Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:21]=3[O:20][CH3:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Reactant: COc1ccc(C)cc1B(O)O
Product: COc1ccc(C)cc1-c1cccc2c(N)c(C(=O)NC3CC3)nnc12
Yield: 73.3 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (143 mg, 0.47 mmol) and 2-methoxy-5-methylphenylboronic acid (155 mg, 0.94 mmol) were reacted. After purification the title compound (120 mg, 74% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.00 (d, J=4.9 Hz, 1H), 8.38 (d, J=7.1 Hz, 1H), 7.74 (t, J=7.7 Hz, 1H), 7.68 (d, J=7.1 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 7.06 (s, 1H), 6.98 (d, J=8.5 Hz, 1H), 3.57 (s, 3H), 2.96 (m, 1H), 2.28 (s, 3H), 0.70(m, 4H). MS APCI, m/z=349.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[CH3:12][Si](C=[N+]=[N-])(C)C>C1COCC1.CO>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(Br)cc1F
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Br)cc1F
Temperature: 25 °C

Procedure:
To a solution of 4-bromo-2-fluorobenzoic acid (2.0 g, 9.1 mmol) in THF (24 mL) and methanol (6 mL) at 0° C. was added a solution of (trimethylsilyl)diazomethane in hexanes (2.0 M, 5.46 mL, 10.9 mmol). The yellow solution was allowed to gradually warm to room temperature over 1 h. The volatile materials were removed and the residue was treated with aqueous hydrochloric acid (1 M). The aqueous mixture was extracted with ethyl acetate. The organic extract was dried over magnesium sulfate, filtered, and concentrated to provide crude methyl 4-bromo-2-fluorobenzoate (2.7 g, quantitative yield). This material was used in the subsequent step without further purification. 1H NMR (400 MHz, CDCl3): 7.85-7.81 (m, 1H), 7.38-7.33 (m, 2H), 3.93 (s, 3H); MS (EI) for C8H6BrFO2: 232, 234 (MH+).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2([C:13]3[N:14]([CH3:18])[CH:15]=[N:16][CH:17]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:19]([C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH3:28])[C:22]1=[O:29])[CH3:20]>>[CH2:19]([C:21]1([C:30]2[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=2)[O:36][C:2]2[CH:9]=[C:8]([C:10]3([C:13]4[N:14]([CH3:18])[CH:15]=[N:16][CH:17]=4)[CH2:12][CH2:11]3)[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH3:28])[C:22]1=[O:29])[CH3:20]
Reactant: Cn1cncc1C1(c2ccc(C#N)c(F)c2)CC1
Reactant: CCC1(c2cccc(O)c2)CCCCN(C)C1=O
Product: CCC1(c2cccc(Oc3cc(C4(c5cncn5C)CC4)ccc3C#N)c2)CCCCN(C)C1=O

Procedure:
Using the procedure described in Example 3, the title compound was prepared starting with 2-fluoro-4-[1-(3-methyl-3-H-imidazol-4-yl)-cyclopropyl]-benzonitrile (as described in Step A above) (0.050 g, 0.21 mmol) and 3-ethyl-3-(3-hydroxy-phenyl)-1-methyl-azepan-2-one (0.078 g, 0.21 mmol).
Reaction SMILES: O=O.[CH3:3][O:4][C:5]1[C:10]([N+:11]([O-])=O)=[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[C:7]([CH3:19])[N:6]=1.[H][H]>CCOC(C)=O.[Pd]>[NH2:11][C:10]1[C:5]([O:4][CH3:3])=[N:6][C:7]([CH3:19])=[CH:8][C:9]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(C)nc(OC)c1[N+](=O)[O-]
Agent: [Pd]
Agent: O=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C)nc(OC)c1N
Reaction time: 17 h

Procedure:
To an oxygen free solution of the nitro ester 1-2 from step B (2.5 g, 10.4 mmol) in 50 mL of EtOAc was added 520 mg of 10% Pd on charcoal. Hydrogen gas was added and the reaction mixture was stirred for 17 h. The solution was filtered through a pad of Celite, concentrated and chromatographed (2:3 EtOAc/Hexane) to give the desired amine 1-3 as a white solid.
Reaction SMILES: C([Si](C)(C)O[CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.C([N-]C(C)C)(C)C.[Li+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1.C1C[O:36]CC1>>[F:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]([OH:36])([OH:30])[CH2:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)=[CH:27][CH:26]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccncc1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: OC(O)(Cc1ccncc1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 62 %

Procedure:
To a stirring solution of 2.0 g (11.2 mmol) 4-(t-butyldimethyl-silyloxy)methyl pyridine in 8 ml of THF at −20° C. was added 14.7 mmol of lithium di-iso-propyl amide in THF. Thirty minutes later 4-fluoro-benzaldehyde (1.66 g, 13.4 mmol) was added at which point the solution was allowed to warm slowly to rt. The reaction was quenched with NH4Cl and extracted with ether to afford the crude protected diol which following concentration was dissolved in THF and treated with 17 ml of a 1 molar solution of tetrabutylammonium fluoride in THF overnight. Standard aqueous workup afforded the crude diol which was further purified by column chromatography (hex/EtOAc) to yield 1.6 g (62%) of the titled material.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[N:21]1([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:30]([O:29][C:27]([N:21]1[CH2:26][CH2:25][N:24]([C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:23][CH2:22]1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCN(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)CC1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with benzyl piperazine-1-carboxylate (31166-44-6) in the presence of TBTU and DIEA to obtain the title compound as light brown oil; MS (EI): m/e=487.5 [MH+].
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7](=[O:16])[CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([CH3:18])([CH3:17])[C:4]([C:19]#[C:20][C:21]([CH3:25])=[CH:22][CH:23]=[O:24])=[C:3]1[CH3:26].[BH4-].[Na+].O>C(O)C>[O:1]=[C:2]1[CH:6]([C:7](=[O:16])[CH2:8][O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:5]([CH3:17])([CH3:18])[C:4]([C:19]#[C:20][C:21]([CH3:25])=[CH:22][CH2:23][OH:24])=[C:3]1[CH3:26]
Reactant: CC(C#CC1=C(C)C(=O)C(C(=O)COc2ccccc2)C1(C)C)=CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C#CC1=C(C)C(=O)C(C(=O)COc2ccccc2)C1(C)C)=CCO
Reaction time: 0.17 h

Procedure:
42 g of 5-[3-oxo-4-phenoxyacetyl-2,5,5-trimethyl-cyclopent-1-en-1-yl]-3-methyl-pent-2-en-4-yn-1-al are dissolved in 420 ml of ethanol. The solution is treated at -40° C. with 1.16 g of sodium borohydride and stirred for 10 minutes. The mixture is then introduced into water and extracted with ether. The 5-[3-oxo-4-phenoxyacetyl-2,5,5-trimethyl-cyclopent-1-en-1-yl]-3-methyl-pent-2-en-4-yn-1-ol is obtained as a viscous oil.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[NH:12][C:13]([C:15]1[C:16](=[O:33])[N:17]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:18]2[C:23]([C:24]=1[OH:25])=[CH:22][CH:21]=[CH:20][N:19]=2)=O)(=[O:4])=[O:3].Cl>[OH-].[K+]>[CH2:26]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][N:19]=2)[C:24]([OH:25])=[C:15]([C:13]2[NH:12][C:6]3[CH:7]=[CH:8][C:9]([Br:11])=[CH:10][C:5]=3[S:2](=[O:4])(=[O:3])[N:1]=2)[C:16]1=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NS(=O)(=O)c1cc(Br)ccc1NC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=c1c(C2=NS(=O)(=O)c3cc(Br)ccc3N2)c(O)c2cccnc2n1Cc1ccccc1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
A mixture of the product of Example 84C (0.074 g, 0.14 mmol) in aqueous potassium hydroxide (10%, 5 mL) was heated to reflux for 16 hours, cooled to room temperature and adjusted to pH 3 with 6 M HCl. The mixture was filtered and the filter cake was washed with water, triturated with tetrahydrofuran/water, filtered, and dried under vacuum to give the title compound (0.060 g, 84%). MS (ESI+) m/z 511.0 (M+H)+, 512.9 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 5.62 (s, 2H), 7.21 (m, 1H), 7.27 (m, J=4.41 Hz, 5H), 7.36 (m, 1H), 7.50 (d, J=8.82 Hz, 1H), 7.84 (dd, J=8.82, 1.84 Hz, 1H), 7.95 (s, 1H), 8.51 (dd, J=7.91, 1.65 Hz, 1H), 8.68 (m, 1H). The sodium salt of the title compound was prepared according to the procedure of Example 1D. MS (ESI+) m/z 511.0 (M+H−Na)+, 512.9 (M+H−Na)+; 1H NMR (300 MHz, DMSO-d6) δ 5.52 (s, 2H), 7.17 (m, 2H), 7.24 (m, 5H), 7.71 (m, 1H), 7.76 (d, J=2.21 Hz, 1H), 8.40 (dd, J=7.72, 1.84 Hz, 1H), 8.49 (dd, J=4.60, 2.02 Hz, 1H), 16.09 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[C:35]([C:37](=[O:39])[NH2:38])[CH:34]=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C.C(OCC)(=O)C>[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[C:35]([C:37](=[O:39])[NH2:38])[CH:34]=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: COc1ccc(C(N)=O)cc1NC(=O)c1c(N)ncnc1Cl
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(N)=O)cc1NC(=O)c1c(N)ncnc1N[C@@H](C)c1nn2ccc(C)c2c(=O)n1-c1ccccc1
Temperature: 120 °C
Yield: 80 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (125 mg, 0.44 mmol), 4-amino-N-(5-carbamoyl-2-methoxyphenyl)-6-chloropyrimidine-5-carboxamide (216 mg, 0.67 mmol), DIEA (385 μl, 2.21 mmol) and cesium fluoride (134 mg, 0.88 mmol) were suspended in tert-butanol (7 ml) and the mixture was heated overnight at 120° C. in a sealed tube. The reaction mixture was diluted with ethyl acetate and washed with water and brine. After evaporation of the solvent, the residue (400 mg, 49% purity, 80% yield) was used in the next synthetic step without further purification.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][CH:9]1[NH:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:10]1.[F:24][C:25]([F:41])([F:40])[C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])[N:27]=1>>[CH3:8][CH:9]1[N:14]([C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[C:31]([C:28]3[N:27]=[C:26]([C:25]([F:41])([F:40])[F:24])[O:30][N:29]=3)[CH:32]=2)[CH2:13][CH2:12][N:11]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:10]1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC1CN(Cc2ccc(C#N)cn2)CCN1
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(Cc2ccc(C#N)cn2)CCN1C(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 21 %

Procedure:
This compound was synthesized from 6-((3-methylpiperazin-1-yl)methyl)nicotinonitrile TFA salt and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (60 mg, yield 21%) pale yellow viscous liquid. 1H NMR (400 MHz, MeOD) δ 8.85-8.84 (m, 1H), 8.25-8.22 (dt, J=7.4 Hz, 1.6 Hz, 1H), 8.19-8.16 (dd, J=8.2 Hz, 2.1 Hz, 1H), 8.13 (m, 1H), 7.82-7.80 (d, J=8.3 Hz, 1H), 7.72-7.66 (m, 2H), 3.82-3.70 (m, 3H), 3.50 (m, 2H), 2.89 (m, 1H), 2.74 (m, 1H), 2.43-2.41 (m, 1H), 2.31-2.25 (m, 1H), 1.46-1.44 (d, J=6.5 Hz, 3H). MS (ESI) m/z: Calculated for C22H16F3N6O2: 456.15. found: 457.2 (M+H)+
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[SH:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:21]([O:20][C:18]([CH2:17][S:16][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:19])[CH3:22]
Reactant: CCOC(=O)CS
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)CSc1c(C(=O)OCC)[nH]c2ccccc12
Yield: 21 %

Procedure:
To a solution of ethyl 3-bromoindole-2-carboxylate (1.34 g) and ethyl 2-mercaptoacetate (0.96 ml) in acetone (15 ml) was added potassium carbonate (1.38 g) and the resulting mixture was heated at reflux under argon for 18 hours. The cooled mixture was poured into water and extracted with ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated to a gum which was purified by column chromatography using iso-hexane:ethyl acetate (1:4) to give the desired product (331 mg, 21%) NMR d (CDCl3) 1.05 (t, 3H), 1.45 (t, 3H), 3.6 (s, 2H), 4.0 (q, 2H), 4.5 (q, 2H), 7.2-7.4 (m, 3H), 7.9 (d, 1H), 9.2 (brs, 1H); M/z (+) 308.3 (MH30).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][C:11](OC)=[O:12].[C:15]([OH:19])([CH3:18])([CH3:17])[CH3:16].C(OC(C)C)(C)C>[Zn]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][C:11]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12]
Reactant: CC(C)(C)O
Reactant: COC(=O)CCCOC1CCCCO1
Agent: [Zn]
Solvent: CC(C)OC(C)C
Product: CC(C)(C)OC(=O)CCCOC1CCCCO1
Yield: 92.9 %

Procedure:
Under a nitrogen atmosphere, a mixture of methyl 4-(tetrahydro-2H-pyran-2-yloxy)butyrate (3.0 mmol), t-butanol (3. 6 mmol), a zinc cluster Zn4O (OCOCF3)6 (0.0375 mmol) and diisopropyl ether (5.0 ml) was refluxed for 18 hours. As a result, t-butyl 4-(tetrahydro-2H-pyran-2-yloxy)butyrate was obtained in a yield of 92.9%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([C:19](O)=[O:20])[C:5]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.Cl.[CH2:24]([NH2:26])[CH3:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([C:19]([NH:26][CH2:24][CH3:25])=[O:20])[C:5]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1
Reactant: CCN
Reactant: Cc1c(Cl)cc(C(C)O)c(-c2cc(F)cc(F)c2)c1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1c(C)c(Cl)cc(C(C)O)c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
A mixture of 4-chloro-3′,5′-difluoro-6-(1-hydroxyethyl)-3-methylbiphenyl-2-carboxylic acid (250 mg, 0.76 mmol), ethylamine hydrochloride (94 mg, 1.1 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.51 g, 1.1 mmol) in N,N-dimethylformamide (4 mL) was stirred at rt for 10 min. To the resulting mixture was added N,N-diisopropylethylamine (0.40 mL, 2.3 mmol). After stirred at rt overnight, the reaction was quenched with water, extracted with EtOAc. The combined organic layers were washed with water, brine, dried over magnesium sulfate, and then concentrated to dry. The residue was purified on silica gel, eluting with 0 to 80% EtOAc in hexanes, to give the desired product (185 mg, 68%). LCMS calculated for C18H19ClF2NO2 (M+H)+: m/z=354.1; Found: 354.0.
Reaction SMILES: [OH-].[Li+].C[C@H]1[C@H](C2C=CC=CC=2)OC(=O)N1[C:16](=[O:27])[C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])[CH3:18].C(OCC)(=[O:30])C>O1CCCC1.O>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C@H:17]([CH3:18])[C:16]([OH:27])=[O:30]
Reactant: CCOC(C)=O
Reactant: COc1ccccc1[C@H](C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1[C@H](C)C(=O)O
Reaction time: 3 h

Procedure:
1.52 g of lithium hydroxide are added to a solution, cooled to +5° C., of 4.1 g of (4S,5S)-4-methyl-5-phenyl-3-[(S)-2-(2-methoxyphenyl)-propionyl]-2-oxazolidinone in 60 cm3 of tetrahydrofuran and 30 cm3 of water. The reaction mixture is stirred for 3 hours at this temperature and then, after re-equilibrating to room temperature, ethyl acetate is added, the mixture is decanted and the aqueous phase is acidified with a 1N aqueous solution of hydrochloric acid, extracted with ethyl acetate and the organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is recrystallized from hexane, drained and dried. 0.4 g of (S)-2-(2-methoxyphenyl)-propionic acid is obtained in the form of white crystals; melting point 102° C. [α]D20 =+84.6° (c=1; CHCl3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14]Br)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2
Reactant: C1COCCN1
Reactant: Nc1ncnn2c(CCCBr)cc(Br)c12
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1ncnn2c(CCCN3CCOCC3)cc(Br)c12
Yield: 48.3 %

Procedure:
A solution of 5-bromo-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (931 mg, 2.78 mmol), morpholine (1.214 g, 13.94 mmol, 5.0 eq), triethylamine (1.16 ml, 8.36 mmol, 3.0 eq), and sodium iodide (63 mg, 0.42 mmol, 0.15 eq) in anhydrous DMF (20 mL) was stirred at 55° C. for 17 h. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 followed by saturated brine. It was dried over Na2SO4, filtered, concentrated at reduced pressure to first remove EtOAc followed by some DMF with pumping. The crude was dissolved in THF and then preloaded by evaporation onto about 5 ml silica gel and then chromatographed on 40 g silica gel using a gradient from 0-10% MeOH in CH2Cl2 to provide 457 mg (47.9%) of the desired product as a white solid along with another 435 mg (46%) of mixed fractions contaminated with the dibromide which came from the tribromide contaminant in the starting material as noted above in step 4. 1H-NMR (DMSO-d6) 7.86 (s, 1H), 6.65 (s, 1H), 3.56 (t, 4H, J=4.6), 2.84 (t, 2H), 2.25-2.35 (m, 6H), and 1.80 (pent, 2H, J=7.4); MS LC-MS [M+H]+=340.2/342.2, RT=1.09 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1([NH:8][C:9]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:27][C@H:15]4[C:16]=3[N:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[N:18]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[O:1]=[C:2]1[CH2:5][CH2:6][CH2:7][C:3]1([NH:8][C:9]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:27][C@H:15]3[C:16]=2[N:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[N:18]=1)=[O:10])[CH3:4]
Reactant: O=C(NC1(CO)CCCC1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC1(NC(=O)c2nn(-c3ccc(F)cc3F)c3c2C[C@H]2C[C@@H]32)CCCC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of (1aR,5aR)-2-(2,4-difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1-hydroxymethyl-cyclopentyl)-amide (193 mg, 0.517 mmol) in dichloromethane (4 mL) was added Dess-Martin Periodinane (230 mg, 0.543 mmol). The mixture was stirred at 23° C. for 2 h, and purified by silica gel column chromatography to give the title compound (170 mg) as a white solid. LCMS m/z=372.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([O:26]C)=[O:25])(=[O:17])=[O:16])=[O:13])[N:4]=1.C(O)C.[OH-].[K+]>O.Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([OH:26])=[O:25])(=[O:17])=[O:16])=[O:13])[N:4]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.6 %

Procedure:
A mixture containing 5 g of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide, 20 ml of ethanol, 2.5 ml of water and 2.5 g of potassium hydroxide was stirred at ambient temperature and pressure for 18 hours. The mixture was then diluted with 250 ml of water and 20 ml of concentrated hydrochloric acid was added with stirring. The precipitate was filtered and washed with water and dried to yield 4.85 g of the desired product, melting at 161°-2° C. The infrared absorption peaks at 3500, 3400 and 1700 cm-1 are consistent with the desired structure and the nuclear magnetic resonance absorption peaks at 3.95 ppm, s, 6H, OCH3 of pyrimidine; 5.8 ppm, s, 1H, pyrimidine proton at position 5; and 7.6-8.3 ppm, m, 4H, aromatic protons, are consistent with the desired structure.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].O=[C:10]1[CH:19]2[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12][CH:11]1[C:20](OC)=[O:21]>CN(C)C=O>[NH2:7][C:6]1[N:8]=[C:20]([OH:21])[C:11]2[CH2:12][CH2:13][CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]3[C:10]=2[N:5]=1
Reactant: COC(=O)C1CCC2CCCCC2C1=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CN(C)C=O
Product: Nc1nc(O)c2c(n1)C1CCCCC1CC2
Temperature: 160 °C
Reaction time: 0.17 h

Procedure:
In a 500 mL round bottomed flask, a suspension of guanidine carbonate (11.1 g, 61.4 mmol) in N,N-dimethylformamide (100 mL) was heated with stirring to 160° C. for 10 minutes, and a solution of the product from Example 12A (6.46 g, 30.7 mmol) in N,N-dimethylformamide (15 mL) was added dropwise over 2 minutes. The flask that contained the product from Example 12A was rinsed with an additional 10 mL of N,N-dimethylformamide and this was added to the reaction over 2 minutes. The reaction was heated to 165° C. for 20 minutes, cooled to room temperature and partitioned between 1 M sodium hydroxide (650 mL) and ether (200 mL). The layers were separated and the ether layer was extracted with 1 M sodium hydroxide (25 mL). The ether layer was disposed of. The combined aqueous sodium hydroxide layers were cooled in an ice bath and acidified to pH ˜7 with concentrated hydrochloric acid. After standing at ambient temperature for 15 minutes, the resulting solid was collected by filtration, washed with water and dried overnight in a drying oven with heating under vacuum to provide the title compound: 1H NMR (DMSO-d6) δ 0.78-0.96 (m, 1H), 1.00-1.35 (m, 5H), 1.61-1.74 (m, 3H), 1.75-192 (m, 2H), 2.01-2.18 (m, 1H), 2.28-2.58 (m, 2H), 6.13 (br s, 2H), 10.66 (s, 1H); MS (DCl/NH3) m/z 220 (M+H)+.