Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]#[N:8].[OH-:9].[K+]>O>[NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:8])=[O:9]
Reactant: N#Cc1cccn1N
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: NC(=O)c1cccn1N
Temperature: 0 °C

Procedure:
A solution of 1-amino-1H-pyrrole-2-carbonitrile (100 mg, 0.934 mmol) and potassium hydroxide (1.26 g, 22.5 mmol) in water (3 mL) was stirred at RT for 6 hours. The resulting mixture was then cooled to 0° C. and filtered. The collected solid was washed with cold water until the washings were pH neutral and purified by silica gel chromatography using 0-100% of 90/10/1 CH2Cl2/MeOH/NH4OH in CH2Cl2 to afford 1-amino-1H-pyrrole-2-carboxamide.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]=[O:15].[CH3:16][Mg]Br.CCOCC>C1COCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([OH:15])[CH3:16]
Reactant: Cc1cccc2nc(C=O)c(Br)c(=O)n12
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc2nc(C(C)O)c(Br)c(=O)n12
Temperature: 9 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 3-bromo-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carbaldehyde (1.4162 g, 5.30 mmol) in THF (53.0 mL) was added methyl-magnesium bromide 3 M in Et2O (2.65 mL, 7.95 mmol) dropwise at 0° C. and the mixture was allowed to warm to 9° C. over 2 h. After 2 h, the reaction was quenched with satd aq NH4Cl (50 mL) and water (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with water (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concd under reduced pressure to give an orange solid. The orange solid was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 25 min and 100% isocratic of EtOAc in hexane for 4 min as eluent to give 3-bromo-2-(1-hydroxyethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one as a bright yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.72 (1 H, dd, J=8.6, 7.0 Hz), 7.48 (1 H, d, J=9.4 Hz), 7.01 (1 H, d, J=7.0 Hz), 5.15 (1 H, d, J=6.7 Hz), 4.99 (1 H, qd, J=6.5, 6.3 Hz), 2.94 (3 H, s), 1.35 (3 H, d, J=6.7 Hz); Mass Spectrum (ESI) m/e=283.0 [M+1 (79Br)] and 285.0 [M+1 (81Br)].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Br:15])[C:9]=2[CH3:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Br:15])[C:9]=2[CH3:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(Br)c(C)c2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: CCOC(=O)c1cc2ccc(Br)c(C)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, ISP-MS: m/e=439.5, 441.5 (M+H+), was prepared in accordance with the general method of example 49c) from 6-bromo-7-methyl-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-(1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:4]([CH:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:6]1)[CH:3]=[CH:2]2.[CH2:14]=C1CC2CCC1C=C2.CC1C(C)C2CCC1CC2CC(O)=O.CC1C(C)C2CCC1C=C2.C12CCC(CC1)CC2CC(O)=O.C12CCC(CC1)C=C2.C(C12C(CC)(CC)CC(CC1)CC2CCC(O)=O)C.C=C1CC2CC(CC)(CC)C1(CC)CC2.C12CCC(C=C1)CC2CC(O)=O.C12CCC(C=C1)C=C2.C(C1C(C(C)C)C2CCC1CC2CC(O)=O)(C)C.C(C1C(C(C)C)C2CCC1C=C2)(C)C>>[CH3:14][CH:6]1[CH:1]2[CH2:13][CH2:12][CH:4]([CH2:3][CH2:2]2)[CH:5]1[CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)CCC1CC2C=CC1CC2
Reactant: C=C1CC2C=CC1CC2
Agent: C1=CC2C=CC1CC2
Agent: C1=CC2CCC1CC2
Agent: C=C1CC2CCC1(CC)C(CC)(CC)C2
Product: CC1C2CCC(CC2)C1CCC(=O)O

Procedure:
Similarly in an analogous manner 3-(bicyclo[2.2.2]oct-2-en-5-yl)propionic acid; is prepared from 5-methylenebicyclo[2.2.2]oct-2-ene; 5,6-dimethylbicyclo[2.2.2]oct-2-ylacetic acid from 5,6-dimethylbicyclo[2.2.2]oct-2-ene; bicyclo[2.2.2]oct-2-ylacetic acid from bicyclo[2.2.2]oct-2-ene; 3-(1,7,7-triethylbicyclo[2.2.2]oct-2-yl)propionic acid from 2-methylene-1,7,7-triethylbicyclo[2.2.2]octane; bicyclo[2.2.2]oct-5-en-2-ylacetic acid from bicyclo[2.2.2]octa-2,5-diene and 5,6-diisopropylbicyclo[2.2.2]oct-2-ylacetic acid from 5,6-diisopropylbicyclo[2.2.2]oct-2-ene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N+:12]([O-])=O>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([Si:8]([CH3:10])([CH3:9])[CH3:11])[CH:5]=[CH:4][C:3]=1[NH2:12]
Reactant: C[Si](C)(C)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CCO
Product: C[Si](C)(C)c1ccc(N)c(F)c1
Reaction time: 1 h
Yield: 91.9 %

Procedure:
The 2-fluoro-4-trimethylsilylnitrobenzene (5.45 g, 25.6 mmol) was then dissolved in ethanol (100 mL), transferred to a Parr shaker bottle, flushed with nitrogen, then charged with 10% Pd—C (0.4 g). The reaction mixture was hydrogenated for 1 h on the Parr apparatus (45 psi H2), and then filtered through a plug of Celite. The filter cake was washed with ethanol, and the combined filtrates were concentrated. The resulting residue was purified by flash chromatography (250 mL silica gel, 95:5 hexane-ethyl ether), to afford the title compound as a tan oil (4.31 g, 92%).
Reaction SMILES: [C:1](=[O:14])([O:3][CH2:4][CH:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:2].[O-:15][C:16]#[N:17].[Na+].CS(O)(=O)=O>ClCCl>[NH2:17][C:16]([NH:2][C:1](=[O:14])[O:3][CH2:4][CH:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:15]
Reactant: N#C[O-]
Reactant: NC(=O)OCC(N)Cc1ccccc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)NC(=O)OCC(N)Cc1ccccc1

Procedure:
As shown in Scheme II, 2-amino-3-phenylpropyl carbamate (V) is reacted with sodium cyanate and methansulfonic acid in dichloromethane, to give 2-amino-3-phenylpropyl (aminocarbonyl)carbamate (VI).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@:10]([F:16])([C:13]([O-:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:51]1([CH2:58][CH2:59][NH:60][C:61](=[O:92])[C@H:62]([CH3:91])[C@H:63]([C@@H:66]2[CH2:70][CH2:69][CH2:68][N:67]2[C:71](=[O:90])[CH2:72][C@@H:73]([O:88][CH3:89])[C@@H:74]([N:79]([CH3:87])[C:80](=[O:86])[C@H:81]([CH:83]([CH3:85])[CH3:84])[NH2:82])[C@@H:75]([CH3:78])[CH2:76][CH3:77])[O:64][CH3:65])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=[CH:52]1>ClCCl.CN(C)C=O>[CH:51]1([CH2:58][CH2:59][NH:60][C:61](=[O:92])[C@H:62]([CH3:91])[C@H:63]([C@@H:66]2[CH2:70][CH2:69][CH2:68][N:67]2[C:71](=[O:90])[CH2:72][C@@H:73]([O:88][CH3:89])[C@@H:74]([N:79]([CH3:87])[C:80](=[O:86])[C@@H:81]([NH:82][C:13]([C@@:10]2([F:16])[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)=[O:15])[CH:83]([CH3:84])[CH3:85])[C@@H:75]([CH3:78])[CH2:76][CH3:77])[O:64][CH3:65])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=[CH:52]1
Reactant: CC(C)(C)OC(=O)N1CC[C@](F)(C(=O)[O-])C1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(F)CCN(C(=O)OC(C)(C)C)C1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of #170 (18.2 mg, 0.076 mmol, 1 eq.) in dichloromethane (1.8 mL) and N,N-dimethylformamide (0.3 mL) was added N,N-diisopropylethylamine (0.040 mL, 0.228 mmol, 3 eq.) followed by HATU (29.2 mg, 0.076 mmol, 1 eq.). After stirring for 10 minutes at room temperature, #176 (45 mg, 0.076 mmol, 1 eq.) was added. The reaction was stirred at room temperature for 18 hours and additional HATU (29 mg, 0.076 mmol, 1 eq.) was added. After 8 hours the reaction was concentrated in vacuo to provide #183 (61.0 mg, quantitative) which was taken into the next step without further purification. LC-MS (Protocol Q1): m/z 826.6 [M+Na+], retention time=1.05 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([CH3:17])=[C:12]([CH:18]=[CH2:19])[C:11]=1[O:20][CH3:21])[CH3:9])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([CH3:17])=[C:12]([CH:18]2[CH2:19][O:31]2)[C:11]=1[O:20][CH3:21])[CH3:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=Cc1c(C)c(Cl)cc(C(C)NC(=O)OC(C)(C)C)c1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl[1-(5-chloro-2-methoxy-4-methyl-3-vinylphenyl)ethyl]carbamate (460 mg, 1.4 mmol, from Example 189, Step 1) was stirred in methylene chloride (4.6 mL) and m-chloroperbenzoic acid (2.1 g, 8.5 mmol) was added. The mixture was stirred overnight at room temperature. The suspension was filtered and the collected solids were washed with methylene chloride. The filtrates were evaporated to give the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][N:22]=1)[C:16]([O:18][CH3:19])=[O:17].[ClH:23]>CO.[Pt](=O)=O>[ClH:23].[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[CH:13]1[CH2:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[CH2:20][CH2:21][NH:22]1
Reactant: COC(=O)c1ccnc(-c2ccc(OC(F)(F)F)cc2F)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCNC(c2ccc(OC(F)(F)F)cc2F)C1
Reaction time: 5 h
Yield: 98 %

Procedure:
Methyl 2-(2-fluoro-4-(trifluoromethoxy)phenyl)isonicotinate (4.47 g, 14.18 mmol) was dissolved in methanol and hydrogen chloride (1.25 M in methanol, 17.02 mL, 21.27 mmol) was added. The solvent was evaporated and the residue redissolved in methanol (50 mL). Platinum(IV) oxide (0.322 g, 1.42 mmol) was added and the mixture hydrogenated at 5 bar at room temperature for 5 h. The catalyst was filtered off and the solvent was evaporated. Crude methyl 2-(2-fluoro-4-(trifluoromethoxy)phenyl)piperidine-4-carboxylate hydrochloride (4.97 g, 98%) was obtained as a colorless solid. MS m/z 322 (M+H)+
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([N:10]=[C:11]2[NH:15][CH2:14][CH2:13][NH:12]2)[CH:6]=[CH:7][C:8]=1[CH3:9].[BrH:16]>>[BrH:16].[OH:2][C:3]1[CH:4]=[C:5]([N:10]=[C:11]2[NH:12][CH2:13][CH2:14][NH:15]2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: COc1cc(N=C2NCCN2)ccc1C
Agent: Br
Product: Cc1ccc(N=C2NCCN2)cc1O

Procedure:
A mixture of 6.61 gm of 2-(3-methoxy-4-methylphenylimino)-imidazolidine base (0.032 mol) and 100 ml of 48% hydrobromic acid was refluxed for 12 hours while stirring. Thereafter, the hydrobromic acid was evaporated in value, the residue was dissolved in methanol, the solution was filtered, and ether was added to the filtrate. The crystalline precipitate formed thereby was collected by suction filtration, washed with ether and dried. Yield: 4.85 gm (55.65% of theory) of 2-(3-hydroxy-4-methyl-phenylimino)-imidazolidine hydrobromide, m.p. 164°-165° C., Rf -value 0.4 in mobile phase 75 parts sec. butanol, 15 parts formic acid, 10 parts water. Carrier: silicagel with fluorescent pigment ZS; visualization: ultraviolet light and potassium iodoplatinate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[C:11]([NH2:16])[N:12]=[CH:13][CH:14]=3)[CH2:9][O:8][C:6]=2[CH:7]=1.[C:17](Cl)(=[O:19])[CH3:18]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[C:11]([NH:16][C:17](=[O:19])[CH3:18])[N:12]=[CH:13][CH:14]=3)[CH2:9][O:8][C:6]=2[CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1nccc2c1COc1cc(Cl)ccc1-2
Solvent: c1ccncc1
Product: CC(=O)Nc1nccc2c1COc1cc(Cl)ccc1-2
Reaction time: 2 h

Procedure:
To a stirred solution of 8-chloro-5H-chromeno[3,4-c]pyridin-4-amine (0.08 g, 0.344 mmol) in pyridine (5 mL) at 0° C. was added acetyl chloride (0.024 mL, 0.344 mmol) and the solution was stirred for 2 h. The volatile organics were removed under reduced pressure and the residue was diluted with water (5 mL). The reaction mixture was extracted with CH2Cl2 (2×15 mL). The combined organic extracts were washed with brine (1×10 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude residue was taken to the next step without purification. LCMS (ESI) m/e 273 [(M)−, calcd for C14H10ClN2O2 273.1]; LC/MS retention time (Method C): tR=1.89 min.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][S:21][C:22]=1[O:23][CH:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1)=[O:16].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[S:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][S:21][C:22]=1[O:23][CH:24]1[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2sncc2NC(=O)c2nc(-c3c(F)cccc3F)sc2N)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnsc1OC1CCNCC1
Reaction time: 0.17 h
Yield: 55 %

Procedure:
To a solution of tert-butyl 4-(4-(5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxamido)isothiazol-5-yloxy)piperidine-1-carboxylate (1A) (10 mg, 0.02 mmol) in CH2Cl2 (1 mL) at room temperature (25° C.) was added TFA (trifluoroacetic acid) (0.5 mL), stirred for 10 min and then concentrated in vacuo at room temperature (25° C.) to afford the product 5-amino-2-(2,6-difluorophenyl)-N-(5-(piperidin-4-yloxy)isothiazol-4-yl)thiazole-4-carboxamide (1) (5 mg, 0.011 mmol)
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][C:32]([F:35])([F:34])[F:33])[C:25](O)=O>>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][C:30]=1[O:31][C:32]([F:33])([F:34])[F:35]
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1ccc(OC(F)(F)F)c(Cl)c1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(OC(F)(F)F)c(Cl)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-chloro-4-[(trifluoromethyl)oxy]benzoic acid: MS (APCI) m/z 488 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[CH:3]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[CH3:12][N:13]([CH:15]=[C:3]1[C:2](=[O:1])[CH:7]=[C:6]([CH3:8])[O:5][C:4]1=[O:9])[CH3:14]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CC1=CC(=O)C(=CN(C)C)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-6-methyl-2-pyrone (11.50 g, 91.2 mmol) in toluene (30 mL) is added N,N-dimethylformamide dimethyl acetal (13.00 mL, 97.9 mmol). After stirring for 2 h at room temperature, the reaction mixture is evaporated under reduced pressure and co-evaporated with toluene several times. Yield: 18.5 g; ESI mass spectrum: [M+H]+=182; Retention time HPLC: 0.72 min (Z002—007).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]=[CH:8][C:9]1[CH2:16][C@H:15]2[C@H:11]([CH2:12][C@@H:13]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[C@H:14]2/[CH:17]=[CH:18]/[C:19](=[O:26])[CH:20]([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:10]=1)=[O:4]>CC(C)=O>[CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7]/[CH:8]=[C:9]1\[CH2:10][C@@H:11]2[C@H:15]([CH2:16]\1)[C@@H:14]([CH2:17][CH2:18][C:19](=[O:26])[CH:20]([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:13]([O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[CH2:12]2)=[O:4]
Reactant: CCCCC(F)C(=O)/C=C/[C@H]1[C@H]2CC(C=CCCC(=O)OC)=C[C@H]2C[C@H]1OC1CCCCO1
Solvent: CC(C)=O
Product: CCCCC(F)C(=O)CC[C@@H]1[C@H]2C/C(=C/CCCC(=O)OC)C[C@H]2C[C@H]1OC1CCCCO1
Temperature: 125 °C
Reaction time: 20 h

Procedure:
(1S,5S,6S,7R)-3-[4-Methoxycarbonyl-1(EZ)-butenyl]-6-[4(RS)-fluoro-3-oxo-(E )-1-octenyl]-7-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene (5) (0.109 g) was dissolved in acetone in an autoclave. Into the solution, a tricarbonyl chromium/methyl benzoate complex (0.023 g) was added. The mixture was degassed and the content was stirred under a hydrogen atmosphere (70 kg/cm2) at 125° C. for 20 hours. The reaction mixture was concentrated under reduced pressure. A crude product obtained was chromatographed (hexane/ethyl acetate=10/1-7/1 to give (1S,2R,3R,5S)-7(E)-(4-carbomethoxybutylidene)-2-[4(RS )-fluoro-3-oxo-octyl]-3-tetrahydropyranyloxy-bicyclo[3.3.0]octane (11) as a colorless oily product. Yield: 0.157 g (99%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:36].[NH2:37][CH2:38][CH2:39][N:40]([CH3:48])[C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:37][CH2:38][CH2:39][N:40]([CH3:48])[C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:45])[CH3:46])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[CH:28]=[CH:29][C:30]=3[CH3:31])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:36]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)(=O)=O)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(NCCN(C)C(=O)OC(C)(C)C)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C

Procedure:
3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (1.59 g, 3.1 mmol), was dissolved in CH2Cl2 (140 mL) and stirred under argon at room temperature. 1,1-dimethylethyl (2-aminoethyl)methylcarbamate (0.806 g, 4.65 mmol), and TEA (0.87 mL, 6.2 mmol) were combined in CH2Cl2 (10 mL) and added to the solution of the sulfone. The resulting reaction mixture was stirred under argon overnight. The solvents were pumped off in vacuo. The residue was flash chromatographed on silica gel (150 g) eluted with 0-40% EtOAc/CH2Cl2 to give the title compound as a white amorphous solid. mp 115-118° C. LC-MS m/z 607 (M+H)+, 2.27 min (ret time).
Reaction SMILES: [O-:1][P:2]([O-:5])([O-:4])=[O:3].[O-][P:7]([O-:10])([O-:9])=[O:8].[O-][P:12]([O-:15])([O-])=[O:13].[F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[P:22]([O-])([O-])([O-])=[O:23].P(=O)(O)(O)O>O>[O:3]=[P:2]12[O:5][P:7]3([O:10][P:12]([O:15][P:22]([O:9]3)([O:4]1)=[O:23])(=[O:13])[O:1]2)=[O:8]
Reactant: O=P([O-])([O-])[O-]
Agent: O=P(O)(O)O
Agent: [Ca+2]
Agent: [F-]
Solvent: O
Product: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3

Procedure:
Phosphate rock analyzing 68% bone phosphate of lime (tricalcium phosphate) was comminuted to a fineness such that 90% passed a 100-mesh screen. It was delivered to a pre-reactor having dimensions of 3'×6' at a rate of 200 lbs per ton of product using a weigh belt. Simultaneously water at a rate of 76 lb/ton and phosphoric acid (51.4% P2O5) at a rate of 266 lb/ton were also delivered to the prereactor. The phosphoric acid feed was selected to provide a total P2O5 :CaO ratio of 2.16 by weight (equivalent to a mole ratio of 0.85). The amount of water was selected to dilute the phosphoric acid to 40.0%. Anti-foam agent 0.08 lb/ton (Defoamer 2617-M made by Southern Sizing Corporation was used; it is described as an anionic fatty emulsion), was also delivered to the pre-reactor. The mixture was heated with agitation to a temperature of 175°-210° F. by steam injection. Silicon tetrafluoride and carbon dioxide vapors released by the reactants were vented to a scrubber. The rate of feed of ingredients to the pre-reactor and the size of the digester were selected to provide a retention time of 90 minutes for a production rate of 20 tons/hour.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[C:10]#N)[CH:5]=[C:6]([CH3:8])[CH:7]=1.O=[CH:24][C:25](=C)[CH3:26]>>[CH3:26][C:25]1[CH:10]=[C:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[CH:24]=1
Reactant: Cc1cc(C)cc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)c1
Reactant: C=C(C)C=O
Product: Cc1cc(C)cc(-c2cc(C)cn2-c2ccc(S(N)(=O)=O)cc2)c1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(3,5-dimethylphenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a slightly brown powder (yield 28%), melting at 163-166° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]3[CH:19]=2)=[CH:6][CH:5]=1)([O-])=O.C1CC=CCC=1>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]3[CH:19]=2)=[CH:8][CH:9]=1
Reactant: Cc1cccn2cc(-c3ccc([N+](=O)[O-])cc3)nc12
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: Cc1cccn2cc(-c3ccc(N)cc3)nc12
Temperature: 25 °C
Yield: 54.4 %

Procedure:
A mixture of the product of Step A (1.48 g) and 1,4-cyclohexadiene (6.2 mL) and palladium (10% wt on activated carbon) (1.4 g) in ethanol (100 mL) was stirred at reflux temperature for 2 hours and cooled to ambient temperature and stirred for 12 hours. The reaction mixture was filtered through a pad of celite and the celite pad rinsed with ethanol (100 mL) and methanol (100 mL). The filtrate was collected and evaporated to yield the title compound (710 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1.C(N(CC)CC)C.[C:32]1([CH2:38][C:39](Cl)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl.CCOC(C)=O>[C:32]1([CH2:38][C:39]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]3[N:15]=[C:14]([N:16]4[C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=5[N:18]=[CH:17]4)[CH:13]=[CH:12][N:11]=3)[CH3:8])[CH2:2]2)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCN(C(=O)Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.7 %

Procedure:
To a solution of 2-[1-(piperidin-3-yl)-ethylamino]-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 18) (28.2 mg, 0.087 mmol) in CH2Cl2 (1.0 mL) was added triethylamine (18 μL, 0.131 mmol) followed by phenylacetyl chloride (17 μL, 0.131 mmol) at 0° C. The reaction mixture was gradually warmed to room temperature and stirred for 5 h. The reaction mixture was diluted with EtOAc (10 mL), washed with saturated aqueous NaHCO3 followed by brine, and dried over Na2SO4. The crude product was purified by preparative thin layer chromatography (1:1 acetone:hexane) to yield 19.8 mg of the title compound. Presence of rotamers in Partial 1H NMR (500 MHz, CDCl3): δ 8.6 (s, 1H); 8.36 (d, J=5.3 Hz, 1H); 8.14 (m, 1H); 7.86 (m, 1H); 7.4-7.22 (aromatic H's, 7H); 6.78 (m, 1H); 4.67 (m, 1H); 3.73 (s, 2H); 1.31 (d, J=6.8 Hz, 1.5H); 1.11 (d, J=6.8 Hz, 1.5H). Mass spectrum 441.4 (ESI, M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:14][NH:15][CH3:16]>>[CH3:14][N:15]([CH3:16])[C:11]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:10][CH2:9]1)=[O:13]
Reactant: O=C(O)C1(c2ccc(Br)cn2)CC1
Reactant: CNC
Product: CN(C)C(=O)C1(c2ccc(Br)cn2)CC1

Procedure:
The title compound was prepared from 1-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid and dimethylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Step 2 for Intermediate 5. Yield: quantitative; LC (method 1): tR=1.65 min; Mass spectrum (ESI+): m/z=269/271 (Br) [M+H]+.