Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][C:27]([CH3:32])([CH3:31])[C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][C:27]([CH3:32])([CH3:31])[C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(CN)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Yield: 50 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (82 mg, 0.26 mmol) and 3-amino-2,2-dimethyl-propionic acid (90 mg, 0.77 mmol) (ChemBridge) in 0.5 M NaOMe/MeOH (1.0 mL, 0.5 mmol) was microwaved at 120° C. for 40 min. Reaction mixture was concentrated and the residue was dissolved in water (70 mL). It was acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried. Crude product was triturated with MeOH (2 mL). solid was collected and dried to provide the title compound 54.4 mg (0.13 mmol) in 51% yield. LC-MS ESI−: 404.03 (M−1)−.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:12][C:13]1[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[N:17]=[CH:16]3)=[N:5][CH:6]=[N:7]2.[CH3:29][O-:30].[Na+]>CO>[CH3:29][O:30][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:12][C:13]1[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[N:17]=[CH:16]3)=[N:5][CH:6]=[N:7]2
Reactant: C[O-]
Reactant: Fc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Agent: [Na+]
Solvent: CO
Product: COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Yield: 99.8 %

Procedure:
A mixture of 5-fluoro-N-[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]quinazolin-4-amine (10.2 g, 27.5 mmol) and sodium methoxide (4.46 g, 82.6 mmol) in methanol (250 ml) was heated at reflux for 24 hours. After cooling and evaporation of the solvents, the residue was dissolved in DCM. This solution was washed with water and brine and dried over MgSO4. Evaporation of the solvents gave 5-methoxy-N-[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]quinazolin-4-amine as a beige solid (10.5 g, 100%); NMR spectrum (CDCl3) 4.11 (s, 3H), 5.75 (s, 2H), 6.87 (d, 1H), 6.91 (d, 1H), 7.19 (m, 1H), 7.57-7.42 (m, 4H), 7.64 (t, 1H), 8.09 (s, 1H), 8.22 (m, 1H), 8.59 (m, 2H), 9.83 (br s, 1H); Mass spectrum MH+ 383.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].C([Li])CCC.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]=O)[CH:35]=1.O>CS(C)=O.C1COCC1.C(OCC)(=O)C>[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])[CH:35]=1
Reactant: O=Cc1cccnc1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(O)CCCCC=Cc1cccnc1
Reaction time: 1 h

Procedure:
To a suspension of 69g of 5-carboxypentyl-triphenylphosphonium bromide in a mixture of 125 mL of DMSO and 250 mL THF cooled to 20° is added 130 mL of a 2.4M solution of n-butyllithium dropwise over a period of 30 minutes. After stirring for 45 minutes a solution of 10.7g 3-pyridine-carboxaldehyde in 25 mL of THF is added dropwise, then the solution is stirred for 1 hour before adding water and ethyl acetate. The aqueous layer is separated, acidified to pH 6 and extracted with ethyl acetate. The ethyl acetate extract is dried over magnesium sulfate, filtered and concentrated to give 7-(3-pyridyl)-hept-6-enoic acid which is converted to methyl 7-(3-pyridyl)-hept-6-enoate by refluxing in methanolic hydrochloric acid.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2[N:16]=[C:15]([NH:17][CH3:18])[N:14]=[C:13]([N:19]3[C@H:24]([CH3:25])[CH2:23][CH2:22][C@H:21]([C:26]([NH:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:20]3)[CH:12]=2)=[CH:5][C:4]=1F)#[N:2].[NH2:37][NH2:38]>C(O)C>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:11]3[N:16]=[C:15]([NH:17][CH3:18])[N:14]=[C:13]([N:19]4[C@H:24]([CH3:25])[CH2:23][CH2:22][C@H:21]([C:26]([NH:28][CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[O:27])[CH2:20]4)[CH:12]=3)=[CH:7][C:8]=2[O:9][CH3:10])[NH:38][N:37]=1
Reactant: CNc1nc(-c2cc(F)c(C#N)c(OC)c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C)n1
Reactant: NN
Solvent: CCO
Product: CNc1nc(-c2cc(OC)c3c(N)n[nH]c3c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C)n1
Temperature: 100 °C

Procedure:
Dissolved (3S,6R)-1-[6-[4-cyano-3-fluoro-5-(methyloxy)phenyl]-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamide (96 mg, 0.196 mmol) with Ethanol (2 mL) in a 5 mL sealable vial then added hydrazine (0.185 mL, 5.89 mmol). The reaction was capped and heat overnight at 100° C. The reaction was concentrated then dissolved in 1 mL of DMSO and purified on HPLC (HPLC condition: open-access Gilson using Unipoint software with a Varian Polaris 5u C18(2) 100A, 50×30.00 mm 5 micron. 10-minute run (35 ml/min, 28% ACN/H2O, 0.1% TFA to 53% ACN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were pooled and the volume was reduced by reduce pressure until most of the MeCN was removed then the aqueous saturated NaHCO3 (10 mL) added. The mixture was then extracted with EtOAc (3×10 mL). The organic was pooled, washed with saturated. NaCl, dried over MgSO4, filtered, and concentrated. Then transferred in to 40 mL vial then water was added then freeze-dried to isolate 36 mg of off white solid. LC-MS (ES) m/z=501 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d ppm 1.17 (d, J=7.07 Hz, 3H) 1.67 (d, J=3.54 Hz, 2H) 1.75 (dd, J=12.88, 3.03 Hz, 1H) 1.80-1.93 (m, 1H) 2.31-2.42 (m, 1H) 2.83 (d, J=4.55 Hz, 3H) 2.98 (br. s., 1H) 3.94 (s, 3H) 4.31 (dd, J=9.73, 5.94 Hz, 2H) 4.78 (br. s., 1H) 5.03 (br. s., 2H) 6.56 (br. s., 2H) 6.94 (br. s., 1H) 7.28 (d, J=7.07 Hz, 2H) 7.31-7.37 (m, 2H) 7.51 (br. s., 1H) 8.50 (t, J=5.94 Hz, 1H)
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[C:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH:19]=[CH:18][C:17]4[CH:26]=[CH:27][CH:28]=[CH:29][C:16]3=4)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[CH:25]1[C:20]2[CH:19]=[CH:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[C:15](=[C:12]3[CH2:11][CH2:10][N:9]([CH2:8][CH:7]=[CH:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:31][CH:30]=4)[CH2:14][CH2:13]3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Product: CS(=O)(=O)Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Yield: 67 %

Procedure:
This compound was prepared from 1-(4-Aminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (compound 5) and methanesulfonyl chloride. Yield 67.0%
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][CH:5]([CH2:7][CH2:8][CH2:9][CH:10]([CH2:12][CH2:13][CH2:14][CH:15]([CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:16])[CH3:11])[CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]([CH2:7][CH2:8][CH2:9][CH:10]([CH2:12][CH2:13][CH2:14][CH:15]([CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:16])[CH3:11])[CH3:6]
Reactant: CNC(=O)CC(C)CCCC(C)CCCC(C)CCCC(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCC(C)CCCC(C)CCCC(C)CCCC(C)C

Procedure:
A mixture of N-methylphytanamide (4.0 g) and lithium aluminium hydride (pellets 95%, 2.0 g) in tetrahydrofuran (100 ml) was heated under reflux for two hours. The reaction mixture cooled, excess lithium aluminium hydride destroyed, and solid salts were filtered off. The crude product was dissolved in dichloromethane and washed with water, dried (MgSO4) and the solvent removed. The crude product was chromatographed on flash silica (1% aqueous ammonia, 10-20% methanol in dichloromethane ) to give pure N-methylphytanamine as a colourless liquid. Yield 2.08 g, 54%. 1H-n.m.r. (CDCl3) δ0.82-1.5(m, 39H, phyt), 2.439 (s, 3H, NCH3), 2.54 (m, 2H, CH2CH2NH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]([CH2:23][CH3:24])[C:11](=[O:25])[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1>[C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]([CH2:23][CH3:24])[C:11](=[O:25])[CH2:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CCN1C(=O)CN=C(c2ccc(Br)cc2)c2cc(OC)c(OC)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCN1C(=O)CN=C(c2ccc(-c3ccccc3)cc2)c2cc(OC)c(OC)cc21
Temperature: 90 °C
Yield: 57.3 %

Procedure:
Heat at 90° C. for 12 hours under an inert atmosphere a mixture of 100 mg (0.27 mmol) of 5-(4-bromophenyl)-1-ethyl-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIbl), 35 mg (0.30 mmol) of benzene boronic acid, 215 μl of 2M Na2CO3, 25 mg (0.020 mmol) of tetrakis(triphenylphosphine)Pd(0) and 250 μl of EtOH in 5 ml of degassed toluene. Allow to cool to room temperature. Evaporate to dryness. Purify by chromatography (AcOEt). Recrystallize in Et2O. One obtains 62 mg of the abovenamed product in the form of colorless crystals. Yield: 52%. M: 149–150° C. 1H-NMR (CDCl3, 200 MHz): d 1.13 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 3.95 (AB system, ? d=0.57, JAB=13.7, 2H, —NCH2), 3.98 (s, 3H, OCH3), 4.29 (AB system, ? d=0.99 JAB=10.0, 2H, CH2), 6.75 (s, 1H Ar), 6.86 (s, 1H Ar), 7.37–7.75 (m, 9H Ar).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[C:43]1([C:49]2[C:53]([C:54](O)=[O:55])=[CH:52][O:51][N:50]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[C:43]1([C:49]2[C:53]([C:54]([N:1]3[CH2:5][CH2:4][CH:3]([C:6]4[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=4)[CH2:2]3)=[O:55])=[CH:52][O:51][N:50]=2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: c1cncc(C2CCNC2)c1
Reactant: O=C(O)c1conc1-c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1conc1-c1ccccc1)N1CCC(c2cccnc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
A solution of 3-pyrrolidin-3-yl-pyridine (8 mg, 0.06 mmol), TBTU (22 mg, 0.12 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (10 μL, 0.06 mmol) in DMF (0.6 mL) was added to 3-phenylisoxazole-4-carboxylic acid (11 mg, 0.06 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents from the pure fractions, the residue was dissolved in chloroform and washed with diluted NaOH to provide the neutral compound in the organic phase that was dried (Na2SO4) and evaporated and dried in vacuum to yield the title compound (12 mg). MS (ESI, pos. ion) m/z calcd for C19H17N3O2: 319.1321, found 319.1326.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[H][H]>CCO.CCOC(C)=O.O=[Pt]=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2cccnc2)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(F)c(-c2cccnc2)c1
Yield: 100 %

Procedure:
A suspension of 3-(2-fluoro-5-nitrophenyl)pyridine (26 g, 119 mmol) in EtOH (200 ml) and EtOAc (200 ml) was treated with PtO2 (1.35 g, 6 mmol) then exposed to 50 psi hydrogen until uptake ceased (circa 3 hours). The reaction was filtered through glass-microfibre filter paper and concentrated to gave 3-(2-fluoro-5-aminophenyl)pyridine (22.4 g) as a dark oil which solidified on standing: δH (360 MHz, CDCl3) 3.65 (2H, s), 6.65-6.72 (2H, m), 6.99 (1H, dd, J 9 and 9), 7.33-7.37 (1H, m), 7.84-7.86 (1H, m), 8.58 (1H, d, J 4), 8.76 (1H, m).
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)#[N:2].BrC1C=C(NC(=NC#N)[O-])C=CC=1.[CH3:36][C:37]1[C:45]2[C:44]([N:46]3[CH2:51][CH2:50][NH:49][C@@H:48]([CH3:52])[CH2:47]3)=[N:43][CH:42]=[N:41][C:40]=2[NH:39][CH:38]=1.C(N(CC)CC)C>C(O)(C)C>[C:1]([N:3]=[C:4]([N:49]1[CH2:50][CH2:51][N:46]([C:44]2[C:45]3[C:37]([CH3:36])=[CH:38][NH:39][C:40]=3[N:41]=[CH:42][N:43]=2)[CH2:47][C@@H:48]1[CH3:52])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:7]=1)#[N:2]
Reactant: Cc1c[nH]c2ncnc(N3CCN[C@@H](C)C3)c12
Reactant: N#CN=C(Nc1cccc(C(F)(F)F)c1)Oc1ccccc1
Agent: N#CN=C([O-])Nc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCN(C(=NC#N)Nc4cccc(C(F)(F)F)c4)[C@@H](C)C3)c12
Temperature: 140 °C

Procedure:
Phenyl N′-cyano-N-(3-(trifluoromethyl)phenyl)carbamimidate, prepared analogously to N-3-bromophenyl-N′-cyanocarbamimidate from Example 5, step A (36 mg, 0.12 mmol), (S)-5-methyl-4-(3-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine, from Example 1, step B, (35 mg, 0.15 mmol), and triethylamine (0.05 ml, 0.36 mmol) were combined in isopropanol in a microwave vessel. The reaction was heated at 140° C. for 30 min. under microwave conditions. The solvent was evaporated, and the residue was washed with CH2Cl2 (3×10 ml). The crude product was purified by Prep-HPLC to afford (S)—N′-cyano-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-(trifluoromethyl)phenyl)-piperazine-1-carboximidamide as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[N:13][CH:14](Cl)[CH2:15][Cl:16])[C:11](=[O:18])[N:10]([CH3:19])[C:9]1=[O:20].[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].C(N(CC)CC)C.Cl>C(#N)C.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[N:13][CH:14]([NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[Cl:21])[CH2:15][Cl:16])[C:11](=[O:18])[N:10]([CH3:19])[C:9]1=[O:20]
Reactant: Nc1ccccc1Cl
Reactant: CN1C(=O)C(=NC(Cl)CCl)N(c2ccccc2F)C1=O
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1C(=O)C(=NC(CCl)Nc2ccccc2Cl)N(c2ccccc2F)C1=O
Reaction time: 0.17 h

Procedure:
In this example 0.02 mol of 1-(2-fluorophenyl)-3-methyl-5-(1,2-dichloroethyl)imino-1,3-diazolidine-2,4-dione is dissolved in 20 ml of acetonitrile and then 0.02 of mol of 2-chloroaniline is added. After about 10 minutes, triethylamine is added to neutralize the byproduct HCl produced by the reaction. The mixture is stirred for five hours and 20 ml of ethyl ether is then added. The mixture is filtered and the filtrate evaporated under high vacuum affording 1-(2-fluorophenyl)-3-methyl-5-(1-2'chlorophenylamino-2-chloroethyl)imino-1,3-diazolidine-2,4-dione.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=1[CH2:12][NH:13][C:14](=[O:20])[C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na].[CH:27]1([C:30]([OH:40])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:31](O)=[O:32])[CH2:29][CH2:28]1.CN1CCOCC1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:27]1([C:30]([OH:40])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:31]([N:16]2[CH2:17][CH2:18][CH2:19][C@H:15]2[C:14]([NH:13][CH2:12][C:11]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:10]=2[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:20])=[O:32])[CH2:29][CH2:28]1
Reactant: O=C(O)C(O)(c1ccccn1)C1CC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)C(O)(c1ccccn1)C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide (120 mg, 0.316 mmol), the sodium salt of 2-cyclopropyl-2-(2-pyridyl)hydroxyacetic acid from the previous step (63 mg, 0.326 mmol), and NMM (36 μL, 0.326 mmol) in DMF (5 mL) at ambient temperature under nitrogen atmosphere was added BOP reagent (173 mg, 0.391 mmol). The mixture was stirred at ambient temperature for 3 h. The solvent was removed under reduced pressure. The residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL). The EtOAc layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using a gradient of 95:5 to 0:100 (water:CH3CN containing 0.1% TFA) over 60 min with a flow rate of 60 mL/min. After concentration of desired fractions in vacuo, the two diastereomers of 1-(2-cyclopropyl-2-(2-pyridyl)hydroxyacetyl)-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide were obtained as amorphous solids (isomer 1 (less polar) 50 mg; HPLC RT=3.06 min, method A; LC-MS m/z=543.2; 1H NMR, 400 MHz, CDCl3, 7.81 ppm (d, 1H), 7.74 ppm (t, 2H), 7.28 ppm (d, 2H), 7.22 ppm (d, 1H), 7.14 ppm (t, 1H), 5.45 ppm (br s, 1H), 5.0 ppm (br s, 1H), 4.8 ppm (d, 1H), 4.6 ppm (dd, 1H), 4.42 ppm (d, 1H), 4.35 ppm (m, 1H), 4.2 ppm (m, 1H), 3.43 ppm (m, 1H), 3.1 ppm (br t, 1H), 2.25 ppm (m, 1H), 2.1 ppm (m, 1H), 1.8 ppm (m, 2H), 1.48 ppm (m, 1H), 1.45 ppm (s, 9H), 1.0 ppm (m, 1H), 0.85 ppm (m, 1H), 0.65 ppm (m, 1H), 0.5 ppm (m, 1H); isomer 2 (more polar)38 mg; HPLC RT=2.99 min, method A; LC-MS m/z=543.2).
Reaction SMILES: [BH4-].[Na+].[C:3]1([S:9]([CH2:12][C:13]2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([OH:23])[C:16]([C:24]3[CH:28]=[CH:27][O:26][C:25]=3[CH:29]=[O:30])=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl-].[NH4+].C(OCC)(=O)C>CO.C1COCC1.O>[C:3]1([S:9]([CH2:12][C:13]2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([OH:23])[C:16]([C:24]3[CH:28]=[CH:27][O:26][C:25]=3[CH2:29][OH:30])=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2C=O)c1O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2CO)c1O
Yield: 96.5 %

Procedure:
Sodium borohydride (0.031 g) was added to a solution of methyl 6-(benzenesulfonylmethyl)-3-(2-formylfuran-3-yl)-2-hydroxybenzoate (Intermediate 28, 0.67 g) in methanol (6 mL) and THF (12 mL) at 0° C. and the resultant mixture was stirred at 0° C. for 10 minutes. Saturated aqueous ammonium chloride, ethyl acetate and water were added and the organic layer was separated, washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 30-80% to give methyl 6-(benzenesulfonylmethyl)-2-hydroxy-3-(2-hydroxymethylfuran-3-yl)-benzoate (0.65 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O.C(Cl)(=O)C(Cl)=O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(Cl)c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Cc1cccc(Cl)c1C(=O)Cl

Procedure:
In one embodiment, the step comprises combining 2-chloro-6-methylbenzoic acid with, e.g., thionyl chloride or oxalyl chloride, optionally in the presence of a catalytic amount of DMF, to afford 2-chloro-6-methylbenzoyl chloride.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.Cl[C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][CH3:17])[N:12]=[C:11]([S:18]([CH3:21])(=[O:20])=[O:19])[N:10]=1.[CH:22]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)([CH3:24])[CH3:23]>C(COC)OC.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>[CH:22]([C:25]1[CH:30]=[C:29]([C:9]2[CH:14]=[C:13]([CH2:15][CH2:16][CH3:17])[N:12]=[C:11]([S:18]([CH3:21])(=[O:20])=[O:19])[N:10]=2)[CH:28]=[CH:27][CH:26]=1)([CH3:24])[CH3:23]
Reactant: CCCc1cc(Cl)nc(S(C)(=O)=O)n1
Reactant: CC(C)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCCc1cc(-c2cccc(C(C)C)c2)nc(S(C)(=O)=O)n1
Yield: 23.9 %

Procedure:
Potassium carbonate (0.850 g, 6 mmol), water (1 ml) and tetrakis(triphenylphosphine)palladium (0.695 g, 0.6 mmol) were successively added under a nitrogen atmosphere, to a mixture of 4-chloro-2-methanesulfonyl-6-propyl-pyrimidine (1.17 g, 5 mmol) and 3-isopropyl-phenylboronic acid (0.984 g, 6 mmol) in dimethoxyethane (40 mL). The mixture was refluxed for 18 hours then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent: Cyclohexane/Ethyl acetate 7/3) to afford a yellow oil which crystallised in pentane. After filtration, 4-(3-isopropyl-phenyl)-2-methanesulfonyl-6-propyl-pyrimidine (0.380 g) was obtained as an off white solid (mp=82° C.).
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)=O)#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:22][NH2:23]>O1CCOCC1.O1CCCC1>[C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)=[N:22][NH2:23])#[N:2]
Reactant: Cc1cc(C)cc(C(=O)NCCC#N)c1
Reactant: NN
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1cc(C)cc(C(=NN)NCCC#N)c1
Temperature: 100 °C

Procedure:
A mixture of the product from step (vii) (35.68 g) and phosphorus pentachloride (36.86 g) was stirred under a water-aspirator vacuum and heated at 100° C. giving rise to a yellow oil. The oil was further stirred at 100° C. under vacuum for a further 30 min. The boiling phosphorus oxychloride liberated was collected by distillation to leave a dark brown oil which was cooled to room temperature and dissolved in dry 1,4-dioxane (50 ml). This solution was transferred rapidly via cannula to a stirring solution of hydrazine in tetrahydrofuran (1.0M, 882 ml) under nitrogen at room temperature. An exotherm was produced raising the reaction temperature to ˜40° C. The resultant opaque yellow solution was further stirred for 16 h. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was collected, dried over magnesium sulphate and solvent removed under reduced pressure to give the subtitle product as a red oil (34.7 g). This was not purified but used directly in the next step