Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O=S(Cl)[Cl:18].Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([Cl:18])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Agent: Cl
Product: O=C(Cl)c1ccc(-c2ccc(Cl)cc2)o1

Procedure:
A mixture Of 56 g. (0.25 mole) Of 5-(p-Chlorophenyl)-2furoic acid and 100 ml. of SOCl2 is refluxed for 31/2 hours so that HCl gas evolves and there is dissolution. The SOCl2 is removed on a rotary evaporator. Benzene is added to the solid residue and is then removed on the rotary evaporator to give 5-(p-chlorophenyl)-2-furoyl chloride
Reaction SMILES: [O:1]=[C:2]1[C:10](=[N:11][N:12]=[CH:13][C:14]2[NH:18][C:17]([CH3:19])=[C:16]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](O)=[O:29])=[O:21])[C:15]=2[CH3:31])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.Cl.C(N=C=NCCCN(C)C)C.O[C:45]1[C:53]2[N:52]=N[NH:50][C:49]=2[CH:48]=[CH:47][CH:46]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[O:1]=[C:2]1[C:10](=[N:11][N:12]=[CH:13][C:14]2[NH:18][C:17]([CH3:19])=[C:16]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:50][C:49]3[CH:48]=[CH:47][CH:46]=[CH:45][C:53]=3[NH2:52])=[O:29])=[O:21])[C:15]=2[CH3:31])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccccc32)c(C)c1C(=O)NCCCCCC(=O)O
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccccc32)c(C)c1C(=O)NCCCCCC(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.9 %

Procedure:
6-(5-(((2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-hexanoic acid (423 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (395 mg, 77% yield) as a red solid. LC-MS (m/z) 514 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11](O)=[O:12])=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]1[C@H:41]2[C@@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:35][CH2:34][NH:33]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:7]2[O:6][C:5]([C:3](=[O:4])[C:2]([CH3:21])([CH3:1])[CH3:20])=[C:9]([CH2:10][C:11]([N:33]3[CH2:34][CH2:35][C@H:36]4[C@@H:41]([CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:32]3)=[O:12])[C:8]=2[CH:14]=1
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Reactant: C1CC[C@H]2CNCC[C@@H]2C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)N3CC[C@@H]4CCCC[C@H]4C3)c2c1
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 12.3 mg trans-decahydroisoquinoline followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 65-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.34 min. (m/Z=412.3, 328.2, 434.2).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12.C([O-])([O-])=O.[K+].[K+].I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN1CCCC1=O.[Cu]I>[C:18]1([N:1]2[C:5](=[O:6])[CH2:4][N:3]3[C:7](=[O:10])[CH2:8][CH2:9][CH:2]23)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CN2C(=O)CCC2N1
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C1CCC2N1CC(=O)N2c1ccccc1
Yield: 11.7 %

Procedure:
To a solution of tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione (1 g, 7.14 mmol; prepared as described in J. Med. Chem. 36, 4214-4220, 1994,) in N-methylpyrrolidone (NMP, 12 cc), CuI (0.2 g, 1.05 mmol), K2CO3 (1 g, 7.14 mmol) and Iodobenzene (5 g, 24.5 mmol) were added under stirring. The suspension was heated in a microwave apparatus (250 Watt) for 45 min. Ethyl acetate was added to the suspension and the solid was filtered. The organic phase was washed with water and the aqueous phase was re-extracted with CH2Cl2. The organic phases were gathered and dried over Na2SO4, filtered and concentrated to dryness. The residue was triturated with isopropyl ether. The solid was filtered, triturated with water and filtered to yield 0.18 g of the title compound, mp=185-188° C.
Reaction SMILES: C([O-])(=O)C.[Na+].[F:6][CH:7]([F:33])[C:8]1[N:9]=[C:10]([CH2:30][CH2:31][CH3:32])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:12](=[O:14])[CH:13]=1.[Br:34]Br>C(O)(=O)C>[Br:34][C:13]1[C:12](=[O:14])[N:11]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:10]([CH2:30][CH2:31][CH3:32])=[N:9][C:8]=1[CH:7]([F:6])[F:33]
Reactant: BrBr
Reactant: CCCc1nc(C(F)F)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1nc(C(F)F)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 4 h
Yield: 61 %

Procedure:
To a solution of sodium acetate (1 g) and 4′-{[4-(difluoromethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (4.4 g) in acetic acid (44 mL) was added bromine (0.62 mL), and the mixture was stirred for 4 hr. Acetic acid was removed in vacuo, and the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow solid (2.7 g, 61%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[CH:6][N:5]=[C:4]2[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[N:13][C:3]=12.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[Cl-].[Na+]>C(O)CO>[CH:22]1([NH:28][C:2]2[C:7]([C:8](=[O:10])[CH3:9])=[CH:6][N:5]=[C:4]3[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[N:13][C:3]=23)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(=O)c1cnc2c(ncn2COCC[Si](C)(C)C)c1Cl
Reactant: NC1CCCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: OCCO
Product: CC(=O)c1cnc2c(ncn2COCC[Si](C)(C)C)c1NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
1-[7-Chloro-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridin-6-yl]ethanone (89.6 mg, 0.275 mmol) and cyclohexylamine (214 mg, 2.16 mmol) in ethylene glycol (2 mL) were stirred at 180° C. for 1 hour under microwave irradiation. The reaction mixture was allowed to cool to room temperature and, after addition of saturated aqueous sodium chloride, extracted with chloroform. The organic layer was stirred with 2 M hydrochloric acid (12 mL) at room temperature for 1 hour. The reaction mixture was basified with 10 M aqueous sodium hydroxide and extracted with chloroform, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography hexane/ethyl acetate=1/1 (v/v)) to give the title compound as a dark brown oil (88.9 mg, yield 83%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[CH:29]=[CH:28][C:12]2[O:13][CH2:14][C:15](O)([CH3:26])[C:16]3[S:20][C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:18][C:17]=3[C:11]=2[CH:10]=1.[SiH](CC)(CC)CC>ClCCl>[Br:8][C:9]1[CH:29]=[CH:28][C:12]2[O:13][CH2:14][CH:15]([CH3:26])[C:16]3[S:20][C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:18][C:17]=3[C:11]=2[CH:10]=1
Reactant: CCOC(=O)c1nc2c(s1)C(C)(O)COc1ccc(Br)cc1-2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc2c(s1)C(C)COc1ccc(Br)cc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
TFA (891 mg, 7.88 mmol, 30.00 equiv) was added dropwise to a stirred solution of ethyl 9-bromo-4-hydroxy-4-methyl-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate (100 mg, 0.26 mmol, 1.00 equiv) and Et3SiH (454 mg, 3.90 mmol, 15.00 equiv) in dichloromethane (5 mL) at 0° C. After being stirred at room temperature overnight the reaction was quenched with 10 mL of saturated NaHCO3, extracted with 5×20 mL of ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:15) to give 70 mg (73%) of the titled compound as a light yellow solid; LC-MS (ES, m/z) 368, 369 [M+11]+.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH3:9][C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:20]=[CH:21][C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][N:24]=2)[N:15]=1)([CH3:8])[C:6]([OH:5])=[O:26]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(Br)cn2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCNc2ncc(-c3ccccc3)cn2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound obtained using 2-[(4-{2-[(5-bromopyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 162-1 and phenylboronic acid as starting materials and by an operation similar to that of Example 162-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the obtained solid was triturated and washed with hexane-ethyl acetate to give the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:14][CH:13]3[O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]4[O:38][CH2:37][C:36](=[O:39])[N:35]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:34]=4[CH:45]=3)=[CH:8][CH:7]=2)[CH2:2]1.Cl[C:47]1[O:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1>C(Cl)(Cl)Cl>[O:48]1[C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=[C:47]1[N:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:19])[CH2:14][CH:13]3[O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]4[O:38][CH2:37][C:36](=[O:39])[N:35]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:34]=4[CH:45]=3)=[CH:8][CH:7]=2)[CH2:2]1
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC4CNC4)cc3)cc21
Reactant: Clc1nc2ccccc2o1
Solvent: ClC(Cl)Cl
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC4CN(c5nc6ccccc6o5)C4)cc3)cc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 0.382 g of benzyl 4-[4-(azetidin-3-yloxy)phenyl]-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate in 10 ml of chloroform is admixed at 0-5° C. with 0.156 ml of 2-chlorobenzoxazole. The reaction solution is stirred at room temperature over 20 hours and subsequently poured onto an ice-water mixture. The reaction mixture is extracted with ethyl acetate (2×50 ml) and the combined organic phases are washed with 50 ml of brine, dried over sodium sulphate, filtered and concentrated. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (2:1 EtOAc-heptane); Rt=4.99.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:17]1([C:23]2[CH:24]=[CH:25][C:26]3[NH:27][C:28]4[C:33]([C:34]=3[CH:35]=2)=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1.CCCCCC>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:27]2[C:26]3[CH:25]=[CH:24][C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2nc3ccccc3o2)cc1
Reactant: c1ccc(-c2ccc3[nH]c4ccccc4c3c2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc3c(c2)c2ccccc2n3-c2ccc(-c3nc4ccccc4o3)cc2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
In a 100 mL three-neck flask were put 1.0 g (3.7 mmol) of 2-(4-bromophenyl)benzoxazole, 0.89 g (3.7 mmol) of 3-phenyl-9H-carbazole, and 0.77 g (8.0 mmol) of sodium tert-butoxide. The atmosphere in the flask was replaced with nitrogen. To this mixture were added 30 mL of toluene and 0.10 mL of a 10% hexane solution of tri(tert-butyl)phosphine. This mixture was degassed by reducing the pressure in the flask by using an aspirator. After that, the atmosphere in the flask was replaced with nitrogen. To this mixture was added 0.058 g (0.10 mmol) of bis (dibenzylideneacetone)palladium(0), followed by stirring under a nitrogen stream at 80° C. for 15 hours. After that, toluene was added to this mixture, and this suspension was washed with a saturated aqueous sodium carbonate solution and saturated brine in that order. After that, magnesium sulfate was added to the organic layer to dry it. Next, this mixture was suction filtered, whereby a filtrate was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:19]([O:22][CH2:23][CH2:24][C@@H:25]([NH:29][C:30]1[C:35]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH2:46]OS(C)(=O)=O)=[CH:39][C:38]=2[O:52][CH3:53])=[C:34]([CH3:54])[N:33]=[C:32]([NH2:55])[N:31]=1)[CH2:26][CH2:27][CH3:28])(=[O:21])[CH3:20]>C(#N)C.O.C(OC([O-])=O)(O)=O.[Na+]>[C:19]([O:22][CH2:23][CH2:24][C@@H:25]([NH:29][C:30]1[C:35]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH2:46][N:7]3[CH2:8][CH2:9][CH2:10][C@H:6]3[C:4]([O:3][CH3:2])=[O:5])=[CH:39][C:38]=2[O:52][CH3:53])=[C:34]([CH3:54])[N:33]=[C:32]([NH2:55])[N:31]=1)[CH2:26][CH2:27][CH3:28])(=[O:21])[CH3:20]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CCC[C@@H](CCOC(C)=O)Nc1nc(N)nc(C)c1Cc1ccc(OCCCOS(C)(=O)=O)cc1OC
Agent: Cl
Agent: O=C([O-])OC(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CCC[C@@H](CCOC(C)=O)Nc1nc(N)nc(C)c1Cc1ccc(OCCCN2CCC[C@H]2C(=O)OC)cc1OC
Temperature: 70 °C
Reaction time: 16 h
Yield: 75.4 %

Procedure:
(S)-methylpyrrolidine-2-carboxylate hydrochloride (44 mg) was added to the mixture of potassium carbonate (74 mg), potassium iodide (3 mg) and the crude product (75 mg) from step (v) in acetonitrile (2 mL). After the mixture was stirred at 70° C. for 16 h, the reaction mixture was cooled to RT, diluted with water and sat. sodium hydrogen dicarbonate and extracted with EtOAc. The combined organic layer was dried and concentrated under reduced pressure. The residue was purified by flash column chromatography on amino silica gel to afford the sub-title compound (60 mg) as a colourless oil; 1H NMR (CDCl3); 6.80 (1H, d), 6.44 (1H, d), 6.37 (1H, dd), 4.85 (2H, br s), 4.24-4.15 (1H, m), 4.00-3.87 (4H, m), 3.85 (3H, s), 3.67 (3H, s), 3.57 (2H, s), 3.22-3.14 (2H, m), 2.89-2.78 (1H, m), 2.61-2.50 (1H, m), 2.42-2.30 (1H, m), 2.34 (3H, s), 2.16-2.05 (1H, s), 1.97 (3H, s), 1.97-1.70 (6H, m), 1.63-1.49 (1H, m), 1.46-1.32 (1H, m), 1.29-1.15 (1H, m), 1.12-0.98 (2H, m), 0.77 (3H, t); LC-MS: m/z 572.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][CH:12]([CH3:35])[CH:13]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=2)[N:25]=1)=[O:20])[C:14]([O:16][CH3:17])=[O:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:10])[NH:32][C:29]2[CH:30]=[CH:31][C:26]([C:24]3[N:25]=[C:21]([C:19]([NH:18][C@@H:13]([CH:12]([CH3:35])[CH3:11])[C:14]([O:16][CH3:17])=[O:15])=[O:20])[S:22][CH:23]=3)=[CH:27][CH:28]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Reactant: O=C=Nc1cccc(Cl)c1
Product: COC(=O)[C@@H](NC(=O)c1nc(-c2ccc(NC(=O)Nc3cccc(Cl)c3)cc2)cs1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 23, using 3-chlorophenyl isocyanate and intermediate 3. 1HNMR (DMSO-d6, 300 MHz): δ 8.959 (s, 1H), 8.940 (s, 1H), 8.826-8.798 (d, J=8.4 Hz, 1H), 8.325 (s, 1H), 8.058-8.030 (d, J=8.4 Hz, 2H), 7.734 (s, 1H), 7.596-7.567 (d, J=8.7 Hz, 2H), 7.318-7.294 (m, 2H), 7.046-7.023 (m, 1H), 4.395-4.343 (t, J=7.8 Hz, 1H), 3.700 (s, 3H), 2.320-2.274 (m, 1H), 1.001-0.953 (t, J=6.9, 7.5 Hz, 6H); MS (ESI) m/z 485 (M−H), 487 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1.[CH3:16][O:17][C:18]1[C:23](B(O)O)=[CH:22][CH:21]=[CH:20][N:19]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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:12]([C:4]1[CH:3]=[C:2]([C:23]2[C:18]([O:17][CH3:16])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:7]=[CH:6][C:5]=1[O:8][CH:9]([F:11])[F:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(Br)ccc1OC(F)F
Reactant: COc1ncccc1B(O)O
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: CO
Solvent: ClCCl
Product: COc1ncccc1-c1ccc(OC(F)F)c(C(C)(C)C)c1
Temperature: 115 °C
Yield: 57.5 %

Procedure:
step 2—A sealed tube containing 20 (129 mg, 0.464 mmol), 2-methoxy-3-pyridine boronic acid (37, 108 mg, 0.706 mmol, CASRN 163105-90-6), Pd(PPh3)4 (39 mg, 0.034 mmol) and Na2CO3 (147 mg, 1.387 mmol) in a mixture of MeOH (3 mL) and DCM (1 mL) was heated in a microwave synthesizer at 115° C. for 30 min. The organic volatiles were removed under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with a EtOAc/hexane gradient (0 to 5% EtOAc) to afford 82 mg (58%) of 3-(3-tert-butyl-4-difluoromethoxy-phenyl)-2-methoxy-pyridine (22) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11]3=[C:12]([C:14]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16](=O)[C:15]=4[N:10]3[CH2:9][CH2:8][CH2:7]2)[CH:13]=1)([O-])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCOCC1>[CH:13]1[C:12]2[C:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[N:10]3[C:11]=2[C:6]([CH2:7][CH2:8][CH2:9]3)=[CH:5][C:4]=1[NH2:1]
Reactant: O=C1CCCCc2c1n1c3c(cc([N+](=O)[O-])cc23)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
A solution of 2-nitro-8-oxo-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinoline (0.17 g, 0.60 mmol; prepared in Example 23, Step 1) in dioxane (5 mL) is added dropwise to a refluxing slurry of LiAlH4 (0.24 g, 6 mmol) in dioxane (20 mL). The reaction mixture was refluxed overnight. After cooling to ambient temperature, the mixture was poured onto ice water and extracted with ethyl acetate. The combined organic extracts were dried over MgSO4 and concentrated to give 0.11 g of 5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-amine.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[S:18][C:17](=[S:19])[NH:16][C:15]2=[O:20])=[CH:9][C:8]=1[O:21][CH3:22].COCCOC.[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>CCOC(C)=O.C(O)(=O)C>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]2[S:18][C:17](=[S:19])[NH:16][C:15]2=[O:20])=[CH:9][C:8]=1[O:21][CH3:22]
Reactant: COc1cc(C=C2SC(=S)NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(CC2SC(=S)NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 368 %

Procedure:
To a N2-purged flask was added ′5-[1-[4-(2,4-bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-methylidene]-2-thioxo-thiazolidin-4-one (42 mg, 85 μmol) and DME (4 mL). To the solution was added NaBH3CN (20 mg, 255 μmol) followed by acetic acid (2 mL). The reaction was stirred at rt for 2 h. The reaction solution was then diluted with EtOAc (100 mL), neutralized by successive washings of sat NaHCO3 (100 mL×3), washed with sat. NaCl (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was chromatographed (SiO2, DCM/MeOH 100:0 to 98:2) to provide intermediate compound (155 mg, 50% yield). 1H NMR (CDCl3) δ 9.29 (1H, br s), 7.99 (1H, d, J=8.1 Hz), 7.94 (1H, s), 7.83 (1H, d, J=8.1 Hz), 6.72-6.81 (3H, m), 5.38 (2H, s), 4.60 (1H, dd, J1=3.9 Hz, J2=9.8 Hz), 3.92 (3H, s), 3.48 (1H, dd, J=3.9 Hz, J2=14.2 Hz), 3.14 (1H, m); MS (ESI) 496 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:12]([CH:15]=2)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=1.[O:23]1[CH2:28][CH:27]=[C:26]([C:29]2[CH:30]=[CH:31][C:32]([NH2:35])=[N:33][CH:34]=2)[CH2:25][CH2:24]1>>[O:23]1[CH2:24][CH:25]=[C:26]([C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:2]3[CH:7]=[C:6]([C:8]4[CH:9]=[CH:10][C:11]([O:16][CH:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[C:12]([CH:15]=4)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=3)=[N:33][CH:34]=2)[CH2:27][CH2:28]1
Reactant: N#Cc1cc(-c2ccnc(Cl)c2)ccc1OC1CCOCC1
Reactant: Nc1ccc(C2=CCOCC2)cn1
Product: N#Cc1cc(-c2ccnc(Nc3ccc(C4=CCOCC4)cn3)c2)ccc1OC1CCOCC1
Yield: 23 %

Procedure:
With 5-(2-chloropyridin-4-yl)-2-(tetrahydropyran-4-yloxy)benzonitrile and the 5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-ylamine prepared, 5-{2-[5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-ylamino]pyridin-4-yl}-2-(tetrahydropyran-4-yloxy)benzonitrile is obtained in 23% yield under the Buchwald-Hartwig conditions indicated; HPLC-MS Rt. [min] 1.717; HPLC-MS [M+H] 455;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.S(=O)(=O)(O)O.[I:14](O)(=O)(=O)=O.II.[OH-].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[C:7]([I:14])=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: Nc1ccc(Cl)cn1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncc(Cl)cc1I
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a mixed solution of 2-amino-5-chloropyridine (2.6 g, 0.020 mol) in acetic acid/water (7.8 mL/1.8 mL) that cooled with ice bath, conc.sulfuric acid (0.26 mL, 4.9 mmol) was added dropwise, and then periodic acid (0.95 g, 4.2 mmol) and iodine (2.0 g, 8.0 mmol) were added. The reaction mixture was stirred at 80° C. for 6 h. Cooled to ambient temperature, the reaction mixture was poured into ice water, and neutralized by aqueous 5M sodium hydroxide solution. After removal of the precipitate by filtration, the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated sodium thiosulfate solution, aqueous 1M sodium hydroxide solution and brine then dried over sodium sulfate and concentrated to afford 2-amino-5-chloro-3-iodopyridine as solid (4.4 g, y. 85%).