 mmol) was added and the mixture heated at 100° C. for 0.75h. The mixture was allowed to cool, then purified on silica gel 60 eluting with ethanol and dichloromethane (1:9) to give the title compound (0.28 g, 98%).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH2:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:22][C:21]([CH3:24])([CH3:23])[C@@H:20](O)[C@H:19]([NH2:26])[C:18]=2[CH:27]=1)[CH3:13]>CC(O)C>[C:1]([O:11][C@H:20]1[C@H:19]([NH2:26])[C:18]2[CH:27]=[C:14]([CH2:12][CH3:13])[CH:15]=[CH:16][C:17]=2[O:22][C:21]1([CH3:23])[CH3:24])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: CCc1ccc2c(c1)[C@@H](N)[C@H](O)C(C)(C)O2
Reactant: O=C(O)C(O)c1ccccc1
Solvent: CC(C)O
Product: CCc1ccc2c(c1)[C@@H](N)[C@H](OC(=O)C(O)c1ccccc1)C(C)(C)O2

Procedure:
(+)-Mandelic acid (0.57 kg) and trans-6-ethyl-4-amino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol** (0.75kg) were dissolved in warm 2-propanol (18 L). The solution was concentrated to 12 L and crystallised to give the title compound (0.523 kg).
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[S:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:27](O)(=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].Cl>CN(C)C=O>[OH:3][C:2]1[CH2:4][S:5][C:6](=[O:7])[C:1]=1[C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: O=C1CSC(=O)C1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCC/C=C\CCCCCCCC(=O)C1=C(O)CSC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To a stirring solution of 1.71 g (14.75 mmol) of thiotetronic acid in 10 mL of dimethylformamide is added 2.22 mL (17.2 mmol) of triethylamine and 592 mg (4.85 mmol) of 4-diemthylaminopyridine at 0° C. Next, 3.38 g (17.6 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 5.0 g (17.7 mmol) of oleic acid are added and the reaction mixture is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted three times with diethyl ether. The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is subjected to HPLC chromatography (2 inch Dynamax silica gel column, 25 mL/min) eluting with 100% ethyl acetate to give 1.85 g (33%) of 4-hydroxy-3-[(Z)-1-oxo-9-octadecenyl]-2(5H)-thiophenone as an oil.
Reaction SMILES: CON(C)[C:4](=[O:32])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:6]=1.[C:34]([Mg]Br)#[C:35][CH2:36]C>C1COCC1>[O:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:7]3[CH:6]=[C:5]([C:4](=[O:32])[C:34]#[C:35][CH3:36])[CH:10]=[CH:9][CH:8]=3)[CH:17]=2)=[CH:20][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCC#C[Mg]Br
Reactant: CON(C)C(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Solvent: C1CCOC1
Product: CC#CC(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-methoxy-N-methyl-3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzamide (50 mg, 0.11 mmol) in THF (0.5 mL) at 0° C. was added a THF solution of 1-butynylmagnesium bromide (1.1 mL, 1.1 mmol). The reaction mixture was allowed to come to rt and was stirred at rt for 30 min. The reaction mixture was quenched with saturated NH4Cl solution (0.5 mL) and was extracted with EtOAc (2×3 mL). The combined EtOAc layer was washed with brine, was dried over anhydrous Na2SO4, was filtered and was concentrated under reduced pressure to give a white solid, which h was further purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) to give 1-(3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)phenyl)but-2-yn-1-one (I-88) as an off-yellow solid. 1H NMR (DMSO-d6) δ ppm: 2.22 (s, 3H), 6.16 (s, 1H), 6.97 (d, J=8.6 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 7.1 (t, J=7.2 Hz, 1H), 7.35-7.39 (m, 2H), 7.48 (t, J=8 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.66 (d, J=7.2 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 8.32 (s, 1H), 8.39 (s, 1H), 9.22 (s, 1H), 9.47 (s, 1H); LCMS: m/e 421.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH:19]([C:21]1[NH:22][C:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:28]=2[C:29]=1[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=O>N1CCCCC1.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13](=[CH:19][C:21]4[NH:22][C:23]5[CH2:24][CH2:25][CH2:26][CH2:27][C:28]=5[C:29]=4[CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Reactant: COc1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c3c(c2CCC(=O)O)CCCC3)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A mixture of 103 mg 6-(4-methoxyphenyl)-2-oxindole, 95 mg 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid and piperidine (3 drops) in ethanol (2 mL) was heated to 90° C. in a sealed tube and held there for 4 hrs. The reaction mixture was concentrated and acidified with 6 N hydrochloric acid. Ethyl acetate was added upon which a solid precipitated from the aqueous layer. The precipitate was collected by filtration, and washed with water and hexane to give 57 mg of 3-{2-[6-(4-Methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-4,5,6,7-tetrahydro-1H-indol-3-yl}-propionic acid as a brown solid (30%).
Reaction SMILES: [F:1][C:2]1([F:16])[CH:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.CC([O-])(C)C.[K+].C1COCC1.[N:28]1[N:29]=[C:30]([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[C:40](F)[CH:41]=[C:42]([F:47])[CH:43]=3)[N:38]=2)[N:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=12>CN(C=O)C>[N:28]1[N:29]=[C:30]([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[C:40]([O:8][CH:7]4[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:3][C:2]4([F:1])[F:16])[CH:41]=[C:42]([F:47])[CH:43]=3)[N:38]=2)[N:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=12
Reactant: Fc1cc(F)c2nc(-c3nnc4ccccn34)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(F)(F)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)C(F)(F)C1
Reaction time: 0.25 h

Procedure:
tert-Butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate (0.0706 g, 0.298 mmol) was treated with 1 M KOtBu in THF (0.283 mL, 0.283 mmol) and stirred for 15 minutes. The solution was treated with 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6,8-difluoroquinoline (0.042 g, 0.149 mmol) and DMF (0.80 mL) then the mixture was stirred at ambient temperature for 16 hours. The mixture was directly chromatographed on SiO2 eluting with a gradient of 2% NH4OH in isopropanol/ethyl acetate. The desired product was collected and concentrated to a colorless oil, (72 mg). MS APCI (+) m/z 500.0 (M+1) detected.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH3:20][NH:21][CH3:22].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:20][N:21]([CH3:22])[S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: CNC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N(C)C)s2)s1
Reaction time: 1 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (110 mg; 0.33 mmol; 1 eq), is dissolved in DMF (10 ml). Dimethylamine (0.1 ml; 1.65 mmol; 5 eq) and DIEA (0.17 ml; 0.98 mmol; 3 eq) are added. After one hour, the solvents are evaporated to dryness. The crude product is re-dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is precipitated in a mixture of DCM and diethyl ether, affording after filtration, Compound (18) as a yellow powder (52 mg; 46%).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].C(O[C:15]([S-:17])=[S:16])C.[K+]>CN1CCCC1=O>[SH:17][C:15]1[S:16][C:2]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=2[N:4]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc2sc(S)nc2c1
Temperature: 140 °C
Yield: 86.2 %

Procedure:
2-Bromo-5-nitroaniline (10 g) was dissolved in N-methyl-2-pyrrolidone (50 mL), and potassium ethylxanthate (14.8 g) was added thereto. The mixture was stirred at 140° C. with heating. The reaction mixture was concentrated under reduced pressure, and water (300 mL) and conc. hydrochloric acid (10 mL) were added to the residue. The precipitated solid was collected by filtration, which was then dissolved in 1 mol/L aqueous sodium hydroxide solution (80 mL). After washing with chloroform, 1 mol/L hydrochloric acid was added thereto, and the precipitated solid was collected by filtration to give 2-mercapto-5-nitrobenzothiazole (8.43 g) as an orange powder.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][NH:16][C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:33](O)(=[O:37])[CH2:34][CH2:35][CH3:36].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl>C(Cl)Cl>[C:33]([N:16]([CH2:15][C:13]1[CH:12]=[CH:11][C:3]([O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:2]([CH3:1])[CH:14]=1)[C:17]1[CH:18]=[C:19]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:27][CH:28]=2)[CH:20]=[CH:21][CH:22]=1)(=[O:37])[CH2:34][CH2:35][CH3:36]
Reactant: CCOC(=O)COc1ccc(CNc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Reactant: CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)N(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48.7 %

Procedure:
To a solution of ethyl [2-methyl-4-({[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}methyl)phenoxy]acetate (0.07 g, 0.16 mmol) in anhydrous CH2Cl2 (2 mL) at 0° C. under nitrogen was added butyric acid (0.016 mL, 0.17 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (33 mg, 0.17 mmol) was then added in portions followed by triethylamine (0.022 mL, 0.16 mmol). After stirring for 15 mins at 0° C. the reaction was allowed to attain room temperature and stirred for 18 h. The reaction mixture was diluted with CH2Cl2 (20 mL) and shaken with 1 M HCl (5 mL). The organic extract was separated by hydrophobic frit and the solvent removed in vacuo. Purification by Biotage™ chromatography (Silica, 12 g) eluting 9:1 cyclohexane:EtOAc afforded the title compound as a colourless oil (40 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][C:38]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[NH:40][CH:39]=2)[CH2:32][CH2:31]1>C1COCC1>[NH:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38]([CH2:37][CH2:36][N:33]2[CH2:32][CH2:31][CH:30]([NH:29][C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=[CH:2][CH:3]=3)=[O:13])[CH2:35][CH2:34]2)=[CH:39]1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: O=C(O)c1ccnc2ccccc12
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(CCc2c[nH]c3ccccc23)CC1)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
A suspension of quinoline-4-carboxylic acid (0.87 g, 5.03 mmol) and triethylamine (0.6 g, 5.94 mmol) in dry THF (10 cm3) was stirred at -20° C. while a solution of isobutylchloroformate (0.65 g, 5.01 mmol) was added dropwise. The mixture was allowed to warm to room temperature over 31/2 hours then was cooled to -20° C. again and a solution of 3-[2-(4-amino-1-piperidyl)ethyl]indole (1.2 g, 4.94 mmol) in dry THF (20 cm3) was added dropwise. The mixture was stirred at room temperature overnight then the solvent was evaporated and the residue triturated with water and aqueous potassium carbonate to give 1.39 g of crude title compound.