Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[O-].[Na+].[C:5]1([NH2:12])[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].C([O:15][C:16](=O)[C:17](=[N:23][O:24][CH3:25])[C:18](OCC)=[O:19])C.Cl>C(O)C.C(#N)C>[CH3:25][O:24][N:23]=[C:17]1[C:18](=[O:19])[NH:12][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:11][C:16]1=[O:15]
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)C(=NOC)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Product: CON=c1c(=O)[nH]c2ccccc2[nH]c1=O
Temperature: 70 °C
Yield: 75.7 %

Procedure:
Dissolve 21 wt % NaOEt in EtOH solution (164 g, 0.507 mol) in 2B-3 ethanol (331 mL) and add 1,2-phenylenediamine (27.4 g, 0.253 mol). Stir the resulting mixture allow to stir at ambient temperature for approximately 30 minutes during which time all the solid material dissolves producing a dark amber solution. Add 2-methoxyimino-malonic acid diethyl ester (51.5 g, 0.253 mol). Heat the resulting mixture to 70° C. and stir under nitrogen for approximately 4 hours monitoring by HPLC analysis (Zorbax RX C18, 55% ACN/45% 0.1% TFA, 1 mL/min, 233 nm). Allow the reaction mixture to cool to ambient temperature. Lower the pH of the reaction mixture from 11.6 to 1.2 by the addition of 700 mL of aqueous 1N HCl solution. Concentrate the reaction mixture in vacuo to remove the ethanol. Filter the resulting amber slurry through a glass frit. Collect the solid and rinse with aqueous 1N HCl and dry under vacuum at 50° C. to afford 42 g (76% yield) of the title compound as a yellow solid; 1H NMR (300 MHz, CDCl3) δ 11.1 (s, 1H), 10.9 (s, 1H), 7.22 (s, 4H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.7; 159.4, 148.1, 128.5, 127.8, 125.8, 125.7, 122.8, 122.7, 63.1; IR (CHCl3) 3062, 2970, 2902, 1704, 1656, 1606, 1505, 1414, 1058, 1043, 754 cm−1; UV (EtOH) λmax 278 nm (ε 4623), 276 nm (ε 4618), 216 nm (ε 41495); HRMS (ES+) exact mass calc'd for C10H9N3O3 242.0542, Found 242.0553; Anal. calc'd for C10H9N3O3: C, 54.79; H, 4.14; N, 19.17. Found: C, 54.60; H, 4.15; N, 18.94.
Reaction SMILES: [Ca].[CH3:2][CH:3]([C@@H:5]1[C@@:14]([O:31]C(COC)=O)([CH2:15][CH2:16][N:17]([CH2:19][CH2:20][CH2:21][C:22]2[NH:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[N:30]=2)[CH3:18])[CH2:13][CH2:12][C:11]2[CH:10]=[C:9]([F:37])[CH:8]=[CH:7][C:6]1=2)[CH3:4].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.CC([C@@H]1[C@@](OC(COC)=O)(CCN(CCCC2NC3C=CC=CC=3N=2)C)CCC2C=C(F)C=CC1=2)C.Cl.Cl.FC1C=C2C(=CC=1)[C@H](C(C)C)[C@](CCOS(C1C=CC(C)=CC=1)(=O)=O)(O)CC2.N1C2C=CC=CC=2N=C1CCCNC.CCN(C(C)C)C(C)C>>[NH:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=2[N:30]=[C:22]1[CH2:21][CH2:20][CH2:19][N:17]([CH3:18])[CH2:16][CH2:15][C@@:14]1([OH:31])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:37])[CH:10]=2)[C@@H:5]1[CH:3]([CH3:2])[CH3:4]
Reactant: COCC(=O)O[C@]1(CCN(C)CCCc2nc3ccccc3[nH]2)CCc2cc(F)ccc2[C@@H]1C(C)C
Agent: CNCCCc1nc2ccccc2[nH]1
Agent: Cc1ccc(S(=O)(=O)OCC[C@@]2(O)CCc3cc(F)ccc3[C@@H]2C(C)C)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H]1c2ccc(F)cc2CC[C@]1(O)CCN(C)CCCc1nc2ccccc2[nH]1

Procedure:
U.S. Pat. No. 4,808,605 (to Hoffinann-La Roche) discloses various calcium antagonists including mibefradil, (1S,2S)-2-[2-{[3-(1H-benzimidazol-2-yl)propyl]-methylamino }ethyl]-6-fluoro- 1-isopropyl- 1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate, the dihydrochloride salt of which is the active ingredient of the antihypertensive POSICOR®. The synthesis of mibefradil, as described in that patent, involves the reaction of (1S,2S)-6-fluoro-1-isopropyl-2-[2-(4-toluenesulfonyloxy) ethyl]-1,2,3,4-tetrahydronaphthalene-2-ol with [3-(1H-benzimidazol-2-yl)propyl]methylamine in the presence of Hunig base (ethyldiisopropylamine) to form ( 1S,2S)-2-[2-{[3-( 1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol, which is then acylated with methoxyacetyl chloride in chloroform in the presence of ethyldiisopropylamine to form mibefradil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].[Cl:12][C:13]1[C:14]([CH3:23])=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>>[Cl:12][C:13]1[C:14]([CH3:23])=[C:15]([S:19]([NH:9][C:5]2[C:4]([O:10][CH3:11])=[N:3][C:2]([Cl:1])=[C:7]([Cl:8])[N:6]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: COc1nc(Cl)c(Cl)nc1N
Product: COc1nc(Cl)c(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1C

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6-dichloro-3-methoxy-2-pyrazinamine (0.1 g) and 3-chloro-2-methylbenzenesulphonyl chloride (0.14 g). Yield 0.13 g.
Reaction SMILES: [CH2:1]([O:4][NH:5][C:6]1[C:11]([NH:12][CH:13]=O)=[C:10]([Cl:15])[N:9]=[C:8]([NH:16]C=O)[N:7]=1)[CH:2]=[CH2:3]>C(OC(OCC)OCC)(=O)C>[CH2:1]([O:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([NH2:16])=[N:9][C:10]=2[Cl:15])[CH:2]=[CH2:3]
Reactant: C=CCONc1nc(NC=O)nc(Cl)c1NC=O
Agent: CCOC(OCC)OC(C)=O
Product: C=CCOn1cnc2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.9 %

Procedure:
A solution of 4-allyloxyamino-6-chloro-2.5-diformamido pyrimidine (1.23 g, 4.53 mmol) in diethoxymethyl acetate (20 ml) was stirred at 120° C. for 4 hours. The reaction was cooled and evaporated to dryness under reduced pressure. The residue was dissolved in methanol (5 ml) containing 0.88 ammonia (10 ml) and stirred at 25° C. for 16 hours. The solvents were evaporated under reduced pressure and the residue chromatographed on silica gel (eluted with ethyl acetate hexane 1:1) yielding the title compound (520 mg, 51%), m.p. 137°-9° C. UV: λmax (MeOH) 224 (ε 25,700). 247 (ε 5,300), 309 (ε 7.400) nm. IR: υmax (KBr) 3480, 3400. 3310, 3200, 1635, 1615, 1560, 1510, 1465 cm-1. 1H NMR δH [(CD3)2SO] 4.84 (2H, d, J=6 Hz, CH2ON), 5.35 (2H, m, CH2 =CH), 6.13 (1H, m, CH=CH2), 7.10 (2H, br.s, NH2), 8.35 (1H, s, H-8). Found: C, 42.45; H, 3.63; N, 30.39%; M+ 225.0406. C8H8Cl N5O requires C, 42.58; H, 3.57; N, 31.04%; M+ 225.0414.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.O.[C:11]1(C)[CH:16]=[CH:15][C:14]([S:17](O)(=O)=O)=[CH:13][CH:12]=1.C1(S)C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5]([S:17][C:14]2[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH2:3]1
Reactant: CC1(C)CCC(=O)CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Sc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)CC=C(Sc2ccccc2)CC1

Procedure:
A stirred solution of 4,4-dimethylcyclohexanone (1 g.), p-toluene sulphonic acid monohydrate (23 mg.) and thiophenol (0.81 ml.) in toluene (24 ml.) was heated at reflux for 9 hours with azeotropic removal of water using a Dean and Stark apparatus. The mixture was cooled, diluted with toluene (25 ml.) and extracted with saturated sodium bicarbonate solution (2×10 ml.), washed with water (3×10 ml.) and dried (MgSO4). Evaporation of the solvent gave (4,4-dimethylcyclohex-1-enyl)phenylsulphide as an oil (1.66 g.); NMR (CDCl3,90 MHz): 0.94 (6H,s), 1.45 (2H,t), 1.98 (2H,m), 2.18 (2H,m), 6.02 (1H,m) and 7.3 (5H,m).
Reaction SMILES: [OH-].[Na+].[CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:23]=[C:24]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH:25]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][N:14]=1)=[O:11])([CH3:5])[CH3:4].O.Cl>C1COCC1>[CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:23]=[C:24]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH:25]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][N:14]=1)=[O:11])([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(COc3ccccc3F)cc(OC(C)C)c2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1cc(COc2ccccc2F)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Yield: 96.8 %

Procedure:
2M NaOH (0.55 ml, 1.1 mM) was added to methyl 2-[3-isopropyloxy-5-(2-fluorophenoxy) methyl benzoyl]amino-5-pyridine carboxylate (0.16 g, 0.36 mM) in THF (10 ml)/water (10 ml) at ambient temperature. After 4 hrs the reaction mixture was neutralised to pH=4–5 with 2M HCl, concentrated, filtered, washed with water, and dried under high-vacuum to give the title compound as a colourless solid (0.15 g, 98%); 1H NMR δ (d6-DMSO): 1.28 (d, 6H), 4.74 (m, 1H), 5.20 (s, 2H), 6.87–6.97 (m, 1H), 7.10 (m, 1H), 7.16–7.26 (m, 3H), 7.54 (s, 1H), 7.66 (s, 1H), 8.28 (s, 2H), 8.84 (s, 1H), 11.78 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13]#[C:14][C:15]([OH:18])([CH3:17])[CH3:16])=[CH:8][C:9]=1[N+:10]([O-])=O)=[O:4].COC(C1SC(CCC(O)(C)C)=CC=1[N+]([O-])=O)=O>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:13][CH2:14][C:15]([OH:18])([CH3:16])[CH3:17])=[CH:8][C:9]=1[NH2:10])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)O)cc1[N+](=O)[O-]
Agent: COC(=O)c1sc(CCC(C)(C)O)cc1[N+](=O)[O-]
Product: COC(=O)c1sc(CCC(C)(C)O)cc1N

Procedure:
5-(3-Hydroxy-3-methylbut-1-ynyl)-3-nitrothiophene-2-carboxylic acid methyl ester was reduced by method E1 under a pressure of 3 bar to 5-(3-hydroxy-3-methylbutyl)-3-nitrothiophene-2-carboxylic acid methyl ester. The product with the molecular weight of 243.33 (C11H17NO3S) was obtained in this way; MS (ESI): 244 (M+H+).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1B(O)O.BrC1C=CC(N)=CC=1Cl.ClC1C=CC(B(O)O)=CC=1>>[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=1[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc(Br)cc1
Agent: Nc1ccc(Br)c(Cl)c1
Agent: OB(O)c1ccc(Cl)cc1
Product: Nc1ccc(-c2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
The title compound was prepared as described in Example 15 substituting 4-bromoaniline and (2-chloro-4-(trifluoromethyl)phenyl)boronic acid for 4-bromo-3-chloroaniline and (4-chlorophenyl)boronic acid, respectively.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:19]=3)=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1.Cl.FC1C=C(N[C:60](=[O:72])[CH2:61][C:62]([NH:64][C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)=[O:63])C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:30][C:60](=[O:72])[CH2:61][C:62]([NH:64][C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)=[O:63])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[CH:19]=3)=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Oc2ncnn3cc(-c4ccnc(N5CCOCC5)c4)cc23)c(F)c1
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)Nc1ccc(Oc2ncnn3cc(-c4ccnc(N5CCOCC5)c4)cc23)c(F)c1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
To a solution of 3-fluoro-4-(6-(2-morpholinopyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (15 mg, 0.037 mmol) and 3-(4-fluorophenylamino)-3-oxopropanoic acid (8 mg, 0.04 mmol, Compound A of Example 25) in DMF (1 mL) were added DIEA (0.1 mL, 0.57 mmol) and TBTU (13 mg, 0.04 mmol). The reaction mixture was stirred at room temperature overnight and then purified using preparative HPLC. The fraction containing the desired product was collected and concentrated in vacuo. The residue was neutralized with 1 N NH4OH and concentrated again. The solid that formed was filtered, washed with 1 N NH4OH, dissolved in MeOH/H2O, and lyophilized to give the title compound (8 mg, 37%). 1H NMR (DMSO-d6) δ 10.49 (s, 1H), 10.23 (s, 1H), 8.63 (s, 1H), 8.55 (s, 1H), 8.06 (s, 1H), 8.00 (d, 1H, J=7.5 Hz), 7.70 (m, 1H), 7.50 (m, 2H), 7.30-7.45 (m, 3H), 7.04-7.17 (m, 3H), 6.85-6.92 (m, 2H), 3.36 (s, 4H), 3.44 (s, 6H); MS(ESI) m/z 586.2 (M+H)+.
Reaction SMILES: N12CCCN=C1CCCCC2.[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:37][CH2:38][CH2:39]Br)=[C:28]([O:31][CH:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:16]=[CH:17][C:18]=1[F:19].[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:37][CH2:38][CH2:39][N:51]4[CH2:50][CH2:49][N:48]([C:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:47])[CH2:53][CH2:52]4)=[C:28]([O:31][CH:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1ccc(Nc2ncnc3cc(OCCBr)c(OC4CCCC4)cc23)cc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CCOc2cc3ncnc(Nc4ccc(F)c(Cl)c4)c3cc2OC2CCCC2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
340 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene are added at ambient temperature to 940 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-(2-bromoethoxy)-quinazoline and 1.00 g of N-(tert.butyloxycarbonyl)-piperazine in 30 ml of acetonitrile. The reaction mixture is heated to 60° C. for five hours. Then a further 0.2 g of N-(tert.butyloxycarbonyl)-piperazine and some 1,8-diazabicyclo[5.4.0]undec-7-ene are added. The yellow reaction solution is stirred for two hours at 60° C. and then overnight at ambient temperature, during which time a white precipitate is formed. This is suction filtered, washed with a little acetonitrile and dried. 453 mg of the desired product are obtained as a white solid. The mother liquor is concentrated by evaporation and the flask residue is chromatographed over a silica gel column with methylene chloride/methanol (95:5). Another 300 mg of the desired product are obtained.
Reaction SMILES: C([O:8][C:9](=[O:31])[CH:10]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)C1C=CC=CC=1.[OH-].[Na+].Cl>O1CCCC1.CO.O>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:9]([OH:31])=[O:8])=[CH:26][CH:25]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1ccc(C(Cc2ccc([N+](=O)[O-])cc2)C(=O)OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(Cc2ccc([N+](=O)[O-])cc2)C(=O)O)cc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 119.2 %

Procedure:
To 2-(4-tert-Butyl-phenyl)-3-(4-nitro-phenyl)-propionic acid benzyl ester (8.6 g, 20.6 mmol) in 30 ml tetrahydrofuran, 20 ml methanol and 10 ml water was added sodium hydroxide (0.6 g, 24.7 mmol). The reaction mixture was stirred at 23° C. for 16 h, acidified with 4N hydrochloride acid, and concentrated. The residue was partitioned between ethyl acetate and water. The organic phase was washed with water, dried over magnesium sulfate, and concentrated to afford 2-(4-tert-Butyl-phenyl)-3-(4-nitro-phenyl)-propionic acid as a brownish oil (8.04 g, 100%).
Reaction SMILES: C(O)C(N)(CO)CO.CC(CC(C1C=[CH:21][C:20]([O:23]CCOCCO)=[CH:19][CH:18]=1)(C)C)(C)C.[F-].[Na+].C1(CS(F)(=O)=O)C=CC=CC=1.CC(C[C@H](NC(C)=O)C(N[C@H](C([NH:58][C@H:59]([C:67]([OH:69])=[O:68])[CH2:60][CH2:61][CH2:62]N=C(N)N)=O)CC(C)C)=O)C>OCC(CO)O>[NH2:58][C@H:59]([C:67]([OH:69])=[O:68])[CH2:60][C:61]1[CH:62]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1
Reactant: CC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O
Reactant: CC(C)(C)CC(C)(C)c1ccc(OCCOCCO)cc1
Agent: NC(CO)(CO)CO
Agent: O=S(=O)(F)Cc1ccccc1
Agent: [F-]
Solvent: OCC(O)CO
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
Sf21 cells were infected with a baculovirus expression vector for BTK or SYK, as previously described (refs 18 and 19). Cells were harvested, lysed (10 mM Tris pH 7.6, 100 mM NaCl, 1% Nonidet P-40, 10% glycerol, 50 mM NaF, 100 mM Na3VO4, 50 μg/ml phenylmethylsulfonyl fluoride, 10 μg/ml aprotonin, 10 μg/ml leupeptin), and the kinase proteins were purified to homogeneity, as reported (refs 18 and 19).
Reaction SMILES: O[C:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)[CH:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.C(O)(C(F)(F)F)=O.CCCCC>C(Cl)Cl>[C:26]1([C:2]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=2)=[C:3]2[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)(c2ccccc2)c2ccc(C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCCCC
Product: FC(F)(F)c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
To a solution of tert-butyl 4-(hydroxy(phenyl)(4-(trifluoromethyl)phenyl)methyl)piperidine-1-carboxylate (1.0 g, 2.29 mmol) in dry DCM (10 mL) at 0° C. was added TFA (10 mL) dropwise and the resulting solution was stirred at rt for 16 h. The solvents were removed under vacuum. The residue was diluted with DCM, washed with sodium bicarbonate solution and water, dried over sodium sulfate and concentrated under vacuum to afford crude compound which was crashed out of pentane to give 4-(phenyl(4-(trifluoromethyl)phenyl)-methylene)piperidine (0.5 g, 69%) as a grey solid. MS (ESI, pos. ion) m/z: 318 (M+1).
Reaction SMILES: [OH:1][CH:2]([CH2:39][N:40]([CH2:51][CH2:52][OH:53])[CH:41]1[CH2:46][C:45]([CH3:48])([CH3:47])[NH:44][C:43]([CH3:50])([CH3:49])[CH2:42]1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([OH:38])[CH2:23][N:24]([CH:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]3)[CH2:25][CH2:26][OH:27])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:7][CH:6]=1>C(OC(=O)C)(=O)C>[C:17]([O:38][CH:22]([CH2:23][N:24]([CH2:25][CH2:26][O:27][C:2](=[O:1])[CH3:3])[CH:28]1[CH2:33][C:32]([CH3:35])([CH3:34])[N:31]([C:5](=[O:4])[CH3:6])[C:30]([CH3:37])([CH3:36])[CH2:29]1)[CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH:2]([O:1][C:26](=[O:27])[CH3:25])[CH2:39][N:40]([CH:41]3[CH2:42][C:43]([CH3:50])([CH3:49])[N:44]([C:22](=[O:38])[CH3:21])[C:45]([CH3:48])([CH3:47])[CH2:46]3)[CH2:51][CH2:52][O:53][C:52](=[O:53])[CH3:51])=[CH:10][CH:9]=2)([CH3:13])[CH3:12])=[CH:15][CH:16]=1)(=[O:20])[CH3:16]
Reactant: CC1(C)CC(N(CCO)CC(O)COc2ccc(C(C)(C)c3ccc(OCC(O)CN(CCO)C4CC(C)(C)NC(C)(C)C4)cc3)cc2)CC(C)(C)N1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCCN(CC(COc1ccc(C(C)(C)c2ccc(OCC(CN(CCOC(C)=O)C3CC(C)(C)N(C(C)=O)C(C)(C)C3)OC(C)=O)cc2)cc1)OC(C)=O)C1CC(C)(C)N(C(C)=O)C(C)(C)C1

Procedure:
A mixture of 200 ml of acetic anhydride and 7.4 g of 2,2-bis[4-{2-hydroxy-3-[N-(2-hydroxyethyl)-N-(2,2,6,6-tetramethyl-4-piperidyl)amino]propoxy}phenyl]propane, obtained as described in Example 17, was reacted in a manner similar to that described in Example 13, giving the desired compound in the form of a pale yellow, very viscous product. The compound had an Rf value of 0.61 on thin layer chromatography on silica gel developed with a 20:4:2:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:13])[C:6]([NH2:12])=[CH:7][CH:8]=2)[N:3]=1.[CH:14]([CH:16]=O)=O>C(O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[N:12]=[CH:16][CH:14]=[N:13][C:5]=3[C:4]=2[N:3]=1
Reactant: Cc1ccc2ccc(N)c(N)c2n1
Reactant: O=CC=O
Solvent: CCO
Product: Cc1ccc2ccc3nccnc3c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.8 %

Procedure:
To a solution of 2-methylquinoline-7,8-diamine (255 mg, 1.48 mmol) in ethanol (3 mL) was added glyoxal (103 mg, 1.78 mmol). The mixture was stirred at room temperature for 2 h. The mixture was then concentrated to give 9-methylpyrido[2,3-f]quinoxaline as a yellow solid (300 mg). MS (ESI): m/z 196 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([C@H:12]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:14](=[O:27])[C@H:13]1[NH2:28])=[O:11].[C:29]1([CH2:35][C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH3:8][O:9][C:10]([C@H:12]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:14](=[O:27])[C@H:13]1[NH:28][C:36](=[O:37])[CH2:35][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:11]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)[C@@H]1[C@H](N)C(=O)N1Cc1ccc(OC)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1[C@H](NC(=O)Cc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Reaction time: 1 h

Procedure:
Under ice-cooling and stirring, 2.10 ml of triethylamine is added to a solution of 2.94 g of cis-3-amino-1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4-carboxylic acid methyl ester in 40 ml of methylene chloride, and a solution of 2.31 g of phenylacetyl chloride in 15 ml of methylene chloride is then added dropwise over 1 hour. The stirring is continued for another one hour under ice-cooling, and the reaction mixture is then washed successively with dilute hydrochloric acid, 5% aqueous sodium hydrogen carbonate and an aqueous sodium chloride solution, and dried over magnesium sulfate, and the solvent is distilled off in vacuo. Ether is added to the residue and the precipitated crystals are collected by filtration to give cis-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-2-oxoazetidine-4-carboxylic acid methyl ester, m.p. 124°-126° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]3[N:17]([CH2:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]4)[C:18]([N:20]4[CH2:24][CH2:23][CH2:22][C@H:21]4[CH2:25][F:26])=[N:19][C:15]=3[CH:14]=[C:13]([C:35]#[N:36])[N:12]=2)[CH:8]=[N:9][CH:10]=1>CO>[CH3:1][O:2][C:35]([C:13]1[N:12]=[C:11]([C:7]2[CH:8]=[N:9][CH:10]=[C:5]([Cl:4])[CH:6]=2)[C:16]2[N:17]([CH2:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]3)[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[CH2:25][F:26])=[N:19][C:15]=2[CH:14]=1)=[NH:36]
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3CF)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1cc2nc(N3CCC[C@H]3CF)n(C[C@H]3CC[C@H](C)CC3)c2c(-c2cncc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium methoxide (5.20 mg, 0.096 mmol) was added to a solution of 4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Example 3.1, Step 1; 150 mg, 0.321 mmol) in methanol (321 μL), and the vial was sealed and allowed to stir at ambient temperature overnight. The reaction was concentrated to afford crude methyl-4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-carbimidate. MS ESI calc'd. for C26H32ClFN6O [M+H]+ 499. found 499. This material was taken on to Step 2 without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@H:10]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH:20]=1)[O:11][CH2:12][C:13]1(CC#N)[CH2:15][CH2:14]1.[OH-].[K+].CCO.[CH3:38][C:39]([OH:41])=[O:40]>CCOC(C)=O.C1(C)C=CC=CC=1.CC(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@H:10]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH:20]=1)[O:11][CH2:12][C:13]1([CH2:38][C:39]([OH:41])=[O:40])[CH2:15][CH2:14]1
Reactant: CC(=O)O
Reactant: N#CCC1(CO[C@H](CCc2ccccc2Br)c2cccc(COC3CCCCO3)c2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(O)CC1(CO[C@H](CCc2ccccc2Br)c2cccc(COC3CCCCO3)c2)CC1
Yield: 75 %

Procedure:
A mixture of the nitrile of Step 6 (13.22 g, 26.5 mmol), 8N KOH (330 mL), and EtOH (130 mL) was heated to reflux for 17 hr. 25% Aq. NH4OAc (500 mL) and AcOH (190 mL) were than added at room temperature (to give pH~6) and the product was extracted in EtOAc and dried over Na2SO4. Hash chromatography of the residue with EtOAc:toluene:AcOH 10:90:1 afforded 10.34 g (75% yield) of the title acid.