Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1I.N#N.B(O)(O)[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:16]1([CH3:19])[CH:15]=[CH:14][C:13]([C:3]2[N:4]=[CH:5][C:6]([NH2:8])=[N:7][C:2]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Nc1cnc(I)c(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(-c2ncc(N)nc2-c2ccc(C)cc2)cc1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A solution of 6-chloro-5-iodopyrazin-2-amine (step 1) (13.74 g, 53.8 mmol) in dioxane (300 ml) was degassed with N2 and treated with p-tolylboronic acid (17.55 g, 129 mmol), K2CO3 (22.30 g, 161 mmol) and PdCl2(dppf)-CH2Cl2-adduct (4.39 g, 5.38 mmol). The orange suspension was stirred at 110° C. for 2 days. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. The crude mixture was absorbed onto silica and purification by chromatography eluting with 0-60% EtOAc in iso-hexane afforded the titled compound as a beige coloured solid;
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=O)[NH:13][CH:12]=[N:11][C:10]=3[O:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:14]1[C:15]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Product: Clc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12

Procedure:
Add 570 ml of phosphorus oxychloride to 57 g (200 mmol) of 5,6-diphenylfuro[2,3-d]pyrimidin-4(3H)-one. Stir the mixture under reflux for 3 h, then cool it and concentrate it under reduced pressure. Stir the residue with ice-water for 30 min and then admix it with dichloromethane. Wash the resulting organic phase three times with water, dry it over sodium sulphate and concentrate it under reduced pressure. 58 g (93.2% of theory) of the target product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:16][CH:17]=[CH:18][C:11]=23)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=[C:22]([NH2:32])[N:21]=1.Cl.C(=O)(O)[O-].[Na+]>O>[NH2:32][C:22]1[N:21]=[C:20]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[CH:18][C:11]=34)=[CH:8][C:2]=2[F:1])[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)cc1F
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]ccc34)cc2F)cc(-c2ccncc2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
11 mg (50 μmol) of 2-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline (from example XX) are suspended in 5 ml of water. 9.3 mg (50 μmol) of 4-chloro-6-(4-pyridinyl)-2-pyrimidineamine (from example XXIX) and 0.01 ml of concentrated hydrochloric acid are added, and the mixture is stirred at 100° C. overnight. For work-up, the reaction solution is made alkaline with saturated sodium bicarbonate solution and extracted 3× with ethyl acetate, and the extracts are dried over sodium sulfate and concentrated using a rotary evaporator.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]#[N:9])[CH2:3]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1>C1COCC1>[C:8]([C:4]1([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]1)#[N:9]
Reactant: CC1CCCC(C#N)C1
Reactant: CCCCCc1ccc(-c2ccc(CCBr)cc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(CCC3(C#N)CCCC(C)C3)cc2)cc1

Procedure:
A mixture of 3.1 g of 3-methylcyclohexanecarbonitrile and 30 ml of THF has added to it at -78° a solution of lithium diisopropylamide (prepared from 3.3 g of diisopropylamine, 30 ml of THF and 19 ml of 1.6-molar butyllithium solution in hexane) and then a solution of 9.7 g of 1-bromo-2-(4'-pentylbiphenyl-4-yl)ethane in 30 ml of THF. Working up as in Example 1 gives 1-(1-cyano-3-methylcyclohexyl)-2-(4'-pentylbiphenyl-4-yl)ethane, m.p. 73°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])=[CH:4][CH:3]=1.ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O.CC1(C)N([O])C(C)(C)CCC1.[CH3:57][N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1.C([BH3-])#N.[Na+]>C(Cl)Cl.CO.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][N:61]5[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]5)=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])=[CH:4][CH:3]=1
Reactant: O=c1c2cnn(-c3ccc(CO)cc3)c2nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Reactant: CN1CCNCC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCN(Cc2ccc(-n3ncc4c(=O)n(-c5ccc(Cl)cc5)c(-c5ccc(Cl)cc5Cl)nc43)cc2)CC1
Reaction time: 0.5 h

Procedure:
5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(4-hydroxymethyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (90.0 mg, 0.181 mmol) is dissolved in 10 mL of CH2Cl2. Trichloroisocyanuric acid (42.0 mg, 0.181 mmol) and TEMPO (1 mg) are added sequentially to the reaction mixture. The reaction mixture is allowed to stir for 30 min and the organic layer is washed with sodium bicarbonate and water, thus resulting in pure aldehyde. A portion of the aldehyde (40.0 mg, 0.0807 mmol) is dissolved in 2 mL of dry methanol. 200 μL of acetic acid and 100 μL of N-methylpiperazine are added to the reaction mixture and the mixture is allowed to stir for 10 min at room temp. Sodium cyanoborohydride (15 mg, 0.238 mmol) is added and the reaction mixture is stirred for 10 min and then quenched with ammonium hydroxide. The crude material is purified by column chromatography. 1H NMR (CDCl3, 400 MHz) δ 8.34(s, 1H), 8.06 (d, 2H), 7.44 (m, 2H), 7.34-7.28 (m, 3H), 7.18 (m, 2H), 7.03 (m, 1H), 5.31 (s, 2H), 3.66 (m, 2H), 2.89 (m, 6H), 2.71 (s, 3H). HPLC-MS calculated for C29H25Cl3N6O (M+H+) 579.1. Found: 579.1.
Reaction SMILES: C(O[C@H:5]1[C@H:14]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:21][CH2:22][CH2:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:12]=2)[O:7][C:6]1([CH3:30])[CH3:29])(=O)C.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.CC(=O)OCC>[F:28][C:25]([F:26])([F:27])[CH2:24][CH2:23][CH2:22][O:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[O:7][C:6]([CH3:30])([CH3:29])[CH:5]=[C:14]2[N:15]([CH3:20])[S:16]([CH3:19])(=[O:17])=[O:18]
Reactant: CC(=O)O[C@H]1[C@H](N(C)S(C)(=O)=O)c2cc(OCCCC(F)(F)F)ccc2OC1(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C1=CC(C)(C)Oc2ccc(OCCCC(F)(F)F)cc21)S(C)(=O)=O
Yield: 56 %

Procedure:
A solution of 3.5 g of (±)-trans-N-[3-acetoxy-6-(4,4,4-trifluorobutoxy)-2,2-dimethylchroman-4-yl]-N-methyl-methanesulfonamide (example 21) and 6.8 g of DBU in 30 ml of toluene was heated at 105° C. for 20 h. The reaction mixture was diluted with EA and washed with hydrochloric acid until the aqueous phase gave an acidic reaction. The mixture was washed with sodium bicarbonate solution, dried over magnesium sulfate, concentrated i. vac. and triturated with heptane, giving 1.7 g N-[6-(4,4,4-trifluorobutoxy)-2,2-dimethyl-2H-chromen-4-yl]-N-methyl-methanesulfonamide; m.p. 118° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.Cl.C(N=C=NCCCN(C)C)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([N:40]2[CH2:39][CH2:38][N:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH3:29])[CH2:42][CH2:41]2)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cc1onc(-c2ccccc2F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C(=O)c2c(-c3ccccc3F)noc2C)CC1
Yield: 73.4 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(2-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (532 mg, 1.35 mmol, 73%) was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[N:19][NH:20]2)=[CH:16][CH:15]=1.C(N(CC)CC)C.O>CO>[NH:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]([NH:13][C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=3)[CH:22]=2)[CH:18]=[N:19]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc([N+](=O)[O-])c(Nc2ccc3cn[nH]c3c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To the solution of 2-chloro-6-methoxy-3-nitropyridine (5 g) and 6-aminoindazole (3.9 g) in methanol (60 ml) was added triethylamine (4.1 ml), and then the solution was reacted at 55-60° C. for 14 hr. The reaction mixture was cooled at room temperature, added H2O 30 mi slowly at 25° C., and then stirred for 0.5 hr. The reaction mixture was filtered, washed with 50% aqueous methanol solution (15 ml) and obtained a solid product. The solid product was dried at 50° C. in vacuo to obtain the desired compound (6.8 g, 90%).
Reaction SMILES: C(O[C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1Cl)=[O:5])C.[NH2:26][CH2:27][CH2:28][OH:29]>>[CH2:23]([N:20]1[C:9]2[N:10]=[C:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[CH:13][C:8]=2[C:7]([NH:26][CH2:27][CH2:28][OH:29])=[C:6]([C:4]([NH:26][CH2:27][CH2:28][OH:29])=[O:5])[C:21]1=[O:22])[CH3:24]
Reactant: NCCO
Reactant: CCOC(=O)c1c(Cl)c2cnc(-c3ccccc3)nc2n(CC)c1=O
Product: CCn1c(=O)c(C(=O)NCCO)c(NCCO)c2cnc(-c3ccccc3)nc21

Procedure:
To 2 g. (0.0056 mole) of 5-chloro-7,8-dihydro-8-ethyl-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (prepared by the method of the first paragraph of Example 3) was added 20 ml. of 2-aminoethanol and this mixture was heated at reflux for 1.5 hours. The reaction mixture was chilled in ice and the product collected on a filter and recrystallized from ethanol to give 1.7 g. of product.--m.p. 250°-253° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:13]([C:15]1[S:16][CH:17]=[C:18]([C:20]([N:22]2[CH2:27][C:26]3([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[O:25][CH2:24][CH2:23]2)=[O:21])[N:19]=1)[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:30]1[CH2:31][CH2:32][C:26]2([O:25][CH2:24][CH2:23][N:22]([C:20]([C:18]3[N:19]=[C:15]([CH2:13][CH3:14])[S:16][CH:17]=3)=[O:21])[CH2:27]2)[CH2:28][CH2:29]1
Reactant: CCc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: O=Cc1cccc(CCO)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4Cl)CC3)C2)cs1
Reaction time: 1.15 h
Yield: 107 %

Procedure:
To a solution of 2-chloro-3-(2-hydroxyethyl)benzaldehyde (1.1 molar equivalents) in DCM (12 volumes) was added to (2-ethylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone ((limiting reagent) (step b). Triethylamine (2 molar equivalents) was added and the mixture was stirred for 1.15 hr. Sodium triacetoxyborohydride (2.5 molar equivalents) was added portion-wise over 15 minutes maintaining the temperature below 25° C. The reaction mixture was stirred at ambient temperature for 22.5 hr. Saturated aq. sodium bicarbonate solution (8 volumes) was added slowly and the mixture was stirred vigorously for 1 hr; the aqueous was separated and extracted with DCM (5.3 volumes). The combined organics were washed with 20% brine solution (5.3 volumes), dried over anhydrous sodium sulfate, filtered and evaporated to give a brown oil. Yield 107% of theoretical.
Reaction SMILES: C([C@@H]([C@H](C(O)=O)O)O)(O)=O.[CH3:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[CH3:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: C[C@@H]1CCCN1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(2R)-2-Methylpyrrolidine L-tartrate (4.0 g, 17.0 mmol), 1-(2-bromoethyl)-4-nitrobenzene (9.8 g, 43 mmol), and potassium carbonate (12 g, 85 mmol), were combined in DMF (20 mL) in a sealed tube at 50° C. and stirred vigorously for 16 hours. The mixture was allowed to cool to room temperature, diluted with diethyl ether (100 mL), washed with water (2 times, 100 mL and then 50 mL), and extracted with 1M HCl (2 times, 50 mL and 25 mL). The aqueous acidic extractions were combined, washed with diethyl ether (50 mL), cooled to 0° C., adjusted to pH 14 with 50% NaOH solution, and extracted with dichloromethane (3 times, 50 mL). The dichloromethane extractions were combined, dried (MgSO4), filtered, and the filtrate concentrated to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 1.08 (d, J=6 Hz, 3 H), 1.43 (m, 1 H), 1.75 (m, 2 H), 1.93 (m, 1 H), 2.19 (q, J=9 Hz, 1 H), 2.34 (m, 2 H), 2.91 (m, 2 H), 3.03 (m, 1 H), 3.22 (td, J=8, 3 Hz, 1 H), 7.38 (d, J=9 Hz, 2 H), 8.15 (d, J=9 Hz, 2 H); MS (DCl/NH3) m/z 235 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:15][C:16]2[CH:17]=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH3:28][CH:27]([CH3:29])[CH2:26][N:14]([CH2:15][C:16]1[CH:17]=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)CN(Cc1cnc2ccccc2c1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CC(C)CN(Cc1cnc2ccccc2c1)C1CCNCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
4-{Isobutyl-[(quinolin-3-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester is added to a stirred solution of dichloromethane (5 ml) and anisole (9.0 ml, 82.8 mmol). The reaction is cooled to 0° C. Trifluoroacetic acid (6.0 ml, 72.9 mmol) is then added. The reaction is stirred for 1 h at 0° C. and then for 2 h at room temperature. The reaction is loaded onto a pre-washed SCX-2 (10 g) column and washed with methanol (200 ml). The product is then eluted with 2M ammonia in methanol (100 ml) and concentrated on a rotary evaporator to yield (0.74 g, 99%) of N-(2-methylpropyl)-N-[(quinolin-3-yl)methyl]piperidin-4-amine: mass spectrum (ion spray): m/z=298.2 (M+1); 1H NMR (CDCl3): δ=8.93 (1H, d), 8.08 (1H, d), 8.02 (1H, d), 7.79-7.77 (1H, m), 7.68-7.64 (1H, m), 7.54-7.50 (1H, m), 3.79 (2H, s), 3.13-3.10 (2H, m), 2.59-2.46 (3H, m), 2.28 (2H, d), 2.06 (1H, br s), 1.80-1.77 (2H, m), 1.72-1.61 (1H, m), 1.55-1.44 (2H, m), 0.84 (6H, d).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>>[CH3:31][O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][N:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([N:3]2[C:2]([Cl:1])=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]3)=[N:4]2)=[CH:16][CH:15]=1
Reactant: COC(=O)CCCBr
Reactant: Clc1c2ccccc2nn1-c1ccc(OC[C@@H]2CCCN2)cc1
Product: COC(=O)CCCN1CCC[C@H]1COc1ccc(-n2nc3ccccc3c2Cl)cc1
Yield: 74.6 %

Procedure:
The title compound was prepared from product from 3-chloro-2-[4-((S)-1-pyrrolidin-2-ylmethoxy)-phenyl]-2H-indazole (0.33 g, 0.94 mmol) and methyl 4-bromobutyrate (0.25 g, 1.4 mmol) using the procedure of Step 1 of the Example 17 to provide the title compound (0.30 g, 75%).
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13])C1C=CC=CC=1>C(O)C.[C].[Pd]>[CH3:16][N:14]([CH3:15])[C:12](=[O:13])[C@H:11]([CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[NH2:10]
Reactant: CN(C)C(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N(C)C
Agent: [Pd]
Solvent: CCO
Product: CN(C)C(=O)C[C@H](N)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 109.2 %

Procedure:
To a solution of benzyl[(2S)-1,4-bis(dimethylamino)-1,4-dioxobutan-2-yl]carbamate (550 mg) in ethanol (5 mL) was added 10% palladium carbon (182 mg) at room temperature. The reaction mixture was stirred at room temperature for 5 hr under a hydrogen atmosphere. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (350 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([NH:14][C:15](=[O:31])[CH2:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[O:29][N:28]=[C:27]([CH3:30])[CH:26]=3)[CH:20]=2)=O)=[CH:12][C:11]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[C:10]([O:39][CH2:40][C:41]([F:44])([F:43])[F:42])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:11]1[C:10]([O:39][CH2:40][C:41]([F:42])([F:44])[F:43])=[CH:9][C:8]2[N:7]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[O:29][N:28]=[C:27]([CH3:30])[CH:26]=4)[CH:20]=3)[CH2:16][C:15](=[O:31])[NH:14][C:13]=2[CH:12]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(-c5ccccc5F)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from [2′-fluoro-5-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-2-(2,2,2-trifluoro-ethoxy)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example M23) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (21 mg).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=O.C=O.CO.[C:14](#[N:16])C>C(O)C.C(Cl)Cl>[CH:8]1[N:16]=[CH:14][N:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=12
Reactant: CC#N
Reactant: O=Cc1ccccn1
Agent: C=O
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: c1ccn2cncc2c1
Temperature: 25 °C

Procedure:
Imidazo[1,5-a]pyridine fluorophores were prepared by adding 1 equivalent (equiv) of 3 M hydrochloric acid in ethanol (an additional equivalent of acid was used in reactions with basic substrates) and picolinaldehyde or other 2-acylpyridine to 1 equiv of a 0.5 M solution of 1 equiv of primary amine in dry ethanol or acetonitrile and 1.5 equiv of formalin. The reaction was stirred at room temperature for the specified period of time (i.e., from about 15 min to about 12 hours) and monitored by analytical thin layer chromatography (TLC) (10% methanol in DCM) for the appearance of a blue fluorescent product spot by UV light. Crude reaction mixtures were concentrated in vacuo (˜15 Torr) and dried under high vacuum at 0.2 Torr (for from 2 to 12 hours).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C:22]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:23]([NH:25][CH3:26])=[O:24]>>[CH2:27]([C:22]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:23](=[O:24])[NH:25][CH3:26])[CH2:29][CH3:30])[CH3:28]
Reactant: CCC(N)(CC)C(=O)NC
Reactant: O=C(O)c1ccc(C2CCOCC2)c(OCC2CC2)n1
Product: CCC(CC)(NC(=O)c1ccc(C2CCOCC2)c(OCC2CC2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (Example 9 f) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e=404.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][NH:13][C:12](=[O:18])[CH:11]=2)[CH:3]=1.[H-].[Na+].Cl[CH:22]([O:28][CH2:29][CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][N:13]([CH:22]([O:28][CH2:29][CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:12](=[O:18])[CH:11]=2)[CH:3]=1
Reactant: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CCOC(=O)C(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(OCC)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon and at 0° C., 10 min apart two portions of in total 350 mg (purity 82%, 1.10 mmol) of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile were added to a suspension of 53 mg (1.32 mmol, 1.2 eq.) of sodium hydride (60% in mineral oil) in 2.1 ml of dimethylformamide. The reaction mixture was stirred at RT for 60 min and then cooled back to 0° C., 245 mg (purity 90%, 1.32 mmol, 1.2 eq.) of ethyl 2-chloro-2-ethoxyacetate were added and the mixture was stirred at RT for 2 h. This batch together with an analogous test batch was combined with 50 mg (purity 82%, 0.16 mmol) of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile. After addition of 20 ml of water and phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (IR-50Si, petroleum ether/ethyl acetate 15-50%). Yield: 277 mg (55% of theory based on in total 1.26 mmol of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile employed)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(N(CC)CC)C.Cl.[C:28]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36])([O:30][CH3:31])=[O:29].O>C(#N)C>[CH3:31][O:30][C:28]([C:32]1[CH:33]=[C:34]([CH2:35][NH:36][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])[CH:37]=[CH:38][CH:39]=1)=[O:29]
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: COC(=O)c1cccc(CN)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cccc(CNc2ccc(-c3nc4ccccc4o3)cc2[N+](=O)[O-])c1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (250 mg, 0.968 mmol) in acetonitrile (5 mL) was added triethylamine (245 mg, 2.42 mmol) and 3-carbomethoxybenzylamine hydrochloride (215 mg, 1.07 mmol), and this was heated to reflux for 2 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (365 mg, 94% yield).