Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:6][C:5]=1[NH2:23])([O-])=O>CO.[Pd]>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([O:10][C:8]3[CH:9]=[C:4]([NH2:1])[C:5]([NH2:23])=[CH:6][CH:7]=3)[N:16]=2)[CH:18]=1
Reactant: Nc1ccc(Oc2nccc(-c3cccnc3)n2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Oc2nccc(-c3cccnc3)n2)cc1N

Procedure:
The mixture containing 2-nitro-4-(4-(3-pyridyl)pyrimidin-2-yloxy)phenylamine in methanol with catalytic amount of 10% Pd/C was hydrogenated until disappearance of yellow color to yield 4-(4-(3-pyridyl)pyrimidin-2-yloxy)benzene-1,2-diamine. MS: MH+=279.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[OH:15].Cl[CH2:17][CH2:18][NH:19][C:20](=[O:24])[O:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:15][CH2:17][CH2:18][NH:19][C:20](=[O:24])[O:21][CH2:22][CH3:23]
Reactant: CCOC(=O)NCCCl
Reactant: Oc1cc(Oc2ccccc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)NCCOc1cc(Oc2ccccc2)ccc1Cl
Temperature: 0 °C
Yield: 10.1 %

Procedure:
To a solution of 0.91 g of 2-chloro-5-phenoxyphenol in 20 ml of N,N-dimethylformamide, there were added 0.69 g of ethyl 2-chloroethylcarbamate and 1.14 g of potassium carbonate with stirring, and the resultant mixture was stirred at 50° C. for 7 hours. The reaction mixture was poured into 100 g of ice-water and extracted twice with 100 ml of ethyl acetate. The extracts were combined together, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 0.14 g of ethyl 2-(2-chloro-5-phenoxyphenoxy)ethylcarbamate. Yield: 10%. nD22 : 1.5608.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:12]=[N:13][CH:14]=2)O1.Cl[C:21]1[N:22]=[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]2[C:30]=1[C:31]#[N:32].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]2[N:24]([C:30]([C:31]#[N:32])=[C:21]([C:9]3[CH:14]=[N:13][CH:12]=[C:11]([C:15]([OH:18])([CH3:16])[CH3:17])[CH:10]=3)[N:22]=2)[CH:25]=1
Reactant: N#Cc1c(Cl)nc2ccc(F)cn12
Reactant: CC(C)(O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(O)c1cncc(-c2nc3ccc(F)cn3c2C#N)c1
Temperature: 100 °C

Procedure:
To a solution of the title compound from Example 2 Step D (0.053 g, 0.202 mmol) and the title compound from Example 4 Step A (0.033 g, 0.169 mmol) in tetrahydrofuran (0.84 mL) were added palladium acetate (0.0038 g, 0.017 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.014 g, 0.034 mmol), and potassium phosphate tribasic (0.107 g, 0.506 mmol). The resulting mixture was heated at 100° C. for 18 hours, then filtered with the aid of ethyl acetate and concentrated under reduced pressure. Purification by flash chromatography on silica gel (80% acetone in hexanes) provided the title compound: LCMS m/z 296.96 [M+11]+; 1H NMR (500 MHz, CDCl3) δ 9.28 (d, J=1.9 Hz, 1H), 8.87 (d, J=2.0 Hz, 1H), 8.55 (t, J=2.1 Hz, 1H), 8.35 (s, 1H), 7.79 (dd, J=9.8, 4.7 Hz, 1H), 7.45-7.41 (m, 1H), 1.98 (br s, 1H), 1.69 (s, 6H).
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][C@H:3]([C:14]([OH:16])=[O:15])[NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>O>[C:24]([N:2]1[C@@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:1]1)([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@H]1Cc2c([nH]c3ccccc23)CN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@H]1Cc2c([nH]c3ccccc23)CN1C(=O)OCc1ccccc1
Reaction time: 0.08 h

Procedure:
5.00 g (3R)-1,2,3,4-Tetrahydro-9H-pyrido[3,4-b]-indole-3-carboxylic acid is suspended in 50 ml water/50 ml tetrahydrofuran and 5.15 g sodium carbonate is added. The mixture is stirred for 5 minutes and 3.94 g benzyl chloroformate is added and the mixture stirred overnight. The mixture is evaporated in vacuo to remove the THF, the aqueous residue acidified with 1N hydrochloric acid and the resulting solid extracted into ethyl acetate. The organic solution is washed with 1N HCl, water, brine, and dried over sodium sulfate. The solution is filtered, evaporated and the residue crystallized from toluene to give (3R)-2-carbobenzoxy-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid, m.p. 181°-184° C.
Reaction SMILES: CO[CH2:3][NH:4][CH2:5][CH2:6][C@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8]>CO.[Ni]>[CH3:3][NH:4][CH2:5][CH2:6][C@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8]
Reactant: COCNCC[C@@H](O)c1ccccc1
Agent: [Ni]
Solvent: CO
Product: CNCC[C@@H](O)c1ccccc1
Reaction time: 12 h

Procedure:
The oily product of (R)-3-methoxymethylamino-1-phenyl-1-propanol obtained in example 2 was dissolved in 100 mL of methanol again with 1.2 g of Raney-nickel in a glass autoclave. The resulting solution was hydrogenated at 50° C. for 12 hours. Upon completion of hydrogenation, the reaction mixture was filtered and the solvent was removed under reduced pressure to obtain an objective compound as an oily compound (39.0 g, 96.5% by HPLC assay, 99% ee). The crude product was further purified by re-crystallization in toluene and heptane with optical purity as high as 100% ee. 1H NMR (400 MHz, CDCl3) δ (ppm)=1.7-1.8 (m, 1H), 1.8-1.9 (m, 1H), 2.5 (s, 3H), 2.8-2.9 (m, 2H), 4.9 (dd, J=3, 8.6 Hz, 1H), 7.3-7.4 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:10]2[S:11][CH:12]=[CH:13][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:22][O:23]C(Cl)Cl>O.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:10]2[S:11][C:12]([CH:22]=[O:23])=[CH:13][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCc2ccsc2C1
Reactant: COC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C1CCc2cc(C=O)sc2C1
Reaction time: 0.25 h

Procedure:
A mixture of 6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (0.80 g) and dichloromethane (CH2Cl2) was dropwise added to a mixture of aluminum chloride (AlCl3) (1.01 g) and CH2Cl2 (5 ml) under ice-water cooling, and was stirred under the same conditions for 15 minutes. A mixture of 1,1-dichloromethyl methyl ether (0.52 ml) and CH2Cl2 (3 ml) was thereto added, and was stirred under the same conditions for 10 minutes. The reaction mixture was added into a mixture of CHCl3, ice, and water. The separated organic layer was washed with water, and brine, and dried over MgSO4. After evaporation of the filtrate, the resulting oil was purified by chromatography on silica gel (n-hexane-AcOEt as eluent) to give 6-ethoxycarbonyl-2-formyl-4,5,6,7-tetrahydrobenzo[b]thiophene (0.33 g).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[S:17])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O>O>[CH2:1]([NH:8][C:9]1[S:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: S=C(NCc1ccccc1)Nc1ccccc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: c1ccc(CNc2nc3ccccc3s2)cc1

Procedure:
240.0 Parts of N'-benzyl-N-phenylthiourea are added, while stirring, over a period of 90 minutes to 334.6 parts of thionyl chloride of approximately 65° C. The reaction mixture is then refluxed (65° to 70° C.) for 5 hours while stirring. The cyclization melt obtained is hydrolyzed with 3,200 parts of water analogously to Example 53 and further treated as described in said Example. 221.5 Parts (92.3% of the theory) of 2-benzylamino-benzthiazole melting at 159° C. are obtained.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1.C(N(CC)CC)C>C1COCC1>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:5]=3[N:4]([CH3:20])[C:3]2=[O:21])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cccc2c1N(C)C(=O)C(N)N=C2c1ccccc1
Reactant: COc1cccc(N=C=O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)NC2N=C(c3ccccc3)c3cccc(C)c3N(C)C2=O)c1
Reaction time: 0.33 h

Procedure:
Equimolar amounts of 3-(R,S)-amino-1,3-dihydro-1,9-dimethyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 3-methoxyphenylisocyanate and triethylamine were mixed in THF at 0° C. and stirred 20 minutes. Removal of THF in vacuo, dissolution of the residue in CH2Cl2 and flash chromatography on silica gel (12% Et2O in CH2Cl2) gave the title compound which was crystallized as a white fluffy solid from Et2O: m.p. 215°-217° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([CH3:17])[C:3]=12.[N:18]1([CH2:23][CH2:24]O)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:24][CH2:23][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:15]=[C:16]([CH3:17])[C:3]=12
Reactant: OCCN1CCCC1
Reactant: Cc1n[nH]c2nnc(-c3ccccc3)c(Cl)c12
Product: Cc1nn(CCN2CCCC2)c2nnc(-c3ccccc3)c(Cl)c12

Procedure:
Compound XIIId was synthesized from 4-chloro-3-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine and 2-(pyrrolidin-1-yl)ethanol following the general procedure for the Mitsunobu reaction described in Example 20.
Reaction SMILES: S([O-])(=O)(=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:17][C@@H:16](OS(C)(=O)=O)[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:27][CH2:26]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[SH:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][OH:35]>>[C:6]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([S:31][C:32]2[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=2[CH2:34][OH:35])[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:26][CH2:27]1)=[O:12])([CH3:8])([CH3:9])[CH3:7]
Reactant: OCc1ccccc1S
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)NC1(C#N)CC1
Agent: CS(=O)(=O)[O-]
Product: CC(C)(C)OC(=O)N1C[C@H](Sc2ccccc2CO)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
The reaction of the mesylate from experiment A2 with 2-mercaptobenzyl alcohol yielded (2S,4R)-2-(1-cyano-cyclopropylcarbamoyl)-4-(2-hydroxymethyl-phenylsulfanyl)-pyrrolidine-1-carboxylic acid t-butyl ester as a colorless oil. MS: 416.5 [M−H]−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26](O)=[O:27])[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:43][O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:43][O:44][CH:45]4[CH2:50][CH2:49][CH2:48][CH2:47][O:46]4)=[O:27])[CH:19]=3)[O:14]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)NOC3CCCCO3)ccc1O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (E)-3-{1′-tert-butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (387 mg, 1 mmol) in DCM (15 ml) was cooled down to 0° C. EDC (383 mg, 2 mmol) and HOBT (135 mg, 1 mmol) were added, and the mixture was stirred at RT for 1 h. NH2OTHP (146 mg, 1.25 mmol) in DCM (1 ml) was added dropwise and the mixture was stirred at RT. After 4 h, the reaction mixture was washed with a saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated. The crude residue was purified by column chromatography (eluent: DCM/MeOH 98:2) to give (E)-3-{1′-tert-butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)[CH:21]=[C:22]1[S:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]>>[Br:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][CH:35]([NH:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]2[C:14]3[NH:13][C:12](=[O:15])[NH:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:34][CH2:33]1)[CH:21]=[C:22]1[S:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1CCN(c2ccc(C=C3SC(=O)NC3=O)cc2Br)CC1
Product: O=C1NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)c(Br)c2)S1

Procedure:
The title compound was prepared from 4-((2S)-3-amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one (U.S. Pat. No. 5,786,356/1998) and 5-[3-bromo-4-(4-oxo-piperidine-1-yl)-benzylidene]-thiazolidine-2,4-dione (which was obtained in Example 58) according to the procedure of Example 63 as an olive green solid; 1H NMR (300 MHz, DMSO-d6) δ 1.66-1.77 (m, 4H), 2.10-2.19 (m, 4H), 2.68-2.76 (m, 2H), 3.07-3.14 (m, 3H), 3.99-4.09 (m, 2H), 5.62 (brs, 1H), 6.58-6.66 (m, 2H), 6.88 (t, J=8.1 Hz, 1H), 7.20-7.25 (m, 3H), 7.50 (dd, J=8.5, 2.0 Hz, 25 1H), 7.75 (d, J=2.0 Hz, 1H), 10.55 (s, 1H), 10.65 (s, 1H); MS (ES) m/z: 589.9 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:27])[CH:25]=2)[NH:20][CH:19]=1)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:27])[CH:25]=2)[NH:20][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2ccc(Br)cc12)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
(R)-3-(N-Benzyloxycarbonylpyrrolidin-2-yl-carbonyl)-5-bromo-1H-indole (0.67 g, 1.57 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and at room temperature under nitrogen was added lithium borohydride (2 molar in tetrahydrofuran) (1.2 mL, 2.4 mmol). The reaction mixture was stirred at room temperature for 3 hours and warmed to reflux for 16 hours. After cooling to room temperature, 2NHCl (10 mL) was added dropwise and the reaction mixture partitioned between ethyl acetate and water. The separated organic phase was washed with saturated aqueous sodium hydrogen carbonate (2x), brine (1x), dried (Na2SO4), and evaporated in vacuo to give a colourless oil. Purification by column chromatography on silica gel, eluting with dichloromethane gave the title compound as an oil (0.32 g). TLC (SiO2 :CH2Cl2): Rf =0.2.
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](C)[C:6]=1[CH3:12])C.[OH:16][CH:17]1[CH2:21][CH2:20][N:19]([CH2:22]CC#N)[CH2:18]1>>[OH:16][CH:17]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:15][C:14]2[NH:3][C:4](=[O:13])[C:5]3[C:6]([CH:12]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:18]1
Reactant: N#CCCN1CCC(O)C1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Product: O=c1[nH]c(CCN2CCC(O)C2)cc2ccccc12
Yield: 13.5 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-diethyl-2,3-dimethylbenzamide (4.347 g) and 3-(3-hydroxypyrrolidin-1-yl)propionitrile (1.6 g), 3-[2-(3-hydroxypyrrolidin-1-yl)ethyl]-2H-isoquinolin-1-one (397.6 mg) was obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@@H:10]([CH2:17][C:18]3[N:19]=[C:20]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[S:21][CH:22]=3)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@@H:10]([CH2:17][C:18]3[N:19]=[C:20]([CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[S:21][CH:22]=3)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)C[C@H](Cc1csc(CCCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)n1)c1ccc2c(c1)OCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C[C@H](Cc1csc(CCCCO)n1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(3S)-Ethyl 3-(1,3-benzodioxol-5-yl)-4-[2-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-1,3-thiazol-4-yl]butanoate 6.55 g, 10.39 mmol) was dissolved in THF (20 mL) and tetrabutyl ammonium fluoride (1M, 23.39 mL, 23.39 mmol) was added. The reaction was stirred at ambient temperature for 2 hours. Dilute with diethyl ether, and wash with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo and purified via silica gel chromatography (eluent: 4:1 Hexane:Ethyl Acetate) to give the product as a colorless oil. Yield: 3.08g (76%) 1H NMR (DMSO-d6) δ6.95–6.92 (m, 1H), 6.85–6.83 (m, 1H), 6.75–6.71 (m, 1H), 6.63–6.59 (m, 1H), 5.94 (s, 2H), 3.95–3.85 (q, 2H), 3.46–3.38 (m, 3H), 2.98–2.85 (m, 4H), 2.68–2.51 (m, 2H), 1.75–1.65 (m, 2H), 1.50–1.41 (m, 2H), 1.08–1.02 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH:19]([O:22][CH2:23][C:24]1[CH:25]=[C:26]([C:30]2[O:34][CH:33]=[N:32][C:31]=2[C:35](O)=[O:36])[CH:27]=[CH:28][CH:29]=1)([CH3:21])[CH3:20]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:35]([C:31]3[N:32]=[CH:33][O:34][C:30]=3[C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][O:22][CH:19]([CH3:21])[CH3:20])[CH:25]=3)=[O:36])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: CC(C)OCc1cccc(-c2ocnc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(COC(C)C)c3)n2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-isopropoxymethyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.03 min; [M+H]+=449.63.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:32])[CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=23)=[O:11])[C:6]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH:29]([F:31])[F:30])=[N:5]1.[CH:33](=O)[CH3:34].[BH3-]C#N.[Na+]>CCO>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH:29]([F:30])[F:31])=[C:21]([C:6]2[C:7]([NH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[N:17][C:16]=34)=[O:11])=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][CH2:33][CH3:34])[CH3:32])[N:5]=2)[CH:26]=1
Reactant: CC=O
Reactant: C[C@H](N)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCN[C@@H](C)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 11.5 %

Procedure:
To a solution of N-[1-[(2S)-2-aminopropyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (200 mg, 0.43 mmol) in EtOH (20 mL) was added acetaldehyde (48 mg, 40% aqueous solution) and NaBH3CN (32.7 mg, 0.52 mmol). The resulting solution was stirred at room temperature for 12 h and concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 5% MeOH in DCM. The crude product (60 mg) was purified by Prep-HPLC with the following conditions (3#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 10 mM NH4CO3 and MeCN (26.0% MeCN up to 40.0% in 8 min); Detector, 254/220. 24.2 mg product was obtained. This resulted in 24.2 mg (11%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-(ethylamino)propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 28) [M+H]+=490.1, RT=0.86 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.68-8.67 (m, 2H), 8.34 (s, 1H), 7.64 (d, 1H, J=2.1 Hz), 7.60 (dd, 1H, J=2.8, 8.4 Hz), 7.44 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.0, 7.2 Hz), 7.04 (t, 1H, J=73.2 Hz), 4.11 (dd, 1H, J=6.0, 13.6 Hz), 4.01 (dd, 1H, J=6.2, 13.6 Hz), 3.08-3.00 (m, 1H), 2.68-2.50 (m, 2H), 1.52 (br, 1H), 0.97 (t, 3H, J=7.0 Hz), 0.95 (d, 3H, J=6.4 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=2)[CH:6]([C:22]([O:24]CC2C=CC=CC=2)=[O:23])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].[H][H]>[Pd].O1CCCC1>[C:1]([C:4]1[CH:5]([C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=2)[CH:6]([C:22]([OH:24])=[O:23])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)C(C(=O)OCc2ccccc2)C1c1ccc(C#N)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)C(C(=O)O)C1c1ccc(C#N)cc1
Reaction time: 0.25 h

Procedure:
A stirred suspension of benzyl 5-acetyl-4-(4-cyanophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyridine-3-carboxylate (7.5 g, 14 mmol) (Example 6A) and 10%. palladium on charcoal (255 mg) in tetrahydrofuran (975 ml) is treated with hydrogen gas at room temperature under atmospheric pressure. After 15 minutes, the reaction is stopped and the solution is filtered and concentrated. The residue is immediately used in the next step without further purification and characterisation.
Reaction SMILES: C([CH2:20][CH2:21][O:22][CH:23]([OH:25])[CH3:24])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[I:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[I:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:20][CH2:21][O:22][CH:23]([OH:25])[CH3:24])=[CH:29][CH:28]=1
Reactant: CC(O)OCCC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc(I)cc1
Product: CC(O)OCCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 13 was allowed to react with 4-iodophenol as described in example 1. When the reaction was completed (ca. 2 h) the solvent was evaporated off and the residue was suspended in diethyl ether and passed though a short column of silica gel. The eluent was removed in vacuo and the residue was dissolved in the mixture of TFA and ethanol (9:1, v/v) and stirred overnight at ambient temperature after being concentrated. The residue was taken in methylene chloride and washed with sat. NaHCO3, dried (Na2SO4) and concentrated. Purification was performed on silica gel. The column was eluted initially with methylene chloride to remove trityl carbinol and then with the mixture of CH2Cl2:MeOH (9:1, v/v) to elute the desired product. Compound 14: 1H NMR (CDCl3): δ 7.53 (2H, d, J 9.0); 6.68 (2H, d, J 9.0); 4.07 (2H, m); 3.83 (2H, m); 3.73 (2H, m); 3.64 (2H, m); 2.26 (1H, br).