Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[C:32]([F:36])=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37](O)=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[F:36][C:32]1[C:24]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]3[CH2:11][C@@H:10]([C:37]([N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)=[O:38])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13]3)=[O:20])=[N:22][C:23]=2[CH:35]=[CH:34][CH:33]=1
Reactant: C1CCNC1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2cccc(F)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCCC3)CN(C(=O)OC(C)(C)C)C2)nc2cccc(F)c21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (1.65 g), pyrrolidine (500 μl), HOBt (270 mg) and triethylamine (1.27 ml) were dissolved in DMF (50 ml), WSC.HCl (1.15 g) was added, and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95)-ethyl acetate-ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object product (170 mg).
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.C(O)(=O)C.[C:49]([NH:52][CH2:53][CH2:54][NH2:55])(=[O:51])[CH3:50].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[C:49]([NH:52][CH2:53][CH2:54][NH:55][CH2:1][C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:36][CH:37]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)(=[O:51])[CH3:50]
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(=O)NCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C=C(C)[C@@H]1CC[C@]2(CNCCNC(C)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.1 g, 0.167 mmol) in DCE (2 ml) was added acetic acid (0.019 ml, 0.334 mmol) and N-acetylethylenediamine (0.048 ml, 0.501 mmol). The mixture was stirred for 2 h at rt then to the mixture was added sodium triacetoxyborohydride (0.177 g, 0.835 mmol). The mixture was stirred at rt for 3 days then was diluted with 7 ml of sat. NaHCO3 and was extracted with dichloromethane (3×7 ml). The combined organic layers were dried with Na2SO4, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude material was used in the next step with no additional purification. LCMS: m/e 685.4 (M+H)+, 3.86 min (method 6).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13](=[NH:15])[NH2:14])=[N:6]1.[CH3:20][O:21][CH:22]([C:25]#[N:26])[C:23]#[N:24].O>CN(C=O)C>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:14]=[C:25]([NH2:26])[C:22]([O:21][CH3:20])=[C:23]([NH2:24])[N:15]=2)=[N:6]1
Reactant: COC(C#N)C#N
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2c1CCC2
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(N)nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1N
Temperature: 100 °C

Procedure:
100 mg of 1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboximidamide 1-2-4 (0.39 mmol, 1.0 eq.) and 37 mg methoxymalononitrile (0.39 mmol, 1.0 eq.; for preparation see: US2003/144538 A1, 2003) were dissolved in 1 mL DMF. The mixture was heated for 30 min in a microwave oven at 100° C. After addition of 10 mL water, the precipitated, crude product was filtered off and was purified by flash chromatography yielding 66 mg (0.19 mmol, 48%) of analytically pure target compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:5][C@H:4]([NH:6][C:7]2[C:8]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[N:12]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42]>C(Cl)Cl>[CH3:19][N:17]1[CH:18]=[C:14]([NH:13][C:11]2[N:12]=[C:7]([NH:6][C@H:4]3[CH2:3][C@H:2]([NH:1][C:40](=[O:43])[CH:41]=[CH2:42])[CH2:5]3)[C:8]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:9]=3[N:10]=2)[CH:15]=[N:16]1
Reactant: C=CC(=O)Cl
Reactant: Cn1cc(Nc2nc(N[C@H]3C[C@H](N)C3)c3ccn(COCC[Si](C)(C)C)c3n2)cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N[C@H]1C[C@H](Nc2nc(Nc3cnn(C)c3)nc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N4-((trans)-3-aminocyclobutyl)-N2-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (87 mg, 0.2 mmol) was dissolved in DCM (5 mL). DIPEA (53 μL, 0.3 mmol) was added and the reaction was cooled to 0° C. Acryloyl chloride (16 μL, 0.2 mmol) was added via a 10 μL syringe and the reaction was allowed to stir at 0° C. for 1 hr. The reaction was concentrated and purified via flash chromatography eluting with a gradient of 1%-20% EtOH in DCM. The fractions containing the product were pooled and dried down to afford the title compound as a tan solid (confirmed to be product by LCMS). This tan solid was taken directly to the final step.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([O:21][C:22](=[O:39])[C@H:23]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=1)[NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH3:20]>C(C(C)=O)C.[I-].[K+]>[CH2:19]([O:21][C:22](=[O:39])[C@H:23]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=2)[CH:33]=1)[NH:24][C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH3:20]
Reactant: CCOC(=O)[C@H](Cc1cccc(O)c1)NC(=O)C(F)(F)F
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)[C@H](Cc1cccc(OCc2ccc3ccccc3c2)c1)NC(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 14 h
Yield: 78.8 %

Procedure:
2-(Bromomethyl)naphthalene (453 mg, 1.97 mmol), potassium carbonate (340 mg, 2.46 mmol) and potassium iodide (14 mg, 0.084 mmol) were added in turn to a solution of N-trifluoroacetyl-3-hydroxy-L-phenylalanine ethyl ester (500 mg, 1.64 mmol) in methyl ethyl ketone (20 ml) and the mixture was stirred under argon atmosphere at 60° C. for 14 hrs. The reaction mixture was cooled to room temperature and the insoluble materials were filtered off and washed with ethyl acetate. The filtrate and washings were combined and washed with water and brine and then dried. The solvent was distilled off under reduced pressure. The residue was purified, by column chromatography on silica gel (n-hexane/ethyl acetate=12) to give N-trifluoroacetyl-3-[(2-naphthyl)methoxy]-L-phenylalanine ethyl ester (576 mg, 79%) as colorless crystals.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22]>>[C:20]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[CH2:7][O:6][C:5]1[CH:13]=[CH:14][CH:15]=[C:16]([N+:17]([O-:19])=[O:18])[C:4]=1[C:2]#[N:3])(=[O:24])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)C(=O)Cl
Reactant: N#Cc1c(OC[C@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: [Cl-]
Product: CC(C)C(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 176b from (R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride and isobutyryl chloride in 100% yield as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 0.96 (dd, J=6.6, 3.5 Hz, 6H), 1.93 (m, 4H), 2.14 (m, 1H), 2.66 (sept, J=6.6 Hz, 1H), 3.55 (m, 1H), 4.28 (m, 3H), 7.79 (dd, J=7.6, 1.8 Hz, 1H), 7.89 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([F:24])[CH:23]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][C@@H:16]([CH3:20])[CH2:17][O:18][CH3:19])[CH:14]=1)[C:9]([OH:11])=O.[CH2:25]([O:27][C:28](=[O:37])[CH2:29][S:30][C:31]1[S:35][C:34]([NH2:36])=[N:33][CH:32]=1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:37])[CH2:29][S:30][C:31]1[S:35][C:34]([NH:36][C:9](=[O:11])[C:8]2[CH:12]=[C:13]([O:15][C@@H:16]([CH3:20])[CH2:17][O:18][CH3:19])[CH:14]=[C:6]([O:5][C:4]3[CH:21]=[C:22]([F:24])[CH:23]=[C:2]([F:1])[CH:3]=3)[CH:7]=2)=[N:33][CH:32]=1)[CH3:26]
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: COC[C@H](C)Oc1cc(Oc2cc(F)cc(F)c2)cc(C(=O)O)c1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(Oc3cc(F)cc(F)c3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from 3-(3,5-difluoro-phenoxy)-5-((S)-2-methoxy-1-methyl-ethoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: [C:1](Cl)(=O)C.[OH:5][C:6]1[C:7]([CH3:15])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10]>CO>[CH3:1][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([OH:5])[C:7]=1[CH3:15]
Reactant: CC(=O)Cl
Reactant: Cc1c(O)cccc1C(=O)O
Solvent: CO
Product: COC(=O)c1cccc(O)c1C
Temperature: 25 °C
Yield: 87.3 %

Procedure:
Acetyl chloride (5.4 ml, 5.96 g, 76 mmol) was added dropwise to methanol (15 ml) at 0° C. in a sealed 50 ml round-bottom flask. This solution was allowed to warm to room temperature for 1 hour while stirring. To this solution 3-hydroxy-2-methyl-benzoic acid (519 mg, 3.4 mmol) was added and the solution was stirred at room temperature for 42 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and solid sodium bicarbonate. The volatiles were removed in vacuo and the basic aqueous solution was then extracted with dichloromethane (4×40 ml). The combined organic extracts were dried (MgSO4), filtered, and the solvent evaporated in vacuo affording 493 mg (87%) of 3-hydroxy-2-methyl-benzoic acid methyl ester as a solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30]([O:32]CC)=O)[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36]1([NH2:40])[CH2:39][CH2:38][CH2:37]1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30]([NH:40][CH:36]3[CH2:39][CH2:38][CH2:37]3)=[O:32])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Reactant: NC1CCC1
Product: CS(=O)(=O)c1ccc(Cn2c(=O)c(C(=O)NC3CCC3)c(O)c3ncc(Cc4ccccc4)cc32)cc1

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-1-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclobutylamine employing methods similar to those described in Example 2. The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.19 (1H, br d, J=7.4 Hz), 8.61 (1H, d, J=1.1 Hz), 7.82 (2H, d, J=8.4 Hz), 7.30 (3H, m), 7.18 (2H, d, J=8.4 Hz),7.06 (1H, s), 7.03 (2H, m), 5.41 (2H, br), 4.54 (1H, m), 4.05 (2H, s), 3.02 (3H, s), 2.44 (2H, m), 2.08 (2H, m), 1.83 (2H, m); HRMS calcd for C28H27N3O5S+H+: 518.1740. Found: 518.1741.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.Cl[CH2:17][CH2:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21].C1(C)C=CC=CC=1.[NH2-].[Na+]>O>[C:1]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:2]=[CH:3][C:4]([CH:7]([CH2:17][CH2:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[C:8]#[N:9])=[CH:5][CH:6]=1
Reactant: CC(C)N(CCCl)C(C)C
Reactant: N#CCc1ccc(-c2ccccc2)cc1
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N(CCC(C#N)c1ccc(-c2ccccc2)cc1)C(C)C
Temperature: 80 °C

Procedure:
The solution of 100 parts of α-(4-biphenylyl)acetonitrile and 90 parts of 2-chloro-N,N-diisopropylethylamine in 850 parts by volume of toluene is heated to about 80° C. and then 22 parts of sodium amide is added slowly over a period of 30 minutes keeping the temperature at 80°-85° C. The mixture is heated at 80° C. for another 30 minutes and then cooled to room temperature. 500 Parts by volume of water is then added to the mixture and the organic layer is separated and extracted with dilute hydrochloric acid. The aqueous acidic extract is made alkaline by the addition of dilute sodium hydroxide. The alkaline mixture is extracted with ether and the ether extract is dried over calcium sulfate, filtered and stripped of solvent to afford an oil which solidifies upon standing. The crude oil is crystallized from hexane to afford α-(4-biphenylyl)-α-[2-(diisopropylamino)ethyl]acetonitrile, melting at about 54°-56° C. This compound is represented by the following structural formula ##STR21##
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:26])=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:36]([C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]>C1COCC1>[C:36]([C:40]1[CH:41]=[CH:42][C:43]([C:44]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([NH:17][C:18]4[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=4)[C:11]4[N:12]([CH:14]=[CH:15][N:16]=4)[CH:13]=3)[C:3]=2[CH3:26])=[O:45])=[CH:47][CH:48]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: Cc1c(N)cccc1-c1cn2ccnc2c(Nc2ccc(C#N)cc2)n1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn2ccnc2c(Nc2ccc(C#N)cc2)n1
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
A solution of 4-[6-(3-amino-2-methyl-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-benzonitrile (380 mg; 1.12 mmol) and diisopropylethylamine (187 mg; 1.45 mmol) in anhydrous THF (25 mL) is stirred under nitrogen at rt. A solution of 4-tert-Butyl-benzoyl chloride (230 mg; 1.17 mmol) in 5 mL anhydrous THF is then added dropwise to the stirring reaction solution. After 30 minutes, the mixture is partitioned between ethyl acetate (75 mL) and water (75 mL) and the water layer extracted with ethyl acetate (2×50 mL). The organic layers are pooled, washed with brine and dried over anhydrous sodium sulfate. The filtrate is then concentrated in vacuo and the crude oil dissolved in a minimum volume of CH2Cl2. Diethyl ether is added and the resulting precipitate is filtered and washed with diethyl ether to provide 4-tert-butyl-N-{3-[8-(4-cyano-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-2-methyl-phenyl}-benzamide as a light orange solid (450 mg)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C@H:5]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=1)[NH:6][S:7]([C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][NH:16][CH2:17]2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:2].I[CH:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:29])[C@H:5]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=1)[NH:6][S:7]([C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][N:16]([CH:31]([CH3:33])[CH3:32])[CH2:17]2)=[CH:12][CH:11]=1)(=[O:8])=[O:9])[CH3:2]
Reactant: CC(C)I
Reactant: CCOC(=O)[C@H](Cc1cccc(C#N)c1)NS(=O)(=O)c1ccc2c(c1)CNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@H](Cc1cccc(C#N)c1)NS(=O)(=O)c1ccc2c(c1)CN(C(C)C)CC2
Reaction time: 1 h
Yield: 74.8 %

Procedure:
A stirred mixture of N-(1,2,3,4-tetrahydroisoquinoline-7-sulphonyl)-3-cyano-(S)-phenylalanine ethyl ester (Preparation 23; 1.3 g, 3.14 mmol), 2-iodopropane (641 mg, 377 μl, 3.77 mmol), potassium carbonate (650 mg, 4.7 mmol) and acetonitrile (50 ml) was heated under reflux for 9 hours, more 2-iodopropane (35 μl) added and heating under reflux continued for 1 hour. The solvent was evaporated under reduced pressure and the residue purified by chromatography on silica gel, using a 0-5% methanol in dichloromethane elution gradient, followed by trituration with diisopropyl ether, to afford the title compound (1.07 g) as a white solid, m.p. 110° C. Rf 0.49 (SS 6). Found: C,63.19; H,6.34; N,8.89. C24H29N3 O4S requires C,63.27; H,6.41; N,9.22%.
Reaction SMILES: [C:1]([C:4]1([OH:19])[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[CH:9][CH:5]1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[C:20]1(C=CC(O)=CC=1)O.S(=O)(=O)(O)O>CO>[C:1]([C:4]1([OH:19])[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[CH:9][CH:5]1[C:6]([O:8][CH3:20])=[O:7])(=[O:3])[CH3:2]
Reactant: C=C(C)C(=O)NC1=CC(C(=O)O)C(O)(C(C)=O)C=C1
Reactant: Oc1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: C=C(C)C(=O)NC1=CC(C(=O)OC)C(O)(C(C)=O)C=C1

Procedure:
To a solution of 2-acetyl-5-methacrylamidosalicylic acid and 1% by weight of hydroquinone in methanol was added 0.5% by weight of concentrated sulfuric acid, and the solution was subject to reflux for several hours. After evaporating the solvent, the remaining residue was recrystallized by a mixture of water and methanol to give methyl 2-acetyl-5-methacrylamidosalicylate.
Reaction SMILES: [OH:1][C@@H:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[H-].[Na+].CS(O[CH2:29][CH2:30][CH2:31][O:32][CH2:33][CH3:34])(=O)=O.O>C1COCC1>[CH2:33]([O:32][CH2:31][CH2:30][CH2:29][O:1][C@@H:2]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4]1)[CH3:34]
Reactant: CCOCCCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Yield: 89.9 %

Procedure:
An oven dried flask was charged with (R)-tert-butyl 3-((R)hydroxy(phenyl)methyl)-piperidine-1-carboxylate (3.18 g, 10.9 mmol) and 60% NaH in mineral oil (2.19 g, 54.8, 5 equiv). The flask was purged with N2 gas, cooled to 0° C. and anhydrous THF (100 mL) was added slowly. The mixture was allowed to warm to rt slowly. A solution of 3-ethoxypropyl methanesulfonate (6.0 g, 32.9 mmol, 3 equiv) in anhydrous THF (50 mL) was added. The mixture was heated at reflux for 4 h. LC-MS indicated the reaction completed. The reaction mixture was cooled to 0° C. slowly and water was added dropwise to quench the reaction. After separation, the aqueous layer was extracted with ether three times. The combined organic layers were washed with 5% aq HCl, satd aq NaHCO3, brine, and dried over Na2SO4. After concentration, the crude product was purified by flash chromatography on a 120-g silica gel cartridge eluted with a 0-30% EtOAc in hexanes gradient) to afford (R)-tert-butyl 3-((R)-(3-ethoxypropoxy)(phenyl)methyl)piperidine-1-carboxylate (3.70 g, 90%) as a clear oil. Chiral HPLC indicated 95.5% purity. LC-MS (3 min) tR=2.38 min, m/z 400 (M+Na). 1H NMR (CDCl3) □ 7.26 (m, 5H), 4.39 (d, 1H), 3.89 (t, 2H), 3.53-3.40 (m, 4H), 3.38-3.23 (m, 2H), 2.75-2.60 (m, 2H), 1.85-1.47 (m, 4H), 1.45 (s, 9H), 1.40-1.22 (m, 2H), 1.15 (t, 3H), 1.10-0.96 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[CH2:25][CH2:24][CH2:23][C:22]([CH2:33][C:34]#[N:35])([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[C:21]1=O>C(O)C>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:22]2([CH2:33][C:34]#[N:35])[C:21]3[N:18]=[C:16]([NH:15][C:5]4[CH:6]=[CH:7][C:8]([N:9]5[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[S:17][C:20]=3[CH2:25][CH2:24][CH2:23]2)=[CH:31][CH:30]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: N#CCC1(c2ccc(Cl)cc2)CCCC(Br)C1=O
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3(CC#N)c2ccc(Cl)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 100.7 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (40.2 mg, 0.15 mmol) and of [3-bromo-1-(4-chloro-phenyl)-2-oxo-cyclohexyl]-acetonitrile (50.0 mg, 0.15 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane/methanol/concentrated aqueous NH4OH solution (9:1:0.1 v/v/v) as eluent to yield the title compound (74 mg, 99%) as a yellow gum. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.62 (s, 1H), 7.56 (s, 1H), 7.37 (s, 1H), 7.28 (d, 2H), 7.16 (d, 2H), 6.89 (s, 1H), 3.76 (s, 3H), 3.19 (d, 1H), 3.03 (d, 1H), 2.72 (m, 2H), 2.30 (s, 3H), 2.19 (m, 1H), 1.89 (m, 2H), 1.60 (m, 1H).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([C:14]#[N:15])[C:9](=[CH:12][CH:13]=2)[C:10]#[N:11])=[CH:4][CH:3]=[N:2]1.CS(O[CH2:21][CH2:22][NH:23]C(OC(C)(C)C)=O)(=O)=O>>[NH2:23][CH2:22][CH2:21][N:2]1[CH:3]=[CH:4][C:5]([C:6]2[CH:7]=[C:8]([C:14]#[N:15])[C:9](=[CH:12][CH:13]=2)[C:10]#[N:11])=[N:1]1
Reactant: N#Cc1ccc(-c2ccn[nH]2)cc1C#N
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Product: N#Cc1ccc(-c2ccn(CCN)n2)cc1C#N

Procedure:
The title compound was prepared from 4-(1H-pyrazol-5-yl)phthalonitrile (0.38 g) and 2-(tert-butoxycarbonylamino)ethyl methanesulfonate (0.61 g) using the method of Example 37(c). Yield 0.050 g (as HCl-salt). 1H-NMR (400 MHz; d4-MeOH): δ 3.50 (t, 2H), 4.54 (t, 2H), 6.94 (d, 1H), 7.81 (d, 1H), 7.98 (d, 1H), 8.28 (dd, 1H), 8.49 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13](=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:14]2[C:13](=[S:31])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1nn(-c2ccccn2)c2[nH]c3ccccc3c(=O)c12
Solvent: Cc1ccccc1
Product: Cc1nn(-c2ccccn2)c2[nH]c3ccccc3c(=S)c12
Temperature: 25 °C
Yield: 145.1 %

Procedure:
A solution of 3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one (13.94 g, 50.5 mmol) and Lawesson's Reagent (12.5 g, 30.9 mmol) in toluene (750 mL) was heated under reflux for 1 hour. The solution was cooled to room temperature, and the resulting crude crystals were collected by filtration. The crystals were recrystallized from ethyl acetate to give the title compound (13.11 g, 89% yield).