Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][CH:7]([CH3:26])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:13][CH:12]=1.C(N(CC)CC)C.Cl>ClCCl>[CH3:6][CH:7]([CH3:26])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CCOc1ccc(NCC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCOc1ccc(N(CC(=O)OC(C)(C)C)S(C)(=O)=O)cc1
Reaction time: 3 h
Yield: 55.4 %

Procedure:
Methanesulfonylchloride (93 mg, 63 μL, 0.82 mmol) was added in one portion to a stirred solution of 1,1-dimethylethyl N-{4-[(3-methylbutyl)oxy]phenyl}glycinate (intermediate 6, 0.20 g, 0.68 mmol) and triethylamine (138 mg, 189 μL, 1.36 mmol) in dichloromethane (2 mL) at room temperature under a nitrogen atmosphere. Stirring was continued for 3 h then aqueous hydrochloric acid (1.0 M; 2 mL) was added. The organic phase was separated and the aqueous phase washed with dichloromethane (3×5 mL). The organic phases were combined, dried (magnesium sulfate) then evaporated to dryness. The residue was chromatographed on silica gel (30% diethyl ether:cyclohexane) to give the title compound as a white solid (140 mg, 56%). LC/MS: 3.72 min; z/e 389, calcd (M+18) 389. 1H NMR (400 MHz; CDCl3): 0.95 (6H), 1.45 (9H), 1.70 (2H), 1.85 (1H), 3.10 (3H), 3.95 (2H), 4.30 (2H), 6.85 (2H), 7.35 (2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.C([O-])(=O)C.[Na+].Br[CH2:16][C:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)=O>O.CO>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]2[CH:16]=[C:17]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)[NH:9][C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc(C(=O)CBr)cc1
Reactant: Nc1cc(O)nc(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(-c2cc3c(O)nc(N)nc3[nH]2)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A solution of 2,6-diamino-4-hydroxypyrimidine (CAS: 56-06-4, 1 g, 7.93 mmol) and sodium acetate (0.85 g, 10.32 mmol) in water (180 mL) was stirred at 100° C. for 30 minutes. Methyl 4-(2-bromoacetyl)benzoate (2.24 g, 8.72 mmol) was suspended in MeOH (25 mL) and was added slowly to the above solution. The reaction mixture was then stirred at 100° C. for 16-20 h and then cooled to room temperature. The residue was filtered and dried. It was then stirred in CH2Cl2 (10 mL) and filtered to provide XI-8-I (1.07 g, 47.5%). LCMS: m/z 285 (M+1)+.
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]([CH3:22])([CH3:21])[C:15]#[C:16][CH:17]=[CH:18][CH:19]=O.[BH4-].[Na+]>C(OCC)C.CO>[CH3:13][C:14]([CH3:22])([CH3:21])[C:15]#[C:16][CH:17]=[CH:18][CH2:19][NH:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NCc1cccc2ccccc12
Reactant: CC(C)(C)C#CC=CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)C#CC=CCNCc1cccc2ccccc12

Procedure:
A mixture of 1-naphthalenemethanamine (1.34 g, 8.51 mmol) and 6,6-dimethyl-2-hepten-4-ynal (1.16 g, 8.51 mmol) in 20 ml of dry ethyl ether was stirred over 4A sieves overnight. Sieve material was then removed by centrifugation, washed once with ethyl ether and the combined ether fractions concentrated to afford the crude condensed product. About 8.08 mmol of this material was stirred with sodium borohydride (343 mg, 9.06 mmol) in 20 ml of methanol at room temperature for 3.75 hours. The reaction mixture was partitioned between aqueous sodium bicarbonate and methylene chloride, the aqueous layer extracted twice with methylene chloride, and the combined organic solution washed with water and dried over magnesium sulfate. Removal of the solvent afforded N-(6,6-dimethyl-2-hepten-4-ynyl)-1-naphthalenemethanamine as a mixture of the E and Z isomers. Flash chromatography of this product on silica gel (5 cm column, eluting with 0.2% triethylamine in chloroform) afforded 0.74 g of the pure (E)-N-6,6-dimethyl-2-hepten-4-ynyl)-1-naphthalenemethanamine.
Reaction SMILES: [Br-].[CH2:2]([C:4]1([O:9][C:10](=[O:34])[CH2:11][O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([S+:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22]4[CH:29]=[CH:30][CH:31]=[CH:32][C:21]3=4)=[CH:15][C:14]=2[CH3:33])[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:3].[OH:35][C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[CH2:37]1)[CH2:43]2.[Na].[C:47]([O:50][CH:51]([CH3:62])[C:52]([F:61])([F:60])[C:53]([F:59])([F:58])[S:54]([O-:57])(=[O:56])=[O:55])(=[O:49])[CH3:48].O>ClCCl>[OH:35][C:36]12[CH2:37][CH:38]3[CH2:44][CH:42]([CH2:41][C:40]([CH2:48][C:47]([O:50][CH:51]([CH3:62])[C:52]([F:61])([F:60])[C:53]([F:59])([F:58])[S:54]([O-:57])(=[O:56])=[O:55])=[O:49])([CH2:39]3)[CH2:45]1)[CH2:43]2.[CH2:2]([C:4]1([O:9][C:10](=[O:34])[CH2:11][O:12][C:13]2[C:14]([CH3:33])=[CH:15][C:16]([S+:20]3[C:21]4[CH:32]=[CH:31][CH:30]=[CH:29][C:22]=4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]3=4)=[CH:17][C:18]=2[CH3:19])[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:3]
Reactant: CC(=O)OC(C)C(F)(F)C(F)(F)S(=O)(=O)[O-]
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: CCC1(OC(=O)COc2c(C)cc(-[s+]3c4ccccc4c4ccccc43)cc2C)CCCC1
Agent: [Br-]
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: CC(OC(=O)CC12CC3CC(CC(O)(C3)C1)C2)C(F)(F)C(F)(F)S(=O)(=O)[O-]
Yield: 89.1 %

Procedure:
5-(4-(2-(1-ethylcyclopentyloxy)-2-oxoethoxy)-3,5-dimethylphenyl)-5H-dibenzo[b,d]thiophenium bromide (2.00 g, 3.71 mmol) and sodium 3-hydroxyadamantane-acetoxy-1,1,2,2-tetrafluorobutane-1-sulfonate (1.61 g, 3.78 mmol) were dissolved in dichloromethane (100 mL) and water (100 mL) and stirred at r.t. overnight. The dichloromethane layer was separated and the aqueous phase washed with dichloromethane (3×100 mL). The combined organic layers were washed with water (4×200 mL), concentrated in vacuo and residual water removed via azeotrope with acetonitrile (2×200 mL) to afford the title compound (2.90 g, 91%) as a white solid. 1H NMR (500 MHz, (CD3)2CO) δ: 8.52 (d, J=8 Hz, 2H), 8.34 (d, J=8.5 Hz, 2H), 8.01 (t, J=7.5 Hz, 2H), 7.08 (t, J=7.5 Hz, 2H), 7.51 (s, 2H), 4.55 (s, 2H), 4.32 (t, J=6.5 Hz, 2H), 3.60 (brs, OH), 2.72 (tt, J=14, 6.5 Hz, 2H), 2.29 (s, 6H), 2.12-2.20 (m, 2H), 2.00 (q, J=7 Hz, 2H), 1.50-1.82 (m, 12H), 0.84 (t, J=7 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:21][O:20][C:16]([CH:17]=[CH:18][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)=[O:19]
Reactant: COC(=O)c1cc(C(=O)OC)c(Br)cn1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1cnc(C(=O)OC)cc1C(=O)OC

Procedure:
500 mg of dimethyl 5-bromo-pyridine-2,4-dicarboxylate (from Example 3) are heated at 140° C. in an autoclave with 10 ml of methyl acrylate, 0.5 ml of triethylamine, 11 mg of palladium diacetate and 22 mg of triphenylphosphine for 14 hours. After cooling, the mixture is diluted with ethyl acetate, the solid is filtered off and the solvent is evaporated together with the excess methyl acrylate. The product is chromatographed (silica gel) to give 330 mg of a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O-:15])(=O)=[O:13])=[CH:8][CH:7]=1.[Na+]>CN(C)C=O>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([Cl:3])(=[O:15])=[O:13])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(O)cc1
Temperature: 60 °C
Yield: 61.7 %

Procedure:
Thionyl chloride (44.3 mL, 604 mmol, and 6.91 Eq) and N,N-dimethylformamide (DMF) (1 mL) were added to sodium 4-hydroxybenzenesulfonate (20.3 g, 87.2 mmol, and 1.00 Eq) under an argon atmosphere, and the mixture was stirred under reflux at 60° C. for 4 hours. The resultant mixture was cooled to room temperature and ice (160 g) was added thereto. The mixture was stirred and the water layer was extracted with dichloromethane (1×60 mL, 2×40 mL). The obtained organic layer was washed with ice water (40 mL) and dried with sodium sulfate. The solvent was removed by an evaporator and 4-hydroxybenzene sulfonyl chloride (10.4 g, 53.8 mmol, 62%) was obtained as oil.
Reaction SMILES: [O:1]([C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](O)(=[O:32])/[CH:29]=[CH:30]/[CH3:31]>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([NH:22][C:28](=[O:32])/[CH:29]=[CH:30]/[CH3:31])[CH:23]=[CH:24][CH:25]=2)=[CH:26][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C=C/C(=O)O
Reactant: Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Product: C/C=C/C(=O)Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 56 %

Procedure:
(E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide was prepared from 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and (E)-but-2-enoic acid using Method E (56% yield). HPLC: 98%, RT=4.292 min. MS: m/z=423 [M+H]+, RT=4.28 min. 1H-NMR (DMSO-d6) δ 9.91 (s, 1H), 8.52 (s, 1H), 8.43 (d, 1H), 7.92 (s, 1H), 7.68 (d, 1H), 7.40-7.37 (m, 3H), 7.30 (d, 1H), 7.18-7.12 (m, 3H), 7.08 (d, 2H), 7.02 (d, 2H), 6.83-6.76 (m, 2H), 6.14 (d, 1H), 1.86 (d, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Br[C:9]1[O:13][C:12]2[C:14]([O:20]C(=O)C)=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=2[C:10]=1[C:24](=[O:37])[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1>O1CCCC1.C1(C)C=CC=CC=1>[N:1]1([C:9]2[O:13][C:12]3[C:14]([OH:20])=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:24](=[O:37])[C:25]2[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2c(-n3cncn3)oc3c(O)c(OC)ccc23)cc(OC)c1OC

Procedure:
To a solution of 1,2,4-triazole (22 mg, 0.32 mmol) in dry tetrahydrofuran (2 mL) was added sodium hydride (60%, 24 mg, 0.60 mmol) and resulting suspension was treated with a solution of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzo[b]furan (50 mg, 0.10 mmol) in dry toluene (2 mL). The mixture was stirred at reflux for 6 hours (tlc), quenched with saturated ammonium chloride solution, extracted with dichloromethane (10 mL), dried over magnesium sulphate and the solvent distilled under vacuum. The crude residue was purified by PTLC (eluent=ethyl acetate: 1% triethylamine) to give the title compound as a yellow solid; (22 mg, 50%); 1H NMR (300 MHz, CDCl3) δ 8.64 (bs, 1H), 8.06 (bs, 1H), 7.10 (d, 1H, J=8.60 Hz), 7.05 (s, 2H, benzoyl Hs), 6.98 (d, 1H, J=8.65 Hz), 3.98 (s, 3H, OMe), 3.89 (s, 3H, OMe), 3.77 (s, 6H, 2×OMe).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:33][C:31]([CH3:34])([CH3:32])[CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: CC(C)(O)CN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(C)(C)O)ccc21
Yield: 82.6 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-hydroxy-2-methyl-propyl)-amide (97 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 1-amino-2-methyl-propan-2-ol (24 mg), HBTU (112 mg), and DIEA (65 uL). LC/MS: m/z 480.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (bs, 1H), 8.18 (t, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.80 (d, 1H), 7.73 (d, 1H), 7.49 (d, 1H), 7.36 (d, 1H), 4.60 (s, 1H), 3.64 (s, 3H), 3.29 (d, 2H), 1.14 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[CH2:14][CH:15]([CH3:16])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6]3.[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN1CCCC1=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:25]2[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]2)[C:9]2[CH2:14][CH:15]([CH3:16])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6]3
Reactant: CC1Cc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Reactant: OC1CCNCC1
Solvent: CN1CCCC1=O
Product: CC1Cc2c(N3CCC(O)CC3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Yield: 31 %

Procedure:
7-Amino-8,9-difluoro-2-methyl-6-oxo-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (0.5 g) and 4-hydroxypiperidine (1.0 g) are suspended in N-methylpyrrolidone (5 ml), and the mixture is heated at 110°-120° C. for 5 hours. The reaction mixture is concentrated to dryness under reduced pressure, and to the residue is added ethanol. The resulting crystals are separated by filtration and recrystallized from N,N-dimethylformamide to give 7-amino-8-fluoro-9-(4-hydroxy-1-piperidyl)-2-methyl-6-oxo-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (0.2 g) as yellow cubic crystals. m.p. 287°-292° C. (decomp.)
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:16]([S-:18])#[N:17].[K+].BrBr>C(O)(=O)C>[NH2:17][C:16]1[S:18][C:12]2[CH:13]=[C:7]([O:6][C:5]3[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=3)[CH:8]=[CH:9][C:10]=2[N:11]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Oc3ccc(F)cc3)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.2 %

Procedure:
A solution of 4-(4′-fluorophenoxy)aniline (0.305 g, 1.50 mmol) and KSCN (0.29 g, 3.00 mmol, 2.0 eq) in 3 mL acetic acid was cooled at about 5° C., and was treated dropwise with a solution of bromine (0.077 mL, 1.50 mmol, 1.0 eq) in 2 mL acetic acid. The mixture was stirred at room temperature for about 2 hours. The precipitate was filtered off and washed with Et2O. The mother liquid from the filtration was concentrated, and the residue was combined with the precipitate. The obtained solid was neutralized with saturated sodium carbonate solution, and a new precipitate was formed. It was filtered off, washed with water, and dried under vacuum to give the desired compound 0.403 g (90%). LC/MS 261.2 (M+1); LC retention time 2.44 min.
Reaction SMILES: [CH3:1][O:2][P:3]([C:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([F:9])[CH3:8])([O:5][CH3:6])=[O:4].C(OC(=O)[NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)=[CH:28][C:27]=1[NH2:37])(C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:6][O:5][P:3]([C:7]([C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:16])[NH:37][C:27]2[CH:28]=[C:29]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[CH:30]=[CH:31][C:26]=2[NH2:25])=[CH:17][CH:18]=1)([F:9])[CH3:8])(=[O:4])[O:2][CH3:1]
Reactant: COP(=O)(OC)C(C)(F)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COP(=O)(OC)C(C)(F)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-[1-(Dimethoxy-phosphoryl)-1-fluoro-ethyl]-benzoic acid (50 mg, 0.18 mmol), (2-Amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester (63 mg, 0.22 mmol), BOP (96 mg, 0.22 mmol), and DIPEA (70 mg, 0.54 mmol) were combined and diluted with DMF (0.72 mL). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was purified directly by HPLC (20-85% MeCN in water w/0.025% TFA). Pure fractions were identified, combined, and concentrated in vacuo. The residue was diluted with 5:1 CH2Cl2:TFA. The resulting solution was stirred at ambient temperature for 1 h then concentrated in vacuo to afford the title compound: 1H NMR (DMSO-d6, 600 MHz) 10.15 (s, 1H), 8.05 (d, J=9.0 Hz, 2H), 7.56-7.62 (m, 3H), 7.43-7.48 (m, 2H), 7.37 (d, J=3.5 Hz, 1H), 7.06-7.09 (m, 2H), 3.72 (d, J=10.8 Hz, 3H), 3.57 (d, J=10.8 Hz, 3H), 1.86-1.96 (m, 3H). MS: cal'd 449 (MH+), exp 449 (MH+)
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH3:5][N:6]([CH3:14])[C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[Na]>C(O)(=O)C>[CH3:5][N:6]([CH3:14])[C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[O:13][CH2:3][CH2:2][C:1]#[N:4]
Reactant: CN(C)c1cccc(O)c1
Reactant: C=CC#N
Agent: [Na]
Solvent: CC(=O)O
Product: CN(C)c1cccc(OCCC#N)c1
Yield: 80 %

Procedure:
A 407 g (7.68 moles) portion of acrylonitrile and 500 g (3.65 moles) of m-dimethylaminophenol were placed in a 3-l, 3-necked flask equipped with a stirrer and reflux condenser with a drying tube. The solution was treated with 4 g (0.17 mole) of metallic sodium, over 0.7 hr., with an observed temperature rise from 10° to 24°. The reaction mixture was heated to reflux over 0.8 hr., refluxed for 22 hrs., cooled, treated with 11 ml of glacial acetic acid and the excess acrylonitrile removed under reduced pressure. The residue was taken up in 3.8-l of ether, decanted from a purple resinous material, stored over Darco overnight and filtered. The filtrate was stripped of ether under reduced pressure to give 590 g (80%) of the desired nitrile (brown).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1.CC#N.[CH3:30][C:31]([CH3:35])([CH3:34])[C:32]#[CH:33]>C(N(CC)CC)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:18]([O:17][C:15]([C:14]1[N:13]=[CH:12][N:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:33]#[C:32][C:31]([CH3:35])([CH3:34])[CH3:30])=[CH:26][C:6]=3[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:8][CH2:9][C:10]=12)=[O:16])[CH3:19]
Reactant: C#CC(C)(C)C
Reactant: CCOC(=O)c1ncn2c1CN=C(c1ccccc1)c1cc(Br)ccc1-2
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1ncn2c1CN=C(c1ccccc1)c1cc(C#CC(C)(C)C)ccc1-2
Temperature: 25 °C
Reaction time: 5 h
Yield: 439 %

Procedure:
A mixture of 5 (300 mg, 0.732 mmol) available from procedure [0051] in triethyl amine (5 mL) and CH3CN (8 mL) was stirred with 3,3-dimethyl-1-butyne (12.3 mg, 0.15 mmol) and bis(triphenylphosphine)palladium (II) acetate (38.3 mg, 0.051 mmol) and heated to reflux under nitrogen. After 5 hours, the reaction mixture was cooled to rt and filtered. The filtrate was concentrated under vacuum and the residue was treated with H2O (10 mL), and extracted with CH2Cl2 (3×10 mL). The organic layers were combined and washed with brine and dried (Na2SO4). After removal of solvent under reduced pressure, the residue was purified via flash chromatography (silica gel, EtOAc/hexanes: 1/1) to furnish the t-butylacetylene 24(XLi340) as a yellow powder (271 mg, 90%): mp: 155-156° C.; IR (KBr) 2358, 1717, 1489, 1248, 1074, 803, 668 cm−1; 1HNMR (CDCl3) δ 1.25 (s, 9H), 1.45 (t, 3H, J=7.1 Hz), 4.05 (d, 1H, J=12.3), 4.45 (2H, J=7.1 Hz), 5.95 (d, 1H, J=12.3 Hz), 7.3-7.7 (m, 8H), 7.95 (s, 1H); MS (EI) m/e (relativity intensity) 412 (M+, 46), 365 (46), 337 (100), 322 (8), 277 (16), 219 (14). Anal. Calcd. For C26H25N3O2.½H2O, C 74.26, H 6.23, N 9.99. Found. C, 74.50; H, 6.29; N, 9.89.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H].O.[ClH:16]>[Pt]>[CH2:7]1[CH2:6][CH2:5][CH:4]([CH2:3][C@H:2]([NH2:1])[C:10]([OH:12])=[O:11])[CH2:9][CH2:8]1.[ClH:16]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: [H][H]
Agent: [Pt]
Agent: Cl
Solvent: O
Product: N[C@@H](CC1CCCCC1)C(=O)O
Reaction time: 8 h
Yield: 91 %

Procedure:
A solution of 10.4 g (61.7 mmoles) of L-phenylalanine in 150 ml of 2N aqueous hydrochloric acid was subjected to a medium pressure catalytic hydrogenation reaction in the presence of 1 g of platinum black using a Paar's apparatus under about 4 atmospheres of hydrogen at room temperature for 24 hours. At the end of this time, the precipitated crystalline substance was dissolved by adding 250 ml of water, and the catalyst was removed by filtration. The filtrate was then concentrated to about 150 ml by evaporation under reduced pressure and allowed to stand overnight. The crystalline substance which deposited was collected by filtration and dried to give 12.8 g (yield 91%) of the title compound as white crystals, melting at 232°-234° C.
Reaction SMILES: [Na].CO[C:4](=[O:10])[CH:5]([CH3:9])[C:6]([OH:8])=O.[NH2:11][C:12]([NH2:14])=[O:13].O>C(O)C>[CH3:9][CH:5]1[C:4](=[O:10])[NH:14][C:12](=[O:13])[NH:11][C:6]1=[O:8]
Reactant: COC(=O)C(C)C(=O)O
Reactant: NC(N)=O
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC1C(=O)NC(=O)NC1=O
Reaction time: 0.08 h

Procedure:
46 g (2 mols) of sodium are dissolved in 1 liter of absolute ethanol in a 5-liter flask. To this solution are firstly added 348 g (2 mols) of methyl malonic acid methyl ester; and there is then added dropwise at 70° C. with stirring, within about 5 minutes, a solution of 120 g (2 mols) of urea in 1 liter of absolute ethanol. There is formed a thin suspension, which is diluted with 3.5 liters of ethanol, refluxed for 16 hours and afterwards cooled. There are subsequently added 2 liters of water and, for clearing, a filtering auxiliary (HiFlo) is introduced, and the suspension is filtered. Concentrated hydrochloric acid is then added until a Congo blue colour is indicated, and the mixture is left to stand for several hours in a cool place. A fine white crystalline precipitate is formed, which is filtered and dried. The mother liquor is concentrated by evaporation, diluted with water, and the precipitate is likewise filtered and dried. The crude yield is 263 g of material, which melts at 200°-215° C. After recrystallisation from water, there remain 144 g of white crystals (58% of theory), which melt at 203°-204° C.
Reaction SMILES: [C:1]([N:6]=[C:7]=[O:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCCl>[C:1]([NH:6][C:7](=[O:8])[O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)N=C=O
Reactant: OCc1ccccc1
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)OCc1ccccc1

Procedure:
A solution of methacryloyl isocyanate (11.1 g; 0.1 mol) in 1,2-dichloroethane (50 ml) was dropise added to dry benzyl alcohol (10.8 g; 0.1 mol) under nitrogen stream while cooling with ice. After completion of the addition, 1,2-dichloroethane was evaporated under reduced pressure. The residue (21.8 g) was recrystallized from a mixture of hexane and benzene to give benzyl N-methacryloylcarbamate as colorless needles. M.P., 109°-110° C.