Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][C@H:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[C:4]=1[C:28](OCC)=[O:29].[CH3:33][NH:34][NH2:35]>O1CCOCC1>[CH3:33][N:34]1[CH2:2][C:3]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=3)[C:7](=[O:19])[NH:6][C@H:5]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[C:4]=2[C:28](=[O:29])[NH:35]1
Reactant: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)C(=O)N[C@@H]1c1ccc(C#N)cc1
Reactant: CNN
Solvent: C1COCCO1
Product: CN1CC2=C(C(=O)N1)[C@@H](c1ccc(C#N)cc1)NC(=O)N2c1cccc(C(F)(F)F)c1

Procedure:
101 g (198.7 mmol) of ethyl (4R)-6-(bromomethyl)-4-(4-cyanophenyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 6A) were initially charged in 2400 ml of dioxane. 27.46 g (596.1 mmol) of methylhydrazine were added dropwise to the solution, and the reaction mixture was then stirred at boiling point for 3 h. The mixture was then concentrated, and the residue was dissolved in dichloromethane and washed with water. The organic phase was dried over sodium sulphate and concentrated. The residue that remained was chomatographed on silica gel (mobile phase: dichloromethane/methanol 95:5). The solid which was obtained after concentration of the product fractions was triturated with diethyl ether, filtered off with suction and then dried at 50° C. under reduced pressure for 4 days. This gave 56.8 g (66% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].N1C=CC=CC=1.[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>C1COCC1>[OH:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[NH:1][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Nc1cc(C(=O)O)ccc1O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(O)c(NC(=O)c2ccc(OC(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 57.6 %

Procedure:
To a stirred solution of 3-Amino-4-hydroxy benzoic acid (0.136, 0.00089 mols) and pyridine (0.211 g, 0.00267 mols) in 13 ml dry THF is added 4-trifluoromethoxybenzoyl chloride (0.2 g, 0.00089 mols) and the solution is stirred under nitrogen atmosphere at RT for 10 hrs and then refluxed for 3 hrs. The reaction mixture is rotary evaporated and the residue is slurried in water and filtered to get the amide (0.175 g) which is taken for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[O:4][CH2:5][C@H:6]([CH3:17])[N:7]3[C:8]([C@@H:14]([NH2:16])[CH3:15])=[N:9]2.[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23](Cl)[N:22]=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([NH:16][C@H:14]([C:8]2[N:7]3[C:13]4[C:3]([O:4][CH2:5][C@@H:6]3[CH3:17])=[C:2]([F:1])[CH:12]=[CH:11][C:10]=4[N:9]=2)[CH3:15])[N:22]=[CH:21][N:20]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)c3c2n1[C@@H](C)CO3
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c3c2n1[C@@H](C)CO3
Temperature: 100 °C
Yield: 78.6 %

Procedure:
A mixture of (S)-1-((S)-6-fluoro-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)ethylamine (86 mg, 0.36 mmol), 4-amino-6-chloro-5-cyanopyrimidine (56 mg, 0.36 mmol) and DIPEA (125 μL, 0.92 mmol) in IPA (1 mL) was heated for 18 h at 100° C. After cooling to RT, the volatiles were removed in vacuo and the resulting brown residue was purified by column chromatography (Si—PPC, gradient 0-5% 2M NH3/MeOH in DCM) to afford 440 as a white solid (100 mg, 79%). LCMS (Method K): RT 2.86 min [M+H]+ 354.1. 1H NMR (DMSO, 400 MHz): δ 8.01 (1H, s), 7.08 (1H, dd, J=8.8, 3.1 Hz), 6.94 (1H, dd, J=12.3, 8.8 Hz), 5.67 (1H, q, J=7.0 Hz), 5.04 (1H, qdd, J=6.6, 2.6, 1.7 Hz), 4.47 (1H, dd, J=11.9, 1.7 Hz), 4.20 (1H, dd, J=11.9, 2.6 Hz), 1.71 (3H, d, J=7.0 Hz), 1.45 (3H, d, J=6.6 Hz)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8](O)=[O:9].C(O)(=O)C.[CH:16](N)=[NH:17]>C(OCCO)C>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[C:8](=[O:9])[NH:17][CH:16]=[N:11]2
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: N=CN
Solvent: CC(=O)O
Solvent: CCOCCO
Product: Cc1cccc2nc[nH]c(=O)c12
Yield: 68.1 %

Procedure:
6-Methylanthranilic acid (5 g, 33 mmol) and formamidine acetate (0.4 g, 41 mmol) were refluxed in 2-ethyoxyethanol (50 ml) for 16 h. On cooling the solvent was removed in vacuo, the residue slurried in diethyl ether, the solid filtered, washed with diethyl ether and dried to yield 3.6 g of the title compound. δH (DMSO d6), 7.97 (1H, s), 7.60 (1H, dd, J 7.9, 7.6 Hz), 7.43 (1H, d, J 8.0 Hz), 7.21 (1H, d, J 7.3 Hz), 2.76 (3H, s); m/z (ES+70V)161 (MH+).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S:11]1[CH:15]=[CH:14][C:13]2[CH:16]([N:20]=[C:21]=[O:22])[CH2:17][CH2:18][CH2:19][C:12]1=2>>[CH2:2]([O:9][NH:10][C:21]([NH:20][CH:16]1[C:13]2[CH:14]=[CH:15][S:11][C:12]=2[CH2:19][CH2:18][CH2:17]1)=[O:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C=NC1CCCc2sccc21
Reactant: NOCc1ccccc1
Agent: Cl
Product: O=C(NOCc1ccccc1)NC1CCCc2sccc21

Procedure:
In the manner described in Example 6, O-benzyl hydroxyamine hydrochloride and 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate are allowed to react to afford 1-(benzyloxy)-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, which is recrystallized from 95% ethyl alcohol-methyl isobutyl ketone. The product melts at 96.5° C. to 99° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:4]=[C:5]([C:8]([OH:10])=O)[S:6][CH:7]=1.[NH2:13][C:14]1[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[CH:17]=[CH:16][C:15]=1[C:23](=[O:25])[CH3:24].C(C1C=CC(OC)=CC=1NC(C1SC=C(C(C)C)N=1)=O)(=O)C>>[C:23]([C:15]1[C:14]([NH:13][C:8]([C:5]2[S:6][CH:7]=[C:3]([C:2]([F:1])([F:12])[F:11])[N:4]=2)=[O:10])=[C:19]([CH3:20])[C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:25])[CH3:24]
Reactant: COc1ccc(C(C)=O)c(N)c1C
Reactant: O=C(O)c1nc(C(F)(F)F)cs1
Agent: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(F)(F)F)cs2)c1C
Yield: 74 %

Procedure:
Compound 64b was synthesized from 4-(trifluoromethyl)-1,3-thiazole-2-carboxylic acid and 1-(2-amino-4-methoxy-3-methylphenyl)-ethanone as a beige solid in 74% yield, following the procedure as described for compound 42a.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[O:22]1[C:26]2[CH2:27][NH:28][CH2:29][CH2:30][C:25]=2[CH:24]=[CH:23]1>CCOCC.CS(Cl)(=O)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:28]2[CH2:29][CH2:30][C:25]3[CH:24]=[CH:23][O:22][C:26]=3[CH2:27]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1cc2c(o1)CNCC2
Reactant: OCCCCCCc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: c1ccc(CCCCCCN2CCc3ccoc3C2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 0.39 g (2.2 mmol) of 6-phenylhexan-1-ol and 0.38 ml (2.7 mmol) of triethylamine in 20 ml of ether, methanesulfonyl chloride was added dropwise under ice-cooling, followed by stirring for 10 minutes. The ether solution was washed with water and saturated aqueous sodium chloride, after which it was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The residual oil (crude 6-phenylhexyl methanesulfonate) was dissolved in 30 ml of acetonitrile; 0.289 g (1.811 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride and 0.76 ml (5.4 mmol) of triethylamine were added, followed by refluxing for 3 hours. The solvent was distilled off from the reaction mixture under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH2:16][O:17][CH3:18])[C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:26][C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH2:16][O:17][CH3:18])[C:6]=3[CH:19]=2)=[N:22][CH:23]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)N(CCOC)C(=O)CCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-(2-methoxy-ethyl)-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide to yield a light yellow solid (2.4%). LCMS: m/z=523.17 (M+H+), 1H NMR (400 MHz, CDCl3) δ 11.02 (bs, 1H), 8.55 (d, 3H, J=8.6 Hz), 8.09 (s, 1H), 7.77 (d, 1H, J=8.0 Hz), 7.52 (d, 1H, J=7.6 Hz), 7.37 (m, 3H), 7.27 (m, 1H), 7.09 (m, 1H), 6.82 (bs, 1H), 3.59 (m, 2H), 3.42 (m, 2H), 3.29 (s, 3H), 3.01 (d, 3H, J=4.8 Hz), 2.31 (m, 2H), 1.99 (m, 2H), 1.31 (m, 6H).
Reaction SMILES: Cl.[F:2][C:3]([F:28])([F:27])[C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[CH:6]([O:18][CH:19]1[CH2:22][NH:21][CH2:20]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1.[N-:29]=[C:30]=[O:31]>>[F:28][C:3]([F:27])([F:2])[C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[CH:6]([O:18][CH:19]1[CH2:22][N:21]([C:30]([NH:29][CH2:3][C:4]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:5]=2)=[O:31])[CH2:20]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1
Reactant: [N-]=C=O
Reactant: FC(F)(F)Oc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Product: O=C(NCc1ccccc1)N1CC(OC(c2ccc(OC(F)(F)F)cc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-(trifluoro-methoxy)benzyloxy]azetidine hydrochloride (141) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH:16]1([CH2:19][NH:20][CH2:21][CH2:22][CH3:23])[CH2:18][CH2:17]1>ClCCl.CO>[CH:16]1([CH2:19][N:20]([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=2[O:14][CH3:15])[CH2:21][CH2:22][CH3:23])[CH2:18][CH2:17]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Reactant: CCCNCC1CC1
Solvent: CO
Solvent: ClCCl
Product: CCCN(CCOc1ccc([N+](=O)[O-])cc1OC)CC1CC1

Procedure:
Prepared analogously to Example 1.1.c. from 1 g (3.62 mmol) of 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and 1.51 mL (10.57 mmol) of cyclopropylmethylpropylamine. Yield: 0.95 g (85% of theory); C16H24N2O4 (M=308.37); calc.: molecular ion peak (M+H)+: 309; found: molecular ion peak (M+H)+: 309; Rf value: 0.4 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([OH:15])=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.[ClH:17].[Cl:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[OH-].[K+]>C1(C)C=CC=CC=1.O>[ClH:18].[ClH:17].[N:22]1([CH2:21][CH2:20][CH2:19][O:1][C:2]2[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][C:8]([O:15][CH2:19][CH2:20][CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:9][CH:10]=4)[C:5](=[O:16])[C:4]=3[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: ClCCCN1CCCCC1
Reactant: O=C1c2cc(O)ccc2-c2ccc(O)cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2cc(OCCCN3CCCCC3)ccc2-c2ccc(OCCCN3CCCCC3)cc21
Reaction time: 20 h

Procedure:
A mixture of 63.6 g (0.30 mole) of 2,7-dihydroxy-fluoren-9-one, 188 g (0.95 mole) of 1-(3-chloropropyl) piperidine hydrochloride, 132 g (2.0 mole) of 85% potassium hydroxide in 900 ml of toluene and 300 ml of water is refluxed with vigorous stirring for 20 hours. The layers are separated upon cooling and the organic layer is washed 3 times with water, once with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The mixture is filtered and the solvent removed in vacuo. The residue is taken up in isopropyl alcohol and acidified to Congo Red with ethereal hydrogen chloride. The solid which precipitates is filtered, recrystallized from a mixture of 3 parts isopropyl alcohol to 1 part methanol, and the 2,7-bis(3-piperidinopropoxy)fluoren-9-one dihydrochloride so prepared is dried at 100° C. for 24 hours under vacuum, m.p. 279.5°-80.5° C., λmaxH2O 270, and E1cm1% 1370.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:26]=[CH:25][C:15]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[O:17])=[C:14]([Cl:27])[CH:13]=1>C([O-])(O)=O.[Na+].CCOC(C)=O>[Cl:27][C:14]1[CH:13]=[C:12]([NH:11][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:26]=[CH:25][C:15]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])=[O:17]
Reactant: Cc1ccccc1C(=O)c1ccc(N)cc1Cl
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(=O)c1ccc(Nc2ncccc2[N+](=O)[O-])cc1Cl
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-3-nitro-pyridine (0.32 g, 2.0 mmol) and 4-amino-2-chloro-2′-methylbenzophenone (compound 2) (0.49 g, 2.0 mmol) was mixed thoroughly. The reaction mixture was warmed at 100° C. for 0.5 h and then at 160° C. for 0.5 h. The reaction mixture was cooled to room temperature, and dissolved in saturated aqueous NaHCO3 (10 mL) and EtOAc (30 mL). The phases were separated, and the organic phase was washed with saturated aqueous NaHCO3 (10 mL), dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O.O>[Si:22]([O:21][CH2:20][CH2:19][CH2:18][N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:24])[CH3:23]
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 74.2 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (400 mg) in N,N-dimethylformamide (2.6 mL) was added cesium carbonate (957 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added (3-bromopropoxy)(tert-butyl)dimethylsilane (979 mg), and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine (30 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=85/15→10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (630 mg) as a white solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].[Se](=O)=[O:58]>C(O)(=O)C.O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([OH:58])[CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: O=[Se]=O
Solvent: O
Solvent: CC(=O)O
Product: CCC1C=C(C)C(O)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 41 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (5.15 gm, 0.065 mol) in glacial acetic acid (500 ml) at room temperature, was added a solution of selenium dioxide (9.27 gm, 0.083 mol) in H2O (90 ml). The reaction mixture was stirred at room temperature for 41 hours whereupon, it was poured into a stirred mixture of H2O (3 L) and celite. After stirring for 15 minutes, the mixture was filtered through a pad of celite and extracted with diethyl ether (1×2 L, 2×1 L). The organic fractions were washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtrated and evaporated in vacuo. The product was purified by chromatography (silica, acetone:hexanes 2:5) to give the title compound. MASS and 1H NMR were consistent with the structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].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.C1(C)C=CC=CC=1>[CH3:8][C:7]1[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][C:4]([NH2:9])=[CH:5][CH:6]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(N)cc1Br
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: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(N)cc1-c1ccccc1
Temperature: 25 °C
Yield: 47.1 %

Procedure:
To a dried flask was added 3-bromo-4-methyl-phenylamine (1 g, 5.37 mmol), phenyl boronic acid (2.62 g, 21.5 mmol), aqueous Na2CO3 (2M, 21.5 mL, 43 mmol), ethanol (21.5 mL), and toluene (43 mL). The flask was sparged with Ar, and Pd(PPh3)4 (1.55 g, 1.34 mmol) was added. The reaction mixture was stirred and heated at 80° for 18 hrs, then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with water and brine, then dried over MgSO4. The solvent was removed in vacuo and the residue was purified via column chromatography (SiO2, 5% DCM/hexane) to afford a yellow oil (463 mg, 47%). This was directly used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:33])[CH:18]([N:23]4[C:27]([CH3:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[N:24]4)[CH2:19][C:20](O)=[O:21])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.N.C[N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:33])[CH:18]([N:23]4[C:27]([CH3:28])=[CH:26][C:25]([C:29]([F:32])([F:30])[F:31])=[N:24]4)[CH2:19][C:20]([NH2:36])=[O:21])[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1cc(C(F)(F)F)nn1C(CC(=O)O)C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nn1C(CC(N)=O)C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
To a mixture of 4-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-3-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-4-oxo-butanoic acid (0.029 g, 0.08 mmol) and NH3 (0.3 mL, sat. in CH2Cl2) in DMF (0.6 mL) was added HATU (0.040 g, 0.10 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water. The mixture was partitioned between IPA/CHCl3 (1:2, 50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to afford the desired product (0.014 g, 37%). 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.42 (dd, J=9.2, 4.6 Hz, 2H), 7.16 (dd, J=8.4, 8.0 Hz, 2H), 6.53 (s, 1H), 6.34 (s, 1H), 6.32 (s, 1H), 5.92 (m, 1H), 3.80 (m, 1H), 3.41 (m, 1H), 3.33 (m, 1H), 3.00 (m, 1H), 2.76 (m, 2H), 2.37 (s, 3H), 1.98 (m, 1H), 1.88 (m, 1H); MS: (ES) m/z calculated for C21H20F4N6O2 [M+H]+ 465.1, found 465.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19]>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:21][C:17](=[O:20])[CH:18]=[CH:19][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1Br
Reactant: C=CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccccc1CNC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To compound of Step A (161.0 g, 561.8 mmol) in DMF (800 mL) is added methyl acrylate (58.0 g, 674.2 mmol), TEA (170.5 g, 1685.4 mmol) and dichlorobis(triphenylphosphine)palladium(II) (7.9 g, 11.2 mmol). The mixture is heated at 80° C. for about 32 hours. The mixture is cooled, diluted with 1000 mL of EtOAc and washed with 10% aqueous sodium bisulfate. The aqueous portion is extracted three times with EtOAc and the combined organics are dried (Na2SO4) and concentrated to dryness. The residue is dissolved in a small amount of DCM and filtered through 7 inch of silica gel in a 2 L sintered glass funnel eluting with 25% EtOAc/hexanes. The eluent is concentrated to dryness and recrystallized from EtOAc/hexanes to afford about 116.9 g (71%) of Step B compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1/[CH:4]=[N:16]/[OH:17]
Reactant: NO
Reactant: O=Cc1cc(OC(F)(F)F)ccc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O/N=C/c1cc(OC(F)(F)F)ccc1F
Yield: 87.8 %

Procedure:
A solution of 2-fluoro-5-trifluoromethoxy-benzaldehyde (9.78 g, 47 mmol) in ethanol (50 mL) was treated with hydroxylamine HCl (3.59 g, 52 mmol) and sodium acetate (4.27 g, 52 mmol). The resulting mixture was heated under reflux for 2 h. The solvent was then evaporated and the residue stirred with water (50 mL). The precipitate was filtered off, dried and chromatographed (SiO2, heptanes:ethyl acetate=100:0 to 80:2) to afford the title compound (9.21 g, 88%) as a white solid. MS: m/e=223.0 [M]+.
Reaction SMILES: COC[O:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[CH:25]=[CH:24][C:23]3[C:14](=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[CH:18][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][O:33]COC)[N:27]=3)=[N:16]4)[N:13]=2)[CH:9]=[CH:8][CH:7]=1.Cl>CO>[OH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[CH:25]=[CH:24][C:23]3[C:14](=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[CH:18][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][OH:33])[N:27]=3)=[N:16]4)[N:13]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: COCOCc1cccc(-c2ccc3ccc4ccc(-c5cccc(COCOC)n5)nc4c3n2)n1
Agent: Cl
Solvent: CO
Product: OCc1cccc(-c2ccc3ccc4ccc(-c5cccc(CO)n5)nc4c3n2)n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
To compound (20) (1.09 g; 2.26 mmol), 6N-hydrochloric acid (5 mL) and methanol (25 mL) were added, and the resulting reaction mixture was stirred at 60° C. for 4 hours. The reaction mixture was evaporated under reduced pressure, and while there was some solvent left the mixture was made alkaline with a 5% aqueous sodium carbonate. Solids which precipitated out were separaetd by filtration. The resulting solids were dissolved in chloroform/methanol=3/1, insoluble matters were filtered out and the filtrate was evaporated under reduced pressure to give 0.72 g (yield: 81%) of the title compound (21).