Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:7][P:8]([CH2:17][C:18]([CH3:41])=[CH:19][CH2:20][C:21]2[C:22]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[C:23]3[C:27](=[C:28]([CH3:32])[C:29]=2[O:30][CH3:31])[CH2:26][O:25][C:24]3=[O:33])(=[O:16])[O:9]C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].CCOC(C)=O>C1COCC1>[C:1]1([O:7][P:8]([CH2:17][C:18]([CH3:41])=[CH:19][CH2:20][C:21]2[C:22]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:38])[CH3:39])=[C:23]3[C:27](=[C:28]([CH3:32])[C:29]=2[O:30][CH3:31])[CH2:26][O:25][C:24]3=[O:33])(=[O:9])[OH:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CP(=O)(Oc1ccccc1)Oc1ccccc1)C(=O)OC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CP(=O)(O)Oc1ccccc1)C(=O)OC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
To a solution of {4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonic acid diphenyl ester (75 mg, 0.126 mmol) in THF (5 mL) was added 1N NaOH (0.1 mL) solution. The mixture was allowed to stir at room temperature for 16 hours. EtOAc was added and the resulting mixture was washed with 1H HCl. The organic layer was concentrated to dryness and the residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 24.8 mg (38%) of the desired product. MS (m/z) 517 [M−H]−, 541 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([OH:11])[C:5]2=[C:4]([CH3:12])[CH:3]=1.[N:13]([CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1)=[C:14]=[O:15]>C1COCC1.CN(C=O)C>[CH:16]1([NH:13][C:14]([N:9]2[C:10](=[O:11])[C:5]3[C:6](=[N:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:12])[NH:8]2)=[O:15])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: Cc1cc(Cl)nc2[nH]nc(O)c12
Reactant: O=C=NC1CCCc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(Cl)nc2[nH]n(C(=O)NC3CCCc4ccccc43)c(=O)c12

Procedure:
In analogy to example 1c, 200 mg (1.089 mmol) of 6-chloro-4-methyl-1H-pyrazolo-[3,4-b]pyridin-3-ol were reacted with 226.4 mg (1.2 mmol) of 1-isocyanato-1,2,3,4-tetrahydronaphthalene in THF/DMF at RT. Yield: 142 mg (37%), M+H+: 357.35.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O.[CH3:24][O:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[CH:33]([OH:36])[CH2:34][CH3:35]>C(Cl)Cl>[CH3:24][O:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[C:33](=[O:36])[CH2:34][CH3:35]
Reactant: CCC(O)c1ccc(C)cc1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCC(=O)c1ccc(C)cc1OC
Reaction time: 0.17 h

Procedure:
Dess-Martin periodinane (2.89 g, 6.82 mmol) and H2O (0.123 ml, 6.82 mmol) are added to DCM (20 ml) and left to stir for 10 minutes. This mixture is treated with 1-(2-methoxy-4-methyl-phenyl)-propan-1-ol (step 1) (1.17 g, 6.49 mmol) in DCM (15 ml) and stirred for 1 hour. The reaction mixture is diluted with DCM and washed with Na2S2O3, NaHCO3, water, brine, dried (MgSO4) and concentrated under vacuum to yield the title product as a clear oil; 1H NMR (400 MHz, CDCl3) δ 7.64 (d, 1H), 6.82 (d, 1H), 6.77 (s, 1H), 3.90 (s, 3H), 3.00 (q, 2H), 2.39 (s, 3H), 1.17 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23]>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([O:1][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH:11]=[C:10]([OH:12])[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc(O)cc(OCC=C(C)C)c1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1a, from methyl 3,5-dihydroxybenzoate (11.3 g, 67 mmol), potassium carbonate (18.5 g, 134 mmol), and 1-bromo-3-methyl-but-2-ene (10 g, 67 mmol). Purification by column chromatography eluting with 20% EtOAc in hexane gave a pale yellow solid (3.41 g, 20% yield). 1H NMR (400 MHz, CDCl3) δ 7.17-7.20 (m, 1 H) 7.12-7.17 (m, 1 H) 6.63 (t, J=2.27 Hz, 1 H) 5.41-5.51 (m, 1 H) 5.50 (s, 1H) 4.53 (d, J=6.57 Hz, 2 H) 3.91 (m, 3 H) 1.80 (s, 3 H) 1.69 (s, 3 H); LCMS for C13H16O4 m/z 237.10 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:10]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])=[CH:9][C:8](=[O:20])[NH:7][C:6]1=[S:21].[NH2:22][C:23](=[N:29][C:30](=[O:33])[O:31][CH3:32])N1C=CC=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:32][O:31][C:30](=[O:33])[N:29]=[C:23]([NH2:22])[NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:10]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])=[CH:9][C:8](=[O:20])[NH:7][C:6]1=[S:21]
Reactant: COC(=O)N=C(N)n1cccn1
Reactant: COc1ccc(Cl)cc1-c1cc(=O)[nH]c(=S)n1CCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N=C(N)NCCCn1c(-c2cc(Cl)ccc2OC)cc(=O)[nH]c1=S
Reaction time: 72 h

Procedure:
To a solution of 1-(3-aminopropyl)-6-(5-chloro-2-methoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (prepared in an analogous manner to Example 6; 50 mg, 0.14 mmol) and methyl [amino(1H-pyrazol-1-yl)methylidene]carbamate (28 mg, 0.16 mmol) in DMF (0.46 mL) was added N,N-diisopropylethylamine (0.024 mL, 0.14 mmol) at room temperature, and the mixture was stirred for 72 hours. The solvent was removed under reduced pressure, the residue was dissolved in DMSO (0.9 mL) and purified using mass-triggered automatic purification to give the title compound (4.9 mg) MS (ES+) 425.9 [M+H]+. Retention time: 1.54 min; Method: XBridge C18 5 um 4.6×50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.03% NH4OH). Flow rate: 2 mL/min.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH3:28][C:29]1([CH3:35])[CH2:31][CH:30]1[C:32](O)=[O:33]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:32]([CH:30]3[CH2:31][C:29]3([CH3:35])[CH3:28])=[O:33])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC1(C)CC1C(=O)O
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)C3CC3(C)C)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and rac-2,2-dimethyl-cyclopropanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a colorless amorphous solid. MS (ESI): m/z=375.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[C:26]([N+:33]([O-:35])=[O:34])[CH:25]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:32])=[C:26]([N+:33]([O-:35])=[O:34])[CH:25]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1ccc(Cl)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)cc4[N+](=O)[O-])cc3)c2cc1OC
Yield: 84.7 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (123 mg) was dissolved in toluene (12 ml) with heat, 4-chloro-2-nitrophenyl isocyanate (172 mg) was added, and the admixture was refluxed with heat for 14 minutes. The separated crystals were filtered and then washed with toluene to obtain 174 mg of the title compound (yield: 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:15])[NH:8]2.C(O)(=O)C>[C].[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:15])[NH:8]2
Reactant: COc1ccc(C=O)c2c1CCC(=O)N2
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(C)c2c1CCC(=O)N2
Reaction time: 1 h
Yield: 88.6 %

Procedure:
5-Methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-8-carboxaldehyde (1.00 g) and 10% palladium carbon (100 mg) were added to a mixed solvent of acetic acid (10 ml) and ethanol (10 ml), followed by catalytic reduction at 50° C. for 1 hour. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to extraction with ethyl acetate, and the extract was washed twice with water, washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from an ethyl acetate-diethyl ether mixed solvent to thereby obtain 826 mg (yield: 89%) of 5-methoxy-8-methyl-3,4-dihydro-1H-quinolin-2-one as a white powder.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([OH:24])[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2.C[O:26][C:27](=[O:50])[C@H:28]([C@@H:47]([CH3:49])O)[NH:29]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([O:24][C@H:47]([CH3:49])[C@@H:28]([C:27]([OH:50])=[O:26])[NH2:29])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Reactant: OC1(c2ccc3ccccc3c2)c2ccccc2-c2ccccc21
Product: C[C@@H](OC1(c2ccc3ccccc3c2)c2ccccc2-c2ccccc21)[C@H](N)C(=O)O

Procedure:
from 9-(2-naphthyl)-9H-fluoren-9-ol (Example 3p) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([Cl:25])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:24]=[C:23]([Cl:25])[S:22][C:12]=3[N:13]=2)[CH:17]=1
Reactant: NCc1ccccc1
Reactant: Clc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: Clc1cc2c(NCc3ccccc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-3-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-benzylamino-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH3:3].[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[C:23]1[CH2:24]CNC[CH:28]=1>>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[C:23]1[CH2:24][CH2:3][N:2]([CH2:4][C:5]2[C:13]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[CH2:1][CH:28]=1
Reactant: C1=C(c2cc3ccccc3s2)CCNC1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Product: C1=C(c2cc3ccccc3s2)CCN(Cc2c[nH]c3ncccc23)C1

Procedure:
Reaction of 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine and 4-(benzothiophen-2-yl)-1,2,3,6-tetrahydropyridine in an analogous manner to Example 4 gave the title compound, m.p. 241°-246° C. (dec.); (Found: C, 72.85; H, 5.54; N, 12.06; C21H19N3S requires C, 73.01; H, 5.54; N, 12.16%); δH (DMSO-d6) 2.51 (2H, br s, tetrahydropyridinyl CH2), 2.67 (2H, m, tetrahydropyridinyl CH2), 3.14 (2H, m, tetrahydropyridinyl CH2), 3.76 (2H, s, CH2N), 6.19 (1H, br s, CH=CR), 7.03 (1H, m, ArH), 7.31 (2H, m, 3'-H and ArH), 7.74 (1H, d, J 8 Hz, ArH), 7.86 (1H, d, J 8 Hz, ArH), 8.05 (1H, d, J 8 Hz, ArH), 8.20 (1H, m, ArH), and 11.45 (1H, br s, NH); m/z (CI+, NH3) 346 (M+1)+.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Cl:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1.[OH-].[K+]>C(O)C.O>[Cl:21][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][O:8][CH2:7]2)[C:3]([OH:22])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: COC(=O)C(CC1CCOC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCOC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-3-yl)-propionic acid methyl ester (729 mg, 2.10 mmol) in ethanol (20 mL) was treated with a solution of potassium hydroxide (694 mg, 10.51 mmol) in water (7 mL). The reaction was stirred for 3 h at 25° C., concentrated in vacuo to remove the ethanol, and then was acidified to pH=2 with a 1N aqueous hydrochloric acid solution. The resulting mixture was then extracted with methylene chloride 3×10 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-3-yl)-propionic acid (654 mg, 94%) as a white foam: (ES)+-HRMS m/e calcd for C14H17ClO5S (M+Na)+ 355.0377. found 355.0382.
Reaction SMILES: [C:1]1([N:7]=C=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:10](=O)(=[O:13])([OH:12])[OH:11]>>[S:10]([OH:13])(=[O:12])([C:4]1[CH:5]=[CH:6][C:1]([NH2:7])=[CH:2][CH:3]=1)=[O:11]
Reactant: O=C=Nc1ccccc1
Reactant: O=S(=O)(O)O
Product: Nc1ccc(S(=O)(=O)O)cc1

Procedure:
The reaction of phenyl isocyanate with sulfuric acid is reported by Bieber [J. Am. Chem. Soc. 75, 1405 (1953)] to give sulfanilic acid. ##SPC1##
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]#[N:12])=[CH:4][N:3]=1.[NH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1>CN(C)C=O.C(OCC)(=O)C>[C:11]([C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)=[N:3][CH:4]=1)#[N:12]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: N#Cc1cnc(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cnc(N[C@H]2CC[C@H](O)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-chloro-5-cyano-3-nitropyridine (3.5 g)(obtained according to International Patent Application No.WO9410171) in N,N-dimethylformamide (35 mL) was added trans-4-aminocyclohexanol (4.39 g) at 0° C. The mixture was stirred at room temperature under nitrogen atmosphere for 45 minutes and diluted with ethyl acetate. The mixture was washed with water (3 times) and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual solid was washed with diethyl ether to give 5-cyano-2-(trans-4-hydroxycyclohexylamino)-3-nitropyridine (3.38 g) as a yellow sold.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([N:17]3[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18]3)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[OH:25][C:26]1([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)=[CH:35][N:34]=2)[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCl>[N:40]1[CH:41]=[CH:42][CH:43]=[N:44][C:39]=1[C:36]1[CH:37]=[CH:38][C:33]([C:26]2([OH:25])[CH2:31][CH2:30][CH:29]([NH:22][C@H:19]3[CH2:20][CH2:21][N:17]([C:15]([CH:12]4[CH2:11][CH2:10][N:9]([C:7]5[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[N:8]=5)[CH2:14][CH2:13]4)=[O:16])[CH2:18]3)[CH2:28][CH2:27]2)=[N:34][CH:35]=1
Reactant: N[C@H]1CCN(C(=O)C2CCN(c3cccc(C(F)(F)F)n3)CC2)C1
Reactant: O=C1CCC(O)(c2ccc(-c3ncccn3)cn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CCN(c2cccc(C(F)(F)F)n2)CC1)N1CC[C@H](NC2CCC(O)(c3ccc(-c4ncccn4)cn3)CC2)C1

Procedure:
A solution of (3S)-1-({1-[6-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}carbonyl)pyrrolidin-3-amine (40 mg, 0.1 mmol), 4-hydroxy-4-(5-pyrimidin-2-ylpyridin-2-yl)cyclohexanone (47 mg, 0.18 mmol), sodium triacetoxyborohydride (50 mg, 0.23 mmol), and triethylamine (35 mg, 0.35 mmol) in dichloromethane (10 mL) was stirred at room temperature overnight. The reaction mixture was passed through a silica gel pad. The filtrate was concentrated and purified by HPLC to give the cis- and trans-isomers. MS (M+H) 596.2 for both isomers.
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]([CH2:35][CH2:36][O:37][C:38](=[O:51])[C@H:39]([CH:48]([CH3:50])[CH3:49])[NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:23][N:24]1[CH:32]=[N:31][C:30]2[C:29](=O)[NH:28][C:27]([NH2:34])=[N:26][C:25]1=2)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:65])=O>C(#N)C.[Cl-].C[N+](C)(C)C>[NH2:34][C:27]1[N:26]=[C:25]2[C:30]([N:31]=[CH:32][N:24]2[CH2:23][C@H:22]([CH2:21][O:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:35][CH2:36][O:37][C:38](=[O:51])[C@H:39]([CH:48]([CH3:50])[CH3:49])[NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[C:29]([Cl:65])[N:28]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: CCN(CC)c1ccccc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)Cn1cnc2c(Cl)nc(N)nc21

Procedure:
To a solution of (R)-9-(2-stearoyloxymethyl-4-(N-tert-butoxycarbonyl-L-valyloxy)butyl)guanine from step 2 of Example 1 (646 mg, 0.9 mmole) in acetonitrile were added tetramethylammonium chloride (427 mg, 2.7 mmole), N,N-diethylaniline (0.716 ml, 4.5 mmole) and phosphorous oxychloride (0.417 ml, 4.5 mmole). The reaction was kept under reflux and the progression monitored by TLC. After 3 hours the reaction mixture was evaporated in vacuo and the residue was dissolved in dichloromethane, then poured into cold sodium hydrogen carbonate aqueous solution. The organic phase was evaporated and purified by silica gel column chromatography. Yield: 251 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:12][N:11]=1.C=O.[C:37](O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH3:37])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=2)=[CH:12][N:11]=1
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(NCc3ccc(C(F)(F)F)cc3)cn2)c(OC)c1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CCc1ccc(Oc2ccc(N(C)Cc3ccc(C(F)(F)F)cc3)cn2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 3-{3-methoxy-4-[5-(4-trifluoromethylbenzylamino]pyridin-2-yloxy}phenyl}-propionate (0.8 g, 1.7 mmol) in methanol (15 mL) were added a 37% aqueous formaldehyde solution (0.38 mL, 5.1 mmol) and acetic acid (0.1 mL, 1,7 mmol). The reaction solution was stirred for 30 minutes at room temperature. After that, sodium cyanoborohydride (0.24 g, 3.4 mmol) was added to the reaction solution under ice cooling, and the mixture was stirred under ice cooling for 40 minutes. To the reaction solution was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 0.62 g of the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[C:21]=1[N:29]=[C:30]=[O:31])([CH3:19])[CH3:18]>>[CH2:1]([N:8]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=1)[C:30]([NH:29][C:21]1[C:20]([CH:17]([CH3:18])[CH3:19])=[CH:25][CH:24]=[CH:23][C:22]=1[CH:26]([CH3:28])[CH3:27])=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCc1ccc(NCc2ccccc2)cc1
Product: CCc1ccc(N(Cc2ccccc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 42.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using benzyl(4-ethylphenyl)amine (1.77 g) and 2,6-diisopropylphenyl isocyanate (1.96 g) as starting materials, N-benzyl-N′-(2,6-diisopropylphenyl)-N-(4-ethylphenyl)urea (1.49 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.[CH3:46][NH:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH2:55][N:56]2[CH2:60][CH2:59][CH2:58][CH2:57]2)[CH:50]=1>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:47]([CH3:46])[CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([CH2:55][N:56]4[CH2:60][CH2:59][CH2:58][CH2:57]4)[CH:50]=3)=[O:23])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCc1cccc(CN2CCCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3cccc(CN4CCCC4)c3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AD using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.16 mmol), CDI (48 mg, 0.29 mmol), DIPEA (0.17 mL, 0.97 mmol) and N-methyl-1-[3-(pyrrolidin-1-ylmethyl)phenyl]methanamine (31 mg, 0.14 mmol) in DCE (1.2 mL).
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][C:4](=[O:7])[C:3]2=[CH:8][CH:9]=[CH:10][N:2]12.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Si:11]([O:7][C:4]1[C:3]2[N:2]([CH:10]=[CH:9][CH:8]=2)[N:1]=[CH:6][CH:5]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: O=c1cc[nH]n2cccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccnn2cccc12
Reaction time: 1 h

Procedure:
Pyrrolo[1,2-b]pyridazin-4(1H)-one (2.0 g, 14.9 mmol) and t-butyldimethylsilyl chloride (2.7 g, 17.9 mmol) were dissolved in anhydrous toluene under nitrogen atmosphere. After adding triethylamine (3.1 mL, 22.4 mmol), the mixture was stirred for 1 hour under reflux. Upon completion of the reaction, the produced solid was filtered and washed with a small volume of toluene. The filtrate was concentrated by distillation under reduced pressure. The resulting residue was subjected to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12](OC)[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28]Cl)[C:26]=2[Cl:27])=[O:21])=[CH:4][CH:3]=1.[CH3:31][S-:32].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][S:32][CH3:31])[C:26]=2[Cl:27])=[O:21])=[CH:6][CH:7]=1
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cc2)c1NC(=O)c1scc(CCl)c1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCc1csc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.4 %

Procedure:
To a solution of N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (0.52 g, 1.1 mmol) in DMF (12 mL) was added sodium thiomethoxide (0.39 g, 5.5 mmol) and the reaction mixture stirred at ambient temperature. After 16 hours, the mixture was poured into water (100 mL) and extracted with ethyl acetate (2×80 mL). The combined organics were washed with water (2×80 mL), 1M hydrochloric acid (2×80 mL) and brine (80 mL), dried over MgSO4 and concentrated of all volatiles in vacuo. Purification of the resulting solid by flash chromatography on silica gel afforded 0.36 g (68% yield) of N-(4-chlorophenyl)-2-[((3-chloro-4-((methylthio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; as a pale yellow solid; NMR (DMSO-d6) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (d, 1), 7.8 (s, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 3.7 (s, 2), 2.0 (s 3) ppm.