Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C@:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)([OH:5])[CH3:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:60]1([NH:63][CH:64]2[CH2:69][CH2:68][CH:67]([CH2:70][CH2:71][C:72]#[N:73])[CH2:66][CH2:65]2)[CH2:62][CH2:61]1.Cl>CN(C=O)C>[C:72]([CH2:71][CH2:70][CH:67]1[CH2:68][CH2:69][CH:64]([N:63]([CH:60]2[CH2:62][CH2:61]2)[C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([C@@:3]([OH:5])([CH3:4])[C:2]([F:1])([F:16])[F:15])=[CH:14][CH:13]=2)[CH2:65][CH2:66]1)#[N:73]
Reactant: C[C@](O)(c1ccc(C(=O)O)cc1)C(F)(F)F
Reactant: N#CCCC1CCC(NC2CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@](O)(c1ccc(C(=O)N(C2CCC(CCC#N)CC2)C2CC2)cc1)C(F)(F)F
Reaction time: 0.08 h

Procedure:
To a solution of (S)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoic acid (0.33 g, 1.4 mmol), HBTU (0.64, 1.7 mmol), and HOBt (0.24 g, 1.8 mmol) in DMF (3.3 mL) was added Hünig's base (0.58 mL, 3.4 mmol). The solution was stirred for 5 minutes prior to the addition of 3-(4-(cyclopropylamino)cyclohexyl)propanenitrile prepared in step g (0.32 g, 1.7 mmol). The reaction was stirred at room temperature for 5 h followed by quenching with 3-(dimethylamino)-propylamine (0.1 mL). The reaction contents were poured into 1 N HCl (30 mL) and extracted with CH2Cl2 (2×10 mL). The organic layer was washed with 0.5 N NaOH (10 mL), dried with Na2SO4, and concentrated in vacuo. Silica gel chromatography (60% MTBE in hexanes) separated cis and trans isomers with the desired trans isomer eluting last to provide (S)-N-(4-(2-cyanoethyl)cyclohexyl)-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide. 1H NMR (500 MHz, CDCl3): δ 0.40-0.48 (bs, 2H), 0.58 (bd, J=6 Hz, 2H), 1.05-1.20 (m, 2 H), 1.42-1.56 (m, 1H), 1.60-1.64 (m, 3H), 1.81 (s, 3H), 1.85-1.92 (m, 4H), 1.97-2.00 (m, 2H), 2.41 (t, J=7 Hz, 2H), 2.56-3.00 (m, 1 H), 2.69 (bs, 1H), 4.13 (bs, 1H), 7.48 (d, J=8 Hz, 2H), 7.60 (d, J=8 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH2:7])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][NH2:7]
Reactant: NC(=O)c1ccc(Cl)c(N)c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(Cl)c(N)c1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
3-Amino-2,4-dichloro-benzamide (2.00 g, 9.8 mmol) in THF (45 mL) is added dropwise to LiAlH4 (1 M in THF, 24.4 mL) in THF (45 mL). The reaction mixture is stirred for 1 h at rt and 10 h at reflux. Excess LiAlH4 is destroyed under cooling as described by L. F. Fieser & M. Fieser Vol 1, p 584 Wiley 1967. After 30 min the mixture is filtered and the filtrate is concentrated to give the sub-title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]=1)([CH3:4])([CH3:3])[CH3:2].[BH-](O[C:35]([CH3:37])=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC1C(C=O)=NC=CC=1>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]=1)[CH2:14][C:13]1[C:35]([CH3:37])=[CH:9][CH:10]=[CH:11][N:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(CNCCCCNC(=O)OC(C)(C)C)nc2ccccc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1cccnc1C=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1nc2ccccc2n1C

Procedure:
Using General Procedure B, reaction of {4-[(1-methyl-1H-benzoimidazol-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester in CH2Cl2 and 3-methyl-pyridine-2-carbaldehyde in CH2Cl2 with NaBH(OAc)3 gave {4-[(1-methyl-1H-benzoimidazol-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as a white solid. 1H NMR (CDCl3) δ 1.42 (s, 9H), 1.50-1.60 (m, 2H), 1.78 (s, 2H), 2.27 (s, 3H), 2.60 (t, 2H, J=7.4 Hz), 2.96-3.00 (m, 2H), 3.55 (s, 3H), 3.82 (s, 2H), 3.90 (s, 2H), 4.79-4.80 (m, 1H), 7.09-7.13 (m, 1H), 7.23-7.25 (m, 3H), 7.43 (d, 1H, J=7.4 Hz), 7.70-7.73 (m, 1H), 8.40 (d, 1H, J=4.9 Hz). Deprotection with TFA using General Procedure F gave COMPOUND 226 as a white solid. 1H NMR (CDCl3) δ 1.25-1.34 (m, 4H), 1.50-1.60 (m, 2H), 2.28 (s, 3H), 2.52-2.63 (m, 4H), 3.56 (s, 3H), 3.83 (s, 2H), 3.91 (s, 2H), 7.10-7.14 (m, 1H), 7.22-7.25 (m, 3H), 7.43 (d, 1H, J=7.5 Hz), 7.71-7.73 (m, 1H), 8.41 (d, 1H, J=3.6 Hz). 13C NMR (CDCl3) δ 18.55, 23.95, 29.97, 31.79, 42.19, 51.70, 54.99, 59.43, 109.37, 119.91, 122.15, 122.80, 122.95, 133.34, 136.56, 138.44, 142.55, 146.68, 152.48, 157.02. ES-MS m/z 338 (M+H). Anal. Calcd. for C20H27N5.0.1H2O: C, 70.81; H, 8.08; N, 20.64. Found: C, 70.67; H, 8.02; N, 20.73.
Reaction SMILES: C1(CC([C:10]2[CH:15]=[CH:14][C:13]([C:16]3([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19][C:18]4([O:23][CH2:22][CH2:21][O:20]4)[CH2:17]3)=[CH:12][CH:11]=2)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[Cl:38][C:39]1[C:44]([CH:45]=O)=[C:43]([NH:47][C:48](=O)OC(C)(C)C)[CH:42]=[CH:41][N:40]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:38][C:39]1[N:40]=[CH:41][CH:42]=[C:43]2[C:44]=1[CH:45]=[C:16]([C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1)[C:48]([C:10]1[CH:15]=[CH:14][C:13]([C:16]3([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19][C:18]4([O:20][CH2:21][CH2:22][O:23]4)[CH2:17]3)=[CH:12][CH:11]=1)=[N:47]2
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)Cc3ccccc3)cc2)CC2(C1)OCCO2
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1C=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(Cl)c4cc3-c3ccccc3)cc2)CC2(C1)OCCO2
Temperature: 80 °C

Procedure:
To a solution of tert-butyl {2-[4-(phenylacetyl)phenyl]-5,8-dioxaspiro[3.4]oct-2-yl}carbamate (1-7) (8.8 g, 20.8 mmol) in DMF (100 mL) was added potassium carbonate (14.4 g, 104 mmol) and tert-butyl (2-chloro-3-formyl-4-pyridinyl)carbamate (1-8) (5.33 g, 20.8 mmol) and the reaction mixture was heated 80° C. over night. The reaction mixture was poured into saturated sodium bicarbonate, extracted with EtOAc, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by column chromatography eluting with 1-80% EtOAc/Hexane. The appropriate fractions were combined and the solvent removed in vacuo to give tert-butyl {2-[4-(5-chloro-3-phenyl-1,6-naphthyridin-2-yl)phenyl]-5,8-dioxaspiro[3.4]oct-2-yl}carbamate (1-9). MS (M+H)+: 545.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:27](=[CH:28][CH:29]=1)[CH2:26][C:8]1([C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:9]1=[O:25])[CH2:7]2)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:27](=[CH:28][CH:29]=1)[CH2:26][C@:8]1([C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])[C:9]1=[O:25])[CH2:7]2
Reactant: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)c2cccnc21
Agent: [Pd]
Solvent: CCO
Product: C[Si](C)(C)CCOCN1C(=O)[C@@]2(Cc3ccc(N)cc3C2)c2cccnc21
Reaction time: 18 h

Procedure:
A mixture of 10% Pd/C (3 g) and (±)-5-nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step F (19.1 g, 46.4 mmol) was stirred vigorously in EtOH (400 mL) under an atmosphere of hydrogen (ca. 1 atm). After 18 h, the mixture was filtered through a pad of Celite, washing extensively with MeOH, and the filtrate was concentrated in vacuo to give the crude racemic compound. The enantiomers were resolved by HPLC, utilizing a Chiralcel OD column and eluting with MeOH. The first major peak to elute was (S)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′)-one, and the second major peak to elute was (R)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, the title compound. MS: m/z=382 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[N:7][S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])[N:3]=[N:2]1.[CH3:14][Mg]Br.C(OCC)C>C1COCC1>[NH:1]1[CH:5]=[C:4]([CH:6]([NH:7][S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])[CH3:14])[N:3]=[N:2]1
Reactant: CC(C)(C)S(=O)N=Cc1c[nH]nn1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(NS(=O)C(C)(C)C)c1c[nH]nn1
Temperature: -70 °C

Procedure:
N-((1H-1,2,3-triazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (Preparation 64, 2 g, 10 mmol) was dissolved in THF (80 mL) under nitrogen and cooled to −70° C. A solution of methylmagnesium bromide in diethyl ether (3.5M, 7.5 mL, 22.5 mmol) was added dropwise over a period of 15 minutes, keeping the reaction temperature below −60° C. The reaction was stirred with cooling for a further 40 minutes then the cooling bath was removed and the mixture was stirred at room temperature for 18 hours. The reaction was quenched by the addition of saturated aqueous sodium chloride solution (0.5 mL) followed by 2M (aq) HCl (12 mL). The THF was removed in vacuo and the residue acidifed to pH=4 with 2M (aq) HCl. The solution was extracted with EtOAc (110 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 40-100% EtOAc in heptanes to afford the title compound as a 4:1 mixture of diastereomers (1.09 g, 50%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:18]C(=O)OC(C)(C)C)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[CH2:4][CH2:3]1.N1(C2C=C(NC(=O)OC(C)(C)C)C=C(C(F)(F)F)C=2)CCOCC1>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[C:10]([NH2:18])[CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c2)CC1
Agent: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)cc(C(F)(F)F)c1
Product: CN1CCN(c2cc(N)cc(C(F)(F)F)c2)CC1

Procedure:
Utilising the procedure described in Example 90c, but employing [3-(4-methyl-1-piperazinyl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 94a) in lieu of [3 (4-morpholinyl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester, afforded the title compound as oil. 1H-NMR (400 MHz, DMSO-d6): 2.20 (s, 3H), 2.42 (m, 4H), 3.07 (m, 4H), 3.32 (br s, 2H), 5.34 (s, 1H) and 6.31 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([NH2:15])[N:3]=1.[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=2)[CH2:19][CH2:18][NH:17]1>>[NH2:15][C:4]1[N:3]=[C:2]([N:17]2[CH2:18][CH2:19][C:20]3[C:25](=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[CH2:16]2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=1
Reactant: CN1CCN(c2cc(Cl)nc(N)n2)CC1
Reactant: N#Cc1ccc2c(c1)CNCC2
Product: CN1CCN(c2cc(N3CCc4ccc(C#N)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1 starting from 4-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and 1,2,3,4-tetrahydroisoquinoline-7-carbonitrile (Asta Tech, Cat. No. 48330). LCMS (M+H)+: m/z=350.2.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:41])=[O:40])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:49](C1C=CC(CS(Cl)(=O)=O)=CC=1)(=[O:52])(=[O:51])[NH2:50]>>[NH2:50][S:49]([C:46]1[CH:45]=[CH:44][C:43]([CH2:42][S:39]([NH:38][CH2:37][CH2:36][C:15]2[N:14]([CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:22]3[C:17]([C:16]=2[CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:34][CH:35]=2)=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)(=[O:41])=[O:40])=[CH:48][CH:47]=1)(=[O:52])=[O:51]
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: NS(=O)(=O)c1ccc(CS(=O)(=O)Cl)cc1
Product: NS(=O)(=O)c1ccc(CS(=O)(=O)NCCc2c(CCOc3ccc(C(=O)O)cc3)c3cc(Cl)ccc3n2C(c2ccccc2)c2ccccc2)cc1

Procedure:
The title compound was prepared from 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester (Step 6, Example 1) and (4-Sulfamoyl-phenyl)-methanesulfonyl chloride according to Example 1 Step 7.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[OH:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:9]([O:11][CH3:12])=[O:10].FC(F)(F)S(O)(=O)=O.C(N(CC)CC)C>ClCCl>[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:9]([O:11][CH3:12])=[O:10])([CH3:3])([CH3:1])[CH3:4]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: C=C(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(OC(C)(C)C)c1
Temperature: -70 °C
Reaction time: 3 h

Procedure:
A stirred solution of isobutylene (33 mL) in dichloromethane (60 mL) at -70° C. is treated dropwise with a cooled solution of methyl 3-hydroxy-4-methoxybenzoate (6 g) in dichloromethane (60 mL), followed by trifluoromethanesulfonic acid (0.3 mL). The reaction mixture is vigorously stirred at -70° C. for 3 hours and then between -70° C. and -50° C. overnight. It is then treated with triethylamine (0.6 mL) and allowed to warm to room temperature. The resulting yellow solution is concentrated, and the residue is subjected by mplc, using diethyl ether as eluent, to give methyl 3-tert-butoxy-4-methoxybenzoate (4.93 g), m.p. 98-100° C. [Elemental analysis: C,65.7; H,7.8%; calculated: C,65.5; H,7.6%].
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:20][O:21][C:22]1[CH:31]=[CH:30][C:25]2[NH:26][C:27](=[O:29])[O:28][C:24]=2[CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:20][O:21][C:22]1[CH:31]=[CH:30][C:25]2[N:26]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[C:27](=[O:29])[O:28][C:24]=2[CH:23]=1
Reactant: COc1ccc2[nH]c(=O)oc2c1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)oc(=O)n2CC(=O)N1CCN(c2ccc(Cl)c(OC)c2)CC1

Procedure:
In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), 6-methoxy-3H-benzooxazol-2-one (114 mg, 0.69 mmol, 1.05 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.5 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 6-methoxy-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (17): HPLC retention time, 2.33 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 431.9, found, 431.9.
Reaction SMILES: Cl/[C:2](/[N+]([O-])=O)=[CH:3]\[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[OH:15][C:16]1[CH:21]=[C:20]([OH:22])[N:19]=[CH:18][N:17]=1.N12CCCN=C1CCCCC2>C(O)C>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]2[C:21]3[C:20](=[O:22])[NH:19][CH:18]=[N:17][C:16]=3[O:15][CH:2]=2)=[CH:5][CH:6]=1
Reactant: Oc1cc(O)ncn1
Reactant: COc1ccc(/C=C(\Cl)[N+](=O)[O-])cc1
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2coc3nc[nH]c(=O)c23)cc1

Procedure:
As in the procedure described in the literature [D. Dauzonne, Tetrahedron, 1992, 3069-3080], stir a suspension of 10.1 g (47.4 mmol) 1-[(Z)-2-chloro-2-nitrovinyl]-4-methoxybenzene and 5.8 g (52.2 mmol) 4,6-dihydroxypyrimidine in 200 ml ethanol for ten minutes at 85° C. Next, slowly add 15.6 ml (15.9 g, 104.3 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene. Stir for 15 h at this temperature and then concentrate by vacuum evaporation. Take up the residue in dichloromethane and chromatograph on silica gel (solvent: dichloromethane/methanol 95:5). Mix the solid obtained with acetonitrile and then filter. 2.3 g (20% of theor.) of the target product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].C([Li])CCC.[CH3:20][S:21]SC.Cl>O1CCCC1>[F:1][C:2]1[C:3]([S:21][CH3:20])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:12])([F:13])[F:14])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(F)c1
Reactant: CSSC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1c(C(=O)O)ccc(C(F)(F)F)c1F
Reaction time: 3 h

Procedure:
25.0 g (120.1 mmol) of 3-fluoro-4-trifluoromethylbenzoic acid were dissolved in 250 ml of dry tetrahydrofuran (THF), and 100.9 ml of n-butyllithium (2.5 M in hexane, 252.3 mmol) were added dropwise at −40° C. The mixture was stirred for 3 h, and a solution of 32.5 ml (360.4 mmol) of dimethyl disulfide in 50 ml of dry THF was then added dropwise. The mixture was stirred for 16 h, during which process, after half an hour, the temperature climbed slowly to RT. For work-up, 2 M HCl was added carefully. The mixture was extracted with diethyl ether, and the organic phase was subsequently extracted with 2 M NaOH. The aqueous phase was acidified and extracted with diethyl ether. The organic phase was washed with water, dried, and the solvent was removed in vacuo. The residue was stirred with n-heptane and the solid was separated off by a filtration. This gave 17.0 g of crude product, which was employed in the next synthesis step without further purification.
Reaction SMILES: [S:1]([C:5]1[CH:10]=[C:9]([C:11](O)=[O:12])[C:8]([C:14]([OH:16])=[O:15])=[CH:7][C:6]=1[C:17]([OH:19])=[O:18])([OH:4])(=[O:3])=[O:2]>C(OC(=O)C)(=O)C>[O:12]=[C:11]1[C:9]2[CH:10]=[C:5]([S:1]([OH:4])(=[O:3])=[O:2])[C:6]([C:17]([OH:19])=[O:18])=[CH:7][C:8]=2[C:14](=[O:16])[O:15]1
Reactant: O=C(O)c1cc(C(=O)O)c(S(=O)(=O)O)cc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc(S(=O)(=O)O)c(C(=O)O)cc21
Temperature: 25 °C

Procedure:
5-Sulfo-1,2,4-benzenetricarboxylic acid (9.63 g, 33.2 mmol), prepared according to J. Am. Chem. Soc. (1949) 71, 11, was treated with acetic anhydride (150 mL) and refluxed for 5 hours. After cooling to room temperature, the acetic anhydride was removed under reduced pressure. The residue was washed with diethyl ether (3×30 mL) and then dried under reduced pressure at room temperature to provide the title compound as a tan solid.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>ClCCl>[CH3:24][S:25]([O:11][CH2:10][CH2:9][S:8][C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:27])=[O:26]
Reactant: OCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of 2-(triphenylmethylthio)ethanol (2.66 g, 8.30 mmol) in cold (0° C.) dichloromethane (39 mL) kept under a nitrogen atmosphere was added methanesulfonyl chloride (0.704 mL, 9.10 mmol); the resulting mixture was treated dropwise (15 min) with triethylamine (1.34 mL, 9.6 mmol). After stirring for 15 min, the cooling bath was removed and the reaction mixture was stirred for 7 h then washed successively with water (10 mL), 0.5N citric acid (10 mL), water (10 mL), saturated sodium bicarbonate and water. The organic extracts were dried (MgSO4 -MgO) and concentrated under reduced pressure to a thick syrup which crystallized on standing. Trituration of the crystals in ether afforded white solid 2.1 g (63%) mp 95°-8° C.; ir (KBr) νmax : 1580, 1565 (phenyl), 1350, 1175, 1165 cm-1 (sulfonate); 1Hmr (CDCl3): 2.51 (2H, t, J=6.6 Hz, CH2S), 3.07 (3H, s, CH3SO3-), 3.87 (2H, t, J=6.6 Hz, CH2O), 7.34 (15H, m, phenyl).
Reaction SMILES: I[C@@H:2]1[C@@H:8]2[CH2:9][C@@H:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.[OH-].[Na+].[CH2:13]([OH:15])[CH3:14]>>[CH2:13]([O:15][C:6]([C@H:5]1[CH2:4][CH2:3][C@@H:2]2[C@@H:8]([O:7]2)[CH2:9]1)=[O:10])[CH3:14]
Reactant: CCO
Reactant: O=C1O[C@H]2C[C@@H]1CC[C@@H]2I
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)[C@H]1CC[C@H]2O[C@H]2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(1S,4S,5S)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one (J. Org. Chem., vol. 61, p. 8687 (1996)) (89.3 g) was suspended in ethanol (810 mL), and 2N aqueous sodium hydroxide (213 mL) was added thereto, followed by stirring at room temperature for 3 hours. The solvent was distilled away under reduced pressure, and water was added to the residue. The thus-obtained mixture was extracted with methylene chloride, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=17:3), to thereby give the title compound (41.3 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[N:8][CH:9]=1)([O-])=O.NN>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccncc2)nc1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccc(-c2ccncc2)nc1
Yield: 95 %

Procedure:
5-Nitro-2,4′-bipyridine (10 g) obtained in Example 1 was added to ethanol (400 ml). 10% Pd—C (50% wet with water) (0.14 g) was added, and then, hydrazine.monohydrate (10 g) was dropwise added, for reflux under heating for 3 hours. The reaction solution was filtered and concentrated. The resulting crystal was recrystallized in ethyl acetate, to obtain the object substance (8.13 g; yield of 95%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[CH2:9][NH:10][CH2:11][C:12]([F:15])([F:14])[F:13].C(N(CC)CC)C.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][C:24](=[O:26])[N:10]([CH2:11][C:12]([F:14])([F:15])[F:13])[CH2:9][C:3]=12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ncnc(Cl)c1CNCC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1Nc2ncnc(Cl)c2CN1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
Combine 6-chloro-5-((2,2,2-trifluoroethylamino)methyl)pyrimidin-4-amine (9.57 g, 39.78 mmol), triethylamine (5.50 mL, 2.0 eq), and dichloromethane (795 mL). Cool to 0° C. under nitrogen. Add a solution of triphosgene (11.85 g, 1.0 eq) in dichloromethane (228 mL). Stir at 0° C. for 30 min, and allow to warm to room temperature. Heat the reaction mixture to 40° C. overnight. Add aqueous sodium bicarbonate and extract with ethyl acetate. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with 9:1 dichloromethane:methanol, to give the title compound (4.50 g, 42%). 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.41 (s, 1H), 4.20 (m, 2H), 3.25 (s, 2H).