Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][SH:18]>CCO>[NH2:15][CH2:16][CH2:17][S:18][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([S:18][CH2:17][CH2:16][NH2:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: NCCS
Reactant: Clc1ccc(-c2ccc(Cl)nc2)cn1
Solvent: CCO
Product: NCCSc1ccc(-c2ccc(SCCN)nc2)cn1

Procedure:
The title compound was prepared as described by Constable et al.13 The same reaction was repeated using 6,6′-dichloro-3,3′-bipyridine (0.154 g, 0.684 mmol) in EtOH (150 mL) under reflux for 24 h to give a yellow oil. The crude product showed the presence of cysteamine (1H n.m.r.) and washing with water gave a clean product (1.3 g, 75%). Mass spectrum (ESI): m/z 153.9 [½ (M+2H)2+]; 307.2 (M+H)+. 1H n.m.r. (300 MHz, CDCl3): δ 1.5 (bs, 4H); 3.02 (t, J 6.4 Hz, 4H); 3.32 (t, J 6.4 Hz, 4H); 7.26 (dd, J 8.4, 0.6 Hz, 2H); 7.63 (dd, J 8.4, 2.4 Hz, 2H); 8.60 (d, J 2.4 Hz, 2H). 13C n.m.r. (75 MHz, CDCl3): δ 34.4; 42.1; 122.8; 129.4; 134.3; 147.7; 156.1. Spectra were consistent with literature data13.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]3[CH3:24])[N:15]=[C:14]([C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=O)[O:33]C4C=CC=CC=4)=[CH:27][CH:26]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC1C=CC(S(C(C2C=C(N3CCOC[C@@H]3C)N=C([C:67]3[CH:72]=[CH:71][C:70]([NH:73]C(=O)OC4C=CC=CC=4)=CC=3)N=2)(C)C)(=O)=O)=CC=1>>[CH:70]1([NH:73][C:32](=[O:33])[NH:31][C:28]2[CH:27]=[CH:26][C:25]([C:14]3[N:13]=[C:12]([CH2:11][S:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)(=[O:10])=[O:9])[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]4[CH3:24])[N:15]=3)=[CH:30][CH:29]=2)[CH2:71][CH2:72][CH2:67]1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccc(F)cc2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccc(F)cc2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccc(F)cc2)nc(-c2ccc(NC(=O)NC3CCC3)cc2)n1

Procedure:
The following compounds were made in an analogous fashion from phenyl N-[4-[4-[(4-fluorophenyl)sulfonylmethyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate or phenyl N-[4-[4-[2-(4-fluorophenyl)sulfonylpropan-2-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate and the appropriate amine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:5]=[CH:4][N:3]=1.[CH3:21][P:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([O:32][CH3:33])[CH:26]=1)([CH3:24])=[O:23].Cl>COCCO>[CH3:24][P:22]([C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:5]=[CH:4][N:3]=2)=[C:27]([O:32][CH3:33])[CH:26]=1)([CH3:21])=[O:23]
Reactant: COc1cc(P(C)(C)=O)ccc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1ccnc(Cl)n1
Agent: Cl
Solvent: COCCO
Product: COc1cc(P(C)(C)=O)ccc1Nc1nccc(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 90 °C
Yield: 71.8 %

Procedure:
To a solution of 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-amine (0.017 g, 0.054 mmol) in 0.5 mL of 2-methoxyethanol in a vial was added 4-(dimethylphosphoryl)-2-methyoxyaniline (0.010 g, 0.044 mmol) as the HCl salt. The vial was sealed and the reaction was heated at 90° C. for 16 h. The reaction was quenched with 1N NaOH solution and the solution extracted ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford the desired compound (15 mg, 72% yield). MS/ES+: m/z=475.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[C:11]1([C:17]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@@H:25]3[C@@H:21]([CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24]3)[C:20](=[O:33])[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[Ce+3].[Cl-].[Cl-]>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[C:11]1([C:17]2([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C@@H:25]3[C@@H:21]([CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24]3)[C@@:20]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])([OH:33])[CH2:19][CH2:18]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccccc1[Mg]Br
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@H]2C1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
A suspension of 2-methoxyphenylmagnesium bromide (prepared starting from 75.3 g of 2-bromoanisole and 9.8 g of magnesium) in 100 cm3 of dry tetrahydrofuran is added dropwise while stirring to a suspension of 20 g of (3aS,7aS)-7,7-diphenyl-2-tert-butoxycarbonylperhydroisoindol-4-one and 31.6 g of anhydrous cerium chloride in 250 cm3 of dry tetrahydrofuran at room temperature. The reaction mixture is stirred at room temperature for 24 hours, treatea with 400 cm3 of an aqueous saturated solution of ammonium chloride, diluted with 200 cm3 of ethyl acetate, washed with 300 cm3 of water (twice) and then with 300 cm3 of an aqueous saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a Merck silica gel column (particle size 0.04-0.06 mm, diameter 5.8 cm, height 26.5 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting fractions of 100 cm3. Fractions 9 to 29 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 17.82 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2- methoxyphenyl)-2-tert-butoxycarbonylperhydroisoindol-4-ol are obtained in the form of a white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2O[C:12](=O)[C:11]([C:15]#[N:16])=[C:10]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:8][C:5]4[C:4](=[CH:3][CH:2]=[CH:7][CH:6]=4)[C:12]=3[C:11]([C:15]#[N:16])=[C:10]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccc(F)cc2)oc1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(N2CCCCC2)cc(-c2ccc(F)cc2)c2c1-c1ccccc1C2

Procedure:
A mixture of 6-(4-fluorophenyl)-2-oxo-4-(piperidin-1-yl)-2H-pyran-3-carbonitrile (298 mg), indanone-1 (132 mg) and NaH (36 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. Yellow solid; mp 176-178° C.; FAB MS 368 (M+); IR (KBr) 2220 cm−1 (CN); HRMS calcd. for C25H21FN2 368.16888. Found 368.16806.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][NH:7][N:8]3[C:15](=[O:16])[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:12]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[C:9]32)=[CH:4][CH:3]=1.[CH2:31](I)[CH3:32].[OH-].[Na+].O>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:31]([N:7]1[CH2:6][C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2=[C:12]([C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[O:24])[CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15](=[O:16])[N:8]12)[CH3:32]
Reactant: CCI
Reactant: O=C(c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CN2)N1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCN1Cc2ccc(Cl)cc2-c2c(C(=O)N3CCOCC3)cc(-c3ccccc3)c(=O)n21
Temperature: 25 °C

Procedure:
1.26 g of 4-[(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazin-1-yl)carbonyl]morpholine are dissolved in 30 ml of dichloromethane under argon, whereupon 1.01 g of tetrabutylammonium hydrogen sulfate, 1.4 g of ethyl iodide and 1.45 ml of 50 percent sodium hydroxide solution are added thereto and the mixture is stirred at room temperature until the reaction has finished. Three (3) ml of water are added thereto. The organic phase is separated and dried, and the solvent is removed in vacuo. The residue is chromatographed on silica gel. After recrystallization there is obtained 4-[(6-ethyl-10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazin-1-yl)carbonyl]morpholine as yellow crystals of m.p. 288°-289° (acetonitrile).
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:18](Cl)(=O)C(Cl)=O.CO>C(Cl)Cl.CN(C)C=O>[CH3:18][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[C:2]=1[F:1]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCS(=O)(=O)Nc1cccc(C(=O)O)c1F
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1cccc(C(=O)OC)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
To a 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (50, 5.05 g, 0.0193 mol) in methylene chloride (100 mL) was added N,N-dimethylformamide (0.075 mL, 0.97 mmol) under an atmosphere of nitrogen. The reaction was cooled with ice/water, followed by slow addition of Oxalyl chloride (2.00 M of in methylene chloride, 10.8 mL, 21.6 mmol). The reaction mixture was stirred at room temperature for 3.0 hours. The reaction was cooled with ice/water, followed by addition of methanol (36.0 mL, 0.89 mol) slowly. The reaction was stirred at room temperature overnight. The reaction was concentrate and purified with silica gel column chromatography eluting with 30% ethyl acetate in hexane to give a crude white solid 4.0 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:65][C:66]1[CH:72]=[CH:71][C:69]([NH2:70])=[CH:68][CH:67]=1>C(Cl)Cl>[Cl:65][C:66]1[CH:72]=[CH:71][C:69]([NH:70][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[CH:68][CH:67]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(Cl)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.34 mmol) in methylene chloride (10 mL), HATU (Aldrich, 234 mg, 0.62 mmol) was added followed by the addition of DIPEA (0.30 mL, 1.71 mmol) and 4-chloro-aniline (Aldrich, 88 mg, 0.68 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5-15% EtOAc/hexanes) to give a white solid. 105 mg.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: BrCc1cccnc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2n1Cc1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (423 mg) in DMF (5 mL) was added potassium carbonate powder (868 mg) and 3-(bromomethyl)pyridine hydrogen bromide (615 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (15%-60% EtOAc/hexanes) to yield the title compound as a green solid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[C:20]([F:23])([F:22])[F:21]>CN1C(=O)CCC1.O>[CH2:1]([O:8][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[C:20]([F:21])([F:22])[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c(C(F)(F)F)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
18 g (166.67 mmol) of benzylalcohol was slowly added to a solution of 6.7 g (167.50 mmol) of sodium hydride in 148 mL NMP. The reaction mixture was stirred for 30 min at RT, then a solution of 27 g (139.09 mmol) of 1-fluoro-4-methoxy-2-trifluoromethyl-benzene in 515 mL NMP was added, and this was stirred for 30 min at RT and for 2 h at 100° C. After cooling to RT the mixture was diluted with water and extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried on sodium sulphate and evaporated down. The residue was purified by chromatography (silica gel, petroleum ether/ethyl acetate).
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O1CCCC1.[Br:34][C:35]1[N:39]([CH:40]([CH3:42])[CH3:41])[N:38]=[CH:37][C:36]=1[CH2:43]Br>CC1CCCO1.O>[Br:34][C:35]1[N:39]([CH:40]([CH3:42])[CH3:41])[N:38]=[CH:37][C:36]=1[CH2:43][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: CC(C)n1ncc(CBr)c1Br
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC1CCCO1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2cnn(C(C)C)c2Br)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.9 %

Procedure:
To a stirred solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (14.5 g, 56.3 mmol) in 2-methyl tetrahydrofuran (120 mL) was added, dropwise, 1 M LiHMDS in tetrahydrofuran (57 mL, 56.3 mmol) at −78° C. under argon. After 20 min, 5-bromo-4-(bromomethyl)-1-isopropyl-1H-pyrazole (12.2 g, 43.3 mmol) in 2-methyltetrahydrofuran (10 mL) was added. The mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was diluted with water (200 mL) and the mixture was separated. The organic phase was washed with 10% citric acid solution (2×100 mL), then brine (100 mL), dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude product was purified by flash column chromatography (10-30% ethyl acetate in heptane) to give 1-tert-butyl 4-ethyl 4-((5-bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)piperidine-1,4-dicarboxylate (9.3 g). Also isolated from the column was a 7.1 g mixed fraction of starting ester and desired product. This was stirred with 1 equivalent of sodium hydroxide in 90% ethanol/methanol for 2 hours at room temperature. The solvent was removed in vacuo and ethyl acetate (100 mL) was added. The mixture was washed with 2 N sodium hydroxide (2×50 mL) and then brine (100 mL), dried over sodium sulfate, filtered and the solvent removed in vacuo to give a second crop of 1-tert-butyl 4-ethyl 4-((5-bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)piperidine-1,4-dicarboxylate (5.1 g). The combined yield is 14.4 g (72%). +ESI (M+H) 404.0; 1H NMR (400 MHz, CDCl3, δ): 4.62 (m, 1H), 4.12 (q, 2H), 3.90 (br. s., 2H), 2.82 (m, 2H), 2.63 (s, 2H), 2.08 (d, 2H), 1.66 (m, 2H), 1.42 (s, 9H), 1.21 (t, 3H).
Reaction SMILES: Cl.Br[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(OC(C)C)OC(C)C>>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[F:20])[NH:13][C:7]1[C:6]2[C:11](=[CH:12][C:3]([C:23]3[O:22][CH:26]=[CH:25][CH:24]=3)=[CH:4][CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: CC(C)OB(OC(C)C)c1ccco1
Reactant: Fc1ccc(Nc2ncnc3cc(Br)ccc23)cc1Cl
Agent: Cl
Product: Fc1ccc(Nc2ncnc3cc(-c4ccco4)ccc23)cc1Cl
Yield: 36 %

Procedure:
Using an analogous procedure to that described in Example 1, 7-bromo-4-(3-chloro-4-fluoroanilino)quinazoline hydrochloride salt was reacted with di-isopropyl 2-furylboronate to give 4-(3-chloro-4-fluoroanilino)-7-(2-furyl)quinazoline in 36% yield, m.p.>250° C.;
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:20]1[C:22]2([CH2:27][NH:26][CH2:25][CH2:24][NH:23]2)[CH2:21]1.CS(C)=O>C(N(CC)CC)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:26]4[CH2:27][C:22]5([CH2:20][CH2:21]5)[NH:23][CH2:24][CH2:25]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CNC2(CC2)CN1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC4(CC4)C3)c(F)cc2c1=O
Temperature: 120 °C

Procedure:
200 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 200 mg of crude 4,7-diazaspiro[2,5]octane 25 were added to 10 ml of dimethyl sulfoxide followed by the addition of 0.3 ml of triethylamine. The mixture was heated on a bath of 120° C. for 2 hours. The solvent was then removed under reduced pressure and the residue was subjected to silica gel column chromatography, eluting with chloroform-methanol-water=15:3:1 (v/v). The crude product obtained from the fraction containing the desired compound was recrystallized from ethanol-concentrated aqueous ammonia to give 160 mg of title compound 37.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([S:12][CH2:13][CH2:14][CH3:15])[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:6]1=[O:53])[CH2:2][CH2:3][CH3:4]>CO.Cl>[CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([S:12][CH2:13][CH2:14][CH3:15])[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:6]1=[O:53])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)cc(SCCC)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Agent: Cl
Solvent: CO
Product: CCCCn1c(=O)cc(SCCC)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.8 %

Procedure:
3-Butyl-6-propylthio-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.45 g) was dissolved in a mixed solution of methanol (10 ml) and 1N hydrochloric acid (1 ml) and the solution was stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness and the resulting residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless amorphous powders (0.25 g, 84%).
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.[NH4+].[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:14]2[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:18]([C@@H:27]([CH2:31][CH3:32])[CH2:28][NH:29][CH3:30])[C:17](=[O:33])[C@:16]([CH2:35][C:36]([O-:38])=[O:37])([CH3:34])[CH2:15]2)[CH:11]=[CH:12][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CC(O)=O.CO>[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:14]2[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:18]([C@@H:27]([CH2:31][CH3:32])[CH2:28][N:29]([CH3:30])[CH:3]3[CH2:2][O:1][CH2:4]3)[C:17](=[O:33])[C@:16]([CH2:35][C:36]([OH:38])=[O:37])([CH3:34])[CH2:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC[C@@H](CNC)N1C(=O)[C@@](C)(CC(=O)[O-])C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@@H](CN(C)C1COC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 0.75 h

Procedure:
To a solution of oxetan-3-one (17.78 mg, 0.247 mmol) in DCE (3 mL) was added 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylamino)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid ammonium salt (61 mg, 0.123 mmol) obtained in Step A followed by sodium triacetoxyborohydride (78 mg, 0.370 mmol) and 3 drops AcOH. After 45 minutes, 3 ml MeOH and oxetan-3-one (12 mg, 0.17 mmol) were added. After stirring overnight, oxetan-3-one (12 mg, 0.17 mol) and sodium triacetoxyborohydride (60 mg, 0.32 mmol) were added. After 24 hours, the mixture was diluted with methanol and evaporated onto silica gel. The solid was purified by flash chromatography on silica gel (eluent: 0 to 100% [6:1:0.1 DCM/MeOH/NH4OH] in DCM). The product containing fractions were pooled, concentrated and repurified by preparative thin layer chromatography on silica gel (eluent: 10% MeOH/DCM) to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:43][CH2:44][CH2:45][OH:46]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([NH:43][CH2:44][CH2:45][OH:46])=[O:21])([CH2:18][CH2:19]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: NCCO
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)NCCO)(CC1)CC2
Yield: 62.4 %

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-aminoethanol (6.9 mg) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-2-hydroxyethylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (27.2 mg).