Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[N:15][C:16]([NH:19][C:20]3[N:21]=[CH:22][C:23]4[C:29]([CH3:30])=[C:28](Br)[C:27](=[O:32])[N:26]([CH:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[C:24]=4[N:25]=3)=[CH:17][CH:18]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:51]([O:53][CH2:54][CH3:55])=[CH2:52])CCC>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:38])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[N:15][C:16]([NH:19][C:20]3[N:21]=[CH:22][C:23]4[C:29]([CH3:30])=[C:28]([C:51]([O:53][CH2:54][CH3:55])=[CH2:52])[C:27](=[O:32])[N:26]([CH:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[C:24]=4[N:25]=3)=[CH:17][CH:18]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCC(NC(=O)OC(C)(C)C)C4)cn3)ncc12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCC(NC(=O)OC(C)(C)C)C4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 110 °C
Reaction time: 12 h
Yield: 104.6 %

Procedure:
A 6-dram vial was charged with {1-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (379 mg, 0.65 mmol) and tetrakis(triphenylphosphine) palladium(0) (75 mg, 0.065 mmol) and the atmosphere replaced with argon. Toluene (5 ml) was added followed by tributyl-(1-ethoxy-vinyl)-stannane (352 mg, 0.97 mmol). The vial was heated to 110° C. and stirred for 12 h. The reaction mixture was diluted with chloroform (25 ml) and adsorbed onto silica gel. Chromatographic purification on silica gel (chloroform/2-propanol+1% TEA gradient) gave (1-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester as a yellow solid (394 mg, 0.68 mmol). MS: (APCI +) 576 (M+1, 100), 548.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1.C(Cl)(=O)C(Cl)=O.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:25])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1
Reactant: COCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)O
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Product: COCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)N1CCOCC1
Reaction time: 2 h
Yield: 92.4 %

Procedure:
6-[2-(2-Methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]hexanoic acid (4.1 g, 12 mmol) was treated with oxalyl chloride (1.89 mL, 21.6 mmol) and morpholine (3.15 mL, 36.0 mmol) according to a modification of the method described in Part F of Example 6. The reaction with oxalyl chloride was carried out at ambient temperature, and the reaction with morpholine was complete after two hours. Following the work-up procedure, 4.55 g of 2-(2-methoxyethyl)-1-(6-morpholin-4-yl-6-oxohexyl)-1H-imidazo[4,5-c]quinoline were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2([OH:17])[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:2].[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2([OH:17])[CH2:15][CH2:14][CH:13]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: CCOc1ccc(C2(O)CCC(=O)CC2)cn1
Product: CCOc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-(6-ethoxy-pyridin-3-yl)-4-hydroxy-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([C:5]1[N:6](CC2C=CC=CC=2Cl)[C:7](C=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:20][CH:1]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC(Br)c1ncc[nH]1

Procedure:
A mixture of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde and N-bromosuccinimide in carbon tetrachloride was irradiated to give the 2-(1-bromobutyl)imidazole which was dehydrobrominated by treating 1,8-diazabicyclo[4.5.0]undec-1-ene in tetrahydrofuran to give 2-(1-butenyl)-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]([C:12](=[NH:21])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C([O:32][C:33](=O)[CH:34]([C:36](Cl)=[O:37])[CH3:35])C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:12]1[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:33](=[O:32])[C:34]([CH3:35])=[C:36]([OH:37])[N:21]=1)[CH:9]([CH3:11])[CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=N)NCc1ccccc1
Reactant: CCOC(=O)C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(O)nc(C(NC(=O)OC(C)(C)C)C(C)C)n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.5 %

Procedure:
To a stirred solution of [(R)-1-(N-Benzyl-carbamimidoyl)-2-methyl-propyl]-carbamic acid t-butyl ester (16.37 g, 53.6 mMol) in CH2Cl2 (150 mL) with cooling at 0° C. was added Et3N (9 mL, 64.3 mMol) followed by 2-chlorocarbonyl-propionic acid ethyl ester (10 g, 60.8 mMol) dropwise over 15 minutes. The reaction was allowed to warm to RT and stirred for 4 h, poured into a separatory funnel, washed with water, brine, dried (Na2SO4), and evaporated to dryness under vacuum. The unpurified acylamidine (˜90% pure by LCMS, MS (ES) m/e (M+H)+434.4) was taken up in DMF (150 mL) and heated to 100° C. with stirring for 18 h. The reaction was concentrated under vacuum and purified by flash chromatography (90:10:1, CH2Cl2:EtOAc:HOAc) then (30:70:1, EtOAc:hexane:HOAc) to give the title compound (8.42 g, 41%) as an off-white solid: MS (ES) m/e 388.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH2:10])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1F>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1[NH:10][CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CC1CCN(CCN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CCN(CCNc2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 12.02 g (32.45 mmol) of 2-(4-methylpiperidin-1-yl)ethylamine in 100 mL of DMF is combined with 17.94 g (64.82 mmol) of potassium carbonate and stirred for 15 minutes at ambient temperature. Then 5.81 g (32.45 mmol) of 3-chloro-4-fluoronitrobenzene are added and the reaction mixture is stirred for 18 hours. Then the reaction mixture is poured into ice water and the crystalline residue is filtered off. Yield: 8.85 g (91.6% of theory); C14H20ClN3O2 (M=297.78); calc.: molecular ion peak (M+H)+: 298/300; found: molecular ion peak (M+H)+: 298/300.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1.C(O)(=O)C>C(OCC)(=O)C>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[N:1]1[CH:12]=[CH:16][CH:15]=[CH:14]1)#[N:5]
Reactant: N#Cc1ccccc1N
Reactant: COC1CCC(OC)O1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#Cc1ccccc1-n1cccc1

Procedure:
A mixture of 2-aminobenzonitrile (0.01 mole), 2,5-dimethoxytetrahydrofuran (0.01 mole) and glacial acetic acid (10 ml) was heated under reflux for 30 minutes (TLC check). The acetic acid and ethyl acetate formed was evaporated off and the residue was purified using flash chromatography on silica gel (eluent: CH2Cl2). The pure fraction was recrystallized from the appropriate solvent (mostly ethanol).
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[Br:13][C:14]1[CH:25]=[CH:24][C:17]([C:18](N(OC)C)=[O:19])=[CH:16][CH:15]=1.Cl>C(OCC)C.CCCCCC>[Br:13][C:14]1[CH:25]=[CH:24][C:17]([C:18]([C:12]2[CH:11]=[C:10]3[C:6]([CH:7]=[CH:8][NH:9]3)=[CH:5][CH:4]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CON(C)C(=O)c1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(c1ccc(Br)cc1)c1ccc2cc[nH]c2c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48.9 %

Procedure:
To hexane washed potassium hydride (0.30 g, 1.5 mmol), suspended in anhydrous diethylether (1.5 mL), was added 5-bromoindole (0.241 g, 1.23 mmol) dissolved in diethyl ether (2.0 mL) at 0° C. After 15 min, the mixture was cooled to −78 ° C. and tert-buthyllithium (1.5 mL, 2.55 mmol), pre-cooled to −78° C., was added via cannula. After 10 min 4-bromo-N-methoxy-N-methylbenzamide (0.30 g, 1.2 mmol) in diethylether (2.0 mL), pre-cooled to −78° C., was added. The reaction mixture was kept at −78° C. for 10 min and then allowed to warm up to room temperature and stirred for another hour. HCl (1M, 5 mL) was added and the mixture stirred for 15 min. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over MgSO4, and the solvent was evaporated. The crude product was purified by flash column chromatography on silica using methylene chloride as the eluent affording 176 mg (48% yield) of the title compound as a pale yellow solid: mp 47-49° C.; 1H NMR (400 MHz, CDCl3) δ 8.55 (br s, 1 H), 8.01 (s, 1 H), 7.87 (m, 2 H), 7.72 (m, 2 H), 7.68 (dd, J=8.2 Hz, J=1.4 Hz, 1 H), 7.52 (m, 1 H), 7.35 (s, 1 H), 6.74 (m, 1 H); 13C NMR (100.5 MHz, CDCl3) δ 196.5, 138.0, 135.4, 132.0, 131.9, 131.8, 131.4, 128.5, 127.1, 122.4, 120.8, 114.6, 103.6; MS TSP) m/z 300, 302 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:3]([NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[O:4].[C:18]([O:22][C:23](=[O:28])[NH:24][CH2:25][CH:26]=O)([CH3:21])([CH3:20])[CH3:19].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[C:18]([O:22][C:23](=[O:28])[NH:24][CH2:25][CH2:26][NH:1][C@H:2]([C:3](=[O:4])[NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: N[C@@H](CC1CCCCC1)C(=O)Nc1nccs1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCN[C@@H](CC1CCCCC1)C(=O)Nc1nccs1
Temperature: 50 °C
Reaction time: 3 h
Yield: 34.7 %

Procedure:
A solution of compound 12B (2.03 g, 8 mmol), (2-oxo-ethyl)-carbamic acid tert-butyl ester (1.27 g, 8 mmol) and NaBH(OAc)3 (1.70 g, 8 mmol) in DCM (30 ml) was maintained at ambient temperature overnight followed by the addition of NaBH(OAc)3 (3.39 g, 16 mmol). Reaction mixture was stirred at 50° C. for 3 hours, diluted with EtOAc (200 ml) and extracted with water (200 ml), 5% aq. bicarbonate (200 ml) and brine (200 ml). Organic layer was dried over anh. MgSO4 and evaporated in vacuum. Residue was dissolved in DMSO (5 ml) and subjected to HPLC purification. [Phenomenex Gemini C-18 column, 110 Å (30×100 mm); flow rate=45 ml/min; mobile phase A: 100% water, 0.1% TFA; mobile phase B: 100% ACN, 0.1% TFA; gradient elution from 25% B to 70% B in 70 min., detection 254 nm]. Fractions containing the desired product were combined and neutralized with 1 M NaOH. ACN was evaporated. Residual solution was extracted with EtOAc (2×100 ml). Organic layer was dried over anh. MgSO4 and evaporated in vacuum to provide target product (1.10 g, 35%) as light yellow oil. LC-MS [M+H] 397.2 (C19H32N4O3S+H, requires 397.56).
Reaction SMILES: [CH2:1]([N:4]([C@H:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[O:24][CH3:25])[CH2:15]1)[C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:2][CH3:3].C(N[C@H]1CCC2C(=CC=C[C:36]=2[O:40]C)C1)CC>>[CH2:1]([N:4]([C@H:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:40][CH3:36])[C:20]=2[O:24][CH3:25])[CH2:15]1)[C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:2][CH3:3]
Reactant: CCCN(C(=O)CCCCC(=O)O)[C@H]1CCc2c(cccc2OC)C1
Reactant: CCCN[C@H]1CCc2c(cccc2OC)C1
Product: CCCN(C(=O)CCCCC(=O)O)[C@H]1CCc2c(ccc(OC)c2OC)C1

Procedure:
(S)-N-propyl-N-[5-methoxy-1,2,3,4-tetrahydro-2-naphthyl]-5-carboxypentanamide (Intermediate 31) starting from (S)-N-propyl-5-methoxy-1,2,3,4-tetrahydro-2-naphthylamine, prepared as described in J. Med. Chem., 29, 912 (1986).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][NH:33][CH:34]=2)O1>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:31]=[N:32][NH:33][CH:34]=4)=[CH:3][CH:4]=3)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:16][CH:17]=1
Reactant: CN1CCC(c2ccc(Cl)cc2)(c2ccc(Br)cc2)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CN1CCC(c2ccc(Cl)cc2)(c2ccc(-c3cn[nH]c3)cc2)CC1

Procedure:
4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-1-methyl-piperidine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-B3) Rt 12.90 [M+H]+352. 1H NMR (Me-d3-OD) δ 2.41-2.53 (2H, m), 2.82 (3H, d), 2.97-3.12 (4H, m), 3.56-3.59 (2H, m), 7.28 (2H, s), 7.34 (1H, m), 7.42 (1H, d), 7.49 (1H, d), 7.54 (1H, d), 7.61 (1H, d), 7.75 (1H, d), 8.52 (2H, d).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][C@H:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19](Cl)[C:14]=3[C@H:13]([CH3:21])[CH2:12]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:24]([N:31]1[CH2:36][CH2:35][C:34]2([C:44]3[C:39](=[CH:40][CH:41]=[C:42]([Cl:54])[C:43]=3[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[NH:38][CH2:37]2)[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][C@H:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([N:38]4[C:39]5[C:44](=[C:43]([CH2:45][NH:46][C:47]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:53])[C:42]([Cl:54])=[CH:41][CH:40]=5)[C:34]5([CH2:35][CH2:36][N:31]([CH2:24][C:25]6[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=6)[CH2:32][CH2:33]5)[CH2:37]4)[C:14]=3[C@H:13]([CH3:21])[CH2:12]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(Cl)c21
Reactant: CC(C)(C)OC(=O)NCc1c(Cl)ccc2c1C1(CCN(Cc3ccccc3)CC1)CN2
Product: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c3ccc(Cl)c4CNC(=O)OC(C)(C)C)c21

Procedure:
(5R,7R)-4-(1′-benzyl-4-((tert-butoxycarbonylamino)methyl)-5-chlorospiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate was prepared by the procedures described in Example 1, Step 8, substituting (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine with (5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate, and substituting tert-butyl 5-chlorospiro[indoline-3,4′-piperidine]-1′-carboxylate with tert-butyl (1′-benzyl-5-chlorospiro[indoline-3,4′-piperidine]-4-yl)methylcarbamate. LCMS (APCI+) m/z 739, 741 [M+H]+; Rt=4.53 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C)C=O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: C1COCCN1
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-amino-3-nitrobenzoic acid (7.40 g), 1-hydroxybenzotriazole (6.59 g), dicyclohexylcarbodiimide (10.90 g), dry N,N-dimethylformamide (74 ml), and morpholine (4.3 ml) was stirred at room temperature for 2 hours. The insolubles were filtered out, and washed with N,N-dimethylformamide. The filtrate and the washing were combined, and concentrated to obtain a yellowish brown solid (16.01 g).
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH3:8])[CH:6]([CH3:9])[CH2:5][N:4]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][CH:11]=2)[CH2:3]1.[NH2:21][C:22]1[N:26](C(OC(C)(C)C)=O)[N:25]=[C:24]([CH2:34][CH2:35][C:36]2[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[C:38]([O:44][CH3:45])[CH:37]=2)[CH:23]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:43][O:42][C:40]1[CH:41]=[C:36]([CH2:35][CH2:34][C:24]2[NH:25][N:26]=[C:22]([NH:21][C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([N:4]4[CH2:5][CH:6]([CH3:9])[N:7]([CH3:8])[CH:2]([CH3:1])[CH2:3]4)=[CH:20][CH:19]=3)[CH:23]=2)[CH:37]=[C:38]([O:44][CH3:45])[CH:39]=1
Reactant: CCOC(=O)c1ccc(N2CC(C)N(C)C(C)C2)cc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CC(C)N(C)C(C)C4)cc3)n[nH]2)cc(OC)c1
Yield: 7.4 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(3,4,5- trimethylpiperazin-1-yl)benzamide was prepared following the procedure as for Example 94, but starting from ethyl 4-(3,4,5-trimethylpiperazin-1-yl)benzoate (310 mg, 0.86 mmol), tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (225 mg, 0.65 mmol) and 1M NaHMDS (2.59 ml, 2.59 mmol) in THF (5 ml). The crude product was purified by reverse phase prep. HPLC (basic) using a 38-58% gradient of acetonitrile in water containing 1% 0.880 ammonia. The clean fractions were taken and evaporated to afford the title compound as a white solid (23 mg, 5.6%);1H NMR (399.99 MHz, CDCl3) δ1.09 (6H, d), 2.17-2.28 (2H, m), 2.22 (3H, s), 2.56 (2H, t), 2.81-2.90 (4H, m), 3.48 (2H, d), 3.68 (6H, s), 6.22 (1H, t), 6.28 (2H, s), 6.56 (1H, s), 6.78 (2H, d), 7.68 (2H, d0, 8.86 (1H, s), 9.65 (1H, s). MS: m/z 464 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br>CO>[NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: BrBr
Solvent: CO
Product: Nc1cc(Cl)c(Br)cc1C(=O)O
Temperature: -78 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of 2-amino-4-chlorobenzoic acid (10.0 g, 58.5 mmol) in methanol (150 mL) was added bromine (15.7 mL) at −78° C., and the reaction mixture was stirred at −78° C. for 2 hours. The reaction mixture was quenched with ice water (100 mL) and aq. sodium thiosulfate, and extracted with ethyl acetate (150 mL×3). The organic layers were separated, combined, washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (9 g, 62%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].Cl[C:8]1[S:12][C:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](OCC)=[O:24])=[C:17]([F:28])[C:16]=2[F:29])=[C:10]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][CH:31]=2)[CH:9]=1>>[CH2:36]([C:33]1[CH:32]=[CH:31][C:30]([C:10]2[CH:9]=[CH:8][S:12][C:11]=2[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][OH:24])=[C:17]([F:28])[C:16]=2[F:29])=[CH:35][CH:34]=1)[CH3:37]
Reactant: CCOC(=O)CCc1ccc(OCc2sc(Cl)cc2-c2ccc(CC)cc2)c(F)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1ccc(-c2ccsc2COc2ccc(CCCO)c(F)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 223 by LAH reduction of ethyl 3-(4-[[5-chloro-3-(4-ethylphenyl)thiophen-2-yl]methoxy]-2,3-difluoro phenyl)propanoate to give the desired product as off-white oil. 1H NMR (300 MHz, CD3OD) δ7.41 (d, J=5.1 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.08 (d, J=5.1 Hz, 1H), 6.82 (t, J=8.7 Hz, 1H), 6.68 (t, J=8.7 Hz, 1H), 5.14 (s, 2H), 3.53 (t, J=6.3 Hz, 2H), 2.59-2.66 (m, 4H), 1.70-1.80 (m, 2H), 1.23 (t, J=7.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C22H22F2O2S, 201.1[M-C9H9F2O2]. found 201.1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([CH2:12][C:13]([O:15][C@H:16]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]4[CH2:41][CH2:40]4)[CH:28]=3)[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N+:21]([O-:25])=[CH:20][C:19]=3[Cl:26])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl.N1C=CC=CC=1>[Cl:24][C:23]1[CH:22]=[N+:21]([O-:25])[CH:20]=[C:19]([Cl:26])[C:18]=1[CH2:17][C@@H:16]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:35])[F:36])=[C:29]([O:37][CH2:38][CH:39]2[CH2:40][CH2:41]2)[CH:28]=1)[O:15][C:13](=[O:14])[CH2:12][N:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([NH:1][S:43]([CH3:42])(=[O:45])=[O:44])=[CH:3][CH:4]=2)[C:8]1=[O:11]
Reactant: Nc1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
(S)-4-(2-(2-(6-amino-1-oxoisoindolin-2-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (50 mg, 0.08 mmol) was dissolved in CH2Cl2 (2 ml) and pyridine (50 μl), then methanesulfonyl chloride was added (11 mg, 0.1 mmol) at 0° C. The mixture was stirred at RT for 2 hours, then diluted with CH2Cl2 (20 ml) and quenched with HCl 1N aqueous solution (30 ml). The two phases were separated, and the organic phase washed with HCl 1N aqueous solution (2×20 ml), dried over Na2SO4 and evaporated under vacuum. The crude was purified by preparative HPLC (Method 2) to yield 41 mg of the title compound. (Yield 75%). 1H NMR (400 MHz, acetone) δ ppm 8.71-8.92 (m, 1H), 8.22 (s, 2H), 7.73 (m, 1H), 7.59 (m, 2H), 7.15-7.30 (m, 2H), 7.05 (dd, J=8.38, 1.76 Hz, 1H), 6.93 (t, 1H, CHF2), 6.15 (dd, J=9.70, 4.85 Hz, 1H), 4.49 (s, 2H), 4.44 (d, J=3.53 Hz, 2H), 3.98 (d, J=7.06 Hz, 2H), 3.55 (dd, J=14.11, 9.26 Hz, 1H), 3.32 (dd, J=14.11, 4.85 Hz, 1H), 3.05 (s, 3H), 1.29 (m, 1H), 0.55-0.69 (m, 2H), 0.27-0.47 (m, 2H); MS/ESI+ 686.51 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([C:20]([CH2:24][CH2:25][CH3:26])=[CH:21][CH2:22][CH3:23])[N:17]([CH3:19])[N:18]=[C:11]12>C(O)(=O)C.[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([CH:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[N:17]([CH3:19])[N:18]=[C:11]12
Reactant: CCC=C(CCC)c1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCC(CCC)c1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Reaction time: 12 h
Yield: 24.4 %

Procedure:
7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine (3-1; 41.5 mg) was dissolved in acetic acid (1 mL) and 12 mg of 10% palladium on carbon was added. The mixture was stirred under hydrogen at one atmosphere for 12 h. The mixture was diluted with ethyl acetate and filtered through diatomaceous earth and the residue was washed with ethyl acetate. The ethyl acetate filtrate was washed with aqueous sodium bicarbonate, dried with magnesium sulfate, and concentrated. The residue was chromatographed on silica gel eluting with an acetone/hexane gradient to provide 10.2 mg of 4-1 as a crystalline film: ms (MH+)=374.