Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][C:5]1([CH3:23])[O:9][N:8]=[C:7]([S:10][CH2:11][C:12]2[C:13]([C:19]([F:22])([F:21])[F:20])=[N:14][N:15]([CH3:18])[C:16]=2F)[CH2:6]1.O>CN(C)C=O>[C:1]([C:16]1[N:15]([CH3:18])[N:14]=[C:13]([C:19]([F:22])([F:21])[F:20])[C:12]=1[CH2:11][S:10][C:7]1[CH2:6][C:5]([CH3:23])([CH3:4])[O:9][N:8]=1)#[N:2]
Reactant: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1F
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1C#N
Temperature: 40 °C
Reaction time: 1 h
Yield: 176.7 %

Procedure:
0.2 g (4.0 mmoles) of sodium cyanide was added to a solution of 0.5 g (1.6 mmoles) of 5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 30 ml of N,N-dimethylformamide. The mixture was stirred at 40° C. for 1 hour to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.9 g of crude 3-(5cyano-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41].CC1C=CC(CN2C=CC(N)=N2)=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:36]3[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:35]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: Cc1cccc(C)n1
Agent: Cc1ccc(Cn2ccc(N)n2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (181 μL, 0.36 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (70 μL, 0.61 mmol) was added to the solution at 0° C. After 1 h, crude 1-(4-methyl-benzyl)-1H-pyrazol-3-ylamine (0.42 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(4-methyl-benzyl)-1H-pyrazol-3-yl]-propionamide (86 mg, 57%) as a white solid: ESI-LRMS m/e calcd for C26H30ClN3O3S [M+] 499.2, found 500.3 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.19 (m, 2H, CH2), 1.41-1.95 (m, 8H, 4×CH2), 2.10-2.27 (m, 1H, CH), 2.32 (s, 3H, ArCH3), 3.24 (s, 3H, SO2CH3), 3.55 (t, J=7.6 Hz, 1H, CH), 5.07 (s, 2H, NCH2), 6.67 (d, J=2.3 Hz, 1H, Ar), 7.04 (d, Jo=8.1 Hz, 2H, Ar), 7.11 (d, Jo=8.1 Hz, 2H, Ar), 7.26 (d, J=2.3 Hz, 1H, Ar), 7.43 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.57 (d, Jm=1.7 Hz, 1H, Ar), 8.04 (d, Jo=8.2 Hz, 1H, Ar), 8.31 (s, 1H, NH).
Reaction SMILES: Cl[CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5]CC)=O.[OH:13][C:14]1[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>CCO>[CH2:11]([O:10][C:8]([CH:2]1[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[N:16][C:15]=2[NH:20][C:3]1=[O:5])=[O:9])[CH3:12]
Reactant: Nc1ncccc1O
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1Oc2cccnc2NC1=O

Procedure:
Diethyl chloromalonate (9.73 g, 50 mmol) was added to a stirred mixture of 3-hydroxy-2-aminopyridine (5.51 g, 50 mmol), triethylamine (6.97 mL, 50 mmol) and EtOH (100 mL) at room temperature. The mixture was heated at reflux for 17 h and allowed to attain room temperature. The precipitate formed was filtered off, washed with EtOH and dried to give the product as a white solid: yield 3.85 g (35%); mp 160-162° C. Anal. (C10H10N2O4) C, H, N.
Reaction SMILES: C(Cl)(=O)C.Cl.C(O)(C(F)(F)F)=O.[F:13][C:14]1[CH:15]=[C:16]([CH:42]=[C:43]([F:45])[CH:44]=1)[CH2:17][C@H:18]([NH:34]C(=O)OC(C)(C)C)[C@H:19]([OH:33])[CH2:20][NH:21][C:22]1([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[CH:32])[CH:26]=2)[CH2:24][CH2:23]1>CO>[NH2:34][C@@H:18]([CH2:17][C:16]1[CH:42]=[C:43]([F:45])[CH:44]=[C:14]([F:13])[CH:15]=1)[C@H:19]([OH:33])[CH2:20][NH:21][C:22]1([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[CH:32])[CH:26]=2)[CH2:24][CH2:23]1
Reactant: C#Cc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: CO
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: C#Cc1cccc(C2(NC[C@@H](O)[C@@H](N)Cc3cc(F)cc(F)c3)CC2)c1

Procedure:
Acetyl chloride (84 mL, 1.18 moles, 15 equivalents based on the protected 3,5-difluorobenzyl compound) is added slowly to stirred methanol (250 mL). (Alternatively, HCl or TFA may be utilized.) The mixture is stirred for at least 15 min at which time t-butyl(1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethynylphenyl)cyclopropyl]amino}-2-hydroxypropylcarbamate (WO02/02512, PREPARATION 1, 37.8 g, 0.08 moles, 1 equivalent) dissolved in methanol (100 mL) is added slowly. The mixture is then stirred at 20–25° until the reaction is judged to be complete by HPLC. Once complete, the methanol is removed under reduced pressure and the resulting residue is dissolved in water (500 mL). This mixture is washed with MTBE (2×200 mL) and the combined organic phases are washed with hydrochloric acid (1N, 100 mL). The pH of the combined aqueous phases is adjusted to greater than 10 with base and then extracted with MTBE (2×200 mL). The combined organic phases are then concentrated to dryness under reduced pressure to give the title compound.
Reaction SMILES: C([O:3][C:4]1(OCC)[C:7](OCC)([O:8][CH2:9][CH3:10])[CH2:6][C:5]1=[O:14])C.Cl>>[CH2:9]([O:8][C:7]1[C:4](=[O:3])[C:5](=[O:14])[CH:6]=1)[CH3:10]
Reactant: CCOC1(OCC)CC(=O)C1(OCC)OCC
Agent: Cl
Product: CCOc1cc(=O)c1=O
Yield: 28.9 %

Procedure:
##STR7## 45 g of 2,2,3,3-tetraethoxycyclobutanone are stirred vigorously at 50° C in 4 normal aqueous HCl until the starting material is no longer detectable. The reaction solution is then extracted for 20 hours continuously with diethyl ether and the organic extracts are dried over MgSO4 and concentrated. Precipitated crystals of 1-hydroxycyclobutene-3,4-dione are filtered off sharply and the liquid residue is distilled at 110° C/0.1 Torr to yield 6.65 g (=30% of theory) of the desired 1-ethoxycyclobutene-3,4-dione of the above structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[O:14][C:13]([CH3:15])=[N:12][C:11]=2[C:16]([O:18]CC)=[O:17])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[O:14][C:13]([CH3:15])=[N:12][C:11]=2[C:16]([OH:18])=[O:17])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(C)oc1CCc1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(C(=O)O)c(CCc2cccc(Cl)c2)o1

Procedure:
A solution of the product from step (iv) (24.36 g) and potassium hydroxide (9 g) in ethanol (250 ml) and water (20 ml) was stirred at room temperature for 4 hours and concentrated under reduced pressure. The residue was suspended in water, acidified with 2N HCl and extracted with ethyl acetate. The combined extracts were washed with water and saturated brine. The organic layer was collected, dried (MgSO4) and solvent evaporated to give the subtitle product.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:19])=[O:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCC(=O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=C(Cl)CCCCC(=O)c1ccc(Cl)cc1
Yield: 100 %

Procedure:
5-(4-Chlorobenzoyl)pentanoic acid (9.6g) was dissolved in dry toluene (80 ml) and thionyl chloride (10 ml) added. The reaction mixture was heated to reflux for 4 hours. The excess toluene and thionyl chloride were removed in vacuo, more toluene was added and again removed in vacuo affording 5-(4-chlorobenzoyl)pentanoyl chloride (10.4g 100%) as a pale brown solid.
Reaction SMILES: O[CH:2]1[CH:6](O)[NH:5][C:4](=[O:8])[NH:3]1.[NH2:9][C:10]([NH2:12])=[O:11].Cl>O>[CH:6]12[NH:12][C:10](=[O:11])[NH:9][CH:2]1[NH:3][C:4]([NH:5]2)=[O:8]
Reactant: NC(N)=O
Reactant: O=C1NC(O)C(O)N1
Agent: Cl
Solvent: O
Product: O=C1NC2NC(=O)NC2N1
Temperature: 90 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
590 g (5 mols) of 4,5-dihydroxy-2-imidazolidinone and 300 g (5 mols) of urea were dissolved in 1 liter of water. 30 ml of concentrated hydrochloric acid was added to the solution and the mixture was stirred at 90° C. for 1 hour. After cooling, the crystals thus precipitated were collected by filtration, washed with water and dried to obtain 526 g (yield: 74%) of glycoluril. The melting point of glycoluril was above 300° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][C:8]2[NH:12][CH2:11][CH2:10][N:9]=2)=[CH:5][CH:6]=1.F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-])=[O:22].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[F:20][C:18]1[CH:19]=[C:14]2[C:15]([N+:21]([O-:22])=[C:7]([C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:8]3[N:9]2[CH2:10][CH2:11][N:12]=3)=[CH:16][CH:17]=1
Reactant: c1ccc(CC2=NCCN2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: [O-][N+]1=C(c2ccccc2)C2=NCCN2c2cc(F)ccc21
Temperature: 50 °C
Yield: 54.7 %

Procedure:
A mixture of tolazoline (40 g, 0.25 mol), 2,4-difluoronitrobenzene (39.75 g, 0.25 mol) and potassium carbonate (17.26 g, 0.125 mol) in isopropanol (500 ml) was heated to 50° C. for a period of two days. The solvent was removed in vacuo from the mixture and the residue was dissolved in dichloromethane. The resulting solution was filtered and the solvent removed in vacuo to yield a yellow solid which was chromatographed on silica gel using 2% methanol/chloroform as the eluent to yield 1,2-dihydro-8-fluoro-4-phenylimidazo[1,2-a]quinoxaline 5-oxide (38.5 g) as an orange solid, having a m.p. 188°-193° C., (Found: C, 68.07; H 4.23; N 14.82%; C16H12FN3O requires C 68.33; H 4.27; N 14.95%) and represented by the structural formula ##STR14##
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[O:7][C:8]1[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH3:22][O:21][CH:3]([O:2][CH3:1])[C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[O:7][C:8]1[CH:9]=[C:10]([NH:14][S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(OC)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: COC(OC)c1cc(Oc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenylamine (0.013 mol) in THF (100 mL) and TEA (200 mL) was stirred at room temperature and a mixture of benzenesulfonyl chloride (0.013 mol) in THF (50 mL) was added dropwise, then the reaction mixture was stirred overnight at room temperature and again overnight at 60° C. The solvent was evaporated and the residue was stirred in H2O. After extraction with CH2Cl2, the organic layer was separated, dried, filtered off and the solvent was evaporated. The residue was purified by Biotage column chromatography (eluent: CH2Cl2 100%). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[OH:25][CH2:26][CH2:27][NH:28][C:29]([CH:31]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1)=[O:30].C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[OH:25][CH2:26][CH2:27][NH:28][C:29]([CH:31]1[CH2:36][CH2:35][CH2:34][N:33]([C:2]2[N:3]=[C:4]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[C:5]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:9][S:8][C:6]=3[N:7]=2)[CH2:32]1)=[O:30]
Reactant: O=C(NCCO)C1CCCNC1
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(NCCO)C1CCCN(c2nc(NCc3ccccn3)c3c(-c4ccccc4)csc3n2)C1
Temperature: 200 °C

Procedure:
(2-Chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine (44 mg, 0.124 mmol), Piperidine-3-carboxylic acid(2-hydroxyethyl)amide (Fluorochem, 32 mg, 0.188 mmol, 1.5 eq) and N,N-diisopropylethylamine (Aldrich, 0.188 mmol) were dissolved in N-Methyl Pyrrolidinone (1.5 ml) in a Biotage microwave tube and heated to 200° C. and maintained at this temperature for 30 min. On cooling, the solvents were removed in vacuo. The residue was triturated with DCM (2×10 ml) and the extracts combined, concentrated and purified by prep TLC (eluent 10% MeOH/DCM) to give the product as a yellow oil, which slowly solidified on standing to a waxy solid. The waxy solid may be converted to a free-flowing powder by stirring in diethyl ether for 1-2 h (0.5 g in 10 ml). Yield=18.3 mg (30%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)(=[O:24])=[O:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:37][CH:38]([NH2:42])[CH2:39][O:40][CH3:41]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:42][CH:38]([CH3:37])[CH2:39][O:40][CH3:41])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)(=[O:23])=[O:24])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COCC(C)N
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(=O)(=O)N2CCCC2)c1=O
Product: COCC(C)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(=O)(=O)N2CCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(1-pyrrolidinylsulfonyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxy isopropylamine employing methods similar to those described in Example 202 and was obtained as a white solid: 1H NMR (300 MHz, CDCl3) δ 10.17 (d, J=8.6 Hz, 1 H), 8.56 (s, 1 H), 7.75 (s, 1 H), 7.22 (m, 2 H), 7.02 (t, J=8.7 Hz, 2 H), 4.43-4.33 (m, 3 H), 4.13 (s, 2 H), 3.48 (d, J=4.7 Hz, 2 H), 3.41 (s, 3 H), 3.38-3.33 (n, 4 H), 3.05 (t, J=6.5 Hz, 2 H), 2.17 (m, 2 H), 1.97-1.92 (m, 4 H), 1.31 (d, J=7.0 Hz, 3 H); HRMS C27H33FN4O6S (M+H)+ calcd 561.2105, found 561.2189.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:13][S:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[CH:24][N:25]2[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([NH:36][CH:37]2[CH2:42][CH2:41][CH:40]([C:43]([OH:45])=O)[CH2:39][CH2:38]2)[N:31]=1)(=[O:16])=[O:15].[CH3:46][N:47]([CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH3:48]>CN(C=O)C>[CH3:46][N:47]([CH3:48])[CH:49]1[CH2:54][CH2:53][N:52]([C:43]([CH:40]2[CH2:39][CH2:38][CH:37]([NH:36][C:32]3[N:31]=[C:30]([N:25]4[C:26]5[C:22](=[C:21]([O:20][CH2:19][CH2:18][CH2:17][S:14]([CH3:13])(=[O:15])=[O:16])[CH:29]=[CH:28][CH:27]=5)[CH:23]=[CH:24]4)[CH:35]=[CH:34][N:33]=3)[CH2:42][CH2:41]2)=[O:45])[CH2:51][CH2:50]1
Reactant: CS(=O)(=O)CCCOc1cccc2c1ccn2-c1ccnc(NC2CCC(C(=O)O)CC2)n1
Reactant: CN(C)C1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN(C)C1CCN(C(=O)C2CCC(Nc3nccc(-n4ccc5c(OCCCS(C)(=O)=O)cccc54)n3)CC2)CC1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
CDI (7.13 g, 44.0 mmol) was added to a mixture of 4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid (16.00 g, 33.86 mmol) in dry DMF (100 mL) heated to 40° C. under N2. After stirring for 10 min, 100 mL of DMF was added, heated to 40° C., and stirred for an additional 40 min. N,N-dimethyl-piperidin-4-ylamine (5.00 g, 38.9 mmol) was added and allowed to stir overnight at RT. The reaction mixture was concentrated in vacuo, the residue diluted with EtOAc and washed with cold H2O (4×), 5% NaOH aqueous solution (4×), H2O and brine. The organic layer was dried and the remaining solvent removed in vacuo. The product, (4-dimethylamino-piperidin-1-yl)-(4-{4-[4-(3-methane-sulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone (Compound 275), was crystallized from EtOH/H2O as a white solid (11.9 g, 60.3%). MS M+1 (583), mp 182.4-183° C.
Reaction SMILES: OC1C[N:5](C(=O)C2C=CC3OCOC=3C=2)C(C(O)=O)C1.[OH:21][CH:22]1[CH2:26][N:25]([C:27](=[O:40])[C:28]2[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=2)[CH:24]([C:41]([OH:43])=O)[CH2:23]1>>[OH:21][CH:22]1[CH2:26][N:25]([C:27](=[O:40])[C:28]2[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=2)[CH:24]([C:41]([NH2:5])=[O:43])[CH2:23]1
Reactant: COc1cc(C(=O)N2CC(O)CC2C(=O)O)cc(OC)c1OC
Reactant: O=C(O)C1CC(O)CN1C(=O)c1ccc2c(c1)OCO2
Product: COc1cc(C(=O)N2CC(O)CC2C(N)=O)cc(OC)c1OC
Yield: 60 %

Procedure:
By carrying out the procedure as in Example 9, but replacing 4-hydroxy-1-(3,4-methylenedioxybenzoyl)pyrrolidine-2-carboxylic acid by the 4-hydroxy-1-(3,4,5-trimethoxybenzoyl)pyrrolidine-2-carboxylic acid obtained in Example 8, the title product is obtained.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[CH2:10]=O>O.[Pd]>[CH3:10][N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCNCC1
Reactant: C=O
Agent: [Pd]
Solvent: O
Product: CN1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Isonipecotic acid (50 g, 0.387 mole) was dissolved in water (500 ml) and 37% formaldehyde (125 ml). 10% Palladium on carbon (50 g) was added and the mixture was shaken under a hydrogen atmosphere at 60 psi at room temperature for 18 hours.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:20][NH2:21]>C(O)CCC>[F:18][C:17]1[C:12]([O:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([NH:20][NH2:21])=[O:2])[CH2:6][CH2:7]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ncccc2F)CC1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: NNC(=O)[C@H]1CC[C@H](Oc2ncccc2F)CC1
Temperature: 125 °C

Procedure:
A mixture of trans-4-(3-fluoro-pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester (0.60 g, 2.4 mmol) and hydrazine hydrate (0.53 ml, 11 mmol) in n-butanol (1 ml) was heated at 125° C. for 4 h. After cooling to room temperature the reaction mixture was partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was washed with dichloromethane/75 ml). The combined organic layers were washed with water (75 ml) and brine (75 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.45 g, 83%) as white solid, which was used in the next step without further purification. MS m/e: 254 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[C:24]([F:25])=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][C:20]=1[F:35].Cl>CO.Cl[Pd]Cl>[ClH:1].[Cl:18][C:19]1[C:24]([F:25])=[CH:23][C:22]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:21][C:20]=1[F:35]
Reactant: CC1(C)OB(c2cc(F)c(Cl)c(F)c2)OC1(C)C
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: COC(=O)c1ccnc(-c2cc(F)c(Cl)c(F)c2)c1
Temperature: 100 °C
Yield: 36.8 %

Procedure:
Methyl 2-chloroisonicotinate (3.01 g, 17.53 mmol), PdCl2 (dppf) (0.317 g, 0.44 mmol) and potassium carbonate (1.322 mL, 21.91 mmol) were distributed equally over 3 microwave reaction vials. 2-(4-Chloro-3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.01 g, 14.61 mmol) was dissolved in methanol (45 mL) to give a colorless solution. The solution was split into 3 equal portions and added to the vials. The vials were capped and heated in a single node microwave reactor at 100° C. for 10 min each. The content of the vials was combined and the solvent evaporated. The residue was dissolved in DCM and washed with water. The organic phase was filtered through a phase separator and evaporated. The residue was dissolved in MTBE and solids were filtered off. Hydrogen chloride (4 M in dioxane, 3.65 mL, 14.61 mmol) was added and the precipitate collected to yield methyl 2-(4-chloro-3,5-difluorophenyl)isonicotinate hydrochloride (1.72 g, 42%) as a solid. 1H NMR (400 MHz, cdcl3) δ 4.06 (s, 3H), 7.86 (d, 2H), 8.09 (d, 1H), 8.39 (s, 1H), 8.96 (d, 1H). MS m/z 284 (M+H)+
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:17][N:16]=[C:15]3I)=[O:11])[CH:6]=[CH:7][CH:8]=1>[Pd].CO>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([NH:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:17][N:16]=[CH:15]3)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc2c(NCc3ccccc3)nnc(I)c2c1
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc2c(NCc3ccccc3)nncc2c1
Reaction time: 5 h
Yield: 53.3 %

Procedure:
A mixture of 1-benzylamino-4-iodo-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (24 mg, 0.04 mmol), MeOH (5 mL) and 10% wet Pd/C (catalytic) was evacuated and flushed (3×) with hydrogen. The mixture was stirred under hydrogen for 5 hours. The mixture was filtered through celite, rinsed with MeOH and concentrated under vacuum. Chromatography (hexanes/EtOAc) was used to obtain 1-Benzylamino-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (9 mg, 50%) as a solid, 1H-NMR (CDCl3) δ: 4.80 (bs, 2H), 7.35 (m, 7H), 8.10 (m, 3H), 8.30 (bs, 2H), 8.80 (bs, 1H). m/z (M+1) 423.23.
Reaction SMILES: [Br:1][C:2]1N=[CH:6][C:5]([O:8][C@H:9]2[CH2:13][O:12][CH2:11][C@H:10]2[NH:14][S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[CH:4][CH:3]=1.[CH3:21]S(O[C@H]1[C@H](OC2C=CC(Br)=CC=2)COC1)(=O)=O>>[Br:1][C:2]1[CH:21]=[CH:6][C:5]([O:8][C@H:9]2[CH2:13][O:12][CH2:11][C@H:10]2[NH:14][S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O[C@@H]1COC[C@H]1Oc1ccc(Br)cc1
Reactant: CC(C)S(=O)(=O)N[C@@H]1COC[C@@H]1Oc1ccc(Br)nc1
Product: CC(C)S(=O)(=O)N[C@@H]1COC[C@@H]1Oc1ccc(Br)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of cis-N-{4-[(6-bromopyridin-3-yl)oxy]tetrahydrofuran-3-yl}propane-2-sulfonamide in Preparation 1, except that trans-4-(4-bromophenoxy)tetrahydrofuran-3-yl methanesulfonate was used in place of trans-4-[(6-bromopyridin-3-yl)oxy]tetrahydrofuran-3-yl methanesulfonate, and the chromatographic purification was carried out with a gradient of 15% to 35% acetone in heptane. Yield: 238 mg, 0.65 mmol, 31%. 1H NMR (400 MHz, CDCl3) δ 1.30 (d, J=6.8 Hz, 3H), 1.33 (d, J=6.8 Hz, 3H), 3.11 (septet, J=6.8 Hz, 1H), 3.66 (dd, J=9.1, 8.4 Hz, 1H), 3.89 (dd, J=10.7, 1.7 Hz, 1H), 4.07-4.13 (m, 2H), 4.19 (m, 1H), 4.71 (m, 1H), 5.12 (d, J=9.6 Hz, 1H), 6.75 (d, J=9.0 Hz, 2H), 7.36 (d, J=9.0 Hz, 2H).