Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:33]([F:36])([F:35])[F:34])=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[F:1][C:2]1[C:3]([C:33]([F:34])([F:35])[F:36])=[C:4]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[C:25]4[CH2:24][CH2:23][NH:22][CH2:21][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)n[nH]c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 3-(4-(3,4-difluoro-2-(trifluoro-methyl)phenyl) piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (33, 41.2 g, 80.0 mmol) in CH2Cl2 (150 mL) was added TFA (70 mL). The mixture stirred at ambient temperature for 16 h and was then concentrated under reduced pressure to give ((4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone TFA salt (34) as an off-white solid (40.0 g, >99%). The material was used as is without spectral characterization.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1
Reactant: CC1=NCCc2c(C)cccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1cccc2c1CCNC2C
Yield: 12 %

Procedure:
In close analogy to the procedure described above, 1,5-dimethyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
Reaction SMILES: CN(C)C=O.[C:6]([NH:9][C:10]1[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1)(=O)[CH3:7].Cl.[CH:19]([N:22]([CH:26]([CH3:28])[CH3:27])CCCl)([CH3:21])[CH3:20].[H-].[Na+]>C(O)C>[CH:19]([N:22]([CH:26]([CH3:28])[CH3:27])[CH2:7][CH2:6][NH:9][C:10]1[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1)([CH3:21])[CH3:20]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: CC(=O)Nc1nc(C)cc(C)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1cc(C)nc(NCCN(C(C)C)C(C)C)n1

Procedure:
To 600 ml of dry dimethylformamide is added 2-acetamido-4,6-dimethylpyrimidine (34.8 g., 0.21 mole) and 2-diisopropylaminoethyl chloride hydrochloride (48 g., 0.24 mole). The mixture is stirred under nitrogen and sodium hydride (50% in mineral oil) (24.7 g., 0.515 mole) is added in portions over one hour while the temperature is maintained below 45° C. The mixture is then heated at 75°-78° C. for 1/2 hour and then at 90°-95° C. for 31/2 hours. On cooling, ethanol, 25 ml, is added and the solvents removed under reduced pressure. The residue is suspended in 75 ml of 1-propanol and 400 ml of 5N sodium hydroxide and refluxed with stirring for 18 hours. On cooling the mixture is extracted with methylene chloride. The organic extracts are then extracted with dilute hydrochloric acid. The acid extracts are extracted with hexane and then made alkaline with a molar excess of sodium hydroxide. The crude product is extracted from the basic solution with diethyl ether. The ethereal extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under vacuum. The residue is distilled and the product diamine (37.2 g., 0.149 mole) collected at 130°-134° C./0.4 mm; melting point 79.5°-82° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.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(O)C>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Fc1ccc(Oc2ccc3c(Cl)nncc3c2)cc1
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: COCCOC
Solvent: ClCCl
Solvent: CCO
Product: Fc1ccc(Oc2ccc3c(-c4ccccc4Cl)nncc3c2)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A 10 mL round-bottomed flask under argon was charged with 1-chloro-6-(4-fluorophenoxy)phthalazine (42.90 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium (9 mg, 0.008 mmol), 2-chlorophenylboronic acid (37 mg, 0.23 mmol), ethylene glycol dimethyl ether (1.6 mL), and ethanol (0.4 mL), followed by 2M aqueous sodium carbonate solution (0.23 mL, 0.45 mmol). The reaction was stirred at 90° C. for 3 h. The cooled reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3 and brine, then dried (MgSO4). Flash chromatography eluting with a gradient of 25:10:65, 40:10:50, 50:10:40, 60:10:30, and 70:10:20 ethyl acetate-dichloromethane-hexanes gave the title compound as a tan amorphous solid. MS (ES+): 351.1 (M+H)+.
Reaction SMILES: [C:1](#[N:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:10][OH:11]>O.CCO>[OH:11][N:10]=[C:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC#N
Reactant: NO
Solvent: CCO
Solvent: O
Product: CCCCCCCC(N)=NO
Yield: 74.6 %

Procedure:
Octanonitrile (1 g, 7.99 mmol) and hydroxylamine (50% in water, 0.74 cm3, 0.79 a 12 mmol, 1.5 eq) in EtOH (1 cm3) were stirred at room temperature for 7 days. Water (10 cm3) was then added. This caused crystals to precipitate, these were collected by filtration and dried in high vacuum line to give the product N′-hydroxyoctanimidamide (0.94 g, 74.6%) as a white solid, mp 73-75° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26]>>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=3[C:25]([F:26])([F:27])[F:28])=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(O)cc1C(F)(F)F
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Product: O=C(Nc1ccc(O)cc1C(F)(F)F)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-amino-3-(trifluoromethyl)phenol (prepared according to the method described by Filler, R.; Novar, H. J. in Org. Chem. 1961, 26, 2707-2710″), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(N)c1
Product: CC(=O)Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
m-Toluidine (10 ml; 93 mmol) was added to a stirred solution of acetic anhydride (30 ml). The reaction mixture was stirred for 1.5 h at rt., evaporated to dryness, stirred with H2O and filtered to give 13 g product (94%).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:9][C:10]([F:30])([F:29])[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:26][CH2:25][CH:24]([O:27][NH2:28])[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:6]([O:5][C:3](=[O:4])[C:2]([NH:28][O:27][CH:24]1[CH2:23][CH2:22][N:21]([S:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:30])([F:9])[F:29])=[CH:17][CH:16]=2)(=[O:19])=[O:20])[CH2:26][CH2:25]1)=[O:8])[CH3:7]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl chlorooxoacetate (0.145 ml, 1.30 mmol) was added to a solution of O-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yl)hydroxylamine (390 mg, 1.15 mmol) and triethylamine (0.246 ml, 1.76 mmol) in CH2Cl2 (8 ml) and stirred at room temperature for 2 hours. The reaction mixture was diluted with CH2Cl2 and washed with aqueous NaHCO3 solution (10 ml) and concentrated in vacuo to give crude product of N-[1-(4-trifluoromethoxybenzenesulfonyl)piperidin-4-yloxy]oxalamic acid ethyl ester.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:17]([N:19]1[CH2:55][CH2:54][CH2:53][C@H:20]1[C:21]([NH:23][C@H:24]([C:46]([NH:48][CH2:49][C:50]([OH:52])=[O:51])=[O:47])[CH2:25][CH2:26][CH2:27][NH:28][C:29](=[NH:45])[NH:30][S:31]([C:34]1[C:43]([CH3:44])=[C:41]([CH3:42])[C:38]([O:39][CH3:40])=[CH:37][C:35]=1[CH3:36])(=[O:33])=[O:32])=[O:22])=[O:18])[CH2:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[NH:56]1[C:60](=[O:61])[CH2:59][CH2:58][C@H:57]1[C:62](O)=[O:63]>>[NH:56]1[C:60](=[O:61])[CH2:59][CH2:58][C@H:57]1[C:62]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:17]([N:19]1[CH2:55][CH2:54][CH2:53][C@H:20]1[C:21]([NH:23][C@H:24]([C:46]([NH:48][CH2:49][C:50]([OH:52])=[O:51])=[O:47])[CH2:25][CH2:26][CH2:27][NH:28][C:29](=[NH:45])[NH:30][S:31]([C:34]1[C:43]([CH3:44])=[C:41]([CH3:42])[C:38]([O:39][CH3:40])=[CH:37][C:35]=1[CH3:36])(=[O:33])=[O:32])=[O:22])=[O:18])[CH2:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:63]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](COC(C)(C)C)NC(=O)[C@@H](N)CC(N)=O)C(=O)NCC(=O)O)c(C)c1C
Product: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H]2CCC(=O)N2)C(=O)NCC(=O)O)c(C)c1C

Procedure:
The coupling and Nα -deprotection processes were repeated in the same manner to prepare H-Asn-Ser(But)-Pro-Arg(Mtr)-Gly-resin, and then the coupling process using pGlu-OH were performed to obtain pGlu-Asn-Ser(But)-Pro-Arg(Mtr)-Gly-resin. After drying, the resin was stirred in TFA-anisole (10-1 ml) for 4 hours at room temperature. The resin was removed by filtration and was washed with TFA.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH:16][C@@H:17]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=2)[CH3:18])=[O:15])=[CH:9][CH:8]=1.[H][H]>CCOC(C)=O.[Pd]>[CH2:25]([C:22]1[CH:23]=[CH:24][C:19]([C@H:17]([NH:16][C:14](=[O:15])[CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:3]3[CH:4]=[N:5][O:6][C:2]=3[CH3:1])=[CH:8][CH:9]=2)[CH3:18])=[N:20][CH:21]=1)[CH3:26]
Reactant: C=Cc1ccc([C@@H](C)NC(=O)Cc2ccc(-c3cnoc3C)cc2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccc([C@@H](C)NC(=O)Cc2ccc(-c3cnoc3C)cc2)nc1
Reaction time: 24 h

Procedure:
To a solution of 0.11 g (0.32 mmol) 2-[4-(5-methylisoxazol-4-yl)phenyl]-N-[(1R)-1-(5-vinylpyridin-2-yl)ethyl]acetamide in 1.30 ml EtOAc was added 0.010 g of 10% palladium on carbon. The reaction flask was equipped with a hydrogen balloon. After 24 h at room temperature, the reaction mixture was filter through celite, washed three times with methanol, and concentrated in vacuo. Purification by automated flash chromatography (40 g silica gel cartridge 20-100% EtAOc/hex over 15 min) afforded N-[(1R)-1-(5-ethylpyridin-2-yl)ethyl]-2-[4-(5-methylisoxazol-4-yl)phenyl]acetamide 1H NMR (CDCl3, 400 MHz) 8.35 (s, 1H); 8.31 (d, 1H, J=1.56 hz); 7.47 (dd, 1H, J=2.19 Hz, 7.96 Hz); 7.36 (d, 4H, J=2.29 Hz); 7.13 (d, 1H, J=7.88 Hz); 6.97 (br d, 1H J=7.88 Hz); 5.10 (m, 1H); 3.62 (s, 2H); 2.63 (q, 2H, J=7.60 Hz, 15.11 Hz); 2.57 (s, 3H); 1.43 (d, 3H, J=6.69); 1.24 (t, 3H, J=7.60). HRMS (ES) exact mass calcd for C21H23N3O2: 350.1864, Found: 350.1856.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([N:14]=[C:15]=[O:16])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](C(O)=O)=[CH:22]1>>[C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]([C:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:21][CH:22]=2)=[O:16])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N=C=O
Reactant: O=C(O)c1c[nH]c2ccccc12
Product: CC(C)(C)c1ccccc1Oc1ncccc1NC(=O)c1c[nH]c2ccccc12

Procedure:
Example 72 was prepared from 2-(2-tert-butylphenoxy)pyridin-3-amine (1a) and 1H-indole-3-carboxylic acid using the procedure described for Example 70. LC-MS m/z 386.2 [M+H]+.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17].[CH3:22][C:23]([CH3:25])=[O:24]>C1COCC1.[Cl-].[NH4+].O>[OH:24][C:23]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17])([CH3:25])[CH3:22]
Reactant: CC(C)=O
Reactant: O=C(O)c1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)c1cccc(C(=O)O)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Under argon and at −78° C., 4 ml (9.95 mmol) of a 2.5 M solution of n-butyllithium in a hexane fraction were added dropwise to a solution of 1.0 g (4.97 mmol) of 3-bromobenzoic acid in 20 ml of anhydrous THF. After 20 min, 730 μl (9.95 mmol) of acetone were added dropwise at the same temperature. The reaction mixture was stirred at −78° C. for a further hour and then allowed to warm to RT over the course of about 1 h. The reaction mixture was then hydrolysed by careful addition of a few drops of saturated aqueous ammonium chloride solution. The mixture was diluted with 200 ml of water and extracted five times with in each case about 25 ml of ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and freed from the solvent on a rotary evaporator. The residue obtained was purified in four portions by preparative HPLC (Method 36). Pooling of the product fractions, evaporation and drying under high vacuum gave 356 mg (39% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=2[N:12]([CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29]C)=[O:22])[C:11](=[O:31])[CH:10]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]3[NH:46][N:45]=[N:44][N:43]=3)[CH:37]=2)=[O:34])[N:9]=1.B(Br)(Br)Br.C(OCC)(=O)C.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=2[N:12]([CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])=[O:22])[C:11](=[O:31])[CH:10]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]3[NH:46][N:45]=[N:44][N:43]=3)[CH:37]=2)=[O:34])[N:9]=1
Reactant: COc1ccccc1C(=O)CN1C(=O)C(NC(=O)Nc2cccc(-c3nnn[nH]3)c2)N=C(c2ccccc2F)c2cccc(C)c21
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: Cc1cccc2c1N(CC(=O)c1ccccc1O)C(=O)C(NC(=O)Nc1cccc(-c3nnn[nH]3)c1)N=C2c1ccccc1F
Temperature: 0 °C
Reaction time: 4 h
Yield: 103.3 %

Procedure:
A mixture of N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-methoxyphenacyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]urea (200 mg) and 1N boron tribromide in methylene chloride (3.87 ml) was stirred at 0° C. under nitrogen stream for 4 hours and allowed to stand in a refrigerator overnight. Ethyl acetate and water were added to the reaction mixture. The separated organic layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated in vacuo to afford a pale brown powder, which was washed with diisopropyl ether and collected by filtration to give N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-hydroxyphenacyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]urea (202.0 mg) as a crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([OH:20])=O)=[CH:13][CH:12]=3)=[CH:7][CH:6]=[CH:5][N:4]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[O:54]1[CH2:59][CH2:58][N:57]([CH2:60][CH2:61][CH2:62][NH2:63])[CH2:56][CH2:55]1>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([NH:63][CH2:62][CH2:61][CH2:60][N:57]2[CH2:58][CH2:59][O:54][CH2:55][CH2:56]2)=[O:20])=[CH:13][CH:12]=3)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1-c1cc2cc(C(=O)O)ccc2[nH]1
Reactant: NCCCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[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: COc1ncccc1-c1cc2cc(C(=O)NCCCN3CCOCC3)ccc2[nH]1
Reaction time: 0.08 h
Yield: 87 %

Procedure:
To a solution of 2-(2-methoxypyridin-3-yl)-1H-indole-5-carboxylic acid (0.850 g, 0.317 mmol) in dimethylformamide (5 ml) was added HBTU (1.20 g, 0.317 mmol) and N,N-diisopropylethylamine (0.70 ml, 0.519 g, 0.402 mmol). The reaction mixture was allowed to stir for five minutes and 3-morpholinopropan-1-amine (0.59 ml) was added. The reaction was allowed to stir for 2 hours at room temperature. The reaction was quenched by adding water (25 ml), saturated sodium bicarbonate solution (25 ml) and extracted with EtOAc (2×50 ml). The organic extracts were combined, washed with brine (1×25 ml), dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography (SiO2, 100% EtOAc to 3% MeOH in EtOAc) to give the desired product as a white solid (1.09 g, 87%). M.p.=224-225° C.; 400 MHz 1H NMR (DMSO-d6) δ: 11.55 (s, 1H), 8.36 (t, J=5.4 Hz, 1H), 8.23 (dd, J=1.6 Hz, 7.6 Hz, 1H), 8.17 (dd, J=2.0 Hz, 5.2 Hz, 1H), 8.11 (s, 1H), 7.65 (dd, J=2 Hz, 8.4 Hz, 1H), 7.47 (d, J=8.4, 1H), 7.18-7.12 (m, 2H), 4.06 (s, 3H), 3.60-3.56 (m, 4H), 3.35-3.27 (m, 2H), 2.38-2.31 (m, 6H), 1.76-1.66 (m, 2H); LCMS: 395 [M+H]. Hydrolysis as described in General Procedure O provides compound 55 in Table 2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([NH:9][CH:10]=[O:11])=[CH:7][CH:6]=[N:5]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>C(Cl)Cl>[CH3:19][S:20]([O:1][CH2:2][CH2:3][N:4]1[C:8]([NH:9][CH:10]=[O:11])=[CH:7][CH:6]=[N:5]1)(=[O:22])=[O:21]
Reactant: O=CNc1ccnn1CCO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCn1nccc1NC=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-(2-hydroxyethyl)-5-formamidopyrazole (10 g) and triethylamine (18 ml) in methylene chloride (100 ml) was added dropwise methanesulfonyl chloride (8.5 ml) under ice-cooling. The mixture was stirred at 0° C. for 1.5 hours. The reaction mixture was poured into water (20 ml) and the methylene chloride layer was separated. The aqueous layer was reextracted with tetrahydrofuran twice. The organic layers were combined and dried over magnesium sulfate. The solvent was evaporated and the residue was subjected to column chromatography on silica gel (200 g) using ethyl acetate as an eluent. Fractions containing the object compound were combined and evaporated in vacuo to give 1-(2-methylsulfonyloxyethyl)-5-formamidopyrazole (3.2 g) as crystals.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:15]=1[CH2:16]Cl.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.CC(C)=O>[CH3:11][C:9]1[N:10]=[C:3]2[C:2]([O:1][CH2:16][C:15]3[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:14]=3[CH3:13])=[CH:7][CH:6]=[CH:5][N:4]2[C:8]=1[CH3:12]
Reactant: Cc1cccc(C)c1CCl
Reactant: Cc1nc2c(O)cccn2c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1cccc(C)c1COc1cccn2c(C)c(C)nc12
Yield: 33.7 %

Procedure:
A mixture of 8-hydroxy-2,3-dimethylimidazo[1,2-a]pyridine (1.2 g, 7.41 mmol), 2,6-dimethylbenzylchloride (1.145, 7.41 mmol), sodium iodide (0.3 g), sodium carbonate (2.0 g) and acetone (50 ml) was refluxed for 3 h. After the addition of methylene chloride the reaction mixture was filtered. The solvent was removed in vacuo. The residue was dissolved in CH2Cl2, washed with aqueous NaHCO3, dried over Na2SO4 and evaporated. The residue was chromatographed on silica, eluting with CH2Cl2—MeOH (100:5) to give 0.70 g of the desired product (from ethyl acetate-ether).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([OH:11])=O)[CH:2]([CH3:4])[CH3:3].[CH2:20]([N:22]1[C:26]([OH:27])=[CH:25][CH:24]=[N:23]1)[CH3:21].Cl.CN(C)CCCN=C=NCC.CCN(CC)CC.[Si](C#N)(C)(C)C.[C-]#N.[K+]>C(#N)C>[CH2:1]([NH:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([C:25]1[CH:24]=[N:23][N:22]([CH2:20][CH3:21])[C:26]=1[OH:27])=[O:11])[CH:2]([CH3:3])[CH3:4]
Reactant: CCn1nccc1O
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1NCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: C[Si](C)(C)C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(NCC(C)C)c2C)c1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under nitrogen, 0.43 g (1.5 mmol) of 3-isobutylamino-2-methyl-4-(methyl-sulfonyl)benzoic acid, 0.22 g (2.0 mmol) of 1-ethyl-5-hydroxypyrazole and 0.35 g (1.8 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were dissolved in dry acetonitrile. The mixture was stirred at RT for 1 day and allowed to stand for 2 days. 0.42 ml (3.0 mmol) of NEt3, 0.08 ml (0.6 mmol) of Me3SiCN and a spatula tip of KCN were added, and the mixture was stirred at RT for 2 days. The solvent was removed, and the residue was taken up in CH2Cl2 and 10% strength H2SO4. The organic phase was separated off and dried over MgSO4, and the solvent was removed under reduced pressure. The residue was crystallized from acetonitrile. This gave 0.16 g of a red solid of a purity of 96%.
Reaction SMILES: C(O)(=O)C.C[O:6][C:7]1[CH:8]=[C:9]([C:20]2[C:28]3[C:27]([NH2:29])=[N:26][CH:25]=[N:24][C:23]=3[N:22]([C@H:30]3[CH2:35][CH2:34][C@H:33]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[CH:21]=2)[CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>Br>[NH2:29][C:27]1[C:28]2[C:20]([C:9]3[CH:10]=[CH:11][C:12]([O:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[C:7]([OH:6])[CH:8]=3)=[CH:21][N:22]([C@H:30]3[CH2:31][CH2:32][C@H:33]([N:36]4[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]4)[CH2:34][CH2:35]3)[C:23]=2[N:24]=[CH:25][N:26]=1
Reactant: COc1cc(-c2cn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1Oc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(Oc5ccccc5)c(O)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 120 °C

Procedure:
A mixture of trans-5-(3-methoxy-4-phenoxyphenyl)-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine acetate (50 mg, 0.098 mmol) in 48% aqueous hydrobromic acid (1 mL) was heated at 120° C. for 2 hours. The solution was cooled and concentrated under reduced pressure then purified by preparative RP-HPLC to give trans-5-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-phenoxyphenol (32 mg, 66%): 1H NMR (DMSO-d6, 400 MHz) δ 9.8(bs, 1H), 8.13(s, 1H), 7.39(s, 1H), 7.31(t, 2H), 7.03(m, 3H), 6.89(m, 3H), 6.17(bs, 2H), 4.55(m, 1H), 2.2-2.6(m, 9H), 2.15(s, 3H), 1.8-2.2(m, 6H), 1.44 (m, 2H); MS MH+499.4; RP-HPLC (Hypersil HS, 5 μm, 100 A 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 13.47 min.