Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[N:8]=[N:9][N:10]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]=3)[C:4]=2[CH2:3]1.[Cl:18][C:19]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].ClC1C(C(F)(F)F)=CC=CC=1C(Cl)=O.NC1C(F)=CC=CN=1>>[Cl:18][C:19]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([N:7]1[CH:2]([CH3:1])[CH2:3][C:4]2[N:10]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]=3)[N:9]=[N:8][C:5]=2[CH2:6]1)=[O:22]
Reactant: CC1Cc2c(nnn2-c2ncccc2F)CN1
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Agent: Nc1ncccc1F
Agent: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Product: CC1Cc2c(nnn2-c2ncccc2F)CN1C(=O)c1cccc(Cl)c1Cl

Procedure:
Example 161 was prepared from 6-methyl-1-(3-fluoropyridin-2-yl)-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine using the conditions described in Example 63 Step 5 substituting 2,3-dichlorobenzoyl chloride for 2-chloro-3-(trifluoromethyl)benzoyl chloride. 6-Methyl-1-(3-fluoropyridin-2-yl)-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine was made using the route described in Example 116 beginning from 2-amino-3-fluoropyridine instead of 2-aminopyridine in step A. Subsequent steps were carried out analogous to those described in Example 116 steps B-D. MS (ESI) mass calcd. C18H14Cl2FN5O, 405.06. m/z found, 406.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][N:5]([CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[S:24]([CH3:23])(=[O:26])=[O:25]
Reactant: Fc1ccccc1CNCc1ccncc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1ccncc1)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A 4.2 g. portion of 4-(2-fluorobenzylaminomethyl)pyridine was dissolved in 50 ml. of dichloromethane, and to it was added 3 g. of potassium carbonate and 2.5 g. of methanesulfonyl chloride. The mixture was stirred at ambient temperature for 4 days, and was then diluted with 50 ml. of water and extracted with 150 ml. of dichloromethane. The organic phase was dried over magnesium sulfate, and concentrated under vacuum. The oily residue was chromatographed on silica gel, eluting with 3:2 toluene:acetone. The product-containing fractions were evaporated to obtain an oil which solidified upon standing, and was triturated with petroleum ether to obtain 3.25 g. of the desired product, m.p. 69°-70°.
Reaction SMILES: C([N-:4]C(C)C)(C)C.[Li+].[CH:9]1([O:13][C:14]2[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[CH:19]=[C:18]([N:26]=[C:27]([N:29]3[CH2:35][CH2:34][CH2:33][N:32]([C:36]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[O:37])[CH2:31][CH2:30]3)[CH3:28])[C:15]=2[C:16]#[N:17])[CH2:12][CH2:11][CH2:10]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[NH3:4].[NH2:17][C:16]1[C:15]2[C:18](=[CH:19][C:20]([O:24][CH3:25])=[C:21]([O:22][CH3:23])[C:14]=2[O:13][CH:9]2[CH2:10][CH2:11][CH2:12]2)[N:26]=[C:27]([N:29]2[CH2:35][CH2:34][CH2:33][N:32]([C:36]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:37])[CH2:31][CH2:30]2)[CH:28]=1
Reactant: COc1cc(N=C(C)N2CCCN(C(=O)N3CCOCC3)CC2)c(C#N)c(OC2CCC2)c1OC
Reactant: CC(C)[N-]C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2nc(N3CCCN(C(=O)N4CCOCC4)CC3)cc(N)c2c(OC2CCC2)c1OC
Product: N
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution of lithium diisopropylamide in tetrahydrofuran (10 ml, 0.5M, 0.005 mol) was added to a solution of 2-cyclobutyloxy-3,4-dimethoxy-6-{1-[4-(morpholinecarbonyl)-1,4-diazepan-1-yl]ethylideneamino}benzonitrile (950 mg, 0.002 mol) in tetrahydrofuran (25 ml) at -70° C. and the reaction allowed to warm to room temperature under a nitrogen atmosphere. 1N aqueous citric acid solution (25 ml) was then added and the mixture extracted once with ethyl acetate (25 ml). The aqueous phase was basified using 1N aqueous sodium hydroxide solution and the mixture extracted with further ethyl acetate (60 ml) and these combined organic extracts dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with dichloromethane:methanol:0.880 aqueous ammonia (97:3:1 v/v) and trituration with diethyl ether gave the title compound as a foam (680 mg, 67%). Rf 0.31 (dichloromethane:methanol:0.880 aqueous ammonia, 97:3:1, v/v). MS m/z 486 (MH)+. 1H-NMR (CDCl3): δ=1.45 (1H, m), 1.70 (1H, m), 2.03 (2H, m), 2.30 (4H, m), 3.30 (4H, m), 3.35 (2H, m), 3.60 (8H, m), 3.80 (3H, s), 3.92 (5H, br.s), 4.80 (1H, m), 5.60 (2H, m), 570 (1H, s), 6.73 (1H, s). Found: C, 61.27; H, 7.39; N, 13.92; C25H35N5O5 1(C2H5)2O 0.3 H2O requires C, 61.21; H, 7.40; N, 14.05%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[N+:15]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21])([O-:17])=[O:16]>ClCCl>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[N+:15]([O-:17])=[O:16])=[N:3][CH:4]=1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Cc1ccc(N)nc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccccc2[N+](=O)[O-])nc1
Reaction time: 4 h
Yield: 52.3 %

Procedure:
To a stirring solution of 2-amino-5-methylpyridine (3.1 g, 29 mmol) and pyridine (7.3 mL, 90 mmol) in dichloromethane (200 mL) was added 2-nitrobenzoyl chloride (5.7 g, 30 mmol). After 4 h, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate (500 mL) and water (250 mL). The organic phase was separated and washed again with water (250 mL) followed by brine (250 mL) and then dried with MgSO4, filtered and partially concentrated in vacuo, which resulted in the formation of a precipitate. After standing overnight, the solid was filtered and dried in vacuo to give 3.9 g (52%) of white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][N:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][C:27]([CH3:33])=[N:26]1>CN1CCCC1=O.O>[CH:21]1([C:19]([NH:18][C:16]2[N:17]=[C:12]3[CH:11]=[CH:10][C:9]([S:8][C:4]4[CH:3]=[C:2]([NH:1][C:30]([C:29]5[N:25]([CH3:24])[N:26]=[C:27]([CH3:33])[CH:28]=5)=[O:31])[CH:7]=[CH:6][CH:5]=4)=[N:14][N:13]3[CH:15]=2)=[O:20])[CH2:22][CH2:23]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1cccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C(=O)Nc2cccc(Sc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
To a solution of N-{6-[(3-aminophenyl)sulfanyl]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide (195 mg, 0.6 mmol) in N-methylpyrrolidone (3.0 mL) was added 1,3-dimethylpyrazole-5-carbonyl chloride (159 mg, 1.0 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30) and precipitated from methanol to give the title compound (245 mg, 91%) as a white powder.
Reaction SMILES: Cl[C:2]1[C:13]2=[C:14]3[N:9]([CH2:10][CH2:11][CH2:12]2)[CH:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6](=[O:18])[C:5]3=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CS(C)=O.Cl>[OH-].[Na+]>[N:19]1([C:2]2[C:13]3=[C:14]4[N:9]([CH2:10][CH2:11][CH2:12]3)[CH:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6](=[O:18])[C:5]4=[CH:4][CH:3]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn2c3c(c(Cl)ccc3c1=O)CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1cn2c3c(c(N4CCNCC4)ccc3c1=O)CCC2
Yield: 28.5 %

Procedure:
19.2 g of 8-chloro-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid and 35.5 g of piperazine were added to 350 ml of anhydrous dimethyl sulfoxide and the mixture was heated on an oil bath at 170° to 180° C. for 6 hours while stirring. After completion of the reaction, the solvent was removed under reduced pressure. 500 ml of water was added to the residue and the pH value of the mixture was adjusted to a pH of 2 followed by filtering water-insoluble materials. The filtrate was concentrated to 100 ml under reduced pressure and rendered alkaline (pH=9) with a 10% aqueous sodium hydroxide solution. After extracting the aqueous alkali solution with chloroform to thereby remove chloroform-soluble materials, the aqueous alkali solution layer was allowed to stand to precipitate crystals which were filtered. The crude crystals thus-obtained were dissolved in 10 ml of a 10% aqueous sodium hydroxide solution and the solution was treated with activated carbon and adjusted to a pH of 8 with a 10% aqueous hydrochloric acid solution to precipitate crystals which were filtered and washed with water sufficiently. Recrystallization of the crystals from dimethylformamide gave 6.5 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of 267° to 268° C. 6.4 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid thus-obtained was suspended in 50 ml of water and 15 ml of a 10% aqueous hydrochloric acid solution was added to the resulting solution. After removing the insoluble materials by filtration, the water was distilled off to obtain 5.7 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride as white amorphous crystals having a melting point of 300° C. or more.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.CC1C=CC(C2[O:21]C=CN=2)=CC=1>>[O:10]1[CH:11]=[N:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH:1]=[O:21])=[CH:7][CH:6]=2)=[N:9]1
Reactant: Cc1ccc(-c2ncon2)cc1
Reactant: Cc1ccc(-c2ncco2)cc1
Product: O=Cc1ccc(-c2ncon2)cc1

Procedure:
The title compound is prepared by a procedure analogous to Step B of Reference Example 73 by substituting 3-(4-methylphenyl)-1,2,4-oxadiazole (prepared as described in Bull. Chem. Soc. Jpn. 1978, 51,1484) for the 2-(4-methylphenyl)oxazole of Step B of Reference Example 73. MS 175 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:16]=[C:17]=S.[NH2:19][C:20]1[C:25]([NH2:26])=[CH:24][C:23]([N:27]2[CH2:31][CH2:30][CH:29]([C:32]#[N:33])[CH2:28]2)=[C:22]([Cl:34])[CH:21]=1.CC(C)N=C=NC(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[NH:16][C:17]1[NH:26][C:25]2[CH:24]=[C:23]([N:27]3[CH2:31][CH2:30][CH:29]([C:32]#[N:33])[CH2:28]3)[C:22]([Cl:34])=[CH:21][C:20]=2[N:19]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1
Reactant: N#CC1CCN(c2cc(N)c(N)cc2Cl)C1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(Cl)c(N4CCC(C#N)C4)cc3[nH]2)c1

Procedure:
The title compound was prepared from N-(4-chloro-3-isothiocyanatobenzyl)-2,2-dimethyl-propionamide (66 mg, 0.2 mmol), 1-(4,5-diamino-2-chloro-phenyl)-pyrrolidine-3-carbonitrile (55 mg, 0.2 mmol) in DMF (2 mL) and DIC (39 μL, 0.2 mmol) in analogy to example 6 step (c).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@H:17]([OH:27])[CH2:18][CH2:19]2)/[C:14](=[CH:28]/[CH3:29])/[C:13]3=[O:30])[CH2:10][CH2:9]1)[CH3:7].[OH-].[Na+]>>[OH:27][C@@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@H:15](/[C:14](=[CH:28]/[CH3:29])/[C:13](=[O:30])[C@@H:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:25]2([CH3:26])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C@H:6]([CH3:7])[CH2:5][CH2:4][C:3]([OH:31])=[O:2])[CH2:16]1
Reactant: C/C=C1\C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Agent: [Na+]
Agent: [OH-]
Product: C/C=C1\C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12

Procedure:
Step 4 can also be carried out starting with a compound that is a mixture of E/Z isomer. For example, Step 4 is the reaction of E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid methyl ester (4A) with NaOH to form E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid (5A). In one embodiment, prior to step 4, the residue from step 3 is heated about 45° C. to about 60° C. to remove residual amounts of solvent. In one embodiment, the temperature is about 49° C. to about 55° C. In one embodiment, the ester hydrolysis reaction involving reacting E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid methyl ester (4A) with NaOH is carried out at about 20° C. to about 25° C. in methanol, water, and a NaOH solution. In one embodiment, the NaOH solution is a 50% wt. aqueous solution.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[Cl:12].[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>O1CCCC1>[Cl:12][C:4]1[CH:5]=[C:6]([NH2:9])[CH:7]=[CH:8][C:3]=1[CH2:2][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Product: Nc1ccc(Cn2ccnc2)c(Cl)c1
Yield: 47 %

Procedure:
A solution of 10 g of 4-bromomethyl-3-chloro nitrobenzene and 5.44 g of imidazole in 125 ml of tetrahydrofuran was refluxed for 4 hrs. The solvent was removed and the residue was dissolved in ethyl acetate. The solution was washed with water and dried over magnesium sulfate. The solvent was removed and the residue was extracted several times with ether. The ether extracts were diluted with two volumes of hexanes. 1-(2-Chloro-4-nitrobenzyl)-1H-imidazole (4.3 g) crystallized as a white solid. A 4 g portion of this material was mechanically stirred at reflux with 153 ml of methanol, 52 ml of water, 8.1 g of ammonium chloride, and 6.6 g of iron powder for 2 hrs. The hot mixture was filtered and solids were washed with hot methanol-tetrahydrofuran mixtures. Solvents were removed from the combined filtrates. The residue was extracted several times with hot ethyl acetate, The ethyl acetate solution was treat with magnesium sulfate and activated charcoal. Filtering and removing the solvent gave the 3.9 g of the title compound.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:28]1([S:38](Cl)(=[O:40])=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1>>[C:28]1([S:38]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:40])=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1cccc2ccccc12)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 66 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 1-naphthalenesulfonyl chloride under the conditions used in example 2 giving 66% of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27](O)=[O:28])[CH:22]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:59][N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>CN(C=O)C.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([N:63]3[CH2:64][CH2:65][N:60]([CH3:59])[CH2:61][CH2:62]3)=[O:28])[CH:22]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20]
Reactant: O=C(O)c1cccc(-c2ccc(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)c1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCN(C(=O)c2cccc(-c3ccc(CC4CCN(C5CCCCC5)C4=O)c(Cl)c3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Charge a vial with 3′-chloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-3-carboxylic acid (Example 7) (70 mg, 0.17 mmol), EDCl (2.0 eq.) and HOBt (1.0 eq.). Dissolve in DMF (0.1 M) and add triethylamine (4.0 eq.) and N-methyl piperazine (34 mg, 0.34 mmol) (2.0 eq). Stir at room temperature overnight. Pour into water and extract with ether. Dry over sodium sulfate, filter and concentrate. Purify over silica gel. Dissolve the residue in methylene chloride and acidify with 4N HCl in dioxane. Concentrate in vacuo. Mass spec (apci) m/z=494.3 (M+H-HCl).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:8](=[O:21])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Cl:30][CH2:31][CH2:32][CH2:33]I>>[ClH:30].[ClH:30].[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]([CH:22]2[CH2:27][CH2:26][N:25]([CH2:31][CH2:32][CH2:33][N:25]3[CH2:26][CH2:27][CH2:22][CH2:23][CH2:24]3)[CH2:24][CH2:23]2)[C:8](=[O:21])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CC(C)COc1ccc(CC(=O)N(Cc2ccc(F)cc2)C2CCNCC2)cc1
Reactant: ClCCCI
Product: CC(C)COc1ccc(CC(=O)N(Cc2ccc(F)cc2)C2CCN(CCCN3CCCCC3)CC2)cc1
Product: Cl
Yield: 53.9 %

Procedure:
The desired compound was synthesized from N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl) N-piperidin-4-yl-acetamide 103NLS56 (189 mg, 0.47 mmol), 1-piperidine (61 μL, 0.61 mmol) and 1-chloro-3-iodopropane (61 μL, 0.57 mmol) using the same method as for synthesis of 130AF09-145. Purification of the product by silica gel column chromatography, eluting with 10% methanol in dichloromethane, afforded the title compound (75.6 mg, 31%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C[N:19]1C=CN=[C:20]1[S:24](Cl)(=[O:26])=[O:25].C(N(C(C)C)CC)(C)C.[CH3:37][N:38]([CH:40]=O)[CH3:39]>CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:24]([C:20]4[N:19]=[CH:37][N:38]([CH3:39])[CH:40]=4)(=[O:26])=[O:25])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=12
Reactant: Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Reactant: Cn1ccnc1S(=O)(=O)Cl
Reactant: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc(S(=O)(=O)Nc2ccc(-n3ncc4c(N)ncnc43)cc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 11 %

Procedure:
Title compound 11A, 1-(4-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (33 mg, 1.0 eq, 0.15 mmol), 1-methylimidazole sulphonylchloride (22 mg, 1.0 eq, 0.15 mmol) and diisopropylethylamine (23 μl, 0.9 eq, 0.13 mmol) were added to DMF (1 ml) and the mixture was stirred for 48 hours at room temperature under an inert atmosphere. Methanol was then added (1 ml) and the solvents were removed in vacuo. The resultant residue was purified column chromatography using DCM/MeOH (96:4) as eluen followed by trituration in methanol to yield the title compound as a white solid (6 mg, 0.03 mmol, 11%). LCMS: [M+H]+=371, Rt=1.33 min, 100% purity.
Reaction SMILES: N.[CH2:2](O)[CH:3]([OH:5])[CH3:4].CC(C(O)[C:11]([CH2:14][O:15][C:16]([CH:18]([CH3:20])[CH3:19])=[O:17])(C)C)C.N[C:23]([O:25]CC)=[O:24]>C(C(C)=O)C>[CH3:20][C:18]([C:16]([O:15][CH2:14][CH2:11][O:25][C:23]([CH2:2][C:3]([CH3:4])=[O:5])=[O:24])=[O:17])=[CH2:19]
Reactant: CCOC(N)=O
Reactant: CC(O)CO
Reactant: CC(C)C(=O)OCC(C)(C)C(O)C(C)C
Agent: N
Solvent: CCC(C)=O
Product: C=C(C)C(=O)OCCOC(=O)CC(C)=O
Reaction time: 24 h

Procedure:
A 100 g. portion of each polymer was neutralized to pH=9.5 with ammonia, an additional 0.52 g. of ammonia was added (one equivalent based on acetoacetate) to ensure complete enamine formation. To all three samples was added a premix consisting of 0.32 g. nonionic surfactant (Triton X-405; Union Carbide), 4.4 g. propylene glycol, 4.4 g. coalescent (Texanol) and 1.1 g. a 10% aqueous solution of urethane rheology modifier (QR-708; Rohm and Haas). The formulated mixture was equilibrated for 24 hours and then coatings were applied on glass plates to give 3-4 mil thick coatings. Films were placed outdoors in complete sunlight for 12 days. Film swell ratios in methyl ethyl ketone were obtained.
Reaction SMILES: [F:1][C:2]([C:5]1[C:6]([C:16]([OH:18])=O)=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([F:4])[CH3:3].[CH:19]1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C(Cl)CCl.O/[N:43]=[C:44](/[C:46]1[CH:63]=[CH:62][C:49]([CH2:50][N:51]2[CH2:54][CH:53]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:52]2)=[CH:48][CH:47]=1)\[NH2:45]>C(#N)C>[F:4][C:2]([C:5]1[C:6]([C:16]2[O:18][N:45]=[C:44]([C:46]3[CH:63]=[CH:62][C:49]([CH2:50][N:51]4[CH2:54][CH:53]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:52]4)=[CH:48][CH:47]=3)[N:43]=2)=[N:7][O:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([F:1])[CH2:3][CH3:19]
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Reactant: CC(F)(F)c1c(C(=O)O)noc1-c1ccccc1
Reactant: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCC(F)(F)c1c(-c2nc(-c3ccc(CN4CC(C(=O)OC(C)(C)C)C4)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 4-(1,1-difluoroethyl)-5-phenylisoxazole-3-carboxylic acid (58.7 mg, 0.232 mmol), HOBt (64.0 mg, 0.418 mmol), and diisopropylethylamine (0.162 mL, 0.928 mmol) in acetonitrile (2 mL) was added EDC (105 mg, 0.545 mmol) and (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Int.1, 70.8 mg, 0.232 mmol). The reaction mixture was stirred at 80° C. for 2 h and then concentrated. The residue was diluted with ethyl acetate (3 mL), washed with a saturated aqueous solution of sodium bicarbonate (1 mL), washed with water (1 mL), washed with brine (1 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by preparative HPLC gave tert-butyl 1-(4-(5-(4-(1,1-difluoropropyl)-5-phenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate.
Reaction SMILES: [ClH:1].[S:2]([O:6][CH2:7][C@H:8]1[O:10][CH2:9]1)([CH3:5])(=[O:4])=[O:3]>>[S:2]([O:6][CH2:7][C@@H:8]([OH:10])[CH2:9][Cl:1])([CH3:5])(=[O:4])=[O:3]
Reactant: Cl
Reactant: CS(=O)(=O)OC[C@@H]1CO1
Product: CS(=O)(=O)OC[C@@H](O)CCl
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Concentrated HCl (75 ml) was added to (S)-3-mesyloxy-1,2-epoxypropane (6.8 g, 0.045 m). After stirring for 30 minutes, the water was removed through the addition and subsequent evaporation of ethanol. Finally, the residual ethanol was removed at room temperature and 0.1 mm to give (R)-3-mesyloxy-2-hydroxy-1-chloropropane (7.8 g, 92%). This material was dissolved in ether (50 ml) and methanol (10 ml) in an ice bath and sodium (0.94 g, 0.041 m) was added. After stirring for one hour, the mixture was filtered and concentrated at 30°/25 mm. Added acetone, filtered and reconcentrated at 30°/25 mm. Attempted distillation of the residue led to total decomposition; none of the desired (R)-epichlorohydrin was obtained.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].O.C([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(C)C.O1C[CH2:33][CH2:32][CH2:31]1>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:23][C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([CH:32]([CH3:33])[CH3:31])[CH:29]=3)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: C1CCOC1
Reactant: CC(C)Nc1ccccc1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Solvent: O
Product: CC(C)c1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1

Procedure:
The product is prepared according to the procedure described in Example 19, using 653 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and using a mixture of 10 ml of water and 2 ml of tetrahydrofuran in place of the methanol and 270 mg of isopropylaniline in place of the 3-(tert-butyl)aniline. 235 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-[3-(propan-2-yl)phenyl]acetamide are obtained in the form of a white solid, the characteristics of which are the following: