Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]2[N:13]([CH2:25]O)[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)[Cl:34].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]2[N:13]([CH2:25][Cl:34])[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C1CCCN(CO)c2c1cc(OCc1ccccc1)c1ccccc21
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCCN(CCl)c2c1cc(OCc1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 44.2 %

Procedure:
A solution of 83 (0.105 g, 0.24 mmol, 1 equiv) in CH2Cl2 (2 mL) was treated with CCl4 (0.225 mL, 2.33 mmol, 9.7 equiv) followed by Ph3P (0.212 g, 0.81 mmol, 3.3 equiv) and the mixture was stirred at 25° C. for 2.5 h. The crude reaction solution was passed through a plug of silica gel and concentrated. Radial chromatography (SiO2, 1 mm plate, 5% EtOAc-hexane) provided 86 as a pale yellow oil (0.048 g, 0.108 g theoretical, 44%): 1H NMR (250 MHz, CDCl3) major rotamer δ 8.44-8.36 (m, 1H), 8.15-7.12 (m, 1H), 7.62-7.33 (m, 7H), 6.64 (s, 1H), 5.31-5.15 (m, 2H), 4.46-4.41 (m, 1H), 4.17-4.08 (m, 1H), 3.92-3.81 (m, 1H), 3.74-3.63 (m, 1H), 2.78-2.69 (m, 1H), 2.41-2.35 (m, 1H), 2.17-2.05 (m, 1H), 1.72-1.67 (m, 2H), 1.30 (s, 9H); IR (film) νmax 2971, 2930, 2859, 1693, 1617, 1592 cm−1; FABHRMS (NBA-NaI) m/z 451.1933 (M+, C27H30CINO3 requires 451.1914).
Reaction SMILES: [OH-].[K+].[C:3](O)(=O)[CH2:4][C:5]([CH2:10][C:11]([OH:13])=O)([C:7]([OH:9])=[O:8])O.[CH3:16]N(C)C=O>>[C@@H:4]12[O:13][C@@H:11]([CH:16]=[CH:3]1)[CH2:10][C@@H:5]2[C:7]([OH:9])=[O:8]
Reactant: CN(C)C=O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Product: O=C(O)[C@H]1C[C@@H]2C=C[C@H]1O2
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 1 mmol of (1R,2R)-2-(naphthalene-2-sulphonyl)cyclohexyl ester (exo)-(1R,2S,4R)-7-oxabicyclo[2.2.1]-hept-5-ene-2-carboxylate in 5 ml of N,N-dimethylformamide is mixed with 2 mmol of potassium hydroxide and stirred at 60° C. for 17 hours. The reaction mixture is cooled to room temperature and, after addition of 1M citric acid solution, extracted with tert-butyl methyl ether (3×). The combined organic phases are washed with cold water and cold brine, dried with sodium sulphate and evaporated at room temperature. The title compound is identified by means of the Rf from the residue by flash chromatography (SiO2 60 F).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)Nc2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
5-Bromopyridin-3-amine (1.2 g, 6.94 mmol) was dissolved in dichloromethane (30 ml). Diisopropylethylamine (1.45 ml, 8.32 mmol) first and then a solution of 4-methoxybenzoyl chloride (1.18 g, 6.92 mmol) in dichloromethane (20 ml) were added. After stirring 1 h at room temperature the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to give 2.12 g (80% yield) of the title compound. Purity 78%.
Reaction SMILES: [CH:1]1([C:6]([OH:8])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.ON1C2C=CC=CC=2N=N1.[NH2:20][CH:21]([P:30]([CH2:35][C:36]([N:38]1[CH2:49][CH2:48][CH2:47][C@H:39]1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:37])([O:32][CH2:33][CH3:34])=[O:31])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.II>O1CCCC1.CN(C)C=O.CC(C)=O>[CH:1]1([C:6]([NH:20][CH:21]([P:30]([CH2:35][C:36]([N:38]2[CH2:49][CH2:48][CH2:47][C@H:39]2[C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])=[O:37])([O:32][CH2:33][CH3:34])=[O:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C1CCCC1
Reactant: CCOP(=O)(CC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(N)CCc1ccccc1
Agent: II
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(CCc1ccccc1)NC(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
A solution of cyclopentanecarboxylic acid (0.26 g., 0.0023 mole) and 1-hydroxybenzotriazole hydrate (0.31 g., 0.0023 mole) in tetrahydrofuran (10 ml.) is cooled to 0°, followed by the portionwise addition of N,N-dicyclohexylcarbodiimide (0.47 g., 0.0023 mole). The bath is removed and the mixture is stirred at ambient temperature for 70 minutes. After filtration, the mixture is concentrated in vacuo. To the residue, dissolved in dimethylformamide (8 ml.) plus tetrahydrofuran (10 ml.), is added a solution of (±)-1-[[[1-(amino)-3-phenylpropyl]ethoxyphosphinyl]acetyl]-L-proline, 1,1-dimethylethyl ester (1 g., 0.0023 mole), prepared for example as described in Example 85 (d), and triethylamine (0.25 g., 0.0025 mole) in dimethylformamide (10 ml.). The mixture is stirred at ambient temperature for 16 hours. It is then concentrated in vacuo and the residue is dissolved in ethyl acetate (75 ml.), washed with water, 10% citric acid, saturated sodium bicarbonate, brine, and dried (MgSO4). The solvent is removed in vacuo to give 1.2 g. of an amber oil residue. It is chromatographed on silica gel, eluted with dichloromethane, dichloromethane/acetone (4:1) to give 1.1 g. of (±)-1-[[[[1-(cyclopentylcarbonyl)amino]-3-phenylpropyl]ethoxyphosphinyl]acetyl]-L-proline, 1,1-dimethylethyl ester as an oil in two fractions: 0.8 g., Tlc, silica gel, acetone, shows a single spot at Rf 0.55; and 0.3 g., Tlc, shows two spots, Rf 0.55 and Rf 0.52 (visualized with PMA plus heat, or I2 vapor).
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([I:11])[C:3]=1[C:4]#[N:5].[H-].[Na+].[CH3:14][O:15][CH2:16]Cl>C1COCC1>[F:1][C:2]1[C:9]([O:10][CH2:14][O:15][CH3:16])=[CH:8][CH:7]=[C:6]([I:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(I)ccc(O)c1F
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(I)c(C#N)c1F
Reaction time: 0.08 h
Yield: 72 %

Procedure:
A 0° C. solution of Example 68A (250 mg, 0.95 mmol) in THF (5 mL) at room temperature was treated with NaH (25 mg, 95%, 1.05 mmol), stirred for 5 minutes, treated with chloromethyl methyl ether (0.108 mL, 1.4 mmol), stirred overnight, and partitioned between water and ethyl acetate. The organic extract was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 2% ethyl acetate/hexanes to provide 0.21 g of the desired product. R1=0.4 (10% ethyl acetate/hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19](Cl)[N:18]=1>>[Cl:16][C:17]1[N:18]=[C:19]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:20]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:22]=1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)c1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cc(C(F)(F)F)cc(Cl)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2,6-dichloro-4-trifluoromethyl-pyridine. The title compound was obtained as a yellowish solid (Yield=30%). MS ISP (m/e): 383.1 (39) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.67 (d, 1H), 7.39 (d, 1H), 7.23 (d, 1H), 7.11 (s, 1H), 6.99 (s, 1H), 6.965-6.85 (m, 3H), 3.87 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C@H:12]2[CH2:14][O:13]2)=[C:6]([CH:9]=1)C=O.C1C=C(Cl)C=C([C:22]([O:24]O)=[O:23])C=1>C(Cl)Cl>[CH:22]([O:24][C:6]1[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:10][CH2:11][C@H:12]1[CH2:14][O:13]1)=[O:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1cc(Br)ccc1OC[C@H]1CO1
Solvent: ClCCl
Product: O=COc1cc(Br)ccc1OC[C@H]1CO1

Procedure:
Preparation according to Preparation 2 using 5-bromo-2-[(2R)-oxiran-2-ylmethoxy]benzaldehyde (6.8 g, 26 mmol), DCM (75 ml) and m-CPBA (77%, 8.9 g, 39.5 mmol). Crude yield: 7.0 g. MS m/z (rel. intensity, 70 eV) 274 (M+, 10), 273 (M+, 9), 189 (98), 188 (bp), 57 (77).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[NH2:41][CH:42]1[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:41][CH:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]5)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a mixture of 0.11 g (0.24 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-benzoic acid (I-182), 0.17 mL (0.96 mmole) of ethyldiisopropyl amine, 0.030 g (0.26 mmole) of 4-amino-1-methyl-piperidine and 3.0 mL of dimethylformamide was added 0.11 g (0.26 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-80:20) gave 0.065 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-N-(1-methyl-piperidin-4-yl)-benzamide (I-183) as a white solid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-]=C=O.[NH2:13][C:14]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=2)[CH2:18][N:17]=[C:16]2[O:27][CH:28]=[CH:29][C:15]=12>>[NH2:13][C:14]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[CH:21]=2)[CH2:18][N:17]=[C:16]2[O:27][CH:28]=[CH:29][C:15]=12
Reactant: NC1=c2ccoc2=NCN1c1cccc(N)c1
Reactant: O=C=Nc1ccccc1
Agent: [N-]=C=O
Product: NC1=c2ccoc2=NCN1c1cccc(NC(=O)Nc2ccccc2)c1

Procedure:
The compound was prepared following the procedure described in Example 232(b), using phenyl isocyanate as the isocyanate of choice, and 4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine of choice. MS(ES) m/e 346 [M+H]+.
Reaction SMILES: S([O-])([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=O)=O.[CH3:14][N:15]([CH2:19][CH2:20]O)[CH2:16][CH2:17][OH:18].[OH-].[Na+]>>[CH2:5]([O:4][CH2:20][CH2:19][N:15]([CH2:16][CH2:17][OH:18])[CH3:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCOS(=O)(=O)[O-]
Reactant: CN(CCO)CCO
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCOCCN(C)CCO
Temperature: 200 °C
Reaction time: 3 h

Procedure:
318 grams (1.377 moles) of n-octyl sulfate, Na salt, 491.5 grams (4.130 moles) of N-methyl diethanolamine and 55.1 grams (1.377 moles) of sodium hydroxide were heated with stirring for 3 hours under a nitrogen atmosphere to 200° C. After cooling to 80° C., the mixture was washed four times with saturated sodium chloride solution and then dried at 80° C. under a vacuum in a rotary evaporator. Sodium chloride precipitated from the product was filtered. A red-brown liquid having an amine number of 238 was obtained in a quantity of 254 grams.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]#[C:13][Si](C)(C)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[C:12]#[CH:13]
Reactant: C[Si](C)(C)C#Cc1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the intermediate from step A (2.7 g, 10 mmol) in 10:1 MeOH:H2O (60 mL) was added potassium carbonate (2.76 g, 20 mmol). The reaction was stirred at room temperature for 15 minutes after which the mixture was poured into a pH 7-phosphate buffer and extracted with methylene chloride (3×). The combined organic layers were then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting oil was used without further purification. 1H NMR (CDCl3, 500 MHz): 7.8 (d, J=1.9 Hz, 1H), 7.5 (m, 2H), 3.48 (s, 1H).
Reaction SMILES: [OH-:1].[Na+].Br[C:4]1(Br)[C:8](=[O:9])NN[CH:5]1[C:10]([CH3:13])([CH3:12])[CH3:11].C(#N)C.Cl>O>[CH3:11][C:10]([CH3:13])([CH3:12])[C:5]#[C:4][C:8]([OH:1])=[O:9]
Reactant: CC(C)(C)C1NNC(=O)C1(Br)Br
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)C#CC(=O)O
Temperature: 5 °C

Procedure:
552 g of sodium hydroxide was dissolved in 3.0 liters of water and ice was added thereto to adjust the temperature to 5° C. or lower. Next, while stirring, dibromo-3-t-butyl-5-pyrazolidone was added thereto little by little while maintaining the temperature at 5° C. or lower. If the temperature would rise, ice was added, and acetonitrile was added in order to prevent foaming. After the completion of the reaction, 6 N hydrochloric acid was added to make the reaction solution acidic, and then the solution was subjected to extraction twice with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([OH:28])=O)[N:9]=2)[CH:7]=1.Cl.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:37][CH2:36]1.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:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:44]3[CH2:43][CH2:42][CH:41]([N:38]4[CH2:37][CH2:36][N:35]([CH3:34])[CH2:40][CH2:39]4)[CH2:46][CH2:45]3)=[O:28])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: CN1CCN(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(C2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (200 mg, 0.35 mmol) in DMF (4 mL) was added 1-methyl-4-(piperidin-4-yl)piperazine hydrochloride (170 mg, 0.77 mmol), DIEA (134.4 mg, 1.04 mmol), HATU (160 mg, 0.42 mmol). The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (25.0% up to 34.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 25.0% in 2 min); Detector, UV 254/220 nm. This resulted in 74.3 mg (32%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide formate as a off-white solid. LCMS (Method 20) [M+H]+=628.2, RT=2.20 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.36-9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=9.2 Hz), 7.29 (dd, 1H, J=4.0, 6.8 Hz), 7.09 (t, 1H, J=73.2 Hz), 5.25-5.21 (m, 2H), 4.36-4.29 (m, 1H), 3.98-3.79 (m, 1H), 3.10-3.00 (m, 1H), 2.69-2.51 (m, 1H), 2.49-2.32 (m, 8H), 2.18 (s, 3H), 1.91-1.86 (m, 2H), 1.47-1.41 (m, 1H), 1.39-1.25 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([Cl:22])[CH:15]=1.B(Br)(Br)Br>>[Cl:22][C:16]1[CH:15]=[C:14]([C:7]2[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=2)[CH:19]=[CH:18][C:17]=1[OH:20]
Reactant: CCCn1nc(-c2ccc(OC)c(Cl)c2)c2cccc(Cl)c21
Agent: BrB(Br)Br
Product: CCCn1nc(-c2ccc(O)c(Cl)c2)c2cccc(Cl)c21
Yield: 63.6 %

Procedure:
Prepared according to Method D step C from 7-Chloro-3-(3-chloro-4-methoxyphenyl)-1-propyl-1H-indazole (0.39 g, 1.18mmol), BBr3 (0.11 mL, 1.17 mmol) to give the title compound as a white solid (0.24 g, 0.75 mmol, 64%).
Reaction SMILES: C([O:8][C:9]1[C:10]2[CH2:22][C@:21]3([CH3:41])[C@@H:23]([CH3:40])[CH2:24][CH2:25][C@H:26]4[C:27]([CH3:39])([CH3:38])[C:28](=[N:31][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH2:29][CH2:30][C@@:20]34[O:19][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][C:9]1[C:10]2[CH2:22][C@:21]3([CH3:41])[C@@H:23]([CH3:40])[CH2:24][CH2:25][C@H:26]4[C:27]([CH3:39])([CH3:38])[C:28](=[N:31][N:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)[CH2:29][CH2:30][C@@:20]34[O:19][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1
Reactant: C[C@H]1CC[C@H]2C(C)(C)C(=NN3CCOCC3)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CNC4=O)C[C@]13C
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CC[C@H]2C(C)(C)C(=NN3CCOCC3)CC[C@]23Oc2c(c(O)cc4c2CNC4=O)C[C@]13C
Yield: 81.3 %

Procedure:
To a solution of Compound (61) (224 mg, 0.40 mmol) in 50 ml of methanol containing 1% water was added 180 mg of 10% palladium-carbon, followed by catalytic reduction. After the palladium-carbon was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel 10 g; ethyl acetate:methanol=99:1) and further crystallization from diethyl ether-n-hexane to give 152 mg (79%) of Compound (51f).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([C:11]([O:13]CC)=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[Li].O>CO.C1COCC1.O>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([C:11]([OH:13])=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1coc2c(Br)cccc12
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1coc2c(Br)cccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 7-bromo-1-benzofuran-3-carboxylate (1.0 g, 3.7 mmol) in 20 mL of MeOH/THF/H2O (2/211) was added LiOH H2O (777 mg, 18.5 mmol), and the mixture was stirred at ambient temperature overnight. The solvents were removed under vacuum, and the residue was added 10 mL of water and extracted with ether (100 mL). The aqueous layer was then acidified with 4 N HCl to pH=3 in ice bath, and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 7-bromo-1-benzofuran-3-carboxylic acid.
Reaction SMILES: [C:1]([N:6]1[CH2:27][CH2:26][C:9]2[N:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11]3[CH:12]=[CH:13][C:14](Br)=[CH:15][C:16]=3[C:8]=2[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].[C:28]1([CH3:37])[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[C:1]([N:6]1[CH2:27][CH2:26][C:9]2[N:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11]3[CH:12]=[CH:13][C:14]([C:30]4[CH:29]=[C:28]([CH3:37])[CH:33]=[CH:32][CH:31]=4)=[CH:15][C:16]=3[C:8]=2[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCCCCCCCn1c2c(c3cc(Br)ccc31)CN(C(=O)OCC)CC2
Reactant: Cc1cccc(B(O)O)c1
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: [K+]
Solvent: C1COCCO1
Product: CCCCCCCCn1c2c(c3cc(-c4cccc(C)c4)ccc31)CN(C(=O)OCC)CC2
Yield: 60.4 %

Procedure:
To the mixture of 2-Carbethoxy-8-bromo-5-n-octyl-1,2,3,4-tetrahydropyrido[4,3-b]indole (4b, 1 equiv.), m-tolylboronic acid (1.1 equiv.) and Pd(PPh3)4 (0.05 equiv.) in 12 mL 1,4-dioxane was added 4 mL aqueous solution of K2CO3 (3 equiv.). The mixture was refluxed under N2 atmosphere for about 10 h. On cooling, the solvent was evaporated and the resulting residue was extracted with DCM (20 mL×3), the DCM layer was washed with brine, dried (Na2SO4) and filtered. The residue obtained on removal of the solvent was purified by column chromatography on silica gel with EtOAc/hexane as eluting solvents to give the target compound 2-carbethoxy-8-m-tolyl-5-octyl-1,2,3,4-tetrahydropyrido[4,3-b]indole (7). Yield: 60.4%. 1H NMR (300 Hz, CDCl3) δ 7.67 (br, 1H), 7.48-7.43 (m, 3H), 7.35-7.31 (m, 2H), 7.15-7.12 (m, 1H), 4.76 (s, 2H), 4.22 (q, 2H, J=7.2 Hz), 4.03 (t, 2H, J=7.2 Hz), 3.91 (br, 2H), 2.84 (br, 2H), 2.45 (s, 3H), 1.77-1.73 (m, 2H), 1.35-1.27 (m, 13H), 0.89 (t, 3H, J=6.5 Hz). 13C NMR (75 Hz, CDCl3) δ 156.09, 142.48, 138.10, 135.83, 132.72, 128.50, 128.09, 126.98, 125.57, 124.39, 120.83, 118.99, 116.15, 109.29, 106.70, 61.49, 60.36, 43.21, 41.31, 31.75, 30.38, 29.28, 29.13, 27.04, 22.57, 21.56, 14.73, 14.16, 14.03.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[O:32]1[C:37]2[CH:38]=[CH:39][C:40]([CH:42]=O)=[CH:41][C:36]=2[O:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[ClH:1].[O:32]1[C:37]2[CH:38]=[CH:39][C:40]([CH2:42][NH:3][CH:4]3[CH2:5][CH2:6][N:7]([CH2:10][C@H:11]4[N:21]5[C:22]6[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=6[CH:18]=[CH:19][C:20]5=[O:23])[CH2:12]4)[CH2:8][CH2:9]3)=[CH:41][C:36]=2[O:35][CH2:34][CH2:33]1
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1ccc2ccc(=O)n3c2n1C[C@H]3CN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A suspension of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride (for a preparation see Example 5A(j)) (60 mg, 0.161 mmol) in chloroform (2 ml) and methanol (0.100 ml) at rt under argon was treated with triethylamine (0.067 ml, 0.482 mmol) and stirred at rt for 15 h. The solution was then treated with 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde (commercially available) (23.75 mg, 0.145 mmol) and stirred for a further 30 min. The solution was then treated with sodium triacetoxyborohydride (102 mg, 0.482 mmol) and stirred at rt for 30 min, LC-MS after 30 min showed some starting material present, more sodium triacetoxyborohydride (19 mg) was added, the reaction was stirred for 15 min. This was then treated with saturated aqueous NaHCO3 (10 ml) and extracted with 20% methanol/DCM (3×25 ml). The combined organic extracts were dried (MgSO4), filtered, evaporated and chromatographed (0-20% methanol/DCM) to give the title compound as the free base (48 mg, 67%) as a yellow gum.