Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[CH:10]([NH:12][C:13](=[O:28])[C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)([CH3:16])[CH3:15])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[C-:37]#[N:38].[Na+].C1OCCOCCOCCOCCOCCOC1>O1CCOCC1.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>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][CH:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([C:37]#[N:38])[CH:3]=2)[CH:10]([NH:12][C:13](=[O:28])[C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:20][N:19]=2)([CH3:16])[CH3:15])[CH3:11])=[CH:35][CH:34]=1
Reactant: CC(NC(=O)C(C)(C)Oc1ccc(C(F)(F)F)cn1)C(Cc1ccc(Cl)cc1)c1cc(F)cc(Br)c1
Reactant: [C-]#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(NC(=O)C(C)(C)Oc1ccc(C(F)(F)F)cn1)C(Cc1ccc(Cl)cc1)c1cc(F)cc(C#N)c1
Temperature: 100 °C

Procedure:
A mixture of N-[2-(3-bromo-5-fluorophenyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide (Example 330, 92 mg, 0.16 mmol), sodium cyanide (12 mg, 0.24 mmol), 18-crown-6 (63 mg, 0.24 mmol) and tetrakis(triphenylphosphine)palladium (92 mg, 0.08 mmol) in 2 mL dioxane was heated under nitrogen at 100° C. for 14 h. After cooling to room temperature, the resulting mixture was partitioned between water (50 mL) and EtOAc (50 mL). The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by flash column chromatography on silica gel eluting with 30% EtOAc in hexane to afford the title compound as a racemic mixture. 1H NMR (500 MHz, CD3OD): δ 8.26 (br s, 1H), 7.96 (d, 1H), 7.93 (dd, 1H), 7.30 (br d, 1H), 7.22 (s, 1H), 7.15 (br d, 1H), 7.06 (d, 2H), 7.05 (m, 1H), 6.74 (d, 2H), 4.24 (m, 1H), 3.05 (dd, 1H), 2.91 (m, 1H), 2.63 (dd, 1H), 1.74 (s, 3H), 1.72 (s, 3H), 0.83 (d, 3H). LC-MS: m/e 534 (M+H)+ (4.2 min).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[NH:10][C:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]1[C:20](=[O:36])[C:21]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:22]([C:24]([NH:26][NH2:27])=[O:25])[N:23]=[C:12]21)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][C:53](Cl)=[O:54])=[CH:48][CH:47]=1>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:37])[NH:10][C:11]12[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]1)[CH2:14][N:13]1[C:20](=[O:36])[C:21]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[C:22]([C:24]([NH:26][NH:27][C:53](=[O:54])[CH2:52][C:49]3[CH:50]=[CH:51][C:46]([F:45])=[CH:47][CH:48]=3)=[O:25])[N:23]=[C:12]21)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: NNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1)NNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.78 %

Procedure:
To a solution of benzyl(3-(benzyloxy)-2-(hydrazinylcarbonyl)-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl)carbamate, Intermediate 9 (400 mg, 0.794 mmol) in CH2Cl2 (15 mL) at 0° C. was added triethylamine (0.221 mL, 1.589 mmol) followed by 2-(4-fluorophenyl)acetyl chloride (0.098 mL, 0.715 mmol) and the resulting mixture stirred for 1 h. The mixture was allowed to warm to room temp and stirred for 3 h. The mixture was then concentrated and purified by preparative HPLC to afford the title compound (70 mg, 0.109 mmol, 13.78% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 10.00 (1H, br. s.), 8.35 (1H, br. s.), 7.48-7.53 (2H, m), 7.27-7.38 (10H, m), 7.00-7.07 (2H, m), 6.55 (1H, br. s.), 5.39 (2H, s), 5.05 (2H, s), 4.10 (2H, d, J=3.36 Hz), 3.60 (2H, s), 2.56-2.70 (2H, m), 2.47 (1H, br. s.), 1.88-2.04 (4H, m), 1.59-1.71 (2H, m). LCMS (M+H)=640.35.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22])=[CH:15][CH:14]=1>N1C=CC=CC=1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][S:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:23])=[O:22])=[CH:17][CH:18]=1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)CCc1ccc(Cl)cc1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.7 %

Procedure:
2-Aminobenzenesulfonamide (0.52 g, 3 mmol) was dissolved in pyridine (20 mL) followed by addition of 2-(4-chlorophenyl)ethanesulfonyl chloride (0.80 g, 3.3 mmol) and the reaction was stirred at RT overnight. The solvent was then removed under reduced pressure and the crude material was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (87 mg, 8%) as a white solid.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:13][C@@H:14]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1>C(O)C>[CH3:12][C:2]1[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[F:13][C@@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: F[C@@H]1CCNC1

Procedure:
Prepare using the method of Intermediate 49 with p-toluenesulfonic acid monohydrate (0.356 g, 1.87 mmol), tert-butyl (3R)-3-fluoropyrrolidine-1-carboxylate (See Intermediate50) (0.353 g, 1.87 mmol) and ethanol (2 mL) to give the title compound as a white solid (0.478 g): MS (m/e): 90 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=O>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: COc1ccccc1C(=O)O
Product: COc1ccccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 55 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2-methoxybenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate=95:5 to 50:50, 170 mg, 55%) which was obtained as a white foam. MS: m/e=334.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:20][C:19](=O)[C:18]3[C:13](=[CH:14][C:15]([F:31])=[C:16]([O:22][C:23]4[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:30])[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[Li+].[Cl-].O=P(Cl)(Cl)[Cl:36].CCN(C(C)C)C(C)C>C(#N)C>[Cl:36][C:19]1[C:18]2[C:13](=[CH:14][C:15]([F:31])=[C:16]([O:22][C:23]3[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:30])[CH:17]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]2)[N:20]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(Oc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(-c2nc(Cl)c3cc(Oc4c(C)cccc4C)c(F)cc3n2)c1
Temperature: 25 °C

Procedure:
A mixture of the above 1-[6-(2,6-dimethyl-phenoxy)-7-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (5.0 g, 12 mmol), LiCl (2.5 g, 59 mmol), POCl3 (5.5 ml, 59 mmol), DIEA (10 mL, 59 mmol), and acetonitrile (ACN) (50 mL) was heated to reflux for 6 h. The mixture was allowed to cool to rt and then concentrated. The residue was taken up in a minimal amount of DCM and passed through a pad of silica gel, eluting with 50:50 hexanes/EtOAc. The resulting solution was concentrated to provide the titled compound. (5.2 g, >99%). 1H NMR (500 MHz, DMSO-d6): 9.13 (d, J=0.6 Hz, 1H), 8.23 (d, J=0.6 Hz, 1H), 7.92 (d, J=10.7 Hz, 1H), 7.23-7.19 (m, 3H), 7.07 (d, J=8.6 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 2.19 (s, 6H), 1.40 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]1[C@@H:9]([CH3:12])[CH2:10][OH:11].CO[C:15](OC)([CH3:17])[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>ClCCl>[CH3:16][C:15]1([CH3:17])[O:11][CH2:10][C@H:9]([CH3:12])[C@H:4]2[C@@H:3]([C@@H:7]([CH3:8])[CH2:6][CH2:5]2)[CH2:2][O:1]1
Reactant: C[C@@H](CO)[C@H]1CC[C@H](C)[C@H]1CO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H]1COC(C)(C)OC[C@H]2[C@H]1CC[C@@H]2C
Temperature: 25 °C
Reaction time: 12 h
Yield: 7.9 %

Procedure:
(2R)-2-[(1R, 2R, 3S)-2-(hydroxymethyl)-3-methylcyclopent-1-yl]propan-1-ol (100 mg, 0.00058 mol) (obtained in Definite Example 45) was dissolved in 5 ml of dichloromethane, and 2 ml of 2,2-dimethoxypropan and 5 mg of p-toluenesulfonic acid were added. After being stirred at room temperature for 12 hours, the reaction mixture was poured into 50 ml of ethyl acetate. After the organic layer was washed with an aqueous mixed solution of aqueous sodium bicarbonate (10 ml) and saturated sodium chloride solution (20 ml), it was dried by magnesium sulfate, filtered, and then concentrated under a reduced pressure. The residual substance was purified by a chromatography using silica gel. When the solvent of the fraction obtained from hexane:ether=8:2 eluent was distilled off, a colorless oily substance, i.e., (1R, 7R, 8S, 11S)-4,4,7,11-tetramethyl-3,5-dioxabicyclo[6.3.0]undecane (10 mg, yield=7.9%). This (1R, 7R, 8S, 11S)-4,4,7,11-tetramethyl-3,5dioxabicyclo[6.3.0]undecane had the following physicochemical properties:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C:11]([CH2:26][OH:27])([CH2:24]O)[CH2:12][O:13]S(C3C=CC(C)=CC=3)(=O)=O)[C:4]=2[N:5]=[CH:6][N:7]=1>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C:11]3([CH2:12][OH:13])[CH2:24][O:27][CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(CO)(CO)n2ccc3c(Cl)ncnc32)cc1
Solvent: C1CCOC1
Product: OCC1(n2ccc3c(Cl)ncnc32)COC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 36 %

Procedure:
nButyllithium (12.2 mL, 30.6 mmol, 2.5 M in hexanes) was added to toluene-4-sulfonic acid 2-(4-chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-hydroxy-2-hydroxymethyl-propyl ester (Preparation 210, 5.73 g, 13.9 mmol) in THF (100 mL) at 0° C. and stirred for 5 min. The reaction mixture was then warmed to room temperature and stirred for 16 hours, at which point it was quenched with saturated aqueous ammonium chloride. The resulting mixture was extracted with ethyl acetate (100 mL×3) and the combined organic phases were dried (MgSO4) and concentrated in vacuo. The crude product was triturated with dichloromethane and filtered to afford the title compound in 36% yield, 1.2 g.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.[C:18]([C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[N:24][CH:25]=1)#[CH:19]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:19]=[CH:18]\[C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: C#Cc1ccc(C)nc1
Product: Cc1ccc2c(c1)c1c(n2/C=C\c2ccc(C)nc2)C2CCN(CC2)C1

Procedure:
The coupling of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (453 mg, 2.0 mmol; Example 2B) and 5-ethynyl-2-methylpyridine (937 mg, 8.0 mmol; prepared as described in International Publication No. WO2005090333) was performed according to the procedure described in Example 20 to afford the title compound as the major isomeric product: 1H NMR (300 MHz, methanol-d4) δ ppm 1.65-1.79 (m, 2H), 1.83-1.97 (m, 2H), 2.38 (s, 3H), 2.39 (s, 3H), 2.94-3.08 (m, 3H), 3.10-3.23 (m, 2H), 4.23 (s, 2H), 6.72 (d, J=8 Hz, 1H), 6.84-6.98 (m, 3H), 7.03-7.18 (m, 3H), 7.88 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 344 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:18][N:19](CC)CC.C(OC(Cl)=O)C(C)C.CN>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](=[O:13])[NH:19][CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-t-butoxycarbonyl-iso-nipecotic acid (10 g) and Et3N (5.92 mL) in THF (32 mL) was added drop-wise iso-butylchloroformate (5.66 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min before diluted with THF (120 mL) and added 2M methylamine (80 mL). The reaction mixture was stirred overnight at room temperature. Excess THF was removed under vacuum. The residue was taken into H2O and extracted into EtOAc. The organic extracts were washed with 1N NaOH, followed by brine. After dried over Na2SO4, it was concentrated to give the crude product.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.CS(O[CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1)(=O)=O.O>CN(C=O)C>[N:3]1([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH:21]3[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24]3)=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: Oc1ccc(CN2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(CN3CCCC3)cc2)C1
Temperature: 80 °C
Yield: 64 %

Procedure:
A mixture of NaH (55-65% disp. in oil, 0.62 g, 14.3 mmol) in dry DMF (20 mL) under nitrogen was cooled by an ice-bath. A solution of 4-(pyrrolidin-1-ylmethyl)phenol—see e.g. Bioorganic & Medicinal Chemistry Letters, 15, 3834-3837 (2005)—(2.1 g, 11.9 mmol) in DMF (20 mL) was added drop-wise. The mixture was stirred for one h and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (3.9 g, 15.5 mmol) in DMF (10.0 mL) was added. The mixture was heated to 80° C. overnight and then cooled to RT. Water (150 mL) was added and the mixture was extracted three times with EtOAc (100 mL). The combined organic solutions were washed with brine, dried (MgSO4) and evaporated. The residue was purified twice by column chromatography on SiO2 using 10-100% EtOAc/heptane as eluent. The product was further purified using 0.5% NH3 in MeOH/DCM as eluent. There was obtained 2.5 g (64%) of 1A. 1H NMR (600 MHz, CDCl3): δ 1.43 (s, 9H), 1.77 (s, 4H), 2.47 (s, 4H), 3.54 (s, 2H), 3.95-4.02 (m, 2H), 4.24-4.30 (m, 2H), 4.82-4.88 (m, 1H), 6.67 (d, 2H), 7.23 (d, 2H).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][C:5]1[N:10]=[C:9](Cl)[C:8]([Cl:12])=[C:7]([Cl:13])[N:6]=1>C1COCC1>[Cl:13][C:7]1[C:8]([Cl:12])=[C:9]([O:2][CH3:1])[N:10]=[C:5]([CH3:4])[N:6]=1
Reactant: C[O-]
Reactant: Cc1nc(Cl)c(Cl)c(Cl)n1
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(C)nc(Cl)c1Cl
Temperature: 5 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
1.37 g of sodium methoxide are added to a solution of 5 g of 2-methyl-4,5,6-trichloropyrimidine in 41 ml of THF cooled to 5° C. in an ice bath. The ice bath is removed. The suspension is stirred at ambient temperature for 18 hours. The reaction medium is cooled to 5° C. in an ice bath. 20 ml of water and 100 ml of ethyl acetate are added. After settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure so as to give 4.73 g of 4,5-dichloro-6-methoxy-2-methylpyrimidine in the form of a colorless oil which crystallizes, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[C:9]1(B(O)O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: Brc1ccccc1I
Reactant: OB(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccccc1-c1cccc2ccccc12
Yield: 82.9 %

Procedure:
Under an atmosphere of argon, 2-bromoiodobenzene (7.0 g, 25 mmole), naphthaleneboronic acid (4.0 g, 23 mmole) and tetrakis(triphenyl-phosphine)palladium(0) (0.5 g, 0.43 mmole, 1.7% Pd) were dissolved into toluene (50 ml). To the obtained solution, an aqueous solution of sodium carbonate (7.3 g, 69 mmole, 3 eq/35 ml) was added. The resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloromethane and hexane+10% dichloromethane, successively) and white needle crystals (5.4 g, 83%) were obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN(C)C=O>[C:14]1([CH3:26])[CH:15]=[CH:16][C:17]([S:20]([NH:23][C:24](=[O:25])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:21])=[O:22])=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)NS(=O)(=O)c2ccc(C)cc2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 6 g of ethyl 2-aminothiazole-4-ylglyoxylate, 6 g of p-toluenesulfonyl isocyanate and 40 ml of dimethylformamide. The resulting product was a pale yellow powder having the following physical properties.
Reaction SMILES: C(OC(=O)C)(=O)C.C(OC1C=CC=CC=1NC=[C:15]1[C:19](=[O:20])[N:18]([C:21]2[CH:26]=[CH:25][C:24](S(N)(=O)=O)=[CH:23][CH:22]=2)[N:17]=[C:16]1[CH3:31])C.C[N:37](C1C=CC=CN=1)C>N1C=CC=CC=1>[NH2:37][C:24]1[CH:25]=[CH:26][C:21]([N:18]2[C:19](=[O:20])[CH2:15][C:16]([CH3:31])=[N:17]2)=[CH:22][CH:23]=1
Reactant: CCOc1ccccc1NC=C1C(=O)N(c2ccc(S(N)(=O)=O)cc2)N=C1C
Reactant: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC1=NN(c2ccc(N)cc2)C(=O)C1
Reaction time: 10 h

Procedure:
0.17 ml of acetic anhydride is added dropwise to a solution of 1.0 g of 4-(4-(2-ethoxyanilinomethylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzenesulfonamide and 0.9 g of dimethylaminopyridine in 30 ml of pyridine while cooling in ice, and the mixture is then stirred for 10 hours. The residue obtained after concentration in vacuo is mixed with dilute hydrochloric acid, and the crystals which have separated out are filtered off with suction and triturated with ethanol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH:9]2[CH:12]3[CH2:17][CH2:16][CH:15]([CH:8]2[S:7]1(=[O:19])=[O:18])[CH:14]=[CH:13]3.C(N(CC)CC)C.Cl.[Cl:28][C:29]1[N:34]=[C:33]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:32]=[N:31][CH:30]=1>CN(C)C=O>[ClH:28].[Cl:28][C:29]1[N:34]=[C:33]([N:35]2[CH2:36][CH2:37][N:38]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[CH:9]4[CH:12]5[CH2:17][CH2:16][CH:15]([CH:8]4[S:7]3(=[O:19])=[O:18])[CH:14]=[CH:13]5)[CH2:39][CH2:40]2)[CH:32]=[N:31][CH:30]=1
Reactant: Clc1cncc(N2CCNCC2)n1
Reactant: O=C1C2C3C=CC(CC3)C2S(=O)(=O)N1CCCCBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1C2C3C=CC(CC3)C2S(=O)(=O)N1CCCCN1CCN(c2cncc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 1.0 g (2.9 mmol) of 3a,4,7,7a-tetrahydro-2-(4-bromobutyl)-4,7-ethano-1,2-benzisothiazol-3(2H)-one 1,1-dioxide in 25 ml of anhydrous dimethylformamide is treated with 1.6 g (16 mmol) of triethylamine and 866 mg (3.2 mmol) of 1-(6-chloro-2-pyrazinyl)piperazine, monohydrochloride salt. The mixture is maintained at room temperature with stirring for 15 hours and then is partitioned between water and methylene chloride. The methylene chloride extracts are combined, dried over MgSO4, filtered and rotoevaporated to give crude free base. Preparative HPLC (silica gel; ethyl acetate: methylene chloride (9:1)) followed by evaporation of the appropriate fractions, treatment with ethanolic hydrochloric acid and recrystallization from methanol gives the title compound: mp. 263°-267° C.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH:23]1([CH2:27][S:28]([NH2:31])(=[O:30])=[O:29])[CH2:26][CH2:25][CH2:24]1>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:31][S:28]([CH2:27][CH:23]2[CH2:26][CH2:25][CH2:24]2)(=[O:30])=[O:29])=[O:21])=[CH:19][CH:18]=1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: NS(=O)(=O)CC1CCC1
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)CC1CCC1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with cyclobutyl-methanesulfonamide as described in the preparation of compound 1 to yield the title compound. LCMS (M+H) calcd for C17H22FN2O6S: 401.1; found: 401.0. 1H NMR (500 MHz, CDCl3) δ: 1.87 (overlapping m, 3), 1.96 (m, 1), 2.21 (m, 2), 2.86 (heptet, 1, J=8), 3.55 (d, 2, J=7), 3.66 (s, 3), 4.79 (s, 2), 6.53 (s, 1), 7.02 (m, 2), 7.29 (m, 2). 13C NMR (125 MHz, CDCl3) δ: 19.20, 28.12, 30.01, 48.31, 58.99, 63.23, 92.56, 115.72, 115.89, 130.28, 130.35, 131.05, 159.18, 160.12, 161.71, 163.67, 170.87.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=3)[C:9](=[O:17])[C:8]([C:18]([O:20]CC)=[O:19])=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C(O)(=O)C>[CH:1]1([N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=3)[C:9](=[O:17])[C:8]([C:18]([OH:20])=[O:19])=[CH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1cn(C2CCCC2)c2cc(F)ccc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cn(C2CCCC2)c2cc(F)ccc2c1=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
900 mg of ethyl 1-cyclopentyl-7-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate was dissolved in 6.4 ml of acetic acid, and 0.8 ml of 6 M hydrochloric acid was added, followed by overnight stirring at 120° C. The resulting reaction mixture was cooled to room temperature, and the insoluble materials were collected by filtration and washed with water to obtain 710 mg of 1-cyclopentyl-7-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
Reaction SMILES: [CH:1]1([C:4]2[CH:21]=[CH:20][C:7]([CH2:8][O:9][C:10]([N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]3)=[O:11])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Cl[C:23]1[N:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1.C(N(CC)CC)C>CN(C=O)C>[CH:1]1([C:4]2[CH:21]=[CH:20][C:7]([CH2:8][O:9][C:10]([N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:23]4[N:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=4)[CH2:14][CH2:13]3)=[O:11])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: NCC1CCN(C(=O)OCc2ccc(C3CC3)cc2)CC1
Reactant: Fc1cnc(Cl)nc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc(C2CC2)cc1)N1CCC(CNc2ncc(F)cn2)CC1

Procedure:
A solution of (4-cyclopropyl-benzyl)-4-(aminomethyl)piperidine-1-carboxylate (0.10 g, 0.35 mmol), 2-chloro-5-fluoro-pyrimidine (EXAMPLE 71, Step 1, 0.046 g, 0.35 mmol) and triethylamine (0.097 mL, 0.69 mmol) in DMF (1 mL) was heated at 100° C. for 6 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2/IPA/hexanes) to give 4-[(5-fluoro-pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acid-4-cyclopropyl-benzyl ester.