Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:21][CH2:22][CH2:23][CH3:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[C:25](=O)[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29]1)=[O:27])=O)(C)(C)C.[F-].[Cs+].C[Si]([N:44]=[C:45]=[N:46][Si](C)(C)C)(C)C.Cl.C(=O)(O)[O-]>C(#N)C>[NH2:44][C:45]1[N:46]=[C:25]([C:26]([N:28]2[CH2:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:36]2)=[O:27])[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([CH:15]([CH2:21][CH2:22][CH2:23][CH3:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]=2)[N:8]=1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: CCCCC(C(=O)OCC)c1ccc(NC(=O)OC(C)(C)C)c(C(=O)C(=O)N2Cc3ccccc3C2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CC#N
Product: CCCCC(C(=O)OCC)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3.8 g of ethyl 2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]hexanoate are dissolved in 100 ml of acetonitrile under argon. 1.12 g of caesium fluoride and 2.01 ml of bis(trimethylsilyl)carbodiimide are added to the solution. The mixture is stirred at room temperature for 15 min, and 6 ml of hydrochloric acid (1N) are then added, and the mixture is neutralised using bicarbonate. The aqueous phase is washed three times with 100 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulfate, filtered and evaporated to dryness in vacuo. Yield: 3.2 g (99%) of ethyl 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]hexanoate (oil);
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:21](CC3C=CC(OC)=CC=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]3[N:13]([C:15]([C:18]([NH2:20])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1>FC(F)(F)C(O)=O>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:12]3[N:13]([C:15]([C:18]([NH2:20])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(N)=O)cnc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cnc2c(Nc3ccccc3)cc(N[C@H]3CC[C@H](N)CC3)nn12
Temperature: 50 °C

Procedure:
Crude 6-((trans)-4-aminocyclohexylamino)-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide from 1b was suspended in trifluoracetic acid (1 mL) and heated to 50° C. for 2 h. The mixture was cooled to room temperature and the trifluoractic acid was evaporated under a stream of nitrogen. The residue was suspended in methanol, filtered to remove solids and purified by prep HPLC to provide 2.1 mg of the titled compound as a TFA salt. MS m/e 366 (M+1); 1H NMR (MeOH, δ) 8.1 (1H, s), 7.46 (2H, t, J=8 Hz), 7.39 (2H, d, J=8 Hz), 7.23 (1H, t, J=8 Hz), 6.31 (1H, s), 3.62 (1H, m), 3.17 (1H, m), 2.30 (2H, m), 2.13, (2H, m), 1.55 (2H, m), 1.42 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:17]=1[C:18]([N:20]=[C:21]=[O:22])=[O:19]>ClCCl>[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:17]=1[C:18]([NH:20][C:21]([NH:14][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:13][N:12]=1)=[O:22])=[O:19]
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: ClCCl
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(-c2ccc(Cl)cc2)cn1
Reaction time: 3 h
Yield: 62.4 %

Procedure:
5-(4-Chlorophenyl)-2-pyridylamine (0.6 gram), 2,6-dichlorobenzoyl isocyanate (0.8 gram), in a small amount of dichloromethane were reacted at room temperature. A slight exothermic reaction was followed by an almost immediate precipitate. After 3 hours at room temperature, the reaction mixture was cooled in an ice bath and then filtered to give 770 mg of colorless crystals. The identity of the product was confirmed by NMR analysis, m.p. 230°-233° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][CH2:20][C@H:19]([NH:23][C:24](=[O:26])[OH:25])[CH2:18]4)[C:14]([C:27]#[N:28])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C[Sn](C)(C)[C:31]1[CH:36]=[N:35][CH:34]=[C:33]([CH3:37])[N:32]=1>>[C:27]([C:14]1[C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@H:19]([NH:23][C:24](=[O:26])[O:25][C:5]([CH3:8])([CH3:6])[CH3:4])[CH2:18]2)=[N:16][C:11]([N:10]2[C:4]3[CH:3]=[C:2]([C:31]4[CH:36]=[N:35][CH:34]=[C:33]([CH3:37])[N:32]=4)[N:7]=[CH:6][C:5]=3[CH:8]=[N:9]2)=[CH:12][CH:13]=1)#[N:28]
Reactant: Cc1cncc([Sn](C)(C)C)n1
Reactant: N#Cc1ccc(-n2ncc3cnc(Cl)cc32)nc1N1CCC[C@H](NC(=O)O)C1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C#N)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Temperature: 150 °C
Yield: 188.1 %

Procedure:
A mixture of [(3S)-1-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-3-cyano-2-pyridyl]-3-piperidyl]carbamic acid (0.5166 mmol; 205.5 mg), trimethyl-(6-methylpyrazin-2-yl)stannane (0.7749 mmol; 199.1 mg), and palladium(0)tetrakis (triphenylphosphine); (0.05166 mmol; 59.8 mg) in N,N-Dimethylacetamide (12 mL) was purged with Argon. The reaction mixture was sealed in a pressure vial and heated at 150° C. for 2 hours. The mixture was cooled to room temperature, and then partitioned between EtOAc and water. The organic layer was concentrated and the residue was purified on silica eluted with 0 to 5% MeOH in DCM to afford tert-butyl N-[(3S)-1-[3-cyano-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate as a yellow solid (248.6 mg, 94%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:35])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:34])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:34][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:35])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:26])=[O:27])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)N3CCCCC3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.1 %

Procedure:
Lithium hydroxide monohydrate (0.046 g, 1.1 mmol) was added to a stirred solution of {6-chloro-3-methyl-4-[4-(piperidine-1-sulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.130 g, 0.27 mmol) in a 3:1 mixture of THF—H2O mixture (15 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded {6-chloro-3-methyl-4-[4-(piperidine-1-sulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid (0.125 g, 99%) as a solid. 1H NMR (DMSO-d6) δ: 12.51 (br. s, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.88-7.95 (m, 3H), 7.53 (d, J=8.3 Hz, 2H), 7.50 (dd, J=8.8, 1.5 Hz, 1H), 7.01 (s, 1H), 3.87 (s, 2H), 3.02 (t, J=4.9 Hz, 4H), 2.08 (s, 3H), 1.59 (br. s, 4H), 1.33-1.49 (m, 2H). MS calcd. for C24H25ClNO4S [(M+H)+] 458, obsd. 458.4.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]([CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][C:10]1=[O:21])[CH:6]=O.[NH2:22][CH:23]1[CH2:27][N:26]([C:28]2[CH:29]=[CH:30][C:31]3[O:36][CH2:35][C:34](=[O:37])[NH:33][C:32]=3[CH:38]=2)[C:25](=[O:39])[CH2:24]1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O>[CH3:1][O:2][CH2:3][O:4][CH:5]([CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][C:10]1=[O:21])[CH2:6][NH:22][CH:23]1[CH2:27][N:26]([C:28]2[CH:29]=[CH:30][C:31]3[O:36][CH2:35][C:34](=[O:37])[NH:33][C:32]=3[CH:38]=2)[C:25](=[O:39])[CH2:24]1
Reactant: COCOC(C=O)Cn1c(=O)cnc2ccc(OC)cc21
Reactant: NC1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCOC(CNC1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1)Cn1c(=O)cnc2ccc(OC)cc21
Temperature: 25 °C
Yield: 64.6 %

Procedure:
2-(Methoxymethoxy)-3-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)propanal (0.340 mmol) and 6-(4-amino-2-oxopyrrolidin-1-yl)-2H-1,4-benzoxazin-3(4H)-one (Reference Example 6; 84 mg, 0.340 mmol) were dissolved in a mixed solvent of dichloromethane/N,N-dimethylformamide (10:1,11 ml). Acetic acid (0.039 ml, 0.680 mmol) and anhydrous sodium sulfate (200 mg) were added to this solution, and the mixture was stirred at room temperature for two and a half hours. Sodium triacetoxyborohydride (144 mg, 0.680 mmol) was added thereto, the mixture was stirred for 14 hours and then the solvent was removed under reduced pressure. Chloroform was added to the residue, the resultant was alkalized by adding saturated sodium bicarbonate water under cooling on ice and extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to yield 115 mg (65%) of the title compound in the form of a colorless clear oily product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClC(Cl)C.[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[CH3:19][N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][C:26]#[N:27].Cl>>[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([C:24]1[N:20]([CH3:19])[C:21]([CH2:25][C:26]#[N:27])=[CH:22][CH:23]=1)=[O:13]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Cn1cccc1CC#N
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cn1c(CC#N)ccc1C(=O)c1ccccc1Cl
Temperature: 25 °C

Procedure:
To a cooled suspension of 14 g. (0.105 mole) aluminum chloride in 45 ml. dichloroethane is added dropwise, 18.5 g. (0.105 mole) o-chlorobenzoyl chloride. The resulting solution is added dropwise to a cooled (0° C.) solution of 1-methylpyrrole-2-acetonitrile in 45 ml. dichloroethane keeping the temperature at approximately 10° C. The mixture is stirred at room temperature for about twenty minutes, and then refluxed for three minutes. It is poured into ice acidified with 3N hydrochloric acid, and the resulting two layers are separated. The aqueous fraction is extracted twice with chloroform. The organic fractions are combined and washed twice with N,N-dimethyl-1,3-propanediamine, once with 3N hydrochloric acid and once with saturated sodium chloride solution. The organic fraction is dried over anhydrous magnesium sulfate. The solvent is evaporated, and the resulting oil is chromatographed on a column packed with neutral alumina using benzene and ether as successive solvents. The first compound-bearing fractions contain the desired product. The solvent is evaporated and the resulting oil crystallizes upon treatment with methanol. The solid product, 5-(o-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile, is purified by recrystallization from benzene:cyclohexane solution, m.p. 80-85° C.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[Li+].[Cl-].C1CCN2C(=NCCC2)CC1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:37]2[C:45]3[C:40](=[C:41]([N:46]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[S:47]([CH3:50])(=[O:49])=[O:48])[CH:42]=[CH:43][CH:44]=3)[CH:39]=[N:38]2)([CH2:35][CH3:36])[CH:33]=O)=[CH:28][CH:27]=1>CC#N>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:37]2[C:45]3[C:40](=[C:41]([N:46]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:56])[CH3:57])[S:47]([CH3:50])(=[O:49])=[O:48])[CH:42]=[CH:43][CH:44]=3)[CH:39]=[N:38]2)([CH2:35][CH3:36])/[CH:33]=[CH:3]/[C:1]#[N:2])=[CH:28][CH:27]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCC(C=O)(c1ccc(Cl)cc1)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of diethyl cyanomethylphosphonate (20 mg, 0.12 mmol), LiCl (5 mg, 0.12 mmol) and DBU (18 mg, 0.12 mmol) in MeCN (2 mL) was added a solution of N-(1-(2-(4-chlorophenyl)-1-oxobutan-2-yl)-1H-indazol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methane sulfonamide (50 mg, 0.10 mmol) in MeCN (1 mL). The mixture was stirred at room temperature for 2 h and evaporated. The residue was purified by silica gel chromatography (PE/EA=6/1) to afford the title compound as a white solid. LC/MS m/z=545.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:7]([Cl:26])[CH:6]=1.[OH-].[K+].O.Cl>C(O)C>[Cl:26][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:27])=[O:2])[CH:10]=[CH:9][C:8]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)OC)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)O)cc1Cl
Yield: 59.5 %

Procedure:
A mixture of 69.7 g of product from Example 63, 29.55 g of potassium hydroxide, 45 of water and 800 ml ethyl alcohol is heated at reflux temperature for 89 hours. The cooled solution was made acidic (pH 2) with concentrated hydrogen chloride; followed by heating to distill off the ethyl alcohol. The solution is diluted with diethyl ether and water. The organic layer is dried and concentrated in vacuo. The residue is recrystallized from methylene chloride/hexane to give 40.0 g of the desired product as colorless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:26][C@@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=[CH:10][CH:9]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1ccc(-c2ccccc2Cl)cc1
Product: Clc1ccccc1-c1ccc(CN[C@H]2CCCc3ccccc32)cc1

Procedure:
2′-Chloro[1,1′-biphenyl]-4-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:8]2([CH3:23])[CH2:13][C@@H:12]([CH3:14])[S:11][C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)C.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]([O:17][C:16](=[O:22])[NH:15][C:10]1[S:11][C@H:12]([CH3:14])[CH2:13][C@@:8]([CH3:23])([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:31]3[CH:32]=[N:27][CH:28]=[N:29][CH:30]=3)[CH:3]=2)[N:9]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: C[C@@H]1C[C@@](C)(c2cccc(Br)c2)N=C(NC(=O)OC(C)(C)C)S1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: C[C@@H]1C[C@@](C)(c2cccc(-c3cncnc3)c2)N=C(NC(=O)OC(C)(C)C)S1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39 %

Procedure:
To a 100° C. solution of tert-butyl (4S,6R)-4-(3-bromophenyl)-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazin-2-ylcarbamate in 1,2-dimethoxyethane: water: ethanol [(3:1.5:1), 12 mL] is added, in a single portion, pyrimidine-5-boronic acid (128 mg, 5.9 mmoles, 2.5 equiv), bis(triphenylphosphine)palladium(II) chloride (29 mg, 41 μmoles, 0.1 equiv) and cesium carbonate (1.24 g, 1.24 mmoles, 3 equiv). After 20 minutes, the reaction is cooled to ambient temperature, diluted with water, and extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography eluting with a linear gradient of hexane to hexane:ethyl acetate (5:2) over 20 minutes to give the title compound (39% yield): MS (m/z): 399 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:14])([F:13])[C:7]([OH:12])([CH3:11])[C:8](O)=[O:9].[NH2:15][C:16]1[S:17][C:18]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:20]=1.O>CN(C)C(=O)C>[C:23]1([C:21]([C:18]2[S:17][C:16]([NH:15][C:8](=[O:9])[C:7]([OH:12])([CH3:11])[C:6]([F:14])([F:13])[F:5])=[CH:20][CH:19]=2)=[O:22])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)s1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2ccccc2)s1)C(F)(F)F
Reaction time: 1 h

Procedure:
Thionyl chloride (110 μl, 1.51 mmol) is added to 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (240 mg, 1.52 mmol) in 5 ml of N,N-dimethylacetamide at -15°/-10° C., and the mixture is stirred at this temperature for one hour. Then 2-amino-5-(phenylcarbonyl) thiophene (200 mg, 0.983 mmol) is added and the reaction mixture is equilibrated to room temperature. After the reaction has ended, the reaction mixture is poured into 200 ml of water and subjected to extraction with 3×100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and filtered and the solvent is distilled off. The orange-colored oil which remains is purified by flash chromatography (eluent: 50% v/v ethyl acetate in petroleum ether (40/60)).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:20]N1C(=O)CCC1=O.O>ClCCl>[Br:20][C:10]1[N:9]=[C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]=12
Reactant: CC(=O)N1CCN(c2ncc3c(C)nccn23)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCN(c2nc(Br)c3c(C)nccn23)CC1
Yield: 88.1 %

Procedure:
To 1-(4-(8-methylimidazo[1,5-a]pyrazin-3-yl)piperazin-1-yl)ethanone (0.208 mmol, 54 mg) in dichloromethane (1 ml) at room temperature was added N-bromosuccinimide (0.208 mmol, 37.1 mg). After stirring at room temperature for 5 minutes water was added and the mixture extracted three times with dichloromethane. The combined organic extracts were dried over a phase separation filter and concentrated in vacuo to give 1-(4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)piperazin-1-yl)ethanone (62 mg).
Reaction SMILES: [C:1](=[O:23])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N+:11]=[N-:12].[NH:24]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:25]([C:30]([OH:32])=[O:31])[CH2:26][CH2:27][CH2:28][NH2:29].C(=O)(O)[O-].[Na+].S(=O)(=O)(O)[O-].[K+]>O1CCOCC1.C(OCC)(=O)C.O>[N:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][O:2][C:1]([NH:29][CH2:28][CH2:27][CH2:26][C@H:25]([NH:24][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:30]([OH:32])=[O:31])=[O:23])=[N+:11]=[N-:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)O
Reactant: [N-]=[N+]=Nc1ccccc1COC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1N=[N+]=[N-])C(=O)O
Temperature: 25 °C
Reaction time: 20.25 h
Yield: 102.9 %

Procedure:
2-Azidobenzyl (4-nitrophenyl) carbonate (Compound tk13) (458 mg, 1.459 mmol) was added to a suspension of Boc-Orn-OH (Compound tk56) (308 mg, 1.326 mmol) and sodium bicarbonate (278 mg, 3.32 mmol) in 1,4-dioxane (3 mL)-water (2 mL). The reaction mixture was stirred at room temperature for 20.25 hours and then cooled in an ice bath and diluted with ethyl acetate and water, and a saturated aqueous potassium bisulfate solution (1.5 mL) was added to the resulting mixture. The mixture was extracted with ethyl acetate (×2), and the organic phase was washed with water (10 mL×2) and brine (10 mL) and dried over sodium sulfate. Following concentration under reduced pressure, the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-5-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoic acid (Compound tk61) (556.0 mg, quant.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([CH3:12])[CH:6]=1)=[O:4].Cl[C:14]1[NH:15][CH2:16][CH2:17][N:18]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:11]=[CH:10][C:8]([N:9]=[C:14]2[NH:18][CH2:17][CH2:16][NH:15]2)=[C:7]([CH3:12])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(N)c(C)c1
Reactant: ClC1=NCCN1
Product: COC(=O)c1ccc(N=C2NCCN2)c(C)c1
Yield: 47 %

Procedure:
After reaction of the aniline from Step B with 2-chloro-2-imidazoline substantially as described in Example 2 there is isolated in 47% yield, 2-(4-methoxycarbonyl-2-methylphenylimino)imidazolidine, m.p. 193°-194.5° C.
Reaction SMILES: C1(C2C=NC3C=CC=C(C#N)C=3C=2)C=CC=CC=1.[C:19]1([C:25]2[CH:26]=[N:27][C:28]3[CH:29]=[CH:30][CH:31]=[C:32]([CH:35]=[O:36])[C:33]=3[CH:34]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)=O.[Ni]>[C:19]1([C:25]2[CH:26]=[N:27][C:28]3[C:33]([CH:34]=2)=[C:32]([CH2:35][OH:36])[CH:31]=[CH:30][CH:29]=3)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1cccc2ncc(-c3ccccc3)cc12
Agent: [Ni]
Agent: N#Cc1cccc2ncc(-c3ccccc3)cc12
Solvent: O=CO
Product: OCc1cccc2ncc(-c3ccccc3)cc12
Temperature: 80 °C
Reaction time: 5 h

Procedure:
23 g (0.1 mol) of 3-phenylquinoline-5-carbonitrile (substance from Example 4) are admixed in 150 ml of formic acid with 10 g of Raney nickel. The mixture is stirred for about 5 hours at about 80° C. The slow formation of 3-phenylquinoline-5-carbaldehyde is observed by means of HPLC. In addition, 3-phenyl-5-hydroxymethylquinoline is formed as overreduced product. For the work-up, 300 ml of H2O are stirred in and the mixture is optionally extracted with 200 ml of methylene chloride. The methylene chloride phase is subsequently stirred at 40° C. (reflux) for 2 hours with 10 g of manganese dioxide. After filtration, the solution is evaporated and the residue is recrystallized from isopropanol.
Reaction SMILES: S(=O)(=O)(O)O.N([O-])=O.[Na+].[PH2](O)=O.N[C:14]1[C:19]([Cl:20])=[C:18]([C:21]([O:23][CH3:24])=[O:22])[C:17]([Cl:25])=[CH:16][C:15]=1[C:26]([O:28][CH3:29])=[O:27].N>C(O)(=O)C>[Cl:20][C:19]1[CH:14]=[C:15]([C:26]([O:28][CH3:29])=[O:27])[CH:16]=[C:17]([Cl:25])[C:18]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1cc(Cl)c(C(=O)OC)c(Cl)c1N
Agent: N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c(C(=O)OC)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
In a round bottom flask containing concentrated sulfuric acid (10 mL) was added ice-cold water (10 mL) while maintaining the temperature around 0° C. Sodium nitrite (3.7 g, 53 mmol) was added portion wise followed by the drop wise addition of hypophosphorous acid (8 mL). This was followed by drop wise addition of a solution of dimethyl 2-amino-3,5-dichlorobenzene-1,4-dicarboxylate (5 g, 17.9 mmol, Step a) in acetic acid (10 mL). The resulting reaction mixture was stirred at 0° C. for 2 hours and then stored in a refrigerator at −10° C. for 15 hours. The reaction mixture was stirred at room temperature for additional 2 hours. The reaction mixture was again cooled to 0° C. and neutralized with aqueous ammonia solution, partitioned with ethyl acetate (2×15 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography using ethyl acetate in hexane (4%) to yield dimethyl 2,6-dichlorobenzene-1,4-dicarboxylate as a pale yellow crystalline solid (3.8 g, 79%).