Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C:23]2[C:18](=[C:19]([C:24]3[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[N:27][N:26]4[CH2:35][CH2:36][CH2:37][C:25]=34)[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)=O)(C)(C)C.CO.[OH-].[NH4+]>C(Cl)Cl>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:28]1[C:24]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH:17]=[CH:16][NH:15]3)=[C:25]2[CH2:37][CH2:36][CH2:35][N:26]2[N:27]=1
Reactant: CC(C)(C)OC(=O)n1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)cccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2nn3c(c2-c2cccc4[nH]ccc24)CCC3)nc1
Temperature: 25 °C
Yield: 8 %

Procedure:
Add trifluoroacetic acid (0.4 mL) to a solution of 4-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-indole-1-carboxylic acid tert-butyl ester (34 mg, 0.085 mmol) in methylene chloride (2 mL) at 0° C. Allow the reaction to warm to room temperature slowly over 19 h. Dilute the reaction with methylene chloride and methanol. Add concentrated aqueous ammonium hydroxide (2 mL) and concentrate in vacuo. Purify by flash column chromatography, using the appropriate mixture of methylene chloride, chloroform, methanol, and concentrated aqueous ammonium hydroxide, to provide 11 mg (8% yield over 2 steps) of the title compound as a white solid. MS (APCI) m/e 301 (M+1). 1H NMR (DMSO-d6) δ 10.98 (s, 1H), 8.30 (d, J=4 Hz, 1H), 7.65 (td, J=8, 2 Hz, 1H), 7.46 (d, J=8 Hz, H), 7.26 (d, J=8 Hz, 1H), 7.17-7.13 (m, 2H), 7.00 (t, J=8 Hz, 1H), 6.81 (d, J=7 Hz, 1H), 4.21 (t, J=7 Hz, 2H), 2.85 (dd, J=8, 7 Hz, 2H), 2.64-2.55 (m, 2H). HPLC: >99%, Rt=15.1 min. TLC (SiO2): Rf0.2 (1:1 methylene chloride/[80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]).
Reaction SMILES: C(O[CH:5]([C:28]1[N:41]=[C:31]2[N:32]=[C:33]([CH3:40])[C:34]3[CH2:35][CH2:36][CH2:37][CH2:38][C:39]=3[N:30]2[N:29]=1)[C:6]1(Br)[C:12](=[O:13])[N:11]2[C@@H:7]1[S:8][CH:9]=[C:10]2[C:14]([O:16]CC1C=CC([N+]([O-])=O)=CC=1)=[O:15])(=O)C.C(#N)C>C1COCC1.[Pd]>[CH3:40][C:33]1[C:34]2[CH2:35][CH2:36][CH2:37][CH2:38][C:39]=2[N:30]2[N:29]=[C:28](/[CH:5]=[C:6]3\[C@@H:7]4[N:11]([C:12]\3=[O:13])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][S:8]4)[N:41]=[C:31]2[N:32]=1
Reactant: CC(=O)OC(c1nc2nc(C)c3c(n2n1)CCCC3)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1nc2nc(/C=C3/C(=O)N4C(C(=O)O)=CS[C@H]34)nn2c2c1CCCC2
Temperature: 3 °C

Procedure:
4-nitrobenzyl (5R)-6-[(acetyloxy)(5-methyl-6,7,8,9-tetrahydro[1,2,4]triazolo[1,5-a]quinazolin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (600 mg, 0.93 mmol) was dissolved in THF (20 mL) and acetonitrile (20 mL) and phophate buffer (6.5 pH) (20 ml) and hydrogenated over Pd/C (10%) (200 mg) under 40 psi pressure. At the end, reaction mixture was filtered, cooled to 3° C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate was washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was concentrated under high vacuum at 35° C. to give a yellow precipitate. The product was purified by HP21 resin reverse phase column chromatography. Initially the column was eluted with deionized water (2 L) and latter with 10% acetonitrile:water. The fractions containing the product were collected and concentrated under reduced pressure at room temperature. The yellow solid was washed with acetone, filtered and dried. Yield: 37 mg, 11%; as yellow crystals; mp 250° C. (Dec); (M+H+Na) 392.
Reaction SMILES: [C:1]([OH:11])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O1CCCC1.[N:29]1([CH2:34][CH2:35][CH2:36][NH2:37])[CH:33]=[CH:32][N:31]=[CH:30]1>O>[N:29]1([CH2:34][CH2:35][CH2:36][NH:37][C:1](=[O:11])[CH:2]=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: NCCCn1ccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)NCCCn1ccnc1
Reaction time: 18 h

Procedure:
A mixture of 2.22 g. of trans-cinnamic acid, 2.43 g, of 1,1'-carbonyldiimidazole and 50 ml. of tetrahydrofuran was stirred for 2 hours, then 1.7 ml. of 1H-imidazole-1-propanamine was added. The reaction mixture was stirred for 18 hours, then 5 ml. of water was added, the mixture was heated for 30 minutes and then concentrated. Methylene chloride and 10 ml. of 1N sodium hydroxide were added and then layers were separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated, giving the desired product as a viscous oil.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[I-].[Na+].[NH2:12][CH:13]([C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=1)[CH2:14][N:15]([C:24]([O:26][CH3:27])=[O:25])[CH2:16][CH:17](Cl)[C:18]([O:20][CH2:21][CH3:22])=[O:19].O.C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:27][O:26][C:24]([N:15]1[CH2:14][CH:13]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=2)[NH:12][CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16]1)=[O:25]
Reactant: CCOC(=O)C(Cl)CN(CC(N)c1cc(F)c(F)c(F)c1)C(=O)OC
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1CN(C(=O)OC)CC(c2cc(F)c(F)c(F)c2)N1
Temperature: 80 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
IPEA (1.85 mL) and sodium iodide (795 mg) were added to a solution of ethyl 3-{[2-amino-2-(3,4,5-trifluorophenyl)ethyl]methoxycarbonylamino}-2-chloropropionate (2.03 g) in THF (20 mL), and the reaction solution was stirred at 80° C. for four hours. The reaction solution was left to cool to room temperature. Then, ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane->heptane:ethyl acetate=2:1) to obtain 991 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32])[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=2)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:50])([F:51])[F:52])=[CH:45][CH:44]=2)=[CH:39][CH:40]=1)[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1O)C(=O)OC(C)(C)C
Reactant: FC(F)(F)c1ccc(CCc2ccc(CCl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1OCc1ccc(CCc2ccc(C(F)(F)F)cc2)cc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
1 g (2.27 mmol) of ethyl 5-{(tert-butoxycarbonyl)[2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 69A), 746 mg (2.50 mmol) of 1-(chloromethyl)-4-{2-[4-(trifluoromethyl)phenyl]ethyl}benzene and 784 mg (5.68 mmol) of potassium carbonate in 25 ml of acetonitrile were heated to 110° C. and stirred at this temperature overnight. After cooling, the reaction mixture was filtered, the filter cake was washed repeatedly with acetonitrile and the combined filtrates were concentrated to dryness on a rotary evaporator. The residue obtained was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1→10:1). This gave 1110 mg (1.48 mmol, 65% of theory) of the target compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH:20]2[O:24][C:23](=[O:25])[NH:22][CH2:21]2)[CH:9]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C.CCOC(C)=O.O>[CH2:30]([N:22]1[CH2:21][CH:20]([C:11]2[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=2[C:8]2[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=2[O:26][CH3:27])[O:24][C:23]1=[O:25])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C1CNC(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C1CN(Cc2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 44 mg of 5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one in 1 mL of DMF was added 10 mg of sodium hydride. The mixture was stirred 10 min at room temperature, and then 24 mg of benzyl bromide was added. The mixture was stirred overnight at room temperature, then diluted with 15 mL of EtOAc and 5 mL of water. The phases were separated and the organic phase was washed with 5 mL each of water and brine, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of hexanes, followed by a linear gradient of EtOAc in hexanes from 0 to 50% over 10 CV to provide the title compound. Mass spectrum (ESI) 470.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.86, 7.76 (s, 1H), 7.62 (d, J=8 Hz, 1H), 7.14-7.40 (m, 7H), 7.01, 6.77 (d, J=2.5 Hz, 1H), 6.87, 6.83 (d, J=8.5 Hz, 1H), 5.45, 5.53 (m, 1H), 4.30-4.53 (m, 2H), 3.73, 3.55 (s, 3H), 3.48, 3.30 (m, 1H), 3.10, 2.96 (t, J˜8.5 Hz, 1H), 2.89, 2.82 (septet, J=7 Hz, 1H), 1.24, 1.16 (m, 6H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][C:34]=1[O:35]CC1C=CC=CC=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([O:23][CH2:24][CH:25]([OH:31])[CH2:26][NH:27][CH:28]([CH3:30])[CH3:29])[CH:15]=2)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][C:34]=1[OH:35])[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([O:23][CH2:24][CH:25]([OH:31])[CH2:26][NH:27][CH:28]([CH3:29])[CH3:30])[CH:15]=2
Reactant: CC(C)NCC(O)COc1ccc2c(=O)cc(-c3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)oc2c1
Agent: [Pd]
Solvent: CO
Product: CC(C)NCC(O)COc1ccc2c(=O)cc(-c3ccc(O)c(O)c3)oc2c1

Procedure:
3′,4′-Dibenzyloxy-7-(2-hydroxy-3-iso-propylamino-propoxy)-flavone, 38 (1.0 g, 1.77 mmol) was debenzylated in dry methanol (40 mL) with 10% Pd/C (30 mg) under hydrogen atmosphere as described for 48 to provide 51. Yield 600 mg (88%); mp 187° C. (decomposes); MS (FAB) 386 (M++1); IR (KBr) 3425, 1624; 1H NMR (200 MHz, DMSO-d6) δ 7.96 (d, J=7.1 Hz, 1H), 7.47 (s, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.30 (s, 1H), 7.10 (d, J=8.1 Hz, 1H), 6.95 (d, J=7.6 Hz, 1H), 6.68 (s, 1H), 4.23-4.18 (m, 3H), 3.21-3.18 (m, 3H), 1.27 (d, J=6.2 Hz, 6H). Analysis Calcd for C21H23NO6: C, 65.44; H, 6.02; N, 3.63. Found: C, 65.37; H, 6.18; N, 3.47.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:10][C@@H:11]1[O:15]C(C)(C)[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[CH:31][CH:30]=1)=O)(C)(C)C.Cl>CO>[NH2:8][C@@H:9]([CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[CH2:10][C@H:11]([OH:15])[C@@H:12]([NH:13][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(-c2cccnc2)cc1
Agent: Cl
Solvent: CO
Product: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2cccnc2)cc1)NC(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution containing the product from Example 67A (0.059 g, 0.093 mmol) in a mixture of methanol (3 mL) and aqueous HCl (1 mL, 1 N) was stirred at 50° C. for 2 hours, and concentrated to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1>C1COCC1>[O:15]=[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C1CCC(=O)O1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)NCc1ccccc1
Yield: 52.7 %

Procedure:
A mixture of benzyl amine (10.7 g) and succinic anhydride (10 g) was stirred in THF (1 liter) for 2 days. The solid was filtered and dissolved in 1N NaOH (110 ml). The aqueous phase was washed with Et2O and then made acidic with conc HCl while cooling in an ice-water bath. The solid was collected, washed with water and dried under high vacuum. There was obtained 10.9 g (53%) of the title compound as a white powder m.p. 137.5-138°.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[CH:9]=[CH:10][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[N:12][CH:13]=1>>[CH3:28][C:27]1[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:11]3[N:12]=[CH:13][C:8]([N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])=[CH:9][CH:10]=3)=[O:15])[CH2:17][CH2:18]2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cn3)CC2)c(C)c1
Yield: 71.7 %

Procedure:
Using pyrrolidin-2-one (94 mg) and (5-bromopyridin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (375 mg) described in Preparation Example 134 and by the reaction and treatment in the same manner as in Example 1, the title compound (272 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C@@H:7]([C:9]([NH2:11])=O)[NH2:8])=[CH:4][CH:3]=1.Cl.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>O1CCCC1>[NH2:11][CH2:9][CH:7]([NH2:8])[CH2:6][C:5]1[CH:12]=[CH:13][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: NC(=O)[C@@H](N)Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: NCC(N)Cc1ccc(Cl)cc1

Procedure:
0.1 mole (20 grams) of 4-chlorophenylalanineamide or hydrochloride were added in small portions to a well stirred suspension of 0.3 mole of LiAlH4 in 250 ml of dry tetrahydrofuran. The mixture was stirred for 24 hours under reflux and subsequently under ice cooling hydrolyzed dropwise with 1.2 moles of H2O. After stirring at room temperature for an additional hour it was filtered off from the hydrolysis products accumulating as a slime-like solid. This residue was extracted for 24 hours with 127 ml of tetrahydrofuran. Filtrate and extract were combined.
Reaction SMILES: [N:1]#[C:2]Cl.[Cl:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:11]=1[Cl:12])[NH2:8].C(O)(=O)C.[OH-].[Na+]>C(O)C>[Cl:4][C:5]1[CH:6]=[C:7]([NH:8][C:2]#[N:1])[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: N#CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: N#CNc1ccc(Cl)c(Cl)c1
Yield: 95.2 %

Procedure:
6.1 ml (0.12 mole) of cyanogen chloride were added, at a temperature below 10° C., to 16.3 g (0.1 mole) of 3,4-dichloroaniline in 150 ml of ethanol and 40 g of 50% strength acetic acid. 110 ml of 1N NaOH solution was then added dropwise. The mixture was stirred for a further hour and concentrated under a water pump vacuum until a bath temperature of 30° C. had been reached, and the residue was washed with water. 17.8 g (≅95% of theory) of 3,4-dichlorophenyl cyanamide were obtained. The substance was homogeneous according to examination by thin layer chromatography and gave a clear solution in 2N NaOH.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[C:19]#[N:20].[ClH:21]>C(#N)C>[Cl:21][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[C:19]#[N:20]
Reactant: N#Cc1c(N)ccc2ccccc12
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: N#Cc1c(Cl)ccc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Ethyl cyanoacetate (111.0 g, 982 mmol) was added to a suspension of potassium hydroxide pellets (52.0 g, 789 mmol) and potassium cyanide (16.0 g, 246 mmol) in dry DMF (500 mL). This was stirred at ambient temperature for 30 minutes, then 85% 2-nitro naphthalene (40.0 g, 197 mmol) was added to the reaction mixture. After stirring at room temperature for 22 hours, the reaction was refluxed for 10 minutes, then 10% NaOH (300 mL) was added and refluxing was continued for an additional 2 hours. The resulting mixture was cooled and poured onto crushed ice and extracted with chloroform. The organic phase was washed with water followed with brine, then was dried (MgSo4), decolorized with activated carbon, and filtered through silica gel. The filtrate was concentrated and triturated first with ether and then with 1:1 ethyl acetate/hexane to give 23.0 g of 2-amino 1-naphthonitrile as a yellow solid. tert-Butyl nitrite (23.5 g, 205 mmol) was added dropwise to an ice-water cooled mixture of cupric chloride (20.3 g, 151 mmol) in a solution 2-amino-1-naphthonitrile (23.0 g, 137 mmol) in dry acetonitrile (250 mL). Gas evolution was controlled by the rate of addition of the tert-butyl nitrite. The resulting reaction mixture was stirred at 0° C. for 30 minutes, then at room temperature for 30 minutes. This was poured into cold, dilute aqueous HCl and the precipitate which formed was filtered, vacuum dried, and kugelrohr distilled (180° C., 3.5 torr) to give 15.5 g of white, crystalline 2-chloro-1-naphthonitrile, a 60% yield.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](CCN)=[CH:22][CH:21]=1>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])=[CH:22][CH:21]=1
Reactant: S=C(Nc1nc2ccccc2s1)n1ccnc1
Reactant: COc1ccc(CCN)cc1
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=S)Nc2nc3ccccc3s2)cc1
Temperature: 25 °C
Yield: 61.9 %

Procedure:
A solution of 1-[(2-benzothiazolyl)-thiocarbamoyl] imidazole (1.04 g, 4 mmol) and 2-(4-methoxyphenyl) ethylamine (0.62 g, 4 mmol) in N,N-dimethylformamide (15 mL) was stirred at 100° C. for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.85 g (62%) of the title product:
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:22][CH2:21][CH:20]([CH:23]=O)[CH2:19][CH2:18]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(O)(=O)C.ClCCCl>[N:1]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:22][CH2:21][CH:20]([CH2:23][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH2:19][CH2:18]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: C1COCCN1
Reactant: O=CC1CCC(Nc2nccc(-n3nnc4ccccc43)n2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: c1ccc2c(c1)nnn2-c1ccnc(NC2CCC(CN3CCOCC3)CC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4-benzotriazol-1-yl-pyrimidin-2-ylamino)-cyclohexanecarbaldehyde (39 mg), morpholine (14 μL) and acetic acid (2 drops) in DCE (2 mL) was stirred at RT for 2 hours; sodium triacetoxyborohydride was then added. The resulting mixture was stirred for 3 hours at RT. Water was added; the organic layer was separated and washed 3 times with water. The aqueous layer was re-extracted with DCM. The combined organic extracts were dried over Na2SO4 and filtered; the solvent was evaporated under reduced pressure and the residue was purified via preparative TLC to afford 13.2 mg of (4-benzotriazol-1-yl-pyrimidin-2-yl)-(4-morpholin-4-ylmethyl-cyclohexyl)-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.56 (1 H, d, J=8.31 Hz), 8.36-8.46 (1 H, bd), 8.12 (1 H, d, J=8.31 Hz), 7.55-7.69 (1 H, m), 7.40-7.52 (2H, m), 5.22-5.64 (1 H, m), 3.49-3.96 (5 H, m), 2.12-2.56 (6 H, m), 1.46-2.04 (5 H, m), 1.03-1.46 (4 H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(Cl)=O)C(C)C.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH2:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:12](=[O:14])[NH:29][CH2:28][CH2:27][N:26]([CH3:30])[CH3:25])[CH2:15][CH2:16]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CN(C)CCN
Agent: CC(C)COC(=O)Cl
Product: CN(C)CCNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
4-(2-Dimethylamino-ethylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester was prepared from 1-t-butoxycarbonyl-iso-nipecotic acid (5 g), iso-butylchloroformate (2.83 mL) and N,N-dimethyl-1,2-ethylenediamine (2.63 mL). Exact mass calculated for C15H29N3O3 299.22, found 300.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:15])=O>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:15])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of 4-fluorophenylacetic acid (11.2 g, 73 mmol.) in THF (125 ml) at 0° C. under nitrogen was added oxalyl chloride (7.1 ml, 82 mmol.) then DMF (4 drops) and the resulting effervescing mixture stirred at 0° C. for 30 minutes then at ambient temperature for a further 1 hour. The effervescence had ceased after this time and the solvent was evaporated. To the residue was added toluene (50 ml) and the solvent evaporated. The addition of toluene and evaporation was repeated to leave a residue of 4fluorophenylacetyl chloride.
Reaction SMILES: FC1C=C(F)C=C2C=1C=NN2C.ClC1C=CC2N(C(C=O)=CN=2)N=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([C:35]([C:38]3[C:39]([F:49])=[C:40]4[C:44](=[CH:45][C:46]=3[F:47])[N:43]([CH3:48])[N:42]=[CH:41]4)([OH:37])C)=[CH:33][N:34]=2)[N:31]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([CH:35]([C:38]3[C:39]([F:49])=[C:40]4[C:44](=[CH:45][C:46]=3[F:47])[N:43]([CH3:48])[N:42]=[CH:41]4)[OH:37])=[CH:33][N:34]=2)[N:31]=1
Reactant: Cn1ncc2c(F)c(C(C)(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Agent: Cn1ncc2c(F)cc(F)cc21
Agent: O=Cc1cnc2ccc(Cl)nn12
Product: Cn1ncc2c(F)c(C(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Yield: 41 %

Procedure:
The title compound as a yellow solid (60 mg, 0.172 mmol, 41%) was synthesized from intermediate 4,6-Difluoro-1-methyl-1H-indazole (70 mg, 0.416 mmol) and 6-chloroimidazo[1,2-b]pyridazine-3-carbaldehyde (76 mg, 0.416 mmol) using the same procedure as described in the synthesis of compound 31.1. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.08 (s, 1H), 8.03 (d, 1H), 7.85 (s, 1H), 7.26 (q, 2H), 6.76 (s, 1H), 4.03 (s, 3H). LCMS (method B): [MH]+=349.9, tR=2.12 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]2[CH2:16][CH2:15]2)[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]2[CH2:16][CH2:15]2)[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(C2CC2)c(C(F)(F)F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C4CC4)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared (2-amino-5-cyclopropyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J39) (289 mg, 0.914 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (284 mg, 0.914 mmol) according to the general procedure M. Obtained as a yellow foam (368 mg, 73%).