Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:24][CH:25]([CH3:60])[C:26]([NH:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][O:42][CH3:43])[N:35]=[CH:34][N:33]=[C:32]2[NH:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=2)=[C:47]([Cl:59])[CH:46]=1)=[O:27]>C1COCC1>[Cl:59][C:47]1[CH:46]=[C:45]([NH:44][C:32]2[C:31]3[C:36](=[CH:37][C:38]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[C:29]([NH:28][C:26]([C@H:25]([NH:24][C:1](=[O:5])[CH:2]=[CH2:3])[CH3:60])=[O:27])[CH:30]=3)[N:35]=[CH:34][N:33]=2)[CH:50]=[CH:49][C:48]=1[O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=1
Reactant: C=CC(=O)O
Reactant: COCCOc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)C(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CC(=O)N[C@H](C)C(=O)Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cc1OCCOC
Temperature: 0 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
75 μl of acrylic acid was dissolved in 4 ml of THF, and cooled to 0° C. 180 μl of pyridine and 520 ml of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added thereto, the resulting solution was reacted with 284 mg of 2-amino-N-[4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-(2-methoxy-ethoxy)-quinazolin-6-yl]-propionamide dissolved in 4 ml of THF as a starting material for 30 mins, and then stirred for 3 hours while heating to room temperature. The reacted solution was washed with saturated sodium bicarbonate solution, extracted with a mixture of chloroform and methanol, dried over sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-chloroform:methanol=15:1) to obtain the title compound (87 mg, 28%).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21]I>CN(C=O)C>[C:3]1([C:9]2[N:10]([CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=3)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc2[nH]c(-c3ccccc3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(-c2ccccc2)cc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (1.1 g, 29.0 mmol) is added to 2-phenyl-5-nitro-1H-indole (Example 5b, 6.5 g, 26.0 mmol) in 100 mL of DMF. The mixture is stirred at room temperature for 1 hour. MeI (1.62 mL, 26.0 mmol) is added dropwise and the mixture is stirred at room temperature for 1 hour. The resulting mixture is poured into H2O/ice and the product is filtered off and washed with H2O. The solid is recrystallized from hexane and filtered off. Yield: 6.5 g (99.7%); Rf (2/1 hexane/ethyl acetate): 0.60; IR (KBr): 3434, 2923, 1515, 1462 cm−1; 1H-NMR (d6-DMSO) 8.50 (d, J=1.5 Hz, 1H); 7.90 (dd, J=8.6 Hz, 1.5 Hz, 1H); 7.80-7.30 (m, 6H); 6.75 (s, 1H); 3.75 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([O:16][C:17](=[O:28])[C:18](=[CH:24]OCC)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:15]>>[CH2:14]([O:16][C:17](=[O:28])[C:18](=[CH:24][NH:13][C:12]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:9]=[CH:10][CH:11]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:15]
Reactant: Nc1ccnn1Cc1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccnn1Cc1ccccc1)C(=O)OCC
Temperature: 120 °C
Yield: 75 %

Procedure:
To 2-benzyl-2H-pyrazol-3-ylamine (5.0 g, 0.0289 mol) was added 2-ethoxymethylene-malonic acid diethyl ester (5.78 mL, 0.0289 mol) and the mixture was heated at 120° C. for 4 hours. After cooling down to RT, the crude mixture was purified by column chromatography (SiO2, EtOAc/Heptane 1/1) to give 7.44 g (75%) of the title compound as a light yellow oil.
Reaction SMILES: COC(=O)[C:4]([C:20]#[N:21])([CH:13]([CH:17]([CH3:19])[CH3:18])[CH2:14][CH2:15][CH3:16])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Na+].[Cl-].O>CS(C)=O.[Cl-].[Na+].O>[C:9]([O:8][C:6](=[O:7])[CH2:5][CH:4]([C:20]#[N:21])[CH:13]([CH:17]([CH3:18])[CH3:19])[CH2:14][CH2:15][CH3:16])([CH3:10])([CH3:12])[CH3:11]
Reactant: CCCC(C(C)C)C(C#N)(CC(=O)OC(C)(C)C)C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCC(C(C)C)C(C#N)CC(=O)OC(C)(C)C
Temperature: 130 °C
Yield: 75.2 %

Procedure:
A mixture of 2-cyano-2-(1-isopropyl-butyl)-succinic acid 4-tert-butyl ester 1-methyl ester (1.3 g, 4.2 mmol), NaCl (0.25 g, 4.2 mmol), and H2O (0.15 g, 8.3 mmol) in 25 mL of DMSO is warmed to 130° C. for 12 hours. The mixture is cooled to room temperature and diluted with 100 mL of brine. The organic products are extracted into Et2O (3×50 mL). The organic layers are combined and washed with 50 mL of H2O and 50 mL of brine. Drying over Na2SO4 and evaporation of the solvent gives 0.8 g (75% yield) of 3-cyano-4-isopropyl-heptanoic acid t-butyl ester as an oil.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[CH:29]([N:32]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=2)[C:33]1=[O:50])([CH3:31])[CH3:30]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:37]3[CH:38]=[C:39]4[C:34](=[CH:35][CH:36]=3)[C:33](=[O:50])[N:32]([CH:29]([CH3:31])[CH3:30])[CH2:40]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Reactant: CC(C)N1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CN(C(C)C)C5=O)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 2-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=465.2.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[S:10](Cl)(=[O:12])=[O:11])#[N:2].Cl.[O:15]=[C:16]1[CH2:20][CH2:19][NH:18][CH2:17]1.C(N(CC)CC)C>O1CCCC1>[F:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([S:10]([N:18]2[CH2:19][CH2:20][C:16](=[O:15])[CH2:17]2)(=[O:12])=[O:11])[C:3]=1[C:1]#[N:2]
Reactant: N#Cc1c(F)cccc1S(=O)(=O)Cl
Reactant: O=C1CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1c(F)cccc1S(=O)(=O)N1CCC(=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.6 %

Procedure:
110 mg of 2-cyano-3-fluoro-benzenesulfonyl chloride in 5 ml of tetrahydrofuran are treated with 61 mg of 3-oxo-pyrrolidine hydrochloride and with 0.14 ml of triethylamine, and the mixture is stirred for 16 hours at room temperature. The reaction mixture is concentrated in vacuo, the residue is solved in ethyl acetate and washed with a 1M HCl solution. Purification by Flash chromatography (eluent: cyclohexane/ethyl acetate 1:1) affords 21 mg of 2-fluoro-6-(3-oxo-pyrrolidine-1-sulfonyl)-benzonitrile.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:21])[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[CH2:18]([O:17][C:15]1[C:14]([Br:21])=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:16]=1)[CH:19]=[CH2:20]
Reactant: C=CCOc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCOc1cc2c(cc1Br)C(C)CNCC2
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of N-trifluoroacetyl-7-allyloxy-8-bromo-1-methyl-2,3,4,5tetrahydro-1H-3-benzazepine (1.18 g, 3.00 mmol) in methanol (35 mL) was treated with 15% aqueous NaOH (35 mL), and stirred overnight at 20 C. The product mixture was diluted with water (200 mL), extracted twice with EtOAc (200 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.880 g of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.29 (s, 1 H), 6.63 (s, 1 H), 6.04 (m, 1 H), 5.47 (d, J=17 Hz, 1 H), 5.29 (d, J=11 Hz, 1 H), 4.58 (s, 2 H), 3.01 (m, 3 H), 2.89 (m, 3 H), 2.75 (m, 1 H), 1.31 (d, J=7 Hz, 3 H). MS calculated for C14H18BrNO+H: 296, observed: 296.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:21][C:22]([NH:24][C@@H:25]1[CH2:40][C:39]2=[CH:41][CH:42]=[C:36]([CH:37]=[CH:38]2)[O:35][CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH2:29][C@H:28]([CH:43]([CH3:45])[CH3:44])[NH:27][C:26]1=[O:46])=[O:23])[C:14]([O:16]C(C)(C)C)=[O:15])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:21][C:22]([NH:24][C@@H:25]1[CH2:40][C:39]2=[CH:38][CH:37]=[C:36]([CH:42]=[CH:41]2)[O:35][CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH2:29][C@H:28]([CH:43]([CH3:44])[CH3:45])[NH:27][C:26]1=[O:46])=[O:23])[C:14]([OH:16])=[O:15]
Reactant: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CCCCN)C(=O)O)C(=O)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
0.71 g (1.10 mmol) of tert-butyl (S)-6-tert-butoxycarbonylamino-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)ureido]hexanoate was dissolved in 11 ml of dichloromethane, and the same volume of trifluoroacetic acid was added. Stirring at RT for 4 h was followed by concentration and fractionation of the residue by preparative HPLC. The required fractions were combined and, after evaporation of acetonitrile, mixed with dilute hydrochloric acid, concentrated further and finally freeze dried. 0.42 g of the title compound was obtained as hydrochloride.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11]O)=[CH:10][C:4]=2[O:3]1.C(Br)(Br)(Br)[Br:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:15][CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[O:6][C:2]([F:13])([F:1])[O:3][C:4]=2[CH:10]=1
Reactant: OCc1ccc2c(c1)OC(F)(F)O2
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC1(F)Oc2ccc(CBr)cc2O1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of (2,2-difluorobenzo[d][1,3]dioxol-5-yl)methanol (120 mg; 0.63 mmol) in anh. DCM (5 ml) was treated at rt with CBr4 (211 mg; 0.63 mmol), and with PPh3 (167 mg; 0.63 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 17 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 5-(bromomethyl)-2,2-difluorobenzo[d][1,3]dioxole as a pale yellow oil which was directly used for the next reaction.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([P:17](Cl)(Cl)=[O:18])[CH3:16]>>[CH2:15]([P:17]1(=[O:18])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH2:1][N:8]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:16]
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: CCP(=O)(Cl)Cl
Product: CCP1(=O)c2ccccc2CN1c1ccccc1
Yield: 6 %

Procedure:
The procedure of Example 1 was employed utilizing N-benzylaniline and ethyl phosphonic dichloride. The reaction of the dilithio compound and the ethyl phosphonic dichloride was conducted at -76° C. to yield 1-ethyl-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.45 g, 6% yield) as a pale yellow solid having a melting point of 116°-120° C. and the following analysis:
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=2)([CH3:3])[CH3:2].O=P(Cl)(Cl)Cl.CN([CH:26]=[O:27])C>>[CH:26]([C:12]1[C:11]2[C:6](=[CH:7][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH:1]([CH3:3])[CH3:2])=[O:27]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1ccc2cc(C(C)C)[nH]c2c1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc2c(C=O)c(C(C)C)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-isopropyl-1H-indole-6-carboxylate (Compound 33, 2.00 g, 8.66 mmol) in DMF (12 ml) at 0° C. under argon then added dropwise POCl3 (1.58 ml, 17.3 mmol) was added dropwise. The reaction was stirred for 30 minutes at 25° C. then cooled to 0° C., quenched with saturated NaHCO3, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a light tan solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([P:14](=[O:23])([O:19][CH:20]([CH3:22])[CH3:21])[O:15][CH:16]([CH3:18])[CH3:17])[P:4](=[O:13])([O:9][CH:10]([CH3:12])[CH3:11])[O:5][CH:6]([CH3:8])[CH3:7].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].O>O1CCCC1>[CH:20]([O:19][P:14]([O:15][CH:16]([CH3:18])[CH3:17])([CH:3]([P:4]([O:9][CH:10]([CH3:11])[CH3:12])([O:5][CH:6]([CH3:8])[CH3:7])=[O:13])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:23])([CH3:22])[CH3:21]
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(P(=O)(OC(C)C)OC(C)C)P(=O)(OC(C)C)OC(C)C
Reaction time: 0.17 h
Yield: 27 %

Procedure:
Under a nitrogen atmosphere, 60% sodium hydride (0.132 g) was suspended in dry tetrahydrofuran (4 ml), and tetraisopropyl methylenebisphosphonate (1.1 g) was added dropwise thereto at room temperature. After stirring for 10 minutes, ethyl bromoacetate (0.354 ml) was added dropwise thereto and the resulting mixture was stirred at the same temperature for 1 hour. Water was added thereto, followed by extraction (twice) with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (methanol:methylene chloride=2:98) to obtain ethyl 3,3-bis(diisopropoxyphosphinoyl)propionate (0.37 g, yield 27%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10]([F:14])[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([O:20]CC)=[O:19])=[CH:4]1)[CH3:2].C(O)(=O)C.Cl>O>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10]([F:14])[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2c(F)c(F)c(F)c(F)c2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(F)c(F)c21
Temperature: 100 °C
Yield: 93.3 %

Procedure:
To 20.0 g (63 mmol) of the 1-ethyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, ethyl ester, was added 200 ml of acetic acid and 150 ml of 6N hydrochloric acid in 70 ml of water. The mixture was maintained at 100° C. for two hours. It was cooled, filtered, and washed with diethyl ester, to give 17 g of the title compound, mp 229°-230° C.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[CH:12][N:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.C1(S([Cl:28])(=O)=O)C=CC=CC=1>C(OCC)C.CCOC(C)=O>[C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([Cl:28])=[CH:12][N:13]=1)(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1nccs1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)NS(=O)(=O)c1ncc(Cl)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
To a solution of (tert-butyl)(1,3-thiazol-2-ylsulfonyl)amine (0.15 g, 0.7 mmol) in ethyl ether (3 mL) at −78° C. was added a 1.6M solution of n-butyllithium (0.875 mL, 1.4 mmol) in hexanes via syringe under argon: The reaction mixture was stirred at −78° C. for 1 hr, then neat benzenesulfonyl chloride (90 μL, 0.7 mmol) was added. The resulting suspension was stirred at room temp for 2 hr. The reaction was diluted with EtOAc, washed with water and brine, dried, concentrated in vacuo and chromatographed (15% EtOAc/hexane) to give pure desired compound (58 mg, 33%). ES-MS (M+Na)+=277, 279 (Cl), (M−tBu+H)+=199, 201 (Cl).
Reaction SMILES: [C:1]([CH2:3][C:4]12[CH:20]=[CH:19][CH:18]=[CH:17][CH:5]1C(N(C1C=CC=CC=1)C2=O)=O)#[N:2].C(C[NH2:24])O>>[NH2:24][C:5]1[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=1[CH2:3][C:1]#[N:2]
Reactant: N#CCC12C=CC=CC1C(=O)N(c1ccccc1)C2=O
Reactant: NCCO
Product: N#CCc1ccccc1N
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
100 g of 2-cyanomethyl-N-phenylphthalimide were introduced, a little at a time, into 100 g of monoethanolamine at 80° C. After 10 minutes, the mixture was cooled to 20° C., and 400 g of ice water were added dropwise. The precipitated product was filtered off under suction and washed neutral with ice water.
Reaction SMILES: [CH3:1][O-:2].[Na+].F[C:5]1[C:10]([CH3:11])=[C:9]([I:12])[C:8]([CH3:13])=[CH:7][N:6]=1>CO.C1COCC1>[I:12][C:9]1[C:8]([CH3:13])=[CH:7][N:6]=[C:5]([O:2][CH3:1])[C:10]=1[CH3:11]
Reactant: C[O-]
Reactant: Cc1cnc(F)c(C)c1I
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ncc(C)c(I)c1C
Reaction time: 2 h

Procedure:
A 28% solution of sodium methoxide in methanol (185 mL) was added to 2-fluoro-4-iodo-3,5-dimethylpyridine (97.4 g) in THF (954 mL) at 20° C. The mixture was stirred at 55° C. to 65° C. for two hours. The reaction mixture was cooled and then partitioned by adding MTBE (1 L) and water (1 L). The organic layer was washed with brine. The combined aqueous layers were extracted with MTBE (500 mL×2). The combined organic layers were dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. n-heptane (50 mL) was added to the residue, and the mixture was stirred at 0° C. for one hour. The precipitated solid was collected by filtration. The solid was washed with cooled n-heptane (10 mL). The title compound (42.6 g) was obtained. The filtrate was concentrated under reduced pressure. n-heptane (5 mL) was added to the residue, and the mixture was stirred at 0° C. for 30 minutes. The precipitated solid was collected by filtration. The solid was washed with cooled n-heptane (2 mL) The title compound (20.2 g) was obtained. The filtrate was concentrated under reduced pressure. n-heptane (5 mL) was added to the residue, and the mixture was stirred at 0° C. for 30 minutes. The precipitated solid was collected by filtration. The solid was washed with cooled n-heptane (2 mL). The title compound (10.7 g) was obtained. The combined title compound (73.5 g) was obtained.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH3:18])[CH:9]=1)[CH2:4][CH:5]([OH:7])[CH3:6].[C:19]([NH:22][C:23]1[CH:33]=[CH:32][CH:31]=[C:25]2[C:26]([O:28][C:29](=O)[C:24]=12)=[O:27])(=[O:21])[CH3:20].C(N(CC)CC)C>CN(C)C=O>[CH2:17]([O:16][C:10]1[CH:9]=[C:8]([CH:3]([N:2]2[C:29](=[O:28])[C:24]3[C:25](=[CH:31][CH:32]=[CH:33][C:23]=3[NH:22][C:19](=[O:21])[CH3:20])[C:26]2=[O:27])[CH2:4][CH:5]([OH:7])[CH3:6])[CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[CH3:18]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: CCOc1cc(C(N)CC(C)O)ccc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(CC(C)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Temperature: 85 °C
Yield: 64.8 %

Procedure:
A mixture of 4-amino-4-(3-ethoxy-4-methoxyphenyl)butan-2-ol hydrochloride (0.5 g, 1.81 mmol), 3-acetamidophthalic anhydride (0.37 g, 1.81 mmol) and triethylamine (0.18 g, 1.81 mmol) in dimethylformamide (10 mL) was heated at 80-90° C. for 7 hours. The mixture was concentrated in vacuo to an oil. The oil was dissolved in ethyl acetate, washed with water, brine, dried, filtered and concentrated to an oil. This oil was purified by chromatography (silica gel, methylene chloride/ethyl acetate 8:2) to give N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide as a white solid (0.5 g, 65%); mp 132-134° C.; 1H NMR (CDCl3) δ9.54 (s, 1H), 8.73 (d, J=8.4 Hz, 1H), 7.62 (t, J=7.4 Hz, 1H), 7.46 d, J=7.3 Hz, 1H), 7.12-7.08 (m, 2H), 6.83 (d, J=8.0 Hz, 1H), 5.46 (t, J=7.8 Hz, 1H), 4.12 (q, J=7.1 Hz, 2H), 3.84 (s, 3H), 3.80 (m, 1H), 2.59-2.42 (m, 2H), 2.25 (s, 3H), 1.65 (s, 1H), 1.45 (t, J=7.0 Hz, 3H), 1.27 (d, J=6.3 Hz, 3H); 13C NMR (CDCl3) δ170.36, 169.20, 167.96, 149.04, 148.26, 137.29, 135.70, 131.50, 131.35, 124.60, 120.61, 117.85, 113.10, 111.25, 66.00, 64.39, 55.89, 52.43, 40.19, 24.92, 24.33, 14.73; Anal. Calcd. For C23H26N2O6: C, 64.78; H, 6.15; N, 6.57. Found: C, 64.86; H, 6.10; N, 6.46.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:31])[NH:20][C:21]([CH3:30])=[CH:22][C:23]=2[C:24]2C=CC=[CH:26][CH:25]=2)=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[H][H]>[Pd].CCO.C1COCC1>[CH3:12][CH:11]([N:8]1[C:9]2[CH:10]=[CH:2][CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:31])[NH:20][C:21]([CH3:30])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]=2[CH:6]=[N:7]1)[CH3:13]
Reactant: [H][H]
Reactant: Cc1cc(-c2ccccc2)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cccc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
6-Bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (70.3 mg, 0.15 mmol) in 3:1 EtOH/THF (4 mL) was hydrogenated using Pd/C (10% wet Degussa type) and a balloon of hydrogen. The reaction mixture was stirred at room temperature overnight. It was filtered through Celite, washed with EtOAc and EtOH and the solvent was evaporated. DMF was added with some water and white solids that crashed out were filtered off, air-dried for 15 min and dried in a vacuum oven for 3 h. The residue was purified by Gilson reversed-phase HPLC (30×100 Varian Polaris C18, 15-80% gradient of MeCN in water with 0.1% TFA over 12 minutes). Most of the solvent was removed and saturated NaHCO3 was added. The solids that crashed out were filtered off, air-dried for 15 min and dried in vacuum oven overnight to give the title compound (19 mg, 37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (br. s., 1H) 8.63 (br. s., 1H) 8.34 (s, 1H) 7.85 (d, J=8.34 Hz, 1H) 7.39-7.51 (m, 7H) 5.99 (s, 1H) 5.03 (quin, J=6.57 Hz, 1H) 4.22 (d, J=4.29 Hz, 2H) 2.21 (s, 3H) 1.49 (s, 3H) 1.47 (s, 3H). MS (ES) [M+H]+ 367.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([CH3:11])[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1B(O)O>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=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>[CH3:9][O:8][C:6]1[C:5]([OH:10])=[C:4]([CH3:11])[N:3]=[C:2]([C:15]2[C:14]([O:13][CH3:12])=[CH:19][C:18]([CH3:20])=[CH:17][C:16]=2[CH3:21])[N:7]=1
Reactant: COc1cc(C)cc(C)c1B(O)O
Reactant: COc1nc(Cl)nc(C)c1O
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: CCOC(C)=O
Product: COc1cc(C)cc(C)c1-c1nc(C)c(O)c(OC)n1
Temperature: 95 °C

Procedure:
A mixture of 2-chloro-4-methoxy-6-methylpyrimidin-5-ol (348 mg, 2.0 mmol), 2-methoxy-4,6-dimethylphenylboronic acid (540 mg, 3.0 mmol), tetrakis(triphenylphosphine)palladium (0) (115 mg, 5 mol %) in toluene (12 mL) and sodium carbonate (1M in water, 4 mL) is heated at 95° C. (oil bath temperature) in a pressure tube for 14 hours. The reaction is cooled to room temperature, diluted with ethyl acetate, washed with NaOH (2M) and then brine (2×50 mL). The solvents are dried (sodium sulfate) and removed under reduced pressure. Flash chromatography of the crude product (50% ethyl acetate in hexanes) yields 4-methoxy-2-(6-methoxy-2,4-dimethylphenyl)-6-methylpyrimidin-5-ol as a white solid.