Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:26])[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:16][CH:15]=3)[CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].Br[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]=1[F:37].C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[F:37][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:28]=1[N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:18]=[CH:19][C:14]([C:13](=[O:26])[NH:12][C:9]3[CH:10]=[C:11]4[C:6]([CH:5]=[CH:4][N:3]4[CH2:1][CH3:2])=[CH:7][CH:8]=3)=[CH:15][N:16]=2)[CH2:21][CH2:22]1)[C:32]([OH:34])=[O:33]
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(N4CCNCC4)nc3)cc21
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CCn1ccc2ccc(NC(=O)c3ccc(N4CCN(c5ccc(C(=O)O)cc5F)CC4)nc3)cc21

Procedure:
3-fluoro-4-{4-[5-(1-ethyl-1H-indol-6-ylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was synthesized from N-(1-ethyl-1H-indol-6-yl)-6-piperazin-1-yl-nicotinamide and 4-bromo-3-fluoro-benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C27H26FN5O3 (m/e) 487, obsd 488 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH:6]([CH3:9])[CH2:7][NH2:8].[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C.O>CS(C)=O>[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH:8][CH2:7][CH:6]([O:5][C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[CH3:9]
Reactant: COc1ccccc1OC(C)CN
Reactant: Cc1ccc(S(=O)(=O)OCCCc2c[nH]c3ccc(F)cc23)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccccc1OC(C)CNCCCc1c[nH]c2ccc(F)cc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
A solution of 2-(2-methoxy-phenoxy)propylamine (0.26 g, 1.2 mmol), 5-fluoro-3-(3-p-toluenesulfonyloxypropyl)indole (0.26 g, 0.81 mol) and triethylamine (0.13 g, 1.2 mmol) in anhydrous dimethylsulfoxide (20 ml) was allowed to stir for 8 hours at 90° C. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×100 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) afforded 0.1 g (36%) of product of product as a yellow oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][C@H:14]([CH3:23])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(N(CC)CC)C>ClCCl>[CH3:23][C@@H:14]([CH2:13][O:12][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H](CO)CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H](C)CC(=O)OC(C)(C)C)cc1
Reaction time: 20 h
Yield: 96.5 %

Procedure:
p-Toluenesulphonyl chloride (13.2 g) was added portionwise to a stirred mixture of tert-butyl (3R)-4-hydroxy-3-methylbutyrate (11 g), triethylamine (21 ml) and dichloromethane (120 ml) and the mixture stirred for 20 hours. The mixture was washed in turn with water and dilute aqueous sodium carbonate solution. The organic solution was filtered through phase separating paper and evaporated to give tert-butyl (3R)-3-methyl-4-(p-toluenesulphonyloxy)butyrate as an oil (20 g); NMR (CDCl3) δ 7.6(2H,d), 7.33(2H,d), 3.92(2H,d), 2.45(3H,s), 2.18-2.47(2H,m), 2.0-2.15(1H,m), 1.42(9H,s), 0.95(3H,d).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C1(C)C=CC=CC=1.[F-].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: N#Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
To a solution of 4-bromobenzonitrile (4.0 g, 22 mmol) and 4-fluorophenylboronic acid (4.6 g, 32 mmol) in 4:1 toluene:water (100 mL) were added potassium fluoride (3.8 g, 66 mmol) and Pd(PPh3)4 (2.5 g, 2.2 mmol). The resulting mixture was stirred at reflux for 12 h. The mixture was cooled to room temperature and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification of the crude residue by silica gel chromatography gave 4′-fluorobiphenyl-4-carbonitrile (4.2 g) as a colorless solid. 1H NMR (400 MHz, CD3OD) δ 7.69 (s, 4H), 7.63-7.60 (m, 2H), 7.15-7.10 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:21](=[N:33][O:34]C)[C:22]#[C:23][CH:24]1[CH2:27][CH:26]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25]1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:36]Cl.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:21]1[C:22]([I:36])=[C:23]([CH:24]2[CH2:27][CH:26]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25]2)[O:34][N:33]=1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON=C(C#CC1CC(CC(C)(C)C)C1)C(CCCOCc1ccccc1)CC(=O)OC(C)(C)C
Reactant: ClI
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)CC1CC(c2onc(C(CCCOCc3ccccc3)CC(=O)OC(C)(C)C)c2I)C1
Reaction time: 1 h

Procedure:
tert-Butyl 3-(3-benzyloxypropyl)-6-[3-(2,2-dimethylpropyl)cyclobutyl]-4-methoxyimino-5-hexynoate (3.37 g) and methylene chloride (70 mL) were mixed. To the mixture was added iodine monochloride (1 M in methylene chloride) (7.66 mL) at ice temperature. The mixture was stirred at ice temperature for 1 hr, and then to the mixture was added aqueous solution of sodium sulfite. The mixture was extracted with chloroform. The organic layer was washed with water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (4.21 g) as a crude product.
Reaction SMILES: C1([N:7]2[CH2:12][CH2:11][N:10](C(C3C=CC=CC=3)CC3C=C(C)C=CC=3)[CH2:9][CH2:8]2)CCCCC1.[OH2:28].[C:29]([C@:37]([C:52]([OH:54])=[O:53])([OH:51])[C@:38]([C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([OH:42])[C:39]([OH:41])=[O:40])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C>[OH2:36].[C:43]([C@:38]([C:39]([OH:41])=[O:40])([OH:42])[C@:37]([C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([OH:51])[C:52]([OH:54])=[O:53])(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[OH2:28].[OH2:36].[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:43]([C@:38]([C:39]([OH:41])=[O:40])([OH:42])[C@:37]([C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([OH:51])[C:52]([OH:54])=[O:53])(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: Cc1cccc(CC(c2ccccc2)N2CCN(C3CCCCC3)CC2)c1
Agent: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: CCO
Solvent: O
Product: C1CNCCN1

Procedure:
A warmed mixture of dl-1-cyclohexyl-4-[1-phenyl-2-(3-tolyl)ethyl]piperazine (3.0 g), dibenzoyl-d-tartaric acid monohydrate (3.2 g) and ethanol (100 ml) is allowed to cool. The precipitated crystals are separated by filtration and fractionally recrystallized from 95% ethanol to give l-1-cyclohexyl-4-[1-phenyl-2-(3-tolyl)ethyl[piperazine dibenzoyl-d-tartarate sesquihydrate (1.2 g), melting point: 150°- 151° C. (decomp.), [α D28 = -83.0° (c=1.0, methanol).
Reaction SMILES: C1(O[C:8](=[O:25])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)=[CH:12][CH:11]=2)C=CC=CC=1.[CH2:26]([CH2:28][NH2:29])[OH:27]>>[OH:27][CH2:26][CH2:28][NH:29][C:8]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([B:16]2[O:20][C:19]([CH3:21])([CH3:22])[C:18]([CH3:24])([CH3:23])[O:17]2)=[CH:12][CH:11]=1)=[O:25]
Reactant: CC1(C)OB(c2ccc(NC(=O)Oc3ccccc3)cc2)OC1(C)C
Reactant: NCCO
Product: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2)OC1(C)C

Procedure:
Method as described for intermediate 13 using phenyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (intermediate 17) and ethanolamine to afford a yellow gum (7.6 g) used without further purification.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][C:16](=N)N)[CH:9]=1)[CH3:6].ClC[CH2:21][C:22]#[N:23].[OH-].[Na+]>O.C(O)C>[CH3:6][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][CH2:16][CH2:21][C:22]#[N:23])[CH:9]=1)[CH3:4]
Reactant: CN(C)Cc1ccnc(CSC(=N)N)c1
Reactant: N#CCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)Cc1ccnc(CSCCC#N)c1
Reaction time: 7 h
Yield: 89.9 %

Procedure:
To a solution of S-(4-dimethylaminomethyl-2pyridylmethyl)isothiourea trihydrochloride (21.54 g) and 3-chloropropionitrile (8.01 g) in water (90 ml) and ethanol (65 ml) at 0° C (ice-salt bath) under nitrogen, was added dropwise over 30 minutes, a solution of sodium hydroxide (11.5 g) in water (120 ml), keeping the temperature below 3° C. After having been stirred for 7 hours and allowed to stand for 20 hours, the solution was extracted with 3:1 chloroform:ethanol (3×160 ml). The combined extracts were washed with water and dried (MgSO4) Solvent was evaporated at reduced pressure and the residue vacuum-distilled to give 3-(4-dimethylaminomethy-2-pyridyl-methylthio)propionitrile (13.66 g) as a pale yellow liquid, b.p.0.005 mm 148°-152° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:40].[C:41](Cl)(=O)[O:42]C1C=CC([N+]([O-])=O)=CC=1.[N:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[NH2:60].C(N(CC)CC)C>ClCCl>[Si:33]([O:32][C:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:41]([NH:60][C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][N:54]=4)=[O:42])=[C:3]([F:40])[CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[CH:22][CH:21]=1)([C:24]([F:25])([F:26])[F:27])[C:28]([F:31])([F:29])[F:30])([C:36]([CH3:37])([CH3:39])[CH3:38])([CH3:34])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OC(c1ccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccccn1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC(c1ccc(CN2CCN(C(=O)c3ccc(NC(=O)Nc4ccccn4)c(F)c3)CC2)cc1)(C(F)(F)F)C(F)(F)F
Yield: 28.7 %

Procedure:
(4-Amino-3-fluorophenyl)(4-(4-(2-(tert-butyldimethylsilyloxy)-1,1,1,3,3,3-hexa-fluoropropan-2-yl)benzyl)piperazin-1-yl)methanone (200 mg, 0.337 mmol) and 4-nitro-phenyl carbonochloridate (0.337 mmol, 0.068 g) were combined and stirred at room temperature for 1 hour in dichloromethane (1 mL). Pyridin-2-amine (0.674 mmol, 0.063 g) and triethylamine (0.674 mmol, 0.094 mL, 0.068 g) were added and the reaction mixture heated using microwave irradiation to 120° C. for 10 minutes. The reaction mixture was purified by silica column chromatography (eluant dichloromethane/methanol 0% to 2%) to afford the title compound (69 mg). MS (ESI) m/z 714.2 [M+H]+
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:22]([O:21][C:20]([NH:19][C@@H:3]1[C:2](=[O:1])[N:8]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@@H:4]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:26])([CH3:23])([CH3:25])[CH3:24]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](c2ccccc2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a stirred solution of tert-butyl [(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]carbamate (67a) (150 mg, 0.423 mmol) in dry DMF (4 mL) under nitrogen was added methyl bromoacetate (97 mg, 0.634 mmol) and powdered cesium carbonate (207 mg, 0.635 mmol). The mixture was stirred overnight at ambient temperature then diluted with water and extracted with ethyl acetate three times. The residue from the organic extract was purified by flash chromatography on silica gel eluting with 4:1 (v/v) hexane:ethyl acetate to afford the title compound (175 mg, 97%) as a white solid. TLC Rf=0.20 (4:1 hexane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ1.38 (s, 9H), 3.80 (s, 3H), 4.54 and 4.69 (AB quartet, 2H, J=17.1 Hz), 4.93 (m, 1H), 5.02 (m, 1H), 5.70 (d, 1H, J=7.0 Hz), 7.19-7.29 (m, 4H), 7.35-7.48 (m, 5H). MS APCI, m/z=327 (M-BOC). LC/MS: 2.76 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:7][C:6](=[O:8])[C:5]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:4]=1.CCN(CC)CC.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[C:28]([NH:1][CH2:2][C:3]1[NH:7][C:6](=[O:8])[C:5]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:4]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(CN)NC2=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCC1=NC2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1
Reaction time: 0.33 h
Yield: 87 %

Procedure:
tert-Butyl 2-(aminomethyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (1E) in CH2Cl2 (150 mg, 0.05 M), prepared by the procedure of Example 1, was added Et3N and acetyl chloride at −45° C. The reaction was complete after 20 minutes at −30° C. as determined by LCMS analysis, and then partitioned between ethyl acetate and water. The organics were subsequently washed with NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was passed thorough a pad of silica to afford the tert-butyl 2-(acetamidomethyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (2A, 87%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([C:24]#[N:25])[CH:23]=1>O>[CH3:1][C:2]1([CH3:16])[O:3][C:4](=[O:15])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH:23]=3)[C:24]#[N:25])=[CH:8][C:7]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: N#Cc1cncc(Br)c1
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3cncc(C#N)c3)cc21

Procedure:
Prepared from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 3-bromo-5-cyanopyridine according to Procedure B. Off-white solid: mp 290-291° C.; 1H-NMR (DMSO-d6) δ10.41 (s, 1H, D2O exchangeable), 9.21 (d, 1H, J=2.2 Hz), 8.97 (d, 1H, J=1.7 Hz), 8.68 (t, 1H, J=2.1 Hz), 7.76 (m, 2H), 7.01 (d, 1H, J=8.2 Hz), 1.70 (s, 6H); MS (ESI) m/z 278 (M−H, 96%). Anal. Calc. For C16H13N3O2.0.2 H2O: C, 67.94; H, 4.77; N, 14.85. Found: C, 68.04; H, 4.70; N, 14.58.
Reaction SMILES: [OH-].[Na+].O.[N+:4]([C:7]1[CH:8]=[C:9]([CH2:17][C:18]([O:20]C)=[O:19])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]#[CH:16])([O-:6])=[O:5].Cl>CO>[N+:4]([C:7]1[CH:8]=[C:9]([CH2:17][C:18]([OH:20])=[O:19])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]#[CH:16])([O-:6])=[O:5]
Reactant: C#CCOc1ccc(CC(=O)OC)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#CCOc1ccc(CC(=O)O)cc1[N+](=O)[O-]

Procedure:
In a mixed solution of 0.5g of sodium hydroxide, 5 ml of water and 2ml of metanol 0.7g of methyl 3-nitro-4-propargyloxyphenylacetate was added and heated on a water bath for 30 minutes. After cooling, the solution was neutralized with 10% hydrochloric acid and the thus obtained crystals were recrystallized from ether-n-hexane to give the object compound having m.p. 135° - 137° C in a yield of 0.6g (90.6%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.Cl[C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=O)=[CH:13][N:12]=1.C(=O)([O-])[OH:21].[Na+]>>[Br:9][C:5]1[CH:6]=[C:7]2[N:8]=[C:15]([C:14]3[CH:18]=[CH:19][C:11]([OH:21])=[N:12][CH:13]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: O=C([O-])O
Reactant: Nc1cc(Br)cnc1N
Agent: [Na+]
Product: Oc1ccc(-c2nc3cc(Br)cnc3[nH]2)cn1
Temperature: 140 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
Polyphosphoric acid (3 g) was heated to 140° C. and 2,3-diamino-5-bromopyridine (417 mg, 2.22-mmol) and 6-chloronicotinic acid (525 mg, 3.33 mmol) were added. The reaction mixture was stirred overnight at 140° C. After cooling, ice was added and the pH adjusted to 7 with a saturated solution of sodium hydrogen carbonate. A precipitate was formed which was filtered off and washed with ethyl acetate to afford the title compound (341 mg, 53%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])[CH3:2].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15]>>[C:8]([C:7]1[CH:6]=[C:5]([CH:12]=[CH:11][CH:10]=1)[CH2:4][N:3]([CH2:1][CH3:2])[CH2:15][CH2:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])#[N:9]
Reactant: CCNCc1cccc(C#N)c1
Reactant: C=CC(=O)OC(C)(C)C
Product: CCN(CCC(=O)OC(C)(C)C)Cc1cccc(C#N)c1
Temperature: 80 °C

Procedure:
A mixture of 3-[(ethylamino)methyl]benzonitrile (5 g, 31 mmol) and tert-butyl acrylate (4.6 mL, 31 mmol) was heated neat at 80° C. for 12 hours. The crude mixture was purified by flash chromatography (silica, pet ether/EtOAc) to afford the title compound as colorless oil. 1H NMR (DMSO-d6, 400 MHz) δ 7.69 (m, 2H), 7.62 (d, J=7.8 Hz, 1H), 7.50 (m, 1H), 3.56 (s, 2H), 2.64 (t, 2H), 2.40 (m, 2H), 2.32 (t, 2H), 1.39 (s, 9H), 0.93 (t, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[CH2:2].[F:20][C:21]1[C:31](I)=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:23]([OH:33])[CH:22]=1.CN.CN(C)C(=O)C>C(Cl)(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:20][C:21]1[C:31]([CH:2]=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([S:9]([NH:12][C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=3)(=[O:10])=[O:11])=[CH:7][CH:8]=2)=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:23]([OH:33])[CH:22]=1
Reactant: CCOC(=O)c1cc(I)c(F)cc1O
Reactant: C=Cc1ccc(S(=O)(=O)Nc2ncccc2C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(C=Cc2ccc(S(=O)(=O)Nc3ncccc3C)cc2)c(F)cc1O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
4-Ethenyl-N-(3-methyl-2-pyridinyl)benzenesulfonamide (2.7 g, 10 mmol), ethyl 4-fluoro-2-hydroxy-5-iodobenzoate (3.6 g, 80%, 10 mmol), methylamine (5 ml) and N,N-dimethylacetamide (5 ml) were mixed and heated to 50° C. Palladium acetate (40 mg) was added and the solution kept at 50° C. for 18 h. The solution was poured into water and the precipitate dissolved in chloroform. The solution was dried, applied on top of a short silica gel column and eluted with 30% isobutylmethylketone in toluene. The pure fractions were collected and evaporated to dryness. After trituration with acetonitril the product crystallized. Yield 1.1 g.
Reaction SMILES: [CH3:1][C:2]([O:13][Si](C)(C)C)([CH3:12])[C:3]#[C:4][C:5]([C:7]1[N:8]=[CH:9][S:10][CH:11]=1)=[O:6].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[OH:13][C:2]([CH3:12])([CH3:1])[C:3]#[C:4][C:5]([C:7]1[N:8]=[CH:9][S:10][CH:11]=1)=[O:6]
Reactant: CC(C)(C#CC(=O)c1cscn1)O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(O)C#CC(=O)c1cscn1
Reaction time: 1 h
Yield: 109.8 %

Procedure:
To a stirred solution of 4-methyl-1-(thiazol-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-one (0.15 g, 0.56 mmol) in DCM (3 mL) was added PTSA (0.16 g, 0.84 mmol) at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water (10 mL), the organic layer was washed with a saturated NaHCO3 solution, water, dried over Na2SO4, filtered and then concentrated in vacuo to afford 4-hydroxy-4-methyl-1-(thiazol-4-yl) pent-2-yn-1-one (0.12 g, crude) as an oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=C[C:36]=2N=N1.F[P-](F)(F)(F)(F)F.CN([C:52](N(C)C)=[N+:53]1[C:57]2C=CC=C[C:56]=2[N+:55]([O-])=N1)C.C(N(C(C)C)CC)(C)C.NC1CCOCC1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:55][CH2:56][CH2:57][N:53]([CH3:52])[CH3:36])=[O:27])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: On1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 69.5 %

Procedure:
To a mixture of 0.0560 g (0.129 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-184) and 6 mL of dimethylformamide was added 0.0282 g (0.209 mmole) of 1-hydroxybenzotriazole, 0.079 g (0.208 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.072 g (0.555 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0212 g (0.209 mmole) of 4-aminotetrahydropyran was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0450 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-dimethylamino-ethyl)-3-methyl-benzamide (I-188) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[N:14]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15]1)([O-:3])=[O:2].[H-].[Na+].I[CH3:31].O>CN(C=O)C.C(OCC)C>[CH3:31][N:20]([C@H:16]1[CH2:17][CH2:18][CH2:19][N:14]([C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:15]1)[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To an orange solution of (S)-tert-butyl 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ylcarbamate (1.50 g, 3.9 mmol) in DMF at 0 deg. C. was added sodium hydride, 60% dispersion in mineral oil (0.19 g, 4.8 mmol). Bubbling was observed, and the solution became darker orange. After about 20 min, iodomethane (0.30 ml, 4.8 mmol) was added dropwise via syringe. The orange mixture was allowed to warm to room temperature over 30 min. Water was added, followed by diethyl ether. The organics were washed 1×H2O, 1×brine, dried over anhydrous Na2SO4, filtered, and concentrated to give (S)-tert-butyl methyl(1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-yl)carbamate as an orange semi-solid which was used without further purification. MS m/z=404 [M+H]+. Calc'd for C18H24F3N3O4: 403.