Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N=C(NO)c1ccccc1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(-c3ccccc3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-benzamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.85 min; Mass spectrum (ESI+): m/z=456 [M+H]+.
Reaction SMILES: [O:1]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[S:18][C:17]3[N:19]=[CH:20][CH:21]=[N:22][C:16]=3[NH:15][C:14]=2[CH:23]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C:24](Cl)(=[O:27])[O:25][CH3:26]>>[CH3:26][O:25][C:24]([N:15]1[C:14]2[CH:23]=[C:10]([CH2:9][O:1][Si:2]([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:4])[CH3:3])[CH:11]=[CH:12][C:13]=2[S:18][C:17]2[N:19]=[CH:20][CH:21]=[N:22][C:16]1=2)=[O:27]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)Nc1nccnc1S2
Product: COC(=O)N1c2cc(CO[Si](C)(C)C(C)(C)C)ccc2Sc2nccnc21

Procedure:
4.0 g of 8-(tert-butyldimethylsiloxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine was subjected to the procedure described in Example 1570 but using methyl chlorocarbonate instead of acetyl chloride to thereby give 2.5 g of the title compound as a yellow oily substance.
Reaction SMILES: [CH2:1]([O:3]/[C:4](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:36])[C:24]([O:26]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:18]=2)=[CH:13][CH:12]=1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[CH2:37]([NH2:41])[CH2:38][CH2:39][CH3:40].O>CN(C)C=O>[CH2:37]([NH:41][C:24](=[O:26])[N:23]([C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11](/[CH:10]=[C:4](\[O:3][CH2:1][CH3:2])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=1)[CH3:36])[CH2:38][CH2:39][CH3:40]
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)cc1)OCC
Reactant: CCCCN
Solvent: O
Solvent: CN(C)C=O
Product: CCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)OCC)cc2)c1
Yield: 62.8 %

Procedure:
A solution of 1.75 g (3 mmol) of ethyl (Z)-2-ethoxy-3-{3′-[methyl-(4-nitrophenoxycarbonyl)amino]biphenyl-4-yl}acrylate and 0.4 mL (3.7 mmol) of n-butylamine in 20 mL of dimethylformamide is heated at 80° C. for 2 hours. After addition of water, the reaction medium is extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture. 0.8 g (63%) of ethyl (Z)-3-[3′-(3-butyl-1-methylureido)biphenyl-4-yl]-2-ethoxyacrylate is obtained in the form of a white solid after trituration from pentane.
Reaction SMILES: [C-]1C2C(=CC3C(C=2)=CC=CC=3)C=CC=1.[Na+].[CH3:16][S:17](=[N:24]S(C1C=CC(C)=CC=1)(=O)=O)([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18]>COCCOC>[NH:24]=[S:17]([CH3:16])([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18]
Reactant: Cc1ccc(S(=O)(=O)N=S(C)(=O)N2CCCC2)cc1
Agent: [Na+]
Agent: [c-]1cccc2cc3ccccc3cc12
Solvent: COCCOC
Product: CS(=N)(=O)N1CCCC1

Procedure:
A solution of sodium anthracenide (0.6 M in 1,2-dimethoxyethane; 20 mL) is added drop wise to methyl[(4-methylbenzenesulfonyl)imino]pyrrolidin-1-yl-λ6-sulfanone (2.00 g) in 1,2-dimethoxyethane (10 mL) at 0° C. until the blue color persists for a few minutes. The reaction mixture is quenched with hydrochloric acid (3 N; 3 mL), diluted with dichloromethane (60 mL), and stirred for a few minutes. The aqueous phase is separated, washed with dichloromethane and diethyl ether, and basified with solid sodium carbonate. The water is removed in vacuo and the dry residue is stirred with dichloromethane (20 mL) for 1 h. The extract is filtered, dried over MgSO4, and concentrated in vacuo to give the title compound. Mass spectrum (ESI+): m/z=149 [M+H]+.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:23]1[N:24]=[C:25]([NH2:41])[C:26]2[N:27]=[CH:28][N:29]([C:39]=2[N:40]=1)[C@@H:30]1[O:38][C@H:35]([CH2:36][OH:37])[C@@H:33]([OH:34])[C@H:31]1[OH:32]>>[N+:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][C:10]([N:7]2[CH2:8][CH2:9][CH:4]([CH2:1][C:2]#[C:3][C:23]3[N:24]=[C:25]([NH2:41])[C:26]4[N:27]=[CH:28][N:29]([C:39]=4[N:40]=3)[C@@H:30]3[O:38][C@H:35]([CH2:36][OH:37])[C@@H:33]([OH:34])[C@H:31]3[OH:32])[CH2:5][CH2:6]2)=[O:11])=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: C#CCC1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Nc1nc(C#CCC2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Batch: AB-9-149. 4-nitrophenyl 4-(prop-2-ynyl)piperidine-1-carboxylate, batch JR28-97 (0.630 g, 2.185 mmol) was added to a solution of 2-iodoadenosine (0.727 g, 1.849 mmol) according to general procedure 2. Yield: 1.192 g, 65%. %. 1H NMR (CD3OD) δ 8.26 (m, 1H), 8.25-7.34 (2×m, 4H), 5.94 (d, 1H), 4.72 (m, 2H), 4.32-4.14 (2×m, 3H), 3.91-3.71 (2×d, 2H), 3.17-2.90 (2×bt, 4H), 2.48 (d, 5H), 1.45 (m, 5H). m/z MH+=554.15. HPLC rt=7.3 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2.C(=O)([O-])[O-].[K+].[K+].[C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40]Br)(=[O:35])[CH3:34]>CN(C=O)C>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:21][CH2:22][N:23]([CH2:40][CH2:39][CH2:38][CH2:37][O:36][C:33](=[O:35])[CH3:34])[CH2:24][CH2:25]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCNCC4)n3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCN1CCN(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
100 mg (0.29 mmol) of 1-[6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl]piperazine are dissolved in 2 ml of DMF, and 47 mg (0.29 mmol) of potassium carbonate are added. 42 μl (0.29 mmol) of 4-bromobutyl acetate are subsequently added, and the mixture is stirred at 50° C. for 24 h. A further 11 μl (0.07 mmol) of 4-bromobutyl acetate are subsequently added, and the mixture is stirred at 50° C. for a further 48 h. The reaction mixture is evaporated, water is added to the residue, the mixture is rendered basic using 1 N NaOH and extracted three times with ethyl acetate. The organic phase is dried over Na2SO4 and evaporated. The crude product is purified by means of column chromatography on silica gel.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[C:10]2=[N:11][C:12]([CH3:22])=[C:13]([CH:16]([OH:21])[C:17]([O:19][CH3:20])=[O:18])[C:14]([I:15])=[C:9]2[CH:8]=[CH:7]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[C:10]2=[N:11][C:12]([CH3:22])=[C:13]([C:16](=[O:21])[C:17]([O:19][CH3:20])=[O:18])[C:14]([I:15])=[C:9]2[CH:8]=[CH:7]1
Reactant: COC(=O)C(O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1I
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)C(=O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a solution of methyl 2-(1-(3,4-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-hydroxyacetate (3.68 g, 6.23 mmol) in DCM (60 mL) at 0° C. was added Dess-Martin periodinane (3.17 g, 7.48 mmol) and the mixture was stirred at RT for 30 min. The mixture was diluted with DCM and washed with saturated Na2S2O3/water, saturated NaHCO3/water (2×), dried (Na2SO4), concentrated, and purified by column chromatography to provide methyl 2-(1-(3,4-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-oxoacetate (3.0 g, 6.06 mmol, 97% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.63 (s, 3 H), 3.98 (s, 3 H), 5.45 (s, 2 H), 6.44 (d, J=3.71 Hz, 1 H), 6.92-7.19 (m, 3 H), 7.23 (d, J=3.71 Hz, 1 H); LCMS (m/z) ES+=471 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH:15]=2)[C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH:15]=2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(C)cccc1COc1cccc(OCc2ccc3ccccc3n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(COc2cccc(OCc3ccc4ccccc4n3)c2)c1C(=O)O

Procedure:
A solution of methyl 2-methyl-6-[3-(quinolin-2-ylmethoxy)-phenoxymethyl]-benzoate (1.6 g, 3.8 mmol, example 4) in ethanol (25 mL) is heated with a 10N sodium hydroxide solution (4.0 mL, 40 mmol) at 70° C. for 14 h. The reaction is cooled, neutralized with a 2N HCl solution (20 mL) and concentrated to remove the ethanol. Ethyl acetate is added and washed with water. The aqueous layer is saturated with sodium chloride and back extracted with ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and concentrated to yield a crude solid. The solid is purified by column chromatography (silica, 5 to 10% methanol in dichloromethane) to provide the title compound. An analytically pure sample is prepared by recystallization from methanol: m.p. 167–168° C., 1H NMR (300 MHz, CDCl3)δ0.15 (d, 2H), 7.80 (d, 1H), 7.71 (t, 1H), 7.61–7.51 (m, 2H), 7.26–7.10 (m, 3H), 7.00 (t, 1H), 6.66 (s, 1H), 6.52 (d, 1H), 6.46 (d, 1H), 5.26 (s, 2H), 5.15 (s, 2H), 2.44 (s, 3H); MS (ESI) 400 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1cccc(OC)c1)C(=O)OCC
Reaction time: 3 h

Procedure:
According to Scheme A, ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (VIII) is obtained in four steps from commercially available synthetically accessible m-anisidine (II). m-Anisidine is combined with diethyl ethoxymethylenemalonate at temperatures ranging from 100° C. to about 125° C., preferably 125° C. for a period of 1 to 5 h, preferably about 3 h to provide diethyl 2-(((3-methoxyphenyl)amino)methylene)malonate. Ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (III) is obtained by heating Dowtherm™ at a temperature of 257° C. and diethyl 2-(((3-methoxyphenyl)amino)methylene)malonate for a period of 15 minutes to 2 h. Compound (IV) ethyl 7-methoxyquinoline-3-carboxylate is commercially available or synthetically accessible from ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (III) in two steps. Chlorination of compound (III) under conditions known to one skilled in the art, for example, but not limited to, oxalyl chloride, thionyl chloride, or phosphorus oxychloride, with or without a catalytic amount of DMF, in the presence or absence of a solvent such as DCM or CHCl3, at temperatures ranging from 50° C. to about 70° C., for a period ranging from 2 to 4 h, preferably 2.5 h, provides ethyl 4-chloro-7-methoxyquinoline-3-carboxylate. Subsequent reduction of ethyl 4-chloro-7-methoxyquinoline-3-carboxylate, employing Pd/C under hydrogenation conditions, in a solvent such as MeOH or EtOH, in the presence or absence of an acid such as acetic or formic acid, provides ethyl 7-methoxyquinoline-3-carboxylate (IV). Commercially available or synthetically accessible ethyl 7-methoxyquinoline-3-carboxylate (IV) is reacted under demethylation conditions, for example, HBr in H2O or HOAc, at temperatures ranging from 80° C. to about 110° C., preferably 105° C. for a period of 0.5 h to 24 h, preferably about 2 h, to provide 7-hydroxyquinoline-3-carboxylic acid. Ethyl 7-hydroxyquinoline-3-carboxylate (V), where R3 is H, is obtained by esterification of 7-hydroxyquinoline-3-carboxylic acid, employing methods known to one skilled in the art, for example, but not limited to, reaction of 7-hydroxyquinoline-3-carboxylic acid with an acid such as H2SO4, and the like, in a solvent such as EtOH, at temperatures ranging from 60° C. to about 80° C., preferably 75° C. for a period of about 12 to 24 h, preferably 20 h.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C@@H:10]1[NH:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C.Cl[C:27]1[CH:32]=[CH:31][N:30]2[N:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:29]2[N:28]=1>C(O)(C)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C@@H:10]1[N:14]([C:27]2[CH:32]=[CH:31][N:30]3[N:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:29]3[N:28]=2)[C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11]1
Reactant: CC1(C)CC[C@H](c2cc(F)ccc2F)N1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)c1cnn2ccc(N3[C@@H](c4cc(F)ccc4F)CCC3(C)C)nc12
Temperature: 160 °C
Yield: 28.1 %

Procedure:
A sealed pressure tube was charged with (R)-5-(2,5-difluoro phenyl)-2,2-dimethylpyrrolidine HCl salt (300 mg, 1.21 mmol), diisopropylethylamine (423 μA, 2.42 mmol), ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (273 mg, 1.21 mmol) and isopropanol (2.0 mL). The tube was sealed and the mixture was heated at 160° C. for 3 days. Additional ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (273 mg, 1.21 mmol) was added and the reaction was heated at 160° C. 2 days. The reaction mixture was concentrated and the residue purified by reverse phase HPLC (eluting with 0-60% acetonitrile/H2O) to provide the title compound (136 mg, 28%) as a beige solid. MS (apci) m/z=401.1 (M+H).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>>[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: CC(C)c1ccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Yield: 16.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (100 mg, 0.43 mmol) and 4-isopropylaniline (0.09 mL, 0.65 mmol) to provide 242 (24 mg, 15% yield) as a brown solid. LC-MS (M+H (parent)=330, obsd.=330).
Reaction SMILES: C([NH:14][CH:15]([C:19]1[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=1)[P:16]([OH:18])[OH:17])(C1C=CC=CC=1)C1C=CC=CC=1.C(NC(P(O)O)C(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[NH2:14][CH:15]([C:19]1[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=1)[P:16]([OH:17])[OH:18]
Reactant: CN(C)c1ccc(C(NC(c2ccccc2)c2ccccc2)P(O)O)cc1
Agent: CC(C)C(NC(c1ccccc1)c1ccccc1)P(O)O
Product: CN(C)c1ccc(C(N)P(O)O)cc1

Procedure:
The procedure described in Example 36B was repeated using DL-1-benzhydrylamino-1-(4-dimethylaminophenyl)-methanephosphonous acid instead of DL-1-benzhydrylamino-2-methylpropanephosphonous acid to give DL-1-amino-1-(4-dimethylaminophenyl)-methanephosphonous acid, melting point 223°-224°.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C@H:10]1[C@H:14]([CH2:15][CH2:16][OH:17])[CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:11]1.OC1C=CC=C(OC)C=1[C@H]1[C@H](CCO)CN(C(OC(C)(C)C)=O)C1>>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[C@H:10]3[CH2:11][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C@@H:14]3[CH2:15][CH2:16][O:17][C:2]=2[CH:7]=1
Reactant: COc1ccc([C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CCO)c(O)c1
Agent: COc1cccc(O)c1[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CCO
Product: COc1ccc2c(c1)OCC[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]21

Procedure:
The title compound was prepared as described in Example 272E substituting the product from Example 280D for the product from Example 272D.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][C:26]=1[C:27](O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][C:26]=1[C:27]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(S(C)(=O)=O)ccc2Cl)n1
Temperature: 150 °C
Yield: 26.1 %

Procedure:
A solution was prepared using 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol), 2-chloro-5-(methylsulfonyl)benzoic acid (0.108 g, 0.463 mmol), HATU (0.176 g, 0.463 mmol), triethylamine (0.047 g, 0.463 mmol) and anhydrous DMF (10 mL). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.042 g (26% yield) of pure product: MS (ES) m/z 522 (M+).
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[CH:14][CH:15]=2)C=CC=CC=1.C1(OC(Cl)=O)C=CC=CC=1.[CH3:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.CN(C=O)C>C(Cl)Cl>[CH:22]1([N:19]2[CH2:18][CH2:17][N:16]([C:13]3[N:12]=[CH:11][C:10]([NH:9][C:8]([N:42]4[CH2:43][CH2:44][CH:39]([CH3:38])[CH2:40][CH2:41]4)=[O:27])=[CH:15][CH:14]=3)[CH2:21][CH2:20]2)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C(Nc1ccc(N2CCN(C3CCCC3)CC2)nc1)Oc1ccccc1
Reactant: CC1CCNCC1
Agent: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1CCN(C(=O)Nc2ccc(N3CCN(C4CCCC4)CC3)nc2)CC1
Yield: 45.8 %

Procedure:
A mixture of 29 mg (0.08 mmol) [6-(4-cyclopentyl-piperazin-1-yl)-pyridin-3-yl]-carbamic acid phenyl ester (intermediately built from intermediate 6 and phenylchloroformate) and 12 mg (0.12 mmol) 4-methyl-piperidine (commercially available) in 1 ml DCM and 0.1 ml DMF was stirred at room temperature for 16 h. After evaporation the residue was taken up in methanol/DMF and subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.05% triethylamine). The combined product fractions were evaporated to dryness to yield 13.6 mg (46%) of the title compound. (m/e): 372.3 (MH+; 100%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20].O>CN(C)C=O>[Si:23]([O:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])[CH2:4][CH2:3]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:25])[CH3:24]
Reactant: CON(C)C(=O)C1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Yield: 73.4 %

Procedure:
4-Hydroxy-N-methoxy-N-methylcyclohexanecarboxamide (7.34 g, 39.2 mmol) in N,N-dimethylformamide (200 mL) was stirred with imidazole (4.80 g, 70.6 mmol) and tert-butylchlorodimethylsilane (7.70 g, 51.0 mmol) at room temperature for one day. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=25/1→4/1 (v/v)) to give the title compound as a colorless oil (8.68 g, yield 73%).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([S:19]([C:22]2[C:23]([S:33][CH3:34])=[N:24][N:25]3[C:30](Cl)=[CH:29][C:28]([CH3:32])=[N:27][C:26]=23)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[C:13]1([S:19]([C:22]2[C:23]([S:33][CH3:34])=[N:24][N:25]3[C:30]([N:10]4[CH2:11][CH2:12][N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH2:8][CH2:9]4)=[CH:29][C:28]([CH3:32])=[N:27][C:26]=23)(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Product: CSc1nn2c(N3CCN(c4ccccc4)CC3)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
0.16 g (1 mmol) of N-phenyl-piperazine was added to a solution of 0.17 g (0.5 mmol) of 3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 3 ml of DMF and stirred at 60° for 2 hrs. The reaction solution was cooled to RT and evaporated in a high vacuum. The residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 19:1) and crystallization from EtOH yielded 0.16 g (67%) of 3-benzenesulphonyl-5-methyl-2-methylsulphanyl-7-(4-phenyl-piperazin-1-yl)-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p. >230°.
Reaction SMILES: I.[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](SC)=[NH:16])=[CH:10][C:9]=2[O:19][CH3:20])[CH:7]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([N:30]1[CH:34]=[C:33]([Cl:35])[CH:32]=[N:31]1)[C:27](O)=O.[NH2:36][NH2:37]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:37][N:36]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:6]3[CH:7]=[C:3]([Cl:2])[N:4]=[CH:5]3)=[C:9]([O:19][CH3:20])[CH:10]=2)[N:16]=1)[N:30]1[CH:34]=[C:33]([Cl:35])[CH:32]=[N:31]1
Reactant: O=C(O)C(CCCCCl)n1cc(Cl)cn1
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(Cl)c1
Reactant: NN
Agent: I
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)n3cc(Cl)cn3)n2)ccc1-n1cnc(Cl)c1
Yield: 100 %

Procedure:
Methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylcarbamimidothioate, hydroiodide (500 mg, 1.69 mmol, from preparation A) and 6-chloro-2-(4-chloro-1H-pyrazol-1-yl)hexanoic acid (423 mg, 1.685 mmol, from preparation AK) were coupled and then reacted with hydrazine (0.212 mL, 6.74 mmol) using a procedure analogous to Step A of Example 13 to afford 5-(5-chloro-1-(4-chloro-1H-pyrazol-1-yl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (956 mg, 1.93 mmol, 100% yield). LC-MS (M+H)+ 497.2. The crude products were used in the subsequent step without purification.