Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>CN(C=O)C>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:17]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH:6]=[CH:5]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(C)c2[nH]ccc2c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c([N+](=O)[O-])c(C)cc(C)c32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5,7-dimethyl-4-nitro-1H-indole (CAS; 1190314-35-2, 10 g, 52.6 mmol) in DMF (200 mL) was added portionwise NaH (3.2 g, 60% in mineral oil, 79 mmol) at 0° C., and then the mixture was stirred at room temperature for 0.5 h. The mixture was cooled down to 0° C. To the red suspension was added TsCl (15.0 g, 79 mmol) at 0° C., and then the mixture was stirred at room temperature for 22 h. At this point, the reaction was quenched with half saturated aq. KHSO4 solution. The mixture was diluted with H2O, and then the whole mixture was stirred at room temperature for 1 h. The resulted solid was collected by filtration. The obtained brown solid was successively washed with H2O, MeOH, and heptane. The solid was dried to give the title compound. MS (ESI+) m/z 345.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][NH:10]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:21]([C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Cc1ccc(C2CCCN2)c(C)c1
Product: Cc1ccc(C2CCCN2S(=O)(=O)c2ccc(F)cc2)c(C)c1

Procedure:
The title compound, white solid, m.p. 134° C. and MS: m/e=333 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(2,4-dimethyl-phenyl)-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]3[C:35]([SH:36])=[N:34][C:33]4[C:28]3=[N:29][CH:30]=[N:31][CH:32]=4)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[CH3:37]N(C)C=O.[H-].[Na+].IC>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]3[C:35]([S:36][CH3:37])=[N:34][C:33]4[C:28]3=[N:29][CH:30]=[N:31][CH:32]=4)[CH2:21][CH2:20]2)=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(Cn2c(CC3CCN(CCn4c(S)nc5cncnc54)CC3)nc3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CSc1nc2cncnc2n1CCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred mixture of 34.5 parts of 9-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]-ethyl]-9H-purine-8-thiol and 180 parts of N,N-dimethylformamide were added portionwise 3.2 parts of a sodium hydride dispersion 50%. Upon completion, stirring was continued for 0.5 hours at room temperature. 11.5 parts of iodomethane were added dropwise. After complete addition, the whole was stirred for 1 hour. The reaction mixture was poured into water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 28.3 parts (80%) of 9-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl)methyl]-1-piperidinyl]ethyl]-8-(methylthio)-9H-purine; mp. 133.1° C. (507).
Reaction SMILES: [C:1](/[C:3](=[CH:9]/OCC)/[C:4]([O:6]CC)=[O:5])#[N:2].[CH:13]([NH:16][NH2:17])([CH3:15])[CH3:14]>C(O)C>[NH2:2][C:1]1[N:16]([CH:13]([CH3:15])[CH3:14])[N:17]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(C)NN
Reactant: CCO/C=C(/C#N)C(=O)OCC
Solvent: CCO
Product: CC(C)n1ncc(C(=O)O)c1N
Temperature: 25 °C
Yield: 26.5 %

Procedure:
To a solution of ethyl (2Z)-2-cyano-3-(ethyloxy)-2-propenoate (114.2 g, 0.67 mol) in ethanol (250 mL) was slowly added isopropylhydrazine (55 g, 0.74 mol) in a dropwise manner. The mixture was heated at reflux for 4 h, and then cooled to room temperature. The mixture was concentrated in vacuo. Approximately half of the crude 5-amino-1-isopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (50 g) was suspended in an aqueous solution of sodium hydroxide (4M, 130 mL), and stirred with heating at reflux for 2 h. The reaction mixture was then cooled to room temperature and adjusted to pH=3.5 with concentrated HCl, wherein precipitate formation ensued. The solid was collected by filtration and dried in vacuum oven overnight to afford crude 5-amino-1-isopropyl-1H-pyrazole-4-carboxylic acid (30 g). The solid was suspended in diphenyl ether (120 mL) and stirred with heating at 160-165° C. for 2 h. The solution was then cooled to room temperature and the solvent removed in vacuo. The crude product was purified by silica gel chromatography (eluent: petroleum ether/EtOAc=1:1) to afford the product as 12 g. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (d, 6H, J=6.4 Hz), 4.32 (m, 1H), 5.06 (s, 2H), 5.21 (s, 1H), 7.00 (s, 1H).
Reaction SMILES: [C:1]([C:4]12[CH2:14][C:8]3([OH:15])[CH2:9][C:10]([OH:13])([CH2:12][C:6]([OH:16])([CH2:7]3)[CH2:5]1)[CH2:11]2)([OH:3])=[O:2].[C:17]([O:21][CH2:22][CH2:23]O)(=[O:20])[CH:18]=[CH2:19]>C1(C)C=CC=CC=1>[C:17]([O:21][CH:22]([O:2][C:1]([C:4]12[CH2:5][C:6]3([OH:16])[CH2:7][C:8]([OH:15])([CH2:9][C:10]([OH:13])([CH2:12]3)[CH2:11]1)[CH2:14]2)=[O:3])[CH3:23])(=[O:20])[CH:18]=[CH2:19]
Reactant: O=C(O)C12CC3(O)CC(O)(CC(O)(C3)C1)C2
Reactant: C=CC(=O)OCCO
Solvent: Cc1ccccc1
Product: C=CC(=O)OC(C)OC(=O)C12CC3(O)CC(O)(CC(O)(C3)C1)C2

Procedure:
1 mmol of 1-carboxy-3,5,7-adamantanetriol and 2.5 mmol of 2-hydroxyethyl acrylate were reacted in toluene to give 1-acryloyloxyethoxycarbonyl-3,5,7-adamantanetriol. To 30 ml of tetrahydrofuran were added 5 mmol of 1-acryloyloxyethoxycarbonyl-3,5,7-adamantanetriol, 25 mmol of acetoaldehyde, and 1 mmol of p-toluenesulfonic acid, and the mixture was acetalized in the same manner as in Example 1 to give the object compound 1-acryloyloxyethoxycarbonyl-3,5,7-tri(1-hydroxyethoxy)adamantane (actalilzed compound) shown by the following formula.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)[CH:2]=1.[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20]([NH:12][C:9]2[S:10][CH:11]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[N:8]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1nc(-c2cccnc2)cs1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(-c2cccnc2)cs1

Procedure:
The title compound was prepared from 4-(3-pyridyl)-1,3-thiazol-2-amine and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (21.4 mg) with purity >90%. MS (pos) m/z 366.1.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:28](=O)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[F:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:16][CH:15]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(NCc2ccc(C#Cc3ccccc3)cc2)ccc1F
Reactant: CCCCCC=O
Product: CCCCCCN(Cc1ccc(C#Cc2ccccc2)cc1)c1ccc(F)c(C(=O)OC)c1

Procedure:
The title compound was prepared following the procedure described in Example 23 step b) using methyl 2-fluoro-5-{[4-(phenylethynyl)benzyl]amino}benzoate (213 mg, 0.59 mmol) and hexanal (Aldrich, 0.11 mL, 0.95 mmol). The title compound was obtained as a pale yellow oil (215 mg, 82%). HPLC, Rt: 6.1 min (purity: 94.5%). LC/MS, M+(ESI): 444.2. 1H NMR (CDCl3) δ: 7.51-7.44 (m, 4H), 7.32 (m, 3H), 7.17 (m, 3H), 6.92 (dd, J=9.8, 9.7 Hz, 1H), 6.74 (m, 1H), 4.49 (s, 2H), 3.88 (s, 3H), 3.35 (t, J=7.5 Hz, 2H), 1.61 (m, 2H), 1.29 (m, 6H), 0.88 (m, 3H).
Reaction SMILES: [OH-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[NH:11][C:10]2=[O:18])=[CH:5][CH:4]=1.[CH3:19]I>CO>[CH3:19][N:11]1[C:12]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:9]([C:6]2[CH:5]=[CH:4][N:3]=[CH:8][CH:7]=2)[C:10]1=[O:18]
Reactant: O=c1[nH]c2cccnc2n1-c1ccncc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(=O)n(-c2ccncc2)c2ncccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
5.7 g of sodium hydroxide pastilles were added to a suspension of 15 g of the product of Step B in 700 ml of methanol and complete dissolution occured after a few minutes. The mixture was stirred at room temperature for an hour and after the addition of 45.6 g of methyl iodide thereto, the mixture was stirred at room temperature for another 6 hours. The mixture stood overnight and was then filtered to remove hydroiodide of product melting at 275°-285° C. The filtrate was evaporated to dryness and the combined residue and hydroiodide were dissolved in water. The solution was made alkaline by addition of 30% sodium hydroxide solution and was then extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate and was filtered. The filtrate was evaporated to dryness and the residue was crystallized from 95% ethanol to obtain 4 g (25% yield) of 1-methyl-3-(4-pyridyl)-1,3-dihydro-imidazo-(4,5-b)-pyridin-2-one in the form of a pale crystalline powder melting at 211°-213° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([N:15]1[CH2:21][C:20]2[C:22]([Cl:26])=[CH:23][CH:24]=[CH:25][C:19]=2[S:18][CH2:17][CH2:16]1)(=[O:14])[CH3:13]>ClCCl>[C:12]([N:15]1[CH2:21][C:20]2[C:22]([Cl:26])=[CH:23][CH:24]=[CH:25][C:19]=2[S:18](=[O:9])[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)N1CCSc2cccc(Cl)c2C1
Solvent: ClCCl
Product: CC(=O)N1CCS(=O)c2cccc(Cl)c2C1
Reaction time: 0.25 h

Procedure:
A solution of 3-chloroperbenzoic acid (1.14 g) in dichloromethane (100 ml) was added dropwise with cooling from 0° C. to -2° C. to a stirred solution of 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.34 g, prepared as Example 9 above) in dichloromethane (50 ml). The reaction mixture was stirred for 15 minutes, washed with water, dried and the solvent was removed by evaporation at reduced pressure. Purification of the residue by flash chromatography using dichloromethane/ethanol (95:5) as eluent gave 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide, which was recrystallised from ethyl acetate. Yield 1.15 g (m.p. 119°-121° C.).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[C:7]2=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:32])C=CC=CC=1>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:32])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[C:7]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: COCCOCc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Solvent: ClCCl
Product: COCCOCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
8-Cyclopentyl-6-(2-methoxy-ethoxymethyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.46 g, 4.18 mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (1.31 g, 5.01 mmol) were dissolved in dichloromethane (10 mL) and stirred at ambient temperature for 12 hours. The reaction mixture was then purified by silica gel chromatography to give 8-cyclopentyl-2-methanesulfinyl-6-(2-methoxy-ethoxymethyl)-8H-pyrido[2,3-d]pyrimidin-7-one as a white waxy solid (0.60 g, 39.3%). 1H NMR δ (400 MHz, CDCl3) 8.94 (s, 1H), 7.88 (t, J=1.7 Hz, 1H), 5.95 (m, 1H), 4.52 (d, J=1.7 Hz, 1H), 3.80 (m, 2H), 3.65 (m, 2H), 3.43 (s, 3H), 2.98 (s, 3H), 2.25 (m, 2H), 2.13 (m, 2H), 1.94 (m, 2H), 1.70 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C@@H:11]3[CH2:15][CH2:14][CH2:13][O:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([OH:16])[CH:3]=1.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:17][C:18]1[N:19]=[CH:20][N:21]=[C:22]([O:16][C:4]2[CH:3]=[C:2]([CH3:1])[C:10]3[N:9]=[C:8]([C@@H:11]4[CH2:15][CH2:14][CH2:13][O:12]4)[NH:7][C:6]=3[CH:5]=2)[CH:23]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1cc(O)cc2[nH]c([C@@H]3CCCO3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c([C@@H]3CCCO3)nc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
135 mg (0.62 mmol) (S)-4-methyl-2-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-6-ol and 97 mg (0.63 mmol) 4,6-dichloropyrimidine in 2.0 mL DMF were combined with 97 mg (0.70 mmol) potassium carbonate and stirred overnight at 50° C. Then ice water was added and the mixture was extracted with ethyl acetate. The organic phase was concentrated by rotary evaporation i.vac.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]2=[N:10][CH:11]=[C:12]([OH:14])[CH:13]=[C:8]2[CH:7]=1)=[O:5].[CH:23]([N:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1)([CH3:25])[CH3:24].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:15]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C:9]2=[N:10][CH:11]=[C:12]([O:14][CH:29]3[CH2:30][CH2:31][N:26]([CH:23]([CH3:25])[CH3:24])[CH2:27][CH2:28]3)[CH:13]=[C:8]2[CH:7]=1)=[O:5]
Reactant: CCOC(=O)c1cc2cc(O)cnc2n1C(=O)OC(C)(C)C
Reactant: CC(C)N1CCC(O)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)cnc2n1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
To the turbid solution of 0.2 g (0.65 mmol) 5-hydroxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (as prepared in WO 05/000849) and 1-isopropyl-piperidin-4-ol (commercially available) in 6 ml tetrahydrofuran, 0.26 g (1.3 mmol) tributylphosphine were added and the mixture was cooled to 0° C. Within 60 min. 32.9 mg (1.3 mmol) 1,1′-(azodicarbonyl)dipiperidine were added under stirring and the reaction was allowed to reach room temperature. After 19 hours the brown suspension was filtered and evaporated. The residue was stirred in tert butyl methyl ether, filtered and the clear filtrate was evaporated and flash-chromatographed on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) to give 60 mg (21%) of the product as a yellow oil.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].ON1C2C=CC=CC=2N=N1.[NH2:34][C:35]1[S:36][CH:37]=[CH:38][N:39]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:34][C:35]4[S:36][CH:37]=[CH:38][N:39]=4)=[O:2])([CH2:11][CH2:10]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1nccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3nccs3)(CC1)CC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.3 %

Procedure:
(2S,4S)-1-[[N-(4-Carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg), along with 1-hydroxybenzotriazole, was dissolved in N,N-dimethylformamide (1.0 mL). To this solution, 2-aminothiazole (18.6 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53.4 mg) were added, and the mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure and the resulting residue was purified by preparative thin-layer chromatography (solvent:dichloromethane:methanol=9:1) to give (2S,4S)-4-fluoro-1-[[N-[4-[N-(thiazol-2-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (17.4 mg).
Reaction SMILES: [NH2:1][N:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:3]1=[O:15].[N:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1>C(O)C>[C:11]([O:10][C:8]([NH:7][C@H:4]1[CH2:5][CH2:6][N:2]([N:1]=[C:25]2[CH2:24][CH2:23][N:22]([C:19]3[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=3)[CH2:27][CH2:26]2)[C:3]1=[O:15])=[O:9])([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(N)C1=O
Reactant: O=C1CCN(c2ccncc2)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CCN(N=C2CCN(c3ccncc3)CC2)C1=O
Yield: 111.8 %

Procedure:
A solution of (3S)-1-amino-3-(tert-butoxycarbonylamino)-2-pyrrolidone (1.84 g) and 1-(4-pyridyl)-4-piperidone (1.51 g) in ethanol (30 ml) was dehydrated using a Soxlet extractor packed with molecular sieves 4A while refluxing for 15 hours. The reaction mixture was concentrated to obtain (3S)-3-(tert-butoxycarbonylamino)-1-[1-(4-pyridyl)-4-piperidinylideneamino]-2-pyrrolidone (3.57 g) as a syrup.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]=1.CCO[C:19](/[CH:21]=[CH:22]/[CH2:23]P(OCC)(OCC)=O)=[O:20]>>[CH2:4]([NH:3][C:19](=[O:20])/[CH:21]=[CH:22]/[CH:23]=[CH:5]/[CH2:6][CH2:7][CH2:12][CH2:23][CH2:22][CH2:21][CH2:19][O:20][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]=1)[CH:9]([CH3:10])[CH3:8]
Reactant: FC(F)(F)c1ccc2nc(Cl)ccc2c1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Product: CC(C)CNC(=O)/C=C/C=C/CCCCCCCOc1ccc2cc(C(F)(F)F)ccc2n1

Procedure:
Starting from 2-chloro-6-trifluoromethylquinoline (prepared as for Compound 23 starting from 4-trifluoromethyl aniline (ex. Aldrich)), and using triethyl 4-phosphonocrotonate.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1=[C:18]([Cl:24])[C:19]([O:21][C:22]1=[O:23])=[O:20]>C(Cl)CCl>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:19](=[O:20])[C:18]([Cl:24])=[C:17]([Cl:16])[C:22]([OH:23])=[O:21])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Solvent: ClCCCl
Product: O=C(O)C(Cl)=C(Cl)C(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 10.0 g (0.052 mole) of 2-phenylindole, 8.8 g (0.052 mole) of dichloromaleic anhydride and 150 ml of ethylene dichloride was stirred at ambient temperature for approximately 48 hours. The solid that formed was collected by filtration and dried at 60° C. in vacuo to obtain 4-(2-phenyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid (Formula VIII: R=Y=H; R1 =C6H5) as a tan-colored solid which melted over the range 150°-152° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C@H:9]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:19]>CO.CCCCCC>[CH3:19][O:16][C:15]([CH:9]1[CH2:10][C:11](=[O:14])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C[C@H]1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)C1CC(=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To (2S)-4-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (0.52 g, 2.15 mmol) in methanol (10 mL), 2 M solution of TMS-diazomethane (2 mL, 4 mmol) in hexane was added and stirred at room temperature for 15 min. The reaction solvent was removed and the methyl ester product obtained (4-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester) was used as such for the next reaction (0.55 g, 100%): MS (ESPOS): 258 [M+H]+; 1H NMR (300 MHz, CD3OD) δ 5.13, 4.86 (bs, 1), 4.02-4.11 (m, 1), 3.73 (s, 3), 3.67-3.72 (m, 1), 2.78 (d, J=4.2 Hz, 2), 2.51 (bs, 2), 1.46 (bs, 9).
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][C:5]#[C:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:16][C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=2[F:24])[CH:8]=1)[CH3:2].[CH3:27][C:28](N(C)C)=[O:29]>>[CH2:25]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]#[C:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:16][C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:28](=[O:29])[CH3:27])=[CH:19][C:18]=2[F:24])[CH:8]=1)[CH3:26]
Reactant: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: CC(=O)N(C)C
Product: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(NC(C)=O)cc3F)c2s1
Temperature: 100 °C
Reaction time: 96 h

Procedure:
A 20 mL scintillation vial was charged with polystyrene-2,3,5,6-tetrafluoro-4-(methylcarbamoyl)phenyl acetate (0.179 g, 0.238 mmol). 4-(2-(3-(Diethylamino)-prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorobenzenamine (Example 6, Step B 0.022 g, 0.0595 mmol) in DMA (2 mL) was added to the resin, and the mixture was heated at 100° C. with shaking for 96 hours. The reaction was cooled to room temperature and filtered using a vacuum master and Jones tubes. The filtrate was collected in 13 mm test tubes. The resin was washed with DMA (2 mL) making the total volume 4 mL. The crude material was dried using a GeneVac DD-4 set at 50° C. for the chamber and vial holder. Vacuum was set to aqua speed and reached a pressure of 7 mm Hg. The crude oil was purified by reverse phase chromatography (see purification method A, below). The final product was a TFA salt and a yellow oil (6.9 mg, 16%). Final Purity: 97%, LRMS (APCI pos) m/e 412.1 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:9].[C:10]1([C:16](Cl)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[C:10]1([C:16]([NH:1][C@@H:2]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[OH:9])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N[C@@H]1CCCCC[C@H]1O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O[C@@H]1CCCCC[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of trans-2-aminocycloheptanol (0.97 g; 7.74 mmol), triphenylmethyl chloride (2.16 g; 7.74 mmol) and triethylamine (2.70 ml; 19.35 mmol) are combined in about 100 ml CH2Cl2 and heated to reflux overnight. After removing the heat, the reaction mixture is concentrated in vacuo and flash chromatographed using hexane:ethylacetate; 9:1 to obtain trans-2-triphenylmethylaminocycloheptanol which is used directly in the next step.