Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=3[C:8]=2[C:7]([CH:20]=[O:21])=[CH:6][CH:5]=1.CC(C)=[O:25].[Mn]([O-])(=O)(=O)=O.[K+]>O>[F:22][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=3[C:8]=2[C:7]([C:20]([OH:25])=[O:21])=[CH:6][CH:5]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(OC(F)F)c2oc3ccc([N+](=O)[O-])cc3c12
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(OC(F)F)c2oc3ccc([N+](=O)[O-])cc3c12
Temperature: 72.5 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
In a 20 L 4 necked RB flask, fitted with a mechanical stirrer, reflux condenser, add 4-difluoro methoxy-8-nitro-1-formyl dibenzo[b,d]furan (1 kg, 3.25 M), acetone (7.2 L) and heat to temp. 70-75° C. under stirring. Add a slurry of potassium permanganate (0.48 kg) in water (3 L) to the reaction mixture at 70-75° C. under stirring and maintain for 1 hr. After 1 hr maintenance, the second lot of potassium permanganate (0.120 kg) in water (400 ml) was added at 70-75° C. under stirring and maintain for 1 hr. After 2 hr maintenance, the third lot of potassium permanganate (0.120 kg) in water (400 ml) was added at 70-75° C. under stirring and maintain for 1 hr. The progress of the reaction was monitored by HPLC. After ascertaining the completion of the reaction, acetone (7.2 L) was added at temp. of 70-75° C. under stirring and maintained for 30 min. The reaction mixture was brought to 25-35° C., filtered. The inorganic salt cake was washed with acetone (2 L) collect and combine all the acetone washings. The acetone MLS were distilled at temp. below 75° C. under vacuum, cool the residue to 25-35° C. and maintain under stirring for 30 min. The precipitated product was filtered, dried and the wet cake was subjected to reflux with a solvent mixture of (5 L acetone and 1.25 L water) and maintained for 3 h. Cool the reaction mass to 10-15° C. maintain for 30 min under stirring, filter the precipitated product, wash the product with water (1 L). The wet cake was subjected to azeotropic removal of water by refluxing with toluene (10 L) After complete removal of water, the reaction mixture was brought to 25-35° C., maintained for 30 min, filtered and dried in vacuum oven below 70° C. till LOD<1%. The dried product appears as cream color, solid, weighs about 840-850 g, yield 80-81%, purity˜95% by HPLC, m.p.>270° C. The IR (KBr) spectrum shows 3100 (C—H str), 1695 (—COOH str), 1100 (C—F str) cm−1. The 1H-NMR spectrum shows δ 9.8 (s, 1H), 8.6 (d, 1H), 8.2 (m, 2H), 7.3 (m, 3H), 7.6 (m, 1H). The CI mass shows m/z 322 (M+) The elemental analysis shows calculated % C, 52.03; % H, 2.18; % N, 4.33. Observed % C, 52.04; % H, 2.03; % N, 4.45%.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[CH:11]=[CH:10][N:9]=[N:8]1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.I[C:26]1[C:27]([OH:35])=[N:28][CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[CH:31]=1>[Cu](I)I.O.CS(C)=O>[N+:32]([C:30]1[CH:31]=[C:26]([N:8]2[N:9]=[CH:10][CH:11]=[N:7]2)[C:27]([OH:35])=[N:28][CH:29]=1)([O-:34])=[O:33]
Reactant: c1c[nH]nn1
Reactant: O=[N+]([O-])c1cnc(O)c(I)c1
Agent: I[Cu]I
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c(-n2nccn2)c1
Temperature: 155 °C
Reaction time: 1 h

Procedure:
Cesium carbonate (24.4 g), 1,2,3-triazole (4.35 ml), 2,2,6,6-tetramethyl-3,5-heptanedione (3.89 ml), and copper iodide (7.1 g) were added to a DMSO (100 ml) solution containing 3-iodo-5-nitropyridin-2-ol (10 g) in a nitrogen atmosphere, followed by stirring at 155° C. for 1 hour. The reaction solution was adjusted to room temperature and water was added to the reaction solution. An insoluble precipitate was removed by filtration. 1M hydrochloric acid (110 ml) was added to the resulting filtrate, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, a small amount of ethyl acetate was added to the obtained residue, and insoluble matter was collected by filtration. A yellow solid mixture (4.86 g) of 5-nitro-3-(2H-1,2,3-triazol-2-yl)pyridin-2-ol and 5-nitro-3-(1H-1,2,3-triazol-1-yl)pyridin-2-ol was thus obtained.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=O)=[C:12]([O:19][CH3:20])[CH:11]=1>>[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]2[NH:8][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[N:7]=2)=[C:12]([O:19][CH3:20])[CH:11]=1
Reactant: Nc1ccccc1N
Reactant: COc1cc(Cl)ccc1C(=O)O
Product: COc1cc(Cl)ccc1-c1nc2ccccc2[nH]1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate c, from benzene-1,2-diamine (CAS Reg. No. 95-54-5) and 4-chloro-2-methoxy-benzoic acid (CAS Reg. No. 57479-70-6). Colorless powder (59%). MS (Turbo Spray): m/z=259.4 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][NH:13][C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])[CH:6]=[CH:5]2.Br[CH2:36][C:37]#[N:38].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:37]([CH2:36][O:1][C:2]1[C:3]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][NH:13][C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])[CH:6]=[CH:5]2)#[N:38]
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccccc3)c(O)ccc2c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccccc3)c(OCC#N)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid (6-hydroxy-5-phenyl-naphthalen-2-ylmethyl)-amide (366 mg, 0.813 mmol), prepared in the previous step, bromoacetonitrile (68 μL, 0.976 mmol) and potassium carbonate (562 mg, 4.07 mmol) in 20 mL of DMF was stirred under nitrogen at room temperature for 23 h (overnight). The reaction was diluted with ethyl acetate, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give a brown solid. Purification of the solid on 20 g of silica gel (230-400 mesh) using hexane-ethyl acetate as the eluent gave 2-butyl-benzofuran-3-carboxylic acid (6-cyanomethoxy-5-phenyl-naphthalen-2-ylmethyl)-amide (342 mg, 86%) as a light brown solid, mp 135-138° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH3:36][S:37][CH2:38][CH2:39][CH2:40][NH2:41]>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][CH2:40][CH2:39][CH2:38][S:37][CH3:36])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: CSCCCN
Product: CSCCCNc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Yield: 90 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (110 mg, 0.204 mmol) and [3-(methylthio)propyl]amine (200 mg, 1.90 mmol) the title compound of Step A was obtained (124 mg, 90% yield). MS (ESI): 608.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](B2OC(C)(C)C(C)(C)O2)=[C:8]([NH:10]C(=O)OC(C)(C)C)[CH:9]=1)([O-:3])=[O:2].Br[C:28]1[C:29]([C:34]#[N:35])=[N:30][CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2=[C:28]3[C:29](=[C:34]([NH2:35])[N:10]=[C:8]2[CH:9]=1)[N:30]=[CH:31][CH:32]=[CH:33]3)([O-:3])=[O:2]
Reactant: N#Cc1ncccc1Br
Reactant: CC(C)(C)OC(=O)Nc1cc([N+](=O)[O-])ccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Nc1nc2cc([N+](=O)[O-])ccc2c2cccnc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 5-nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from the previous step) (1.0 eq.) and 3-bromopicolinonitrile (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction mixture was filtered to collect the precipitate. The precipitate was rinsed with EtOAc to give 8-nitrobenzo[f][1,7]naphthyridin-5-amine as a yellow solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O.C(OCC)(=O)C>[C:19]1(/[CH:18]=[CH:16]/[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:14][CH:13]=2)=[O:17])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccc(CCCN2CCCC2)cc1
Reactant: O=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=C(/C=C/c1ccccc1)c1ccc(CCCN2CCCC2)cc1
Yield: 81.5 %

Procedure:
4 g of 4'-[3-(1-pyrrolidinyl)propyl]acetophenone and 2 g of benzaldehyde were dissolved in 80 ml of methanol and treated with a solution of 9.55 g of potassium carbonate in 38 ml of water within 15 minutes while cooling with an ice bath. The mixture was then left to react at room temperature for 18 hours and at about 40° for a further 18 hours. The reaction mixture was taken up in 200 ml of ethyl acetate and extracted with 100 ml of water. The aqueous phase was again extracted with 200 ml of ethyl acetate and the organic phases were again extracted with 100 ml of semi-saturated sodium chloride solution. The combined organic phases were dried over magnesium sulphate and evaporated. The residue was chromatographed on silica gel with acetone. There were obtained 4.5 g (81%) of (E)-3-phenyl-4'-[3-(1-pyrrolidinyl)propyl]acrylophenone as a yellow oil; mass spectrum m/e: M+ 319 (7.1), 131 (1.4), 84 (100), 42 (7.5). For the formation of the hydrochloride, the free amine was dissolved in a small amount of ethanol and treated with 10M ethanolic hydrochloric acid solution. After recrystallization of the resulting material from isopropanol there was obtained the pure hydrochloride; m.p. 211°-213°.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:8][CH:7]=1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>>[CH2:23]([N:25]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:8][CH:7]=1)[CH2:26][CH3:27])[CH3:24].[CH2:14]([NH:18][CH2:17][CH3:16])[CH3:13]
Reactant: ClCCCOc1ccc(/C=C/c2nc3ccccc3o2)cc1
Solvent: CCNCC
Product: CCN(CC)CCCOc1ccc(/C=C/c2nc3ccccc3o2)cc1

Procedure:
The title compound was prepared as described in Example 8 starting with (C) of Example 8 (2.0 g, 6.4 mmol) and using diethylamine in place of dibutylamine to produce 2.8 g (85% yield) diethylamine in place of dibutylamine to produce 2.8 g (85% yield) of the title compound as the HCl salt, mp 225°-226° C. IR(KBr): 1600 cm-1. MS: 351(MH+). 1H NMR (CD3OD): δ 7.99-6.81 (m, 10H), 4.24 (t, J=5.7 Hz, 2H), 3.09 (m, 6H), 2.44 (m, 2H), 0.87 (m, 6H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(N(CC)CC)C>C1COCC1>[CH2:19]([O:18][C:16](=[O:17])[NH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](CNC(=O)OCc2ccccc2)C1
Reaction time: 4 h
Yield: 77.2 %

Procedure:
A mixture of (S)-tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (1.0 g, 5.0 mmol) and 50 mL THF was cooled in an ice bath. To this was added benzyl chloroformate (0.77 mL, 5.5 mmol), followed by triethylamine (1.39 mL, 10 mmol). After removing the ice bath, the reaction was stirred for 4 h. The mixture was poured into ice water and extracted with EtOAc. The organic extracts were washed with water, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using EtOAc in hexanes (0-40%) gave benzyl((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate (1.29 g, 77%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.39-7.28 (m, 5H), 5.10 (s, 2H), 4.87 (s, 1H), 3.52-2.95 (m, 6H), 2.41-2.35 (m, 1H), 2.10-1.79 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[CH:14]=[CH:13]2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]1[C:35](B(O)O)=[C:34]([CH3:39])[O:33][N:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.C(O)C>[CH3:30][C:31]1[C:35]([C:2]2[CH:3]=[C:4]([C:8]([CH3:28])([CH3:29])[CH2:9][C:10]([OH:27])([C:23]([F:24])([F:25])[F:26])[CH2:11][N:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=2)=[C:34]([CH3:39])[O:33][N:32]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: Cc1noc(C)c1-c1cccc(C(C)(C)CC(O)(Cn2ccc(=O)c3ccccc32)C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A mixture of 1-[4-(3-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1-H-quinolin-4-one (30 mg, 0.064 mmol), 3,5-dimethylisoxazole-4-boronic acid (9 mg, 0.064 mmol, 1 equiv.), bisdichlorotriphenylphosphinopalladium (II) (catalytic amount) and cesium carbonate (21 mg, 0.064 mmol) in 1.1 mL of ethylene glycol dimethyl ether-water-ethanol (7:3:2) was degassed, sealed in a vial, and irradiated twice (microwave) at 160° C. for 300 seconds. The reaction was cooled to room temperature and filtered through CELITE® filter aid. The filtrate was diluted with water and extracted with diethyl ether. The combined organic layers were washed with brine and dried with sodium sulfate. Removal of the volatiles in vacuo provided a residue which was purified by HPLC to give 1-{4-[3-(3,5-dimethylisoxazol-4-yl)phenyl]-2-hydroxy-4-methyl-2-trifluoromethylpentyl}-1H-quinolin-4-one.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][OH:11])=[CH:4][C:3]=1[O:12][CH3:13].O1CCC[CH2:15]1.C[Li].[Cl-].[NH4+]>ClC(Cl)C.C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]([OH:11])[CH3:15])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1cc(CO)cc(OC)c1Br
Reactant: C1CCOC1
Agent: [Mn+4]
Agent: [Cl-]
Agent: [Li]C
Solvent: Cc1ccccc1
Solvent: CC(Cl)Cl
Product: COc1cc(C(C)O)cc(OC)c1Br
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of (4-bromo-3,5-dimethoxyphenyl)methanol (14.5 g, 58.7 mmol) in dichloroethane (100 ml) and toluene (140 mL) was added manganese dioxide (25.5 g, 294 mmol) and the mixture was stirred at 80° C. for three hours. After the reaction was completed, the mixture was filtered with Celite and the solvent was distilled off under reduced pressure to obtain a crude compound. To a tetrahydrofuran (153 mL) solution of the crude compound (13.8 g, 56.3 mmol) was added dropwise 1.04M methyllithium (59.5 mL, 61.9 mmol) at −78° C., and the mixture was stirred for four hours. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane/ethyl acetate: 4/1 then 1/1) to obtain the title compound (11.4 g, 43.7 mmol).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].Cl.Cl.[F:17][C:18]([F:31])([F:30])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C@H:27]([NH2:29])[CH3:28])=[N:25][CH:26]=1.C(Cl)CCl.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([NH:29][C@@H:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:18]([F:31])([F:17])[F:30])=[CH:26][N:25]=2)[CH3:28])=[O:14])=[CH:9][CH:10]=1)([CH3:3])[CH3:4]
Reactant: CC(C)(O)c1ccc(CC(=O)O)cc1
Reactant: C[C@@H](N)c1ccc(OCC(F)(F)F)cn1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C[C@@H](NC(=O)Cc1ccc(C(C)(C)O)cc1)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a suspension of [4-(1-hydroxy-1methylethyl)phenyl]acetic acid (266 mg, 1.37 mmol), (1R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethylamine bis-hydrochloride (400 mg, 1.37 mmol), EDC (315 mg, 1.64 mmol), and 1-hydroxy-7-azabenzotriazole (224 mg, 1.64 mmol) in DMF (20 mL) was added N,N-diisopropylethylamine (741 uL, 4.25 mmol). The reaction mixture was stirred at room temperature overnight, then concentrated to ˜5 mL and diluted with CH2Cl2 (50 mL). The solution was washed with water (50 mL) and the aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic layer was washed with water (50 mL), dried over MgSO4, concentrated and purified by normal phase chromatography (15-100% EtOAc/Hexanes) to give 270 mg (50%) of 2-[4-(1-hydroxy-1-methylethyl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide as a white solid. 1H NMR (CDCl3, 400 MHz) 8.20 (d, J=2.75 Hz, 1H), 7.45 (m, 2H), 7.22 (m, 4H), 6.68 (d, J=7.33 Hz, 1H), 5.11 (quint. J=6.96 Hz, 1H), 4.38 (q, J=8.00 Hz, 2H), 3.57(s, 2H), 1.59 (s, 6H), 1.40 (d, J=6.77 Hz, 3H); MS (Electrospray): m/z 397.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.Cl.[Cl:20][C:21]1[CH:30]=[C:29]2[C:24]([CH2:25][CH2:26][CH2:27][NH:28]2)=[CH:23][CH:22]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:20][C:21]1[CH:30]=[C:29]2[C:24]([CH2:25][CH2:26][CH2:27][N:28]2[C:7]([C:6]2[C:5]([O:4][C:3]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:2]=3[Cl:1])=[N:13][CH:12]=[CH:11][CH:10]=2)=[O:9])=[CH:23][CH:22]=1
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Reactant: Clc1ccc2c(c1)NCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccc(Cl)cc21
Temperature: 110 °C
Yield: 9.2 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (42.6 mg, 0.15 mmol, 1.0 equiv; Example 31, Step 1) in anhydrous DMF (1.5 mL) was added 7-chloro-1,2,3,4-tetrahydro-quinoline hydrochloride (33.7 mg, 0.17 mmol, 1.1 equiv; [CAS RN 90562-34-8]), triethylamine (30.4 mg, 42 μL, 0.3 mmol, 2.0 equiv; [CAS RN 121-44-8]) and HATU (62.7 mg, 0.17 mmol, 1.1 equiv; [CAS RN 148893-10-1]). The reaction mixture was heated by microwave irradiation to 110° C. for 30 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 6 mg (10%) of the title compound. MS (ISP): 435.0 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:10]1[CH:15]2[CH2:16][CH2:17][CH2:18][CH:11]1[CH2:12][CH:13]([NH:19]C(=O)OC(C)(C)C)[CH2:14]2)[CH3:9].[ClH:27].C(OCC)C>C(Cl)Cl>[ClH:27].[ClH:27].[CH2:8]([N:10]1[CH:11]2[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:14][CH:13]([NH2:19])[CH2:12]2)[CH3:9]
Reactant: CCN1C2CCCC1CC(NC(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCN1C2CCCC1CC(N)C2
Reaction time: 2 h
Yield: 99 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl 9-ethyl-9-azabicyclo[3.3.1]nonan-3-ylcarbamate from Step C (50 mg, 0.19 mmol) in methylene chloride (1 mL) at room temperature and the mixture was stirred under nitrogen for 2 h. The mixture was concentrated and the residue was dissolved in methanol (1 mL). HCl in diethyl ether (1.0 M, 2.0 mL, 2.0 mmol) was added dropwise at room temperature and the mixture was stirred for 5 min. The mixture was concentrated again and dried under vacuum overnight to give 9-ethyl-9-azabicyclo[3.3.1]nonan-3-amine dihydrochloride (45 mg, 99%) as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 9.75 (br s, 1H), 8.39 (br s, 3H), 4.14 (br s, 1H), 3.73-3.71 (m, 2H), 3.25 (q, J=7.0 Hz, 2H), 2.55-2.48 (m, 2H), 2.05-1.95 (m, 3H), 1.80-1.76 (m, 1H), 1.50-1.22 (m, 7H); MS (ESI+) m/z 169 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[Cl:21].[OH-].[Na+].[NH2:24][C:25]1[C:30]([F:31])=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH:38]3[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)[N:28]=[C:27]([C:41]([O:43]C)=[O:42])[C:26]=1[Cl:45].Cl>CO>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]3[CH2:16][CH2:17]3)=[CH:13][CH:14]=2)[N:5]=[C:4]([C:18]([O:20][CH2:29][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:19])[C:3]=1[Cl:21].[NH2:24][C:25]1[C:30]([F:31])=[C:29]([C:32]2[CH:33]=[CH:34][C:35]([CH:38]3[CH2:39][CH2:40]3)=[CH:36][CH:37]=2)[N:28]=[C:27]([C:41]([OH:43])=[O:42])[C:26]=1[Cl:45]
Reactant: COC(=O)c1nc(-c2ccc(C3CC3)cc2)c(F)c(N)c1Cl
Agent: Cl
Agent: Nc1c(F)c(-c2ccc(C3CC3)cc2)nc(C(=O)O)c1Cl
Agent: [Na+]
Solvent: CO
Product: Nc1c(F)c(-c2ccc(C3CC3)cc2)nc(C(=O)OCc2ccccc2)c1Cl
Temperature: 23 °C
Reaction time: 3 h

Procedure:
4-Amino-3-chloro-6-(4-cyclopropylphenyl)-5-fluoropicolinic acid. A 2 M solution of aqueous NaOH (600 μL, 1.2 mmol, 2.0 equiv) was added to a stirred suspension of methyl 4-amino-3-chloro-6-(4-cyclopropylphenyl)-5-fluoropicolinate (190 mg, 0.59 mmol, 1.0 equiv) in methyl alcohol (3.0 mL) at 23° C. The resulting heterogeneous white mixture was stirred at 23° C. for 3 h. The reaction mixture was adjusted to approximately pH=4 via dropwise addition of concentrated HCl and then concentrated via rotary evaporation. The residue was slurried in water and vacuum filtered to afford the desired product, 4-amino-3-chloro-6-(4-cyclopropylphenyl)-5-fluoropicolinic acid as a white powder (170 mg, 94% yield): mp 147-149° C.; IR (thin film) 3463 (s), 3339 (s), 3202 (m), 3084 (w), 3007 (w), 1721 (m), 1630 (s) cm−1; 1H NMR (300 MHz, DMSO-d6) δ 7.70 (m, 2H), 7.17 (m, 2H), 6.81 (br s, 2H), 1.96 (m, 1H), 0.99 (m, 2H), 0.71 (m, 2H); ESIMS m/z 307 ([M+H]+).
Reaction SMILES: C([O:5][C:6](=[O:38])[C:7]([CH2:14][NH:15][C:16]([C:18]1[N:19]=[C:20]([C:36]#[N:37])[C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[C:23]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:22]=2)=[O:17])([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:36]([C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[C:23]([O:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:22]=2)[C:27]([OH:28])=[C:18]([C:16]([NH:15][CH2:14][C:7]([CH2:11][CH2:12][CH3:13])([CH2:8][CH2:9][CH3:10])[C:6]([OH:38])=[O:5])=[O:17])[N:19]=1)#[N:37]
Reactant: CCCC(CCC)(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(CCC)(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
A mixture of 2-{[(1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-methyl}-2-propyl-pentanoic acid tert-butyl ester (180 mg), TFA (5 mL) and DCM (5 mL) was stirred at rt overnight; then concentrated, the residue was dissolved in water and added 2 M HCl solution, solids were collected via filtration, washed with water and air dried to give the desired product (150 mg). LC MS ESI+: 462 (M+1)+.