Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:42])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:16]([C:39]([NH2:41])=[O:40])[CH2:15]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:50](Cl)(=[O:53])[CH2:51][CH3:52]>ClC(Cl)Cl>[C:1]([C:4]1[CH:9]=[C:8]([NH:10][C:50](=[O:53])[CH2:51][CH3:52])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:42])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:16]([C:39]([NH2:41])=[O:40])[CH2:15]1)(=[O:3])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CC(=O)c1cc(N)ccc1NC(=O)CN1CCN(CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)C(C(N)=O)C1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccc(NC(=O)CN2CCN(CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)C(C(N)=O)C2)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
To a stirred solution of 4.5 parts of N-(2-acetyl-4-aminophenyl)-3-(aminocarbonyl)-4-[5,5-bis(4-fluorophenyl)pentyl]-1-piperazineacetamide in 60 parts of trichlormethane were added 1.17 parts of N,N-diethylethanamine. A solution of 0.78 parts of propanoyl chloride in 45 parts of trichloromethane was added dropwise at room temperature (slightly exothermic reaction, the temperature rose from 24° C. to 30° C.). Upon completion, the whole was stirred for 3 hours at room temperature. The separated organic layer was washed with a sodium carbonate solution in water and water, dried, filtered and evaporated. The residue was crystallized from acetonitrile. After cooling to 0° C., the product was filtered off and dried in vacuo, first at 50° C. and then at 100° C., yielding 2.93 parts (57.7%) of N-[2-acetyl-4-[(1-oxopropyl)amino]phenyl]-3-(aminocarbonyl)-4-[5,5-bis(4-fluorophenyl) pentyl]-1-piperazineacetamide; mp. 163.4° C. (compound 32).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:20]Br>>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:20][N:13]1[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[N:11]=[C:12]1[CH3:15]
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: Fc1ccc(CBr)cc1F
Product: Cc1cc(C#Cc2cn(Cc3ccc(F)c(F)c3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=324.2 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3,4-difluoro-benzylbromide.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[NH:14]C(=O)CCC.CC([O-])(C)C.[K+]>CN1C(=O)CCC1.CCOC(C)=O>[CH:2]([C:3]1[NH:14][C:6]2[C:5]([CH:4]=1)=[CH:10][CH:9]=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=2)([CH3:20])[CH3:1]
Reactant: CCCC(=O)Nc1cc([N+](=O)[O-])ccc1C#CC(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a solution of N-(2-(3-methylbut-1-ynyl)-5-nitrophenyl)butyramide (Compound 119, 900 mg, 3.29 mmol) in NMP (10 ml) was added KOt-Bu (552 mg, 4.94 mmol) and the mixture was stirred at 70° C. for 16 h, cooled to room temperature, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→25% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([C:11]2[C:20]3[C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[S:23][C:19]=3[C:18]([Br:28])=[C:17]3[C:12]=2[CH:13]=[CH:14][CH:15]=[CH:16]3)[CH:8]=[CH:7][C:6]=1[O:29]C(=O)C)(=O)C.BrBr>>[Br:28][C:18]1[C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20]=2[C:11]([C:9]2[CH:10]=[C:5]([OH:4])[C:6]([OH:29])=[CH:7][CH:8]=2)=[C:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2
Reactant: CC(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1OC(C)=O
Agent: BrBr
Product: Oc1ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1O

Procedure:
Prepared from acetic acid 2-acetoxy-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenyl ester (Example 39) according to the procedure for Example 41. White solid: mp 181-182° C.: MS (EI): [M+], 1 bromine isotope pattern, 420 (95%); Anal. Calc. for C22H13BrO2S: C, 62.72, H, 3.11, N, 0.00. Found: C, 62.11, H, 3.10, N, 0.13.
Reaction SMILES: C[O:2][C:3]([CH2:5][NH:6][C:7]1[CH:15]=[C:14]2[C:10](/[C:11](=[C:17](/[NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:27][CH:26]=3)\[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)/[C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1)=[O:4].[OH-].[Na+].Cl>CO.C(Cl)Cl>[C:3]([CH2:5][NH:6][C:7]1[CH:15]=[C:14]2[C:10](/[C:11](=[C:17](/[NH:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:29][CH:30]=3)\[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)/[C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1)([OH:4])=[O:2]
Reactant: COC(=O)CNc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=C(O)CNc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
180 mg of 6-methoxycarbonylmethylamino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone are placed in 10 ml of methanol, 1.0 ml of 1N sodium hydroxide solution are added and the mixture is stirred for 1 hour at 40° C. After cooling it is neutralised with 1.0 ml of 1N hydrochloric acid and the solvent is eliminated. The residue is dissolved in methylene chloride and a little methanol and dried over sodium sulphate.
Reaction SMILES: [C:1]12([CH2:11][C:12]([NH:14][C:15]3[C:16]4[CH2:24][CH2:23][N:22](CC5C=CC=CC=5)[CH2:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>C(O)(=O)C.[Pd]>[C:1]12([CH2:11][C:12]([NH:14][C:15]3[C:16]4[CH2:24][CH2:23][NH:22][CH2:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[O:13])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1ncnc2c1CCN(Cc1ccccc1)C2
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1ncnc2c1CCNC2
Reaction time: 15 h
Yield: 87 %

Procedure:
To a solution of 2-adamantan-1-yl-N-(7-benzyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin 4-yl)-acetamide in glacial acetic acid (15 mL) in a 250 ml round bottom flask was added 10% Pd/C (0.45 g). The resulting mixture was stirred for 15 h under an atmosphere of hydrogen (via a balloon), which was introduced after evacuation of air from the reaction vessel. The reaction was then filtered over celite, washed with EtOAc (20 mL) and the filtrate concentrated under reduced pressure. The residue was re-dissolved on EtOAc (50 mL) and stirred with aq. 10% NaOH solution (50 mL) for 1 h. The layers were separated and the aqueous layer washed with EtOAc (5×50 mL). The combined organics were dried over anhyd. Na2SO4, filtered and concentrated to yield 2-adamantan-1-yl-N-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-acetamide (0.68 g, 2.1 mmol, 87%) as a tan colored solid. LCMS (ESI+) m/z 327.3 [M+H]+
Reaction SMILES: [CH2:1]([O:5][C:6](Cl)=[O:7])[CH2:2][CH2:3][CH3:4].[NH:9]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[NH:13][N:12]=1)[NH2:10]>N1C=CC=CC=1>[CH2:1]([O:5][C:6]([NH:10][NH:9][C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[NH:13][N:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)Cl
Reactant: NNc1n[nH]c2cc(Cl)ccc12
Solvent: c1ccncc1
Product: CCCCOC(=O)NNc1n[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.04 mol of chlorocarbonic acid n-butyl ester is added dropwise at 0° - 5° C, while stirring, to 0.04 mol of 3-hydrazino-6-chloro-indazole in 20 ml of pyridine. The reaction mixture is stirred for 3 hours at room temperature and then poured into ice water, and the colorless crystals which have precipitated are isolated by filtration. 3-n-Butoxycarbonylhydrazino-6-chloroindazole is obtained. After recrystallisation from a mixture of ligroin and ethanol (9 : 1), the melting point is 150° - 152° C. (Yield, 78% of theory).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][CH2:13][C:14]1[C:15]([NH:22][CH3:23])=[N:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=1.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:13][C:14]2[C:15](=[N:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=2)[N:22]([CH3:23])[C:1]1=[O:2]
Reactant: CNc1nc(SC)ncc1CNc1ccccc1C
Reactant: O=C(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1ccccc1C)C2
Reaction time: 1 h
Yield: 101.3 %

Procedure:
A stirred solution, cooled in ice, of 0.7 ml (1.3 mmol) of phosgene (20% in toluene) in 5 ml of tetrahydrofuran was treated dropwise with a solution containing 189 mg (0.69 mmol) of 5-(2-methylphenyl)aminomethyl-4-methylamino-2-methylthiopyrimidine and 0.2 ml (1.4 mmol) of triethylamine in 5 ml of tetrahydrofuran. The mixture was stirred for 1 hour. To the mixture were added 20 ml of tetrahydrofuran and 20 ml of saturated aqueous ammonium chloride solution. The phases were separated and the organic phase was dried over magnesium sulfate, filtered and evaporated to give 210 mg (100%) of 3-(2-methylphenyl)-7-methylthio-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a cream-colored solid. [Mass spectrum (ESI) MH+ =301].
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[CH:12]([CH2:13][C@@H:14]2[O:22][C@@H:15]2[CH2:16]1)[CH2:11][CH2:10]3.O.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>ClCCl>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[CH:12]([CH2:13][C@H:14]([OH:22])[C@@H:15]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:16]1)[CH2:11][CH2:10]3
Reactant: C1CNCCN1
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CCC4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Solvent: O
Solvent: ClCCl
Product: CO[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](O)[C@@H](N5CCNCC5)C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 150 °C
Yield: 69.8 %

Procedure:
To compound 35 (100 mg, 0.33 mmol) was added water (1 mL) and piperazine (3.5g, 41 mmol). The solution was subsequently heated at 150° C. over a period of 24 h. The resulting mixture was diluted with dichloromethane (50 mL) and washed with water, dried with Na2SO4, filtered and evaporated under reduced pressure. The crude compound was purified by flash chromatography (DCM/MeOH: 9:1 containing 0.5% of TEA) to yield compound 36 (90 mg, 70%). 1H NMR (CDCl3) δ: 0.72 (s, 18-CH3), 0.82 (s, 19-CH3), 0.65-2.05 (residual CH and CH2), 2.38, 2.60 and 2.86 (3m, 4×CH2N and 2α-CH), 3.18 (t, J=8.2 Hz, 17α-CH), 3.31 (s, OCH3), 3.82 (m, 3β-CH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH:13]([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:21]([OH:23])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:21]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][CH:13]3[CH3:20])=[O:23])=[CH:27][CH:26]=1
Reactant: CC1OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1ccc(F)cc1
Product: CC1OCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 16, 3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylic acid and 4-fluorobenzylamine. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.67 (3H, d, J=6.6 Hz, CH3), 3.91 (2H, m, CH2), 4.12–4.35 (2H, m, CH2), 4.52 (2H, d, J=5.9 Hz, NCH2), 4.70 (1H, q, J=6.6 Hz, OCH), 5.33 (2H, s, OCH2), 7.02 (2H, m, aromatics), 7.25 (2H, m, aromatics), 7.35 (3H, m, aromatics), 7.47 (2H, m, aromatics), 7.71 (1H, broad t, NH).
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=3[C:17]#[N:18])=[CH:14][C:9]=2[N:8]([CH3:24])[S:7]1(=[O:26])=[O:25].Cl[C:29]1[N:34]=[C:33]([C:35]#[N:36])[CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:17]([C:16]1[CH:19]=[CH:20][C:21]([O:23][C:29]2[N:34]=[C:33]([C:35]#[N:36])[CH:32]=[CH:31][CH:30]=2)=[CH:22][C:15]=1[C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH2:5][CH:3]3[CH2:4][C:2]3([F:1])[F:27])[S:7](=[O:26])(=[O:25])[N:8]([CH3:24])[C:9]=2[CH:14]=1)#[N:18]
Reactant: CN1c2cc(-c3cc(O)ccc3C#N)ccc2N(CC2CC2(F)F)S1(=O)=O
Reactant: N#Cc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1c2cc(-c3cc(Oc4cccc(C#N)n4)ccc3C#N)ccc2N(CC2CC2(F)F)S1(=O)=O
Temperature: 140 °C

Procedure:
2-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}-4-hydroxybenzonitrile (12-2) (300 mg, 0.77 mmol, 1 eq) was dissolved in acetonitrile (2.5 mL) and 6-chloropyridine-2-carbonitrile (212 mg, 1.5 mmol, 2 eq) and potassium carbonate (424 mg, 3.1 mmol, 4 eq) were added. The resulting mixture was heated in the microwave at 140° C. for 1.5 hours. The mixture was filtered washing with acetonitrile. The crude mixture was purified by reverse phase chromatography (Waters Sunfire MSC18, 10-100% acetonitrile in water with 0.1% TFA modifier) to afford 6-(4-cyano-3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}phenoxy)pyridine-2-carbonitrile (12-3) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.90 (t, J=8.0 Hz, 1 H); 7.82 (d, J=8.4 Hz, 1 H); 7.50 (d, J=7.2 Hz, 1H); 7.34 (s, 1H); 7.29 (t, J=10.4 Hz, 1 H); 6.99 (s, 2 H); 6.92 (d, J=8.0 Hz, 2H), 3.92 (d, J=6.8 Hz, 2H); 3.36 (s, 3 H); 2.14 (m, 1 H); 1.65 (m, 1 H); 1.41 (m, 1 H). HRMS m/z (M+H) 494.1097 found, 494.1093 required.
Reaction SMILES: B.[CH3:2]SC.[C:5]([O:9][C:10]([N:12]1[CH2:24][C@@H:23]([CH3:25])[N:22]2[C@H:14]([CH2:15][C:16]3[C:21]2=[N:20][C:19]([CH2:26][O:27]CCO)=[CH:18][CH:17]=3)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>C1COCC1>[C:5]([O:9][C:10]([N:12]1[CH2:24][C@@H:23]([CH3:25])[N:22]2[C@H:14]([CH2:15][C:16]3[C:21]2=[N:20][C:19]([C@@H:26]([OH:27])[CH3:2])=[CH:18][CH:17]=3)[CH2:13]1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: CSC
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCCO)nc3N21
Agent: B
Solvent: C1CCOC1
Product: C[C@H](O)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Reaction time: 0.08 h

Procedure:
To a stirred solution of (R)-Me-CBS-oxazaborolidine (770 μl, 1M in toluene) in THF (3 ml) was added borane-dimethylsulfide (770 μl, 2M in THF) at 0° C. under nitrogen. A solution was stirred for 5 mins, then 6-acetyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 34, intermediate b) (255 mg) in THF (2.5 ml) was added dropwise over 45 mins. A solution was stirred at 0° C. for 3 hours, quenched with methanol and partitioned between aqueous ammonium chloride and EtOAc. The phases were separated and the organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography [SiO2; isohexane-ethyl acetate (1:1)] to afford 6-((1S)-1-hydroxy-ethyl)-(4R,9aR)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (185 mg) as a colorless oil: 1H NMR (400 MHz, CDCl3): 7.16 (1H, d, J 7 Hz), 6.35 (1H, d, J 7 Hz), 4.37–4.31 (1H, br s), 4.31–4.19 (1H, br s), 4.09–3.95 (1H, m), 3.95–3.85 (1H, m), 3.13–2.94 (2H, m), 2.79–2.55 (1H, br s), 2.54 (1H, dd, J 6 and 16 Hz), 1.48 (9H, s), 1.44 (3H, d, J 6.5 Hz) and 1.24 (3H, d, J 6.5 HZ); MS (ES) 334.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23](Cl)(=[O:25])=[O:24]>>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:24])=[O:25]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc3ccccc3c2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-naphthalenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (41.2 mg) with purity >90%. LCMS (pos) m/z 377.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:16](Br)([CH3:18])[CH3:17]>>[CH:16]([N:13]1[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[N:11]=[C:12]1[CH3:15])([CH3:18])[CH3:17]
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: CC(C)Br
Product: Cc1cc(C#Cc2cn(C(C)C)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=240.3 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and isopropylbromide.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C(O)(=O)C>[Fe].CO>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Temperature: 60 °C
Yield: 78 %

Procedure:
An amount of 2 g (6.48 mmol) of, tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate, 1.4 g (25.9 mmol) of iron, and acetic acid (3.1 mL, 48.6 mmol) were placed in a flask. Methanol (30 mL) is added and heat at 60° C. for 2 hours. After cooling to room temperature, the precipitate is filtered, the methanol is removed in a vacuum and saturated sodium bicarbonate is added. The mixture is extracted 3× with ethyl acetate. Dried over sodium sulfate, and evaporated to give 1.43 g (78% yield) as a purple solid. MS (ESI) m/z 279.1(M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([OH:15])=[O:14])[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.O[N:37]=[C:38]([C:40]1[N:45]=[CH:44][CH:43]=[CH:42][N:41]=1)[NH2:39]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([O:15][N:37]=[C:38]([C:40]3[N:45]=[CH:44][CH:43]=[CH:42][N:41]=3)[NH2:39])=[O:14])[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:22][CH:23]=1
Reactant: NC(=NO)c1ncccn1
Reactant: O=C(O)Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=NOC(=O)Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1)c1ncccn1
Reaction time: 2 h

Procedure:
To a suspension of [5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetic acid (200 mg, 0.64 mmol) in THF (2 mL) and DMF (2 mL) was added CDI (240 mg, 1.41 mmol) and stirred for 2 hours forming a clear solution. To this was added N′-hydroxypyrimidine-2-carboximidamide (115 mg, 0.84 mmol) and the resulting suspension stirred for 18 hours at room temperature. The solid was filtered off to yield crude N′-({2-[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}oxy)pyrimidine-2-carboximidamide, and suspended in THF (2 mL) and a solution of TBAF (1 M in THF, 0.64 mL, 0.64 mmol) was added and the mixture stirred for 15 minutes at room temperature. The volatiles were then removed in vacuo and the residue purified by Biotage flash chromatography, eluting with 2-6% MeOH/DCM to afford the title compound as a waxy white solid, 100 mg, 37%. 1H NMR (400 MHz, DMSO-D6) δ ppm 9.00 (d, 2 H), 8.56 (d, 2 H), 7.68-7.73 (m, 3 H), 7.27-7.33 (m, 2 H), 7.05 (t, 2 H), 6.77 (s, 1 H), 6.00 (s, 2 H), 4.18 (s, 2 H); m/z (APCI+) for C22H16N7FO 414.1 (M+H)+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]1[CH:44]=[C:43]([CH:45]=[O:46])[CH:42]=[CH:41][C:38]=1[C:39]#[N:40]>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([CH:45]([OH:46])[C:43]2[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[C:37]([F:36])[CH:44]=2)[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(C=O)cc1F
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(O)c3ccc(C#N)c(F)c3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and 2-fluoro-4-formylbenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10]([C:16](OC)=[O:17])#[C:11][C:12]([O:14][CH3:15])=[O:13]>CO>[CH3:15][O:14][C:12]([C:11]1[CH2:10][C:16](=[O:17])[C:7]2[C:5](=[CH:4][C:3]([CH3:9])=[C:2]([Cl:1])[CH:8]=2)[N:6]=1)=[O:13]
Reactant: Cc1cc(N)ccc1Cl
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)C1=Nc2cc(C)c(Cl)cc2C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
Alternatively, to a solution of 4-chloro-3-methyl aniline (20.0 g, 0.141 mol) in MeOH (400 mL) was added drop-wise dimethyl acetylenedicarboxylate (21.07 g, 0.148 mol). The reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was removed by evaporation and the residue was added to stirred diphenyl ether (300 mL), which has been preheated to 250° C. After 30 minutes, the mixture was cooled to ambient temperature and the resulting precipitate was collected and washed with 1 L of hot petroleum ether to give a mixture (29.0 g) of 2-methoxycarbonyl-6-chloro-7-methyl-4-oxoquinoline and 2-methoxycarbonyl-6-chloro-5-methyl-4-oxoquinoline as a gray solid. The mixture was dissolved in boiling methanol (1 L) and filtered hot. The collected solids were boiled in 1.2 L of methanol and filtered hot to afford (6.45 g, 16%) of 2-methoxycarbonyl-6-chloro-7-methyl-4-oxoquinoline: 1H NMR (DMSO-d6) 2.41 (s, 3), 3.92 (s, 3), 6.58 (s, 1), 7.86 (s, 1), 7.96 (s, 1) ppm.
Reaction SMILES: [C:1]1(=[O:15])[C:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]=2[C:3](=[O:14])O1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[NH2:16][CH:17]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH3:31])[CH:22]=1)[CH2:18][C:19]#[N:20]>C(O)(=O)C>[O:15]=[C:1]1[C:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH:12]=[CH:13][C:4]=2[C:3](=[O:14])[N:16]1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH3:31])[CH:22]=1)[CH2:18][C:19]#[N:20]
Reactant: CCOc1cc(C(N)CC#N)ccc1OC
Reactant: O=C1OC(=O)c2c1ccc1ccccc21
Solvent: CC(=O)O
Product: CCOc1cc(C(CC#N)N2C(=O)c3ccc4ccccc4c3C2=O)ccc1OC
Yield: 48.8 %

Procedure:
A solution of naphtho[1,2-c]furan-1,3-dione (440 mg, 2.2 mmol) and 3-amino-3-(3-ethoxy-4-methoxy-phenyl)-propionitrile (490 mg, 2.2.mmol) in acetic acid (10 mL) was heated to reflux overnight. The solvent was removed in vacuo to give a solid, which was purified with chromatography (Silica Gel, CH2Cl2) to give 3-(1,3-dioxobenzo[e]isoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanenitrile as a yellow solid (430 mg, 48% yield): mp 163.0-165.0° C.; 1H NMR (CDCl3) δ 1.46 (t, J=7 Hz, 3H, CH3), 3.34 (dd, J=7, 17 Hz, 1H, CHH), 3.80-3.92 (m, 1H, CHH), 3.84 (s, 3H, CH3), 4.10 (q, J=7 Hz, 2H, CH2), 5.67 (dd, J=7, 10.1 Hz, 1H, NCH), 6.82-6.86 (m, 1H, Ar), 7.11-7.13 (m, 2H, Ar), 7.61-7.74 (m, 2H, Ar), 7.81 (d, J=8 Hz, 1H, Ar), 7.92 (d, J=7.9 Hz, 1H, Ar), 8.14 (d, J=8.3 Hz, 1H, Ar), 8.87 (d, J=8 Hz, 1H, Ar); 13C NMR (CDCl3) δ 14.66, 21.22, 50.97, 55.91, 64.48, 111.43, 112.19, 117.00, 118.46, 120.03, 124.79, 126.79, 127.96, 128.73, 128.94, 129.24, 129.66, 130.78, 135.37, 136.68, 148.56, 149.72, 168.37, 168.92. Analy. calculated for C24H20N2O4: C 71.99; H 5.03; N 7.00. Found: C 71.81; H 5.04; N 7.00.