Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][NH:3]1.[OH-].[Na+].[C:11](O)(=O)C>O.IC>[CH3:11][S:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)O
Reactant: O=c1cc[nH]c(=S)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CSc1nccc(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-thioxo-2,3-dihydropyrimidin-4(1H)-one (21 g) was added dropwise a solution of sodium hydroxide (13 g) in water (120 mL), iodomethane (11.5 mL) was added thereto, and the mixture was stirred overnight at room temperature. To the reaction mixture was added acetic acid (9.5 mL), and the resulting solid was collected by filtration. The obtained solid was washed with cold water to give the title compound (24 g).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([O:18][C:19]2[C:31]([CH:32]3[CH2:34][CH2:33]3)=[CH:30][C:22]([C:23]([O:25]C(C)(C)C)=[O:24])=[C:21]([F:35])[CH:20]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.FC(F)(F)C(O)=O>[CH:1]([N:14]1[CH2:15][CH:16]([O:18][C:19]2[C:31]([CH:32]3[CH2:33][CH2:34]3)=[CH:30][C:22]([C:23]([OH:25])=[O:24])=[C:21]([F:35])[CH:20]=2)[CH2:17]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(C2CC2)c(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F

Procedure:
A solution of tert-butyl 4-(1-benzhydrylazetidin-3-yloxy)-5-cyclopropyl-2-fluorobenzoate (650 mg, 1.37 mmol) in DCM (10 mL) and trifluoroacetic acid (5 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue was used in the next step without further purification.
Reaction SMILES: [OH-].[Na+].C(O)C.[F:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][C:8]=1[NH:20]C(=O)OC>O>[F:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][C:8]=1[NH2:20]
Reactant: COC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 25 °C
Yield: 99.6 %

Procedure:
2N sodium hydroxide aqueous solution (3.5 ml) was added to an ethanol solution (1.5 ml) of methyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate (1.507 g, 5.24 mmol), and the mixture was heated under reflux for 2 hours. After reaction, the reaction liquid was cooled to room temperature, water was added thereto, and this was extracted with ethyl acetate (20 ml×2). The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The drying agent was taken out by filtration, and the solvent was removed by distillation under reduced pressure, to obtain 2-fluoro-4-chloro-5-cyclopentyloxyaniline (1.20 g, 5.22 mmol). Yield: ~100%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([CH3:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.[CH3:30][C:31]([CH3:33])=O.C([BH3-])#N.[Na+]>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([CH3:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][N:25]([CH:31]([CH3:33])[CH3:30])[CH2:24]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CC(C)=O
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(C)c(C#N)c1C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(C)c(C#N)c1C1CN(C(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
To a mixture of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-3-ethoxy-6-methylbenzonitrile (70 mg, 0.2 mmol) in methanol (50 mL) was added acetone (0.1 mL, 2 mmol) and sodium cyanoborohydride (17 mg, 0.27 mmol). The reaction was stirred at room temperature for 1 h, and was complete by LC/MS. The reaction was quenched with water and was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give the crude product. The product was purified by prep HPLC on a C-18 column eluting water:acetonitrile gradient buffered pH 10 to give the title compound as a white amorphous solid (0.030 g, 40%). The product was isolated as a racemic mixture. LCMS calculated for C24H32N7O(M+H)+: m/z=434.2; found: 434.3. 1H NMR (300 MHz, CD3OD) δ 8.17 (s, 1H), 7.35 (s, 1H), 6.37 (q, J=7.1 Hz, 1H), 4.17-3.98 (m, 4H), 3.90-3.71 (m, 3H), 2.65 (s, 3H), 2.46 (s, 4H), 1.84 (d, J=7.1 Hz, 3H), 1.42 (t, J=7.0 Hz, 3H), 1.03 (dd, J=6.2, 1.4 Hz, 6H).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([F:7])([F:6])[F:5].[NH2:9][C:10]([NH2:12])=[S:11]>C(O)C>[F:5][C:4]([F:7])([F:6])[C:3]1[N:9]=[C:10]([NH2:12])[S:11][CH:2]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc(C(F)(F)F)cs1
Yield: 86.3 %

Procedure:
A solution of 3-bromo-1,1,1-trifluoroacetone (5.0 g, 26.184 mmol) and thiourea (2.0 g, 26.184 mmol) in ethanol was heated to 50-55° C. for 2.0 h till TLC indicated completion of the reaction. The reaction mixture was concentrated and the residue made basic with 5% NaOH. The mixture was then extracted with ethyl acetate and concentrated to yield a residue which was column purified to afford 3.8 g of the desired compound: 1H NMR (300 MHz, DMSO-d6) δ 7.25 (s, 1H), 7.43 (br s, 2H); ESI-MS (m/z) 169.37 (M+H)+.
Reaction SMILES: [C:1]([C:3]([C:19]#[N:20])([CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)#[N:2].[C:21]([Mg]Br)#[CH:22].Cl>O1CCCC1>[C:1]([C:3]([C:19]#[N:20])([CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:4][CH2:5][CH:6]1[CH2:7][CH2:8][C:9]([C:21]#[CH:22])([OH:12])[CH2:10][CH2:11]1)#[N:2]
Reactant: N#CC(C#N)(CCC1CCC(=O)CC1)CCC(F)(F)F
Reactant: C#C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C#CC1(O)CCC(CCC(C#N)(C#N)CCC(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 1.14 g of 4-(3,3-dicyano-6,6,6-trifluorohexyl)cyclohexanone in 10 mL of tetrahydrofuran was added 10 mL of a 0.5 M solution of ethynyl magnesium bromide in tetrahydrofuran at 0° C. under a nitrogen atmosphere, followed by stirring at 0° C. for 5 hours. To the reaction mixture was added 30 mL of a 1 N aqueous hydrochloric acid solution, followed by extraction twice with 30 mL of ethyl acetate. The combined organic layer was washed sequentially with 30 mL of a saturated aqueous sodium hydrogen carbonate solution and 30 mL of a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.78 g of 1-(3,3-dicyano-6,6,6-trifluorohexyl)-4-ethynyl-4-hydroxycyclohexane (hereinafter referred to as the present compound (6)) represented by the following formula:
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:25][CH:24]2[O:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]3[O:49][CH2:48][CH2:47][N:46]([CH2:50][CH2:51][CH2:52][O:53][CH3:54])[C:45]=3[CH:55]=2)=[CH:19][CH:18]=1.[C:56]1(O)[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:54][O:53][CH2:52][CH2:51][CH2:50][N:46]1[C:45]2[CH:55]=[C:41]([CH2:40][O:39][CH:24]3[CH:23]([C:20]4[CH:19]=[CH:18][C:17]([CH2:16][O:15][C:56]5[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=5)=[CH:22][CH:21]=4)[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[O:30])[CH2:25]3)[CH:42]=[CH:43][C:44]=2[O:49][CH2:48][CH2:47]1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CO)cc3)cc21
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(COc4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.0819 g of diisopropyl azodicarboxylate is added dropwise to a solution of 0.180 g of benzyl 4-(4-hydroxymethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 270c), 0.0304 g of phenol and 0.102 g of triphenylphosphine. The solution is stirred at room temperature for 1 hour and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.25 (1:2 EtOAc-heptane); Rt=5.99.
Reaction SMILES: C([Li])CCC.[C:6]1([S:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[CH:17]=[CH:16]2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN([CH:27]=[O:28])C.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:6]1([S:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[CH:17]=[C:16]2[CH:27]=[O:28])(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
n-Butyllithium (11.9 mL, 19.0 mmol, 1.6M in hexanes) was added to a solution of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (3.50 g, 13.6 mmol) in THF (53 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes, and then DMF (4.2 mL, 54.2 mmol) was added. The reaction mixture was warmed up to 0° C. and stirred for 3 hours. It was then treated with saturated aqueous ammonium chloride and ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to afford 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (2.4 g, 62%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[C:33]([O-:36])(=[O:35])[CH3:34].[Na+]>C(Cl)(Cl)(Cl)Cl.O>[C:33]([O:36][CH2:12][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)(=[O:35])[CH3:34]
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(Br)c2ncccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OCc1ccc(Br)c2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
A mixture of 8-bromo-5-methylquinoline (5.4 g, 24.3 mmol), N-bromosuccinimide (5.2 g, 29.2 mmol), and 2,2′-azobis(2-methylpropionitrile) (AIBN) (0.40 g, 24.3 mmol) in carbon tetrachloride (80 mL) was heated at reflux for 3 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered, using hexane for rinsing. The filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (50 mL), and then sodium acetate (4.0 g, 48.8 mmol) was added. The resulting mixture was stirred at 100° C. for 2 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water and extracted with a mixture of ethyl acetate and hexane (3:7). The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using hexanes/ethyl acetate as eluent to afford the title product as a pale yellow solid (4.8 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:19])([C:14]1[NH:15][CH2:16][CH2:17][N:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>O1CCOCC1>[C:20]([N:18]1[CH2:17][CH2:16][N:15]=[C:14]1[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([OH:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: OC(C1=NCCN1)(c1ccccc1)c1ccccn1
Solvent: C1COCCO1
Product: CC(=O)N1CCN=C1C(O)(c1ccccc1)c1ccccn1
Temperature: 60 °C

Procedure:
Dissolve 12.8 g. of 2[(2-pyridyl)hydroxybenzyl] imidazoline in 25 ml. of dioxane and, with vigorous stirring, slowly add 2.4 ml. of acetic anhydride in a drop-wise fashion. After each 0.5 ml. addition warm the solution to 60° C for 5 min. and then cool the solution to 20° C before adding additional anhydride. Continue the stirring for 20 hours, filter the precipitated acetate salt and concentrate the resulting filtrate to about 10 mls. Recrystallize the desired product from alcohol to yield 1-acetyl-2[(2-pyridyl)-hydroxybenzyl]imidazoline, m.p. 150°-153° C.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[NH2:12][C:13]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:14]=1[C:15](O)=[O:16].[NH4+].[Cl-]>CCCCCC.CCOCC>[NH2:12][C:13]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:14]=1[C:15]([C:8]1[N:7]([CH3:6])[CH:11]=[CH:10][N:9]=1)=[O:16]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: Cn1ccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: Cn1ccnc1C(=O)c1cc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.6 %

Procedure:
To a solution of nBuLi (0.0730 mol) in hexane was added N-methyl imidazole (0.0608 mol) drop wise at -40° C. over 30 min under a nitrogen atmosphere. The resulting yellow solution was stirred for a further 3 hr at rt, and then refluxed for 1 h. 2-amino-5-chlorobenzoic acid (1.74 g, 0.01014 mole) in dry ether (60 ml) was then added to the reaction mixture. The reaction mixture was stirred overnight at rt. To the reaction mixture was added saturated NH4Cl solution and the resulting mixture extracted with ethyl acetate (2×150 ml). The combined organic layers were dried over Na2SO4. After removal of solvent, the residue was purified by the flash chromatography using ethyl acetate/hexane (1:4) as eluent. Crystallization of the product from Et2O/hexane mixture gave 300 mg (13.7%) of product as yellow solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[S:6][C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)C=Cc1ccc(Br)s1
Reactant: OB(O)c1ccc(F)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
Product: O=C(O)C=Cc1ccc(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1 g (4.3 mmol) of 3-(5-bromo-thiophen-2-yl)-acrylic acid and 247 mg (0.2 mmol) of tetrakis(triphenylphosphine)palladium were dissolved in 50 ml of degassed DME and stirred at room temperature for 10 min. 0.900 g (6.4 mmol) of 4-fluoro -phenylboronic acid and 4 ml of a 2 M aqueous sodium carbonate solution were added together with an additional 5 ml of degassed DME. The reaction mixture was heated to 95° C. for 4 h and then stirred at room temperature for 16 h. Solids were removed by filtration, and the solution was evaporated to dryness. The residue was dissolved in ethyl acetate and washed three times with a saturated sodium hydrogencarbonate solution and once with a saturated sodium chloride solution. The organic phase was dried with sodium sulfate, filtered, and the solvent was removed under reduced pressure. Yield: 500 mg.
Reaction SMILES: [N:1]1([C:10]2[S:14][C:13]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[BH4-].[Na+]>CO>[N:1]1([C:10]2[S:14][C:13]([CH:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCCCC(=O)c1ccc(-n2cnc3ccccc32)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCC(O)c1ccc(-n2cnc3ccccc32)s1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
The compound (84) (0.703 mmoles) was dissolved in methanol (10 ml), cooled to 0-5° C., added sodium borohydride in lots at 0-5° C. in 5 minutes, after completion of addition, the reaction mixture was warmed to 25 to 30° C., stirred for 2.0 hrs. After completion of reaction, quenched the reaction with water (10 ml) and extracted in ethyl acetate (2×100 ml), washed with 10% brine, and dried over sodium sulphate. Distilled off the ethyl acetate completely to residue to get the crude compound, The crude compound was purified by using silica gel 60-120 silica gel column chromatography and DCM: methanol: 100-5% as mobile phase to get the pure compound (85).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH:13]2[CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24]>C1C=CC=CC=1>[C:1]([N:15]1[C:16]2[C:12](=[CH:11][C:10]([O:9][CH3:8])=[CH:18][CH:17]=2)[CH:13]([CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24])[C:14]1=[O:19])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)C(=O)N2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C(CCNC(C)=O)C(=O)N2C(C)=O

Procedure:
Acetic anhydride (0.5 ml) is added with stirring to N-[2-(5-methoxy-2-oxo-2,3-dihydroindol-3-yl)ethyl]-acetamide (120 mg) dissolved in benzene (5 ml). The mixture is heated for 1 h in refluxing benzene. The solvent is evaporated off and the crude product is separated on a silica plate. N-[2-(1-acetyl-2-oxo-5-methoxyindol-3-yl)ethyl]acetamide (6) is thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([C:13]2[C:14]3[CH2:15][C:16](=[O:22])[NH:17][C:18]=3[CH:19]=[CH:20][CH:21]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:23]([N:25]([CH2:41][CH3:42])[CH2:26][CH2:27][CH2:28][NH:29][C:30]([C:32]1[C:36]([CH3:37])=[C:35]([CH:38]=O)[NH:34][C:33]=1[CH3:40])=[O:31])[CH3:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([C:13]2[C:14]3[C:15](=[CH:38][C:35]4[NH:34][C:33]([CH3:40])=[C:32]([C:30](=[O:31])[NH:29][CH2:28][CH2:27][CH2:26][N:25]([CH2:41][CH3:42])[CH2:23][CH3:24])[C:36]=4[CH3:37])[C:16](=[O:22])[NH:17][C:18]=3[CH:19]=[CH:20][CH:21]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(NC(=O)c2cccc3c2CC(=O)N3)cc1Cl
Reactant: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1C
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(C(=O)Nc4ccc(OC)c(Cl)c4)c32)c1C
Yield: 93.1 %

Procedure:
2-Oxo-2,3-dihydro-1H-indole-4-carboxylic acid (3-chloro-4-methoxyphenyl)amide (1 g, 3.16 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide (1 g, 3.58 mmol) to give 1.7 g (85%) of the title compound as a yellow-orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:18]([NH:20][CH3:21])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([N:20]([CH2:18][CH3:19])[CH3:21])=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCNC
Reactant: O=C(O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Product: CCN(C)C(=O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Yield: 30 %

Procedure:
The amide was synthesized from 1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (390 mg, 1.43 mmol) and ethylmethylamine using General Procedure G and was isolated in 30% yield as a white solid. HPLC Rt=11.66 min; 1H NMR (400 mHz, CDCl3) 7.40-7.30 (m, 2H), 7.10 (dd, J=2.2, 8.4 Hz, 1H), 3.31 (bs, 2H), 2.59 (bs, 3H), 2.30 (d, J=12.5 Hz, 2H), 1.76-1.55 (m, 7H), 1.32-1.25 (m, 2H), 1.00 (bs, 3H); 13C NMR (100 mHz, CDCl3) 147.0, 132.9, 130.8, 130.3, 127.5, 125.2, 51.0, 44.5, 36.8, 25.9, 23.5; GC-MS (SCOUT) 13.01 min, M+ 313.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[NH:28][S:27](=[O:30])(=[O:29])[CH2:26][C:25]=2[CH:31]=1>C(O)(C)C>[O:29]=[S:27]1(=[O:30])[CH2:26][C:25]2[CH:31]=[C:21]([NH:20][C:14](=[O:16])[C:13]([N:10]3[CH2:9][CH2:8][CH:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:19][CH:18]=4)[CH2:12][CH2:11]3)=[O:17])[CH:22]=[CH:23][C:24]=2[NH:28]1
Reactant: Nc1ccc2c(c1)CS(=O)(=O)N2
Reactant: Cc1ccc(CC2CCN(C(=O)C(=O)O)CC2)cc1
Solvent: CC(C)O
Product: Cc1ccc(CC2CCN(C(=O)C(=O)Nc3ccc4c(c3)CS(=O)(=O)N4)CC2)cc1

Procedure:
The title compound is prepared from [4-(4-methyl-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 119b) and 5-amino-1,3-dihydro-2,1-benzisothiazole-2,2-dioxide according to the method described in Example 94. Melting Point: 186° C. (isopropanol)
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH:26]([CH3:30])[NH:25]1>C(=O)(O)[O-].[Na+]>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10]([N:25]3[CH:26]([CH3:30])[CH2:27][CH2:28][CH2:29][CH:24]3[CH3:23])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC1CCCC(C)N1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1CCCC(C)N1C1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 0.1 %

Procedure:
1-Diphenylmethyl-3-methanesulphonyloxyazetidine (see Preparation 54) (2 g, 1 mol. equiv.) and 2,6-dimethylpiperidine (6.79 ml, 3 mol. equiv.) were heated together at 110° C. under nitrogen for six hours. Saturated aqueous sodium bicarbonate solution (60 ml) was added and the mixture extracted with ethyl acetate (3×40 ml). The combined organic extracts were dried using magnesium sulphate. The organic solvent was removed under reduced pressure and the residue purified by flash column chromatography on silica gel eluting with methanol:dichloromethane (1:9, by volume) to give the title compound (0.48 g). TLC Rf=0.39 (silica, methanol:dichloromethane, 1:9, by volume). LRMS m/z=335 (m+1)+. Found: C, 80.29; H, 9.00; N, 8.14. C23H30N2 0.125 CH2Cl2 requires C, 80.48; H, 8.84; N, 8.12%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[CH:25]=[N:26][N:27]4[CH:32]=[CH:31][CH:30]=[N:29][C:28]=34)=[O:23])[C:18]([C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[O:40][CH:41]([F:43])[F:42])=[N:17]2)[CH2:10][CH2:9]1.Br[CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47]>CN(C=O)C>[Cl:39][C:37]1[CH:36]=[CH:35][C:34]([O:40][CH:41]([F:43])[F:42])=[C:33]([C:18]2[C:19]([NH:21][C:22]([C:24]3[CH:25]=[N:26][N:27]4[CH:32]=[CH:31][CH:30]=[N:29][C:28]=34)=[O:23])=[CH:20][N:16]([CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][CH:8]([NH:7][CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:9][CH2:10]3)[N:17]=2)[CH:38]=1
Reactant: NC1CCN(CCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC1CCN(CCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
Potassium carbonate (98 mg, 0.71 mmol) was added to a solution of N-[1-[2-(4-aminopiperidin-1-yl)ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (290 mg, 0.55 mmol) and tert-butyl 2-bromoacetate (96 mg, 0.49 mmol) in DMF (5 mL). The resulting mixture was stirred at 50° C. overnight. The resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica eluting with 15% MeOH in DCM to afford 150 mg (43%) of tert-butyl 2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)piperidin-4-yl]amino]-acetate as a yellow solid. LCMS (Method 24) [M+H]+=645.2, RT=1.39 min.