Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Pr+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[C:26]1([CH3:35])[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=1.O>C1(C)C=CC=CC=1>[CH3:35][C:26]1[CH:31]=[CH:30][C:29]([C:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:35])=[CH:27][CH:28]=2)=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Pr+3]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C(=O)c2ccc(C)cc2)cc1
Reaction time: 24 h
Yield: 18.1 %

Procedure:
Praseodymium (III) trifluoromethanesulfonate (3.53 g as a wet solid) and para-toluic acid (1.36 g) were refluxed together in 125 mL toluene with azeotropic removal of the lower water layer (Dean-Stark apparatus). After 24 hours, the mixture was cooled and extracted with 3×25 mL water, then by 2×25 mL saturated sodium bicarbonate solution. The organic layer was dried using anhydrous sodium sulfate, filtered, then concentrated down in vacuo to give crude 4,4′-dimethylbenzophenone (0.65 g, 31% yield) as a cream-colored crystalline solid. This was then recrystallized from methanol to give white needles of pure 4,4′ dimethylbenzophenone (0.19 g,9% yield) (M.P. 90.5-91.5° C.).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[CH3:26]>>[F:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:24][C:25]=1[CH3:26]
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: Cc1ccc(B(O)O)cc1F
Product: Cc1ccc(-c2cc(C#N)cc3c(C)c4n(c23)CCNC4=O)cc1F

Procedure:
The title compound, light yellow solid (53 mg, 64%), MS (ISP) m/z=334.6 [(M+H)+], mp 255° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 3-fluoro-4-methyl-phenylboronic acid (50.0 mg, 0.325 mmol).
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:18])=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-])=O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:1][C:4]1[C:5]([OH:18])=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(c1ccccc1)c1cccc([N+](=O)[O-])c1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc(C(=O)c2ccccc2)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
A mixture of 3-nitro-2-hydroxybenzophenone (600 mg, 2.5 mmol) and tin (II) chloride (1.7 g, 7.5 mmol) in ethanol(50 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(490 mg, 92%). 1H NMR (CD3OD): δ 7.65-7.40 (m, 5H), 6.98 (d, 1H), 6.86 (d, 1H), 6.67 (t, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11]C)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CCCCCC.[Cl:29][C:30]1[N:38]=[CH:37][CH:36]=[CH:35][C:31]=1C(Cl)=O.[Cl-].[NH4+].[Cl-].[Na+]>C1COCC1.O>[Cl:29][C:30]1[C:31]([C:9](=[O:11])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:35][CH:36]=[CH:37][N:38]=1
Reactant: COC(=O)Cc1ccccc1F
Reactant: O=C(Cl)c1cccnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=C(Cc1ccccc1F)c1cccnc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 5.00 g (29.7 mmol) of methyl (2-fluorophenyl)acetate in 80 ml of THF is added dropwise to a 1 N solution of LiHMDS in hexane (35.7 ml, 35.7 mmol) cooled to −78° C. The mixture is stirred at −78° C. for 1 h and then 6.28 g (35.7 mmol) of 2-chloronicotinoyl chloride are added, and the mixture is stirred for a further hour. It is warmed to RT, and saturated ammonium chloride solution is added. The mixture is diluted with water and extracted with diethyl ether. The organic phase is dried over sodium sulfate and concentrated in vacuo. The residue is dissolved in 24 ml of DMSO, and 0.95 g (52.7 mmol) of water and 1.70 g (29.0 mmol) of sodium chloride are added. The solution is heated in 8 portions at 150° C. for 10 min in each case. It is then diluted with water and extracted with tert-butyl methyl ether. The organic phase is dried over sodium sulfate and concentrated in vacuo. The residue is purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1). 3.00 g (46% of theory) of the desired compound are obtained.
Reaction SMILES: B(Br)(Br)Br.[NH:5]([C:12]1[N:17]=[C:16]([CH2:18][O:19]C)[CH:15]=[C:14]([CH3:21])[N:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[NH:5]([C:12]1[N:17]=[C:16]([CH2:18][OH:19])[CH:15]=[C:14]([CH3:21])[N:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COCc1cc(C)nc(Nc2ccccc2)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(CO)nc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.8 %

Procedure:
Boron bromide (3.9 g) was added dropwise to a solution of 3.0 g of 2-anilino-4-methoxymethyl-6-methylpyrimidine in 100 ml of dichloromethane at -70° C. After completion of the dropwise addition, the coolant was removed and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water gradually. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The solid residue was recrystallized from ethanol-hexane to obtain 2.5 g (yield: 89%) of 2-anilino-4-hydroxymethyl-6-methyl-pyrimidine having a melting point of 118°-120° C.
Reaction SMILES: [Cl-].[NH4+].[Br:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([N+:13]([O-])=O)[CH:5]=1>C(O)C.O.[Fe]>[NH2:13][C:6]1[CH:5]=[C:4]([Br:3])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Br)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Iron powder (4.15 g, 74.38 mmol) and ammonium chloride (3.32 g, 62.0 mmol) were added to a solution of 4-bromo-2-nitrobenzoic acid [J. Am. Chem. Soc. 1952, 74, 5621] (3.05 g, 12.4 mmol) in ethanol (50 mL) and water (25 mL) and the mixture was heated at reflux. After 6 h, the reaction was filtered, washed with ethanol, and concentrated in vacuo. The crude material was dissolved in water (150 mL) and concentrated HCl (30 mL) and stirred at ambient temperature for 16 h. The mixture was extracted with ethyl acetate (2×200 mL) and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=216 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][N:13]1[CH2:18][CH2:17][C:16]([CH2:25][NH2:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH:26][CH2:25][C:16]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]1)=[O:6]
Reactant: CN1CCC(CN)(c2ccccc2)CC1
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Product: Cc1ccc(Cl)c(C(=O)NCC2(c3ccccc3)CCN(C)CC2)c1

Procedure:
From 2-chloro-5-methylbenzoic acid and C-(1-methyl-4-phenyl-piperidin-4-yl)-methylamine. LCMS (MH+): m/z=367.0, tR (minutes, Method A)=0.68
Reaction SMILES: B(Cl)(Cl)Cl.C([O:7][C:8]1[C:15]([O:16]CC)=[C:14]([O:19][CH2:20][CH3:21])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11])C.C([O-])(O)=O.[Na+].Cl>C(Cl)Cl>[CH2:20]([O:19][C:14]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([OH:7])[C:15]=1[OH:16])[CH3:21]
Reactant: CCOc1ccc(C=O)c(OCC)c1OCC
Agent: Cl
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCOc1ccc(C=O)c(O)c1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of boron trichloride (3.34 mL, 3.34 mmol 1M in DCM, 1 eq) was added dropwise to a solution of 33 (0.80 g, 3.34 mmol) in DCM at room temperature. The reaction mixture was stirred for 2 hours at this temperature then a further one equivalent of boron trichloride (3.34 mL, 3.34 mmol, 1M in DCM) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0° C. and saturated NaHCO3 aq. was added, then made acidic by the dropwise addition of conc. HCl. The reaction mixture was extracted with TBME (3×) and the organic phase was dried (Na2SO4) and concentrated in vacuo to give the crude product (1.4 g). Purification by column chromatography (SiO2 1:2 EtOAc:cyclohexane) gave 34 compound (0.46 g, 76%):
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[NH:11][C:10]1=[O:19].[F:28][C@@H:29]1[CH2:33][NH:32][C@H:31]([C:34]([O:36][CH3:37])=[O:35])[CH2:30]1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:19])[C:9]2([N:32]1[CH2:33][C@@H:29]([F:28])[CH2:30][C@H:31]1[C:34]([O:36][CH3:37])=[O:35])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: COC(=O)[C@@H]1C[C@H](F)CN1
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](F)CN1C1(c2ccccc2OC)C(=O)Nc2ccc(Cl)cc21
Reaction time: 13 h
Yield: 109.9 %

Procedure:
2.79 g of triethylamine was added under ice cooling and a nitrogen atmosphere to a 50 mL chloroform solution of 1.70 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 1.03 g of the compound obtained in step 4-1, after which the reaction mixture was raised to room temperature and stirred for 13 hours at the same temperature. The reaction solution was stirred while a 50 mL saturated sodium hydrogencarbonate aqueous solution was added, and the reaction mixture was stirred for 15 minutes. After liquid separation, the aqueous layer thus obtained was extracted with chloroform. The combined organic layer was washed with saturated brine and dried with magnesium sulfate, after which the drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 2.54 g of residue (yellow, amorphous). The residue thus obtained purified by column chromatography (silica gel 60, mobile phase: ethyl acetate), and stirred and washed in diisopropyl ether to obtain 1.98 g of a diastereoisomer mixture of the titled compound (pale green, amorphous).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[C:34]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:37])[CH2:35][CH3:36]
Reactant: COc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c(OCC2CC2)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A163) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C@@H:20]2[CH2:25][CH2:24][C:23](=[N:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:22][NH:21]2)=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[BH4-].[Na+].C(=O)([O-])O.[Na+]>C(#N)C.O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C@@H:20]2[CH2:25][CH2:24][C@@H:23]([NH:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:22][NH:21]2)=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CCN(C(=O)OCc2ccccc2)CC1)[C@@H]1CCC(=NOCc2ccccc2)CN1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C(NC1CCN(C(=O)OCc2ccccc2)CC1)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Temperature: -10 °C
Reaction time: 21 h
Yield: 79 %

Procedure:
To 4-[({(2S)-5-[(benzyloxy)imino]piperidin-2-yl}carbonyl)amino]piperidine-1-carboxylic acid benzyl ester (0.4641 g, 1.00 mmol), tetrahydrofuran (3.2 ml) and acetonitrile (0.8 ml) were added, and the obtained mixture was cooled down to −10° C. Sulfuric acid (0.588 g, 6.00 mmol) and subsequently sodium borohydride (0.113 g, 3.00 mmol) were added to the mixture, and after 21 hours of stirring, saturated sodium hydrogen carbonate aqueous solution (5 ml) was added. The reaction mixture was extracted with ethyl acetate (10 ml), and the extracted mixture was analyzed with high performance liquid chromatography to find that the extracted mixture contained 0.366 g of the title compound, and the reduction reaction proceeded with yield of 79%. The diastereo selectivity was (2S,5R)/(2S,5S)=87.3/12.7 (74.6% de).
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl[C:44]1[N:49]=[C:48]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:47]([C:57]([O:59][CH2:60][CH3:61])=[O:58])=[CH:46][N:45]=1.[CH2:62]([NH:64][C:65]([NH2:67])=[O:66])[CH3:63].CC(C)([O-])C.[K+].O>O1CCOCC1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:62]([NH:64][C:65](=[O:66])[NH:67][C:44]1[N:49]=[C:48]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:47]([C:57]([O:59][CH2:60][CH3:61])=[O:58])=[CH:46][N:45]=1)[CH3:63]
Reactant: CCOC(=O)c1cnc(Cl)nc1Nc1ccccc1
Reactant: CCNC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1ncc(C(=O)OCC)c(Nc2ccccc2)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
Palladium (II) acetate (0.240 g, 1.06 mmol) was added to a solution of Xantphos (0.88 g, 1.52 mmol) in degassed 1,4-dioxane (40 mL) at room temperature. The mixture was stirred under N2(g) for 1 h and treated with iii (0.98 g, 3.54 mmol), N-ethylurea (0.470 g, 5.31 mmol), potassium tert-butoxide (0.600 g, 5.31 mmol) and degassed water (96 μL, 5.31 mmol). The mixture was warmed to 100° C. for 2 h, cooled to room temperature and diluted with EtOAc (50 mL). The mixture was poured onto water (50 mL), and the layers separated. The aqueous phase was further extracted with EtOAc (2×50 mL). The combined organic phase was washed with brine (50 mL), dried (MgSO4) and reduced in vacuo to give the crude product as a brown solid. Column chromatography (SiO2), eluting with 1% MeOH in DCM, afforded compound iv (0.501 g, 1.52 mmol, 43%) as an orange solid. 1H NMR (300 MHz, DMSO-d6): δ 10.14 (1H, br s), 9.94 (1H, br s), 8.77-8.74 (2H, m), 7.64 (2H, d, J 7.7), 7.43 (2H, t, J 8.2), 7.20 (1H, t, J 7.7), 4.35 (2H, q, J 7.2), 3.03 (2H, dq, J 5.6 and 7.2), 1.34 (3H, t, J 7.2), 0.88 (3H, t, J 7.2); [M+H]+ m/z=330.1.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][C:18]3=[C:21]([C:24]([NH2:26])=[O:25])[NH:22][N:23]=[C:17]3[CH2:16]2)=[N:13][CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][C:18]3=[C:21]([C:24]([NH2:26])=[O:25])[NH:22][N:23]=[C:17]3[CH2:16]2)=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2CCc3c(n[nH]c3C(N)=O)C2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1[nH]nc2c1CCN(c1ccc(N)cn1)C2

Procedure:
The amine group of the 6-(5-tert-butoxycarbonylaminopyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carboxamide is deprotected in acid medium (trifluoroacetic acid in dichloromethane) and results in the obtaining of 6-(5-aminopyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][CH:12]([CH3:14])[CH3:13])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH2:15][CH:16]([CH2:21][OH:22])[C:17]([O:19][CH3:20])=[O:18].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][CH:12]([CH3:14])[CH3:13])[C:5]([C:6]([NH:15][CH:16]([CH2:21][OH:22])[C:17]([O:19][CH3:20])=[O:18])=[O:8])=[CH:4][N:3]=1
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)O
Reactant: COC(=O)C(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(CO)NC(=O)c1cnc(Cl)cc1NC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-chloro-4-(isopropylamino)nicotinic acid (9) (1.3 g, 6.06 mmol) in DMF (25 mL), methyl 2-amino-3-hydroxypropanoate (12.11 mmol) and DIPEA (18.17 mmol) were added followed by the addition of HATU (30.3 mmol) to the reaction mixture and stirred at room temperature for 2 h. DMF was removed under reduced pressure. The residue obtained was diluted with EtOAC and washed with water and 10% NaHCO3 solution. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by flash chromatography using silica gel and EtOAC: pet ether as eluent to afford the title compound, methyl 2-(6-chloro-4-(isopropylamino)nicotinamido)-3-hydroxypropanoate. LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 μm; Solvent A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% MeOH: 10% H2O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time); retention time: 1.312 min; LCMS (ES-API), m/z 316.0 (M+H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31]C(C)(C)C)=[O:30])[C:26]([C:36]3[CH:37]=[N:38][N:39]([CH2:42][C:43]4([O:49][CH2:50][CH:51]=[O:52])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)[C:40]=3[CH3:41])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[BH4-].[Na+].C(OCC)(=O)C.O>O1CCCC1.ClCCl.C(O)(C(F)(F)F)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([C:36]3[CH:37]=[N:38][N:39]([CH2:42][C:43]4([O:49][CH2:50][CH2:51][OH:52])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)[C:40]=3[CH3:41])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: Cc1c(-c2ccc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)OC(C)(C)C)cnn1CC1(OCC=O)CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cnn1CC1(OCCO)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 167F (56 mg) in tetrahydrofuran (10 mL) was added NaBH4 (15 mg). The mixture was stirred at room temperature overnight. The mixture was added to ethyl acetate (200 mL) and water (60 mL). The organic layer was washed with brine and dried over Na2SO4. Filtration and evaporation of the solvent gave crude product which was dissolved in dichloromethane (2 mL) and TFA (2 mL). After sitting on the bench overnight, the solvent was evaporated. The residue was purified by reverse phase chromatography using a Gilson system, eluting with 20-80% acetonitrile in 0.1% TFA water solution to provide the desired product. 1H NMR (300 MHz, dimethylsulfoxide-dc) 3 ppm 12.85 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.41 (m, 5H), 7.29 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 4.04 (s, 3H), 3.49 (m, 3H), 3.01 (t, 2H), 2.14 (m, 3H), 1.37 (m, 11H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31].CCN=C=NCCCN(C)C>>[OH:26][C:27]1[CH:28]=[C:29]([C:30]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:31])[CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)c1cccc(O)c1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)c4cccc(O)c4)c3)c2c1
Yield: 3.4 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 3-hydroxybenzoic acid (0.098 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 7 mg (3% yield) of the title compound. 1H NMR (DMSOd6) δ 13.4 (br s, 1H), 10.4 (s, 1H), 9.9 (s, 1H), 8.6 (s, 1H), 8.4 (s, 1H), 8.1 (br s, 1H), 7.9 (m, 2H), 7.75 (m, 1H), 7.6 (d, 1H), 7.5 (t, 1H), 7.4 (m, 1H), 7.38–7.28 (m, 2H), 6.8 (m, 1H); ES-MS (m/z) 373 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][C:15](=[O:17])[CH2:16][CH:9]1[CH2:10][O:11][CH2:12]2)=O)(C)(C)C.[BH4-].[Na+].FC(F)(F)C(O)=O>CO.C(Cl)Cl>[CH:9]12[NH:8][CH:13]([CH2:14][CH:15]([OH:17])[CH2:16]1)[CH2:12][O:11][CH2:10]2
Reactant: CC(C)(C)OC(=O)N1C2COCC1CC(=O)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: OC1CC2COCC(C1)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7-oxo-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (100 mg, 0.41 mmol) in MeOH (5 mL) was added NaBH4 (47 mg, 1.24 mmol) in one portion at room temperature. The mixture was stirred at room temperature overnight, and then quenched with sat. NaHCO3. The mixture was extracted with EtOAc (20 mL) three times. The organic layer was washed with sat. NaHCO3 and brine (20 mL) respectively. The organic layer was dried over Na2SO4, and then filtered. The solvent was concentrated under reduced pressure to give a crude product La, which was dissolved in CH2Cl2 (5 mL). Trifluoroacetic acid (2 mL) was added to the solution dropwise at 0° C. After being stirred at room temperature for 2 hours, the mixture was concentrated under reduced pressure. The residue was further dried on high-vacuum to give 3-oxa-9-aza-bicyclo[3.3.1]nonan-7-ol (Compound L) which was directly used for next step. MS: calc'd (MH+) 144, measured (MH+) 144.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[ClH:18]>P(Cl)(Cl)(Cl)=O>[Cl:18][C:6]1[N:1]=[C:2]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:5]=1
Reactant: CCOC(=O)c1ccc[n+]([O-])c1C(=O)OCC
Reactant: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(Cl)nc1C(=O)OCC

Procedure:
A mixture of 75.6 g of diethyl pyridine-2,3-dicarboxylate-N-oxide and 150 mL of phosphorous oxychloride is warmed slowly in a large reaction vessel equipped with a reflux condenser and gas scrubber. Caution: exothermic reaction! At about 70°, an exothermic reaction ensues with vigorous liberation of hydrogen chloride gas. The reaction is heated at reflux after the exotherm subsides for an additional hour. The reaction is cooled and concentrated in vacuo to a syrup. This material is dissolved in methylene chloride, washed cautiously with saturated sodium bicarbonate, dried and concentrated in vacuo to give the desired product as an oil. An analytical sample is obtained by chromatography on silica gel using 2:1 petroleum ether-ether as eluant to give the product as a colorless oil.