Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]([CH:13]([F:15])[F:14])([CH2:9][CH2:10][CH2:11][NH2:12])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].Br.C([NH+:19]=[C:20]([NH2:22])S)C.Cl>[OH-].[Na+]>[C:1]([NH:4][C:5]([CH:13]([F:14])[F:15])([CH2:9][CH2:10][CH2:11][NH:12][C:20]([NH2:22])=[NH:19])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC[NH+]=C(N)S
Reactant: CC(=O)NC(CCCN)(C(=O)O)C(F)F
Agent: Br
Agent: Cl
Agent: [Na+]
Product: CC(=O)NC(CCCNC(=N)N)(C(=O)O)C(F)F

Procedure:
To a solution of 2-acetylamino-5-amino-2-difluoromethylpentanoic acid (0.45 g) in 4 ml of 0.5M aqueous sodium hydroxide is added 1.8 g of ethylthiouroniumhydrobromide. the pH of the solution is adjusted to 9 with a solution of sodium hydroxide and maintained at that pH for 24 hours. The reaction mixture is then neutralized to a pH of 7 with hydrochloric acid and 2-acetylamino-2-difluoromethyl-5-guanidinopentanoic acid is isolated by ion exchange chromatography on an Amberlite IR 120 resin.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:30])[C:11]3[C:16]4[N:17]=[C:18]([N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[N:19]=[C:20]([O:21][CH2:22][CH3:23])[C:15]=4[S:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.B1(C=C)OB([CH:37]=[CH2:38])OB(C=C)O1.C1C=CN=CC=1>>[CH2:22]([O:21][C:20]1[C:15]2[S:14][C:12]3[N:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([CH:37]=[CH2:38])=[CH:3][CH:4]=4)[N:9]=[C:10]([CH3:30])[C:11]=3[C:16]=2[N:17]=[C:18]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:19]=1)[CH3:23]
Reactant: CCOc1nc(N2CCNCC2)nc2c1sc1nc(-c3ccc(Br)cc3)nc(C)c12
Reactant: C=CB1OB(C=C)OB(C=C)O1
Solvent: c1ccncc1
Product: C=Cc1ccc(-c2nc(C)c3c(n2)sc2c(OCC)nc(N4CCNCC4)nc23)cc1

Procedure:
The title substance was prepared by coupling 7-(4-bromophenyl)-4-ethoxy-9-methyl-2-piperazin-1-yl-thieno[2,3-d:4,5-d′]dipyrimidine with 2,4,6-trivinylcyclotriboroxane-pyridine complex in analogy to Example 3. ESI-MS [m/z]: 433, melting point: 165-166° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:9][N:10]([CH3:31])[C:11](=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]1[C:25]([F:26])=[C:24]([F:27])[CH:23]=[C:22]([F:28])[C:21]=1[F:29]>ClCCCl>[CH3:31][N:10]([CH3:9])[C:11](=[O:30])[CH2:12][C:13]1[CH:18]=[C:17]([C:1](=[O:3])[CH3:2])[CH:16]=[CH:15][C:14]=1[NH:19][C:20]1[C:21]([F:29])=[C:22]([F:28])[CH:23]=[C:24]([F:27])[C:25]=1[F:26]
Reactant: CC(=O)Cl
Reactant: CN(C)C(=O)Cc1ccccc1Nc1c(F)c(F)cc(F)c1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc(Nc2c(F)c(F)cc(F)c2F)c(CC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an inert atmosphere, acetyl chloride (29.1 ml, 0.385 mol) is slowly added to a suspension of aluminum chloride (51.2 g, 0.385 mol) stirred in 1,2-dichloroethane (750 ml). After stirring at room temperature for 1 hour a yellow solution is obtained. The solution is cooled in an ice bath and N,N-dimethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetamide (40 g, 0.123 mol) is added. The reaction is allowed to warm to room temperature and then warmed to 80° for 0.5 hours. The reaction is poured over ice and extracted with EtOAc (2×750 ml). The organic extract is washed with water (750 ml), saturated NaHCO3 solution (500 ml) and brine (500 ml). Evaporation on a rotovap and trituration with Et2O gives N,N-dimethyl-5-acetyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetamide as a white solid, m.p. 112-114°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Br:16]Br>C(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[Br:16][C:7]1[CH:6]=[C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrBr
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2C#N)cc1Br
Reaction time: 2 h
Yield: 41 %

Procedure:
A solution of 5.2 g (27 mmol) of 4'-methyl-1,1'-biphenyl-2-nitrile (Example 69, Step B) in 60 mL of methylene chloride at 0° C. was treated with 6.7 g of silver trifluoroacetate (30 mmol). When all the silver trifluoroacetate was dissolved, 1.6 mL of bromine was added dropwise (4.95 g, 31 mmol) with vigorous stirring. After two hours, the reaction mixture was filtered and the solid washed with methylene chloride. The combined organic layers were washed once with dilute (<1N) aqueous sodium hydroxide and once with brine. The organic layer was removed, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative high pressure liquid chromatography on silica, eluting with 10% ether/hexane to give 3 g (41%) of product. 1H NMR (200 MHz, CDCl3): 2.46 (s, 3H), 7.2-7.8 (m,7H).
Reaction SMILES: C(N(CC)C(=O)C1C(=CC=CC=1)O)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:24]1[CH:25]=[C:26]([CH3:31])[CH:27]=[C:28]([CH3:30])[CH:29]=1.[CH3:32][C@@H:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[OH-].[NH4+].CCCCCCCCCCCC>O.C(OCC)(=O)C.CN(C=O)C>[CH3:30][C:28]1[CH:29]=[C:24]([NH:40][C@H:33]([CH3:32])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:25]=[C:26]([CH3:31])[CH:27]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: Cc1cc(C)cc(Br)c1
Agent: CCN(CC)C(=O)c1ccccc1O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCCCCCCC
Solvent: O
Product: Cc1cc(C)cc(N[C@H](C)c2ccccc2)c1
Temperature: 100 °C
Reaction time: 30 h
Yield: 71 %

Procedure:
CuOAc (6 mg, 0.05 mmol), N,N-diethylsalicylamide (39 mg, 0.20 mmol) and K3PO4 (425 mg, 2.0 mmol) were put into a screw-capped test tube with a Teflon-lined septum. The tube was then evacuated and backfilled with argon (3 cycles). 5-Bromo-m-xylene (136 μL, 1.0 mmol), (R)-α-methylbenzylamine (193 μL, 1.5 mmol) and DMF (0.5 mL) were added by syringes. The reaction mixture was stirred at 100° C. for 30 h. The reaction mixture was allowed to reach room temperature. Ethyl acetate (˜2 mL), water (˜10 mL), ammonium hydroxide (˜0.5 mL) and dodecane (227 μL) were added. The organic phase was analyzed by GC or GC-MS. The reaction mixture was further extracted by ethyl acetate (4×10 mL). The combined organic phases were washed with brine and dried over Na2SO4. Solvent was removed in vacuo and the yellow residue was purified by column chromatography on silica gel using hexane/ethyl acetate (20:1) as eluent to afford the desired product as a colorless oil (160 mg, 71% yield, 98% ee). Rf=0.4 (hexane/ethyl acetate=20:1). HPLC conditions: (column: Daciel OD; flow rate: 0.7 mL/min; UV lamp: 254 nm; solvent system: hexane/2-propanol (9:1); retention time: 7.80 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:44]=[CH:43][C:27]([O:28][CH2:29][C:30]([NH:32][C@H:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:34](O)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[NH2:45][C@H:46]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:47]([O:49]C(C)(C)C)=[O:48].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:44]=[CH:43][C:27]([O:28][CH2:29][C:30]([NH:32][C@H:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:34]([NH:45][C@H:46]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:47]([OH:49])=[O:48])=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:6][CH:7]=1
Reactant: O=C(COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)N[C@@H](C(=O)O)c1ccccc1
Reactant: CC(C)(C)OC(=O)[C@H](N)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)N[C@@H](C(=O)N[C@@H](C(=O)O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2R)-({[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl)amino)(phenyl)acetic acid (0.040 g, 0.065 mmol) was dissolved in CH2Cl2 (5 ml) and tert-butyl (2R)-amino(phenyl)acetate (0.016 g, 0.078 mmol) and N-methyl-morphiline (0.020 g, 0.195 mmol) were added. After 5 minutes TBTU (0.027 g, 0.084 mmol) was added. The reaction was allowed to stir at room temperature for 3 h after which the resulting tert-butyl ester was purified on silica gel and eluted with EtOAc/CH2Cl2 25/75. Pure fractions were concentrated. The residue was dissolved in CH2Cl2 (3 ml) and TFA (0.5 ml). The reaction mixture was allowed to stir overnight at room temperature. The resulting acid was concentrated and the remaining trace of TFA was removed by co-evaporation with toluene (3 ml). The acid was dissolved in MeOH (3 ml) and NaBH (0.010 g, 0.260 mmol) was added. After 5 minutes, full conversion to the corresponding alcohol was obtained. The reaction was quenched by the addition of 1 ml of 0.1M NH4OAc buffer. Concentration followed by purification on preparative HPLC using a gradient of 20-50% CH3CN in 0.1M NH4OAc buffer as mobile phase and freeze-drying of the pure fractions afforded the title compound (0.034 g, 70%) as a colourless solid. M/z: 750.4 (M−1). 1H NMR [(CD3)2SO), 400 MHz] δ 2.88-2.94 (m, 2H), 4.23-4.29 (m, 1H), 4.56-4.65 (m, 2H), 4.70-4.78 (m, 1H), 4.91-5.06 (m, 2H), 5.65-5.75 (m, 1H), 6.93-7.42 (m, 22H), 8.54-8.69 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][N:5]1[CH2:29][CH2:28][C:8]2([N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:11](=[O:20])[N:10]=[C:9]2[NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:7][CH2:6]1.[CH3:34][C:35]([CH3:37])=O>>[CH:22]1([NH:21][C:9]2[C:8]3([CH2:28][CH2:29][N:5]([CH2:4][C:3]4[CH:30]=[CH:31][CH:32]=[CH:33][C:2]=4[NH:1][CH:35]([CH3:37])[CH3:34])[CH2:6][CH2:7]3)[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:11](=[O:20])[N:10]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: Nc1ccccc1CN1CCC2(CC1)C(NC1CCCCC1)=NC(=O)N2c1cccc(F)c1
Reactant: CC(C)=O
Product: CC(C)Nc1ccccc1CN1CCC2(CC1)C(NC1CCCCC1)=NC(=O)N2c1cccc(F)c1

Procedure:
Produced using Method Z substituting acetone for the aldehyde and 8-(2-aminobenzyl)-4-(cyclohexylamino)-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one (example 80) for the substrate. MS 492.4
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][C@H:7]([CH2:12][OH:13])[CH2:8][CH2:9][CH2:10]Cl)=[N+:2]=[N-:3].[H-].[Na+].[CH2:24](I)[CH3:25]>CN(C=O)C>[N:1]([CH2:4][C@@H:5]([N:14]([CH2:24][CH3:25])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][C@H:7]1[CH2:8][CH2:9][CH2:10][O:13][CH2:12]1)=[N+:2]=[N-:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])C[C@H](CO)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)[C@H](CN=[N+]=[N-])C[C@H]1CCCOC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.6 %

Procedure:
To a 0° C. solution of crude tert-butyl (2S,4R)-1-azido-7-chloro-4-(hydroxymethyl)heptan-2-ylcarbamate (3.20 g, 10.0 mmol) in anhydrous DMF (50 mL) was added NaH (60% in mineral oil, 2.0 g, 50.0 mmol), 5 min later the temperature was allowed to warm to room temperature and stirred another 1.5 h. Ethyl iodide (4.68 g, 2.4 mL, 30.0 mmol) was added and stirred overnight at room temperature. The reaction was quenched with sat. aq. NH4Cl at 0° C., and extracted with EA (70 mL), the separated organic phase was washed with H2O (2×50 mL), brine (50 mL) successively, and dried over Na2SO4 and concentrated to afford an oil, which was purified on flash chromatography on silica gel and eluted with ethyl acetate/hexane (0-20%) to afford 1.8 g of tert-butyl (S)-1-azido-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-yl(ethyl)carbamate. MS ESI+ve m/z: 313 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=3)[NH2:28])[CH2:19][CH2:18]2)[N:8]=1>N1C=CC=CC=1>[CH3:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[N:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]3[CH:26]=[C:27]([NH:28][S:2]([CH3:1])(=[O:4])=[O:3])[CH:29]=[CH:30][CH:31]=3)[CH2:21][CH2:22]2)[N:8]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NS(C)(=O)=O)c4)CC3)cccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
Methanesulfonyl chloride (8 μL; 1.2 eq) was added dropwise to a solution of 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6)(0.03 g; 1 eq) in pyridine (0.5 mL). The reaction was stirred at r.t. overnight. The reaction mixture was concentrated under reduced pressure, diluted with water (1 mL) and a saturated aqueous solution of sodium hydrogen carbonate (1 mL), extracted into dichloromethane (3×2 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by flash chromatography, eluting with a gradient from dichloromethane to dichloromethane/MeOH (98/2) affording the title compound in 44% yield (0.016 g).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7]O)[CH:3]=[N:2]1.[NH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[SH:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][S:17][C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[NH2:9])[CH:3]=[N:2]1
Reactant: Nc1cc(Cl)ccc1S
Reactant: OCCc1cn[nH]c1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Nc1cc(Cl)ccc1SCCc1cn[nH]c1

Procedure:
Following the General Procedure J, the title intermediate was prepared from 2-(1H-pyrazol-4-yl) ethanol (472 mg, 4.218 mmol), 2-amino-4-chlorobenzenethiol (1.01 g, 6.327 mmol), PPh3 (2.21 g, 8.436 mmol) and di-tert-butylazodicarboxylate (1.9 g, 8.436 mmol) in CH2Cl2 (20 ml).
Reaction SMILES: [CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]#[N:29])=[CH:18][CH:17]=3)[C:7]3=[N:8][CH:9]=[C:10](Br)[C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1.C(O)=O>[Pd].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]#[N:29])=[CH:18][CH:17]=3)[C:7]3=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(Br)cnc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: O=CO
Product: Cc1ccnc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Yield: 78 %

Procedure:
Toluene (30 ml) was added to 2.0 g (4.5 mmol) of 2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine, 1.24 g (27.0 mmol) of formic acid, 4.55 g (45.0 mmol) of rriethylamine and 10% Pd-C (100 mg), followed by heating under reflux for 6 hours. After the reaction liquid was brought to room temperature and filtered to remove the catalyst, vacuum concentration was effected. Chloroform (50 ml) and water (50 ml) were added to the residue and the obtained mixture was caused liquid-liquid separation. The aqueous phase was further extracted with chloroform (30 ml) twice. The organic phases were combined, dried over anhydrous magnesium sulfate and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 1.28 g of 2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine (yield 78%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][NH:10][CH:11]=[O:12])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:13][O:14][C:15](=[O:18])[CH2:16]Cl>>[CH3:13][O:14][C:15](=[O:18])[CH2:16][N:10]([CH2:9][P:4]([O:3][CH2:1][CH3:2])([O:5][CH2:6][CH3:7])=[O:8])[CH:11]=[O:12]
Reactant: COC(=O)CCl
Reactant: CCOP(=O)(CNC=O)OCC
Product: CCOP(=O)(CN(C=O)CC(=O)OC)OCC

Procedure:
The process in the third step of the process of the invention comprises reacting diethyl-N-(formyl)aminomethylphosphonate with methylchloroacetate in the presence of a proton-extracting base and a suitable solvent to produce N-(diethylphosphonomethyl)-N-(formyl)glycine methyl ester.
Reaction SMILES: O[C:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(=O)(O)[O-].[Na+]>>[CH3:35][C:20]1[CH:19]=[C:18]([C:15]2[S:14][C:13]([C:2]3[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]=3)=[N:17][CH:16]=2)[CH:23]=[C:22]([NH:24][C:25]2[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=2)[CH:21]=1
Reactant: CCOC(=O)C1CCC(O)(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCOC(=O)C1CC=C(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Temperature: 60 °C
Reaction time: 0.03 h
Yield: 83.1 %

Procedure:
To a flask containing ethyl 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate (Example 32, 0.18 g, 0.345 mmol) was added Eaton's Reagent (1.3 mL) and the mixture was heated at 60° C. for 2 hours. The reaction was cooled and added dropwise to saturated sodium bicarbonate. After stirring for 2 minutes, the aqueous solution was extracted three times with ethyl acetate. The combined organics were dried under reduced pressure and purified by silica gel chromatography to yield ethyl 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-cyclohex-3-ene-1-carboxylate (0.14 g, 82% yield). MS ESI: [M+H]+ m/z 489.1. 1H NMR (500 MHz, CDCl3) δ 8.65 (d, J=5.2, 1H), 7.96-7.79 (m, 2H), 7.46 (s, 1H), 7.26 (s, 1H), 7.14-6.95 (m, 2H), 6.65 (s, 1H), 4.28-3.96 (m, 2H), 2.90-2.75 (m, 1H), 2.75-2.60 (m, 1H), 2.62-2.47 (m, 3H), 2.39 (s, 3H), 2.26-2.10 (m, 1H), 1.95-1.70 (m, 1H), 1.39-1.17 (m, 3H). rhSYK activity=++
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:36])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:33]=[CH:32][C:18]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)=[O:20])=[C:17]([O:34][CH3:35])[CH:16]=3)[N:10]=2)[CH:8]=1.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:36][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:40]([CH:37]2[CH2:39][CH2:38]2)=[O:41])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:33]=[CH:32][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[O:20])=[C:17]([O:34][CH3:35])[CH:16]=2)[N:10]=1
Reactant: COc1cc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1
Yield: 31 %

Procedure:
The title compound was prepared by following the procedure as described for step-2 of Intermediate-30 by using 4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide (Intermediate-26, 0.060 g, 0.11 mmol), cyclopropylcarbonyl chloride (0.019 g, 0.17 mmol), DIPEA (1 mL) and THF (5 mL) to afford 0.020 g of desired product. 1H NMR (300 MHz, DMSO d6): 1.06 (m, 2H), 1.22 (m, 2H), 3.17 (m, 1H), 3.95 (s, 3H), 4.34 (d, J=6.0 Hz, 2H), 7.44-7.84 (m, 8H), 7.95 (d, J=9.0 Hz, 1H), 8.25 (s, 1H), 8.70 (m, 1H), 10.43 (m, 1H), 12.05 (m, 1H); MS (m/z): 584.35 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1Br.[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)#[CH:33].O>ClCCCl.CC(C)=O.[Cu]I.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>[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1[C:33]#[C:32][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1
Reactant: C#Cc1ccccn1
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)n1nc(-c2nc(C#Cc3ccccn3)c(N)nc2-c2ccccc2)ccc1=O
Reaction time: 18 h

Procedure:
In the presence of copper(I) iodide (3.7 mg) and dichlorobis(triphenylphosphine)palladium(II) (13.7 mg), triethylamine (0.0596 ml) was dropwise added to a mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (150 mg) and 2-ethynylpyridine (0.0431 ml) in 1,2-dichloroethane (1.5 ml) at 30-35° C. The mixture was stirred at the same temperature for 18 hours. Water was added to the reaction mixture to give a solid. The solid was purified by column chromatography on silica gel (EtOAc only) to give a solid. The solid was suspended in acetone to give 6-[5-amino-3-phenyl-6-(2-pyridylethynyl)-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (88 mg).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:12]=2)=[O:8])=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I.CS(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([N:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]4=[O:23])=[CH:18][CH:17]=3)[CH:12]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cc(-c2ccc(I)cc2)no1)c1ccc(Cl)s1
Reactant: Oc1ccccn1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: O=C(NCc1cc(-c2ccc(-n3ccccc3=O)cc2)no1)c1ccc(Cl)s1
Temperature: 120 °C

Procedure:
Aryl iodide (Example 288, 43 mg, 0.1 mmol) and 2-hydroxypyridine (38 mg, 0.4 mmol) were dissolved in 1.2 mL dry dioxane and 0.5 mL dry DMSO in a sealed tube. To it were added N,N′-dimethylethylenediamine (11 μL, 0.1 mmol), CuI (10 mg, 0.05 mmol) and K3PO4 (42 mg, 0.2 mmol) in order. The mixture was stirred and heated in 120° C. bath for 6 hrs. The mixture was filtered and directly subjected to reverse phase preparative HPLC to isolate the title compound as a white powder after lyophilization. MS found for C20H14ClN3O3S as (M+H)+ 412.0, 414.0
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[F:22][C:23]1[C:30]([F:31])=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:28]=[CH:27][C:24]=1[CH:25]=O>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:25][C:24]1[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[C:30]([F:31])[C:23]=1[F:22]
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1F
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: O=C(C=Cc1ccc(C(F)(F)F)c(F)c1F)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and 2,3-difluoro-4-(trifluoromethyl)benzaldehyde (91 ul, 0.633 mmol) similar to Example 18 as a yellow solid (66 mg, 20%). 1H NMR (CDCl3): 7.78 (d, J=15.9 Hz, 1H), 7.64 (d, J=16.2 Hz, 1H), 7.51-7.38 (m, 2H), 7.35 (d, J=3.0 Hz, 1H), 7.18 (dd, J=3.3, 9.0 Hz, 1H), 6.95 (d, J=9.3 Hz, 1H), 4.47-4.35 (m, 4H).