Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH:17]1([OH:23])[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([N+:32]([O-:34])=[O:33])=[C:29](O)[CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C1COCC1.C(Cl)Cl>[F:24][C:25]1[CH:30]=[CH:29][C:28]([N+:32]([O-:34])=[O:33])=[C:27]([CH:26]=1)[O:22][CH:19]1[CH2:20][CH2:21][CH:17]([OH:23])[CH2:18]1
Reactant: OC1CCC(O)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)cc1OC1CCC(O)C1
Temperature: 25 °C

Procedure:
Di-tert-butyl azodicarboxylate was added at 0° C. to a mixture of 1,3-cyclopentandiol (1.02 g), 5-fluoro-2-nitrophenol (0.79 g) and triphenylphosphine (1.97 g) in THF (15.0 ml). After stirring at room temperature over weekend the mixture was treated with 2 M aq. HCl (20.0 ml) and refluxed for 30 min. The reaction mixture was diluted with methylene chloride. The layers were separated. The organic layer was passed through a hydrophobic frit and concentrated in vacuo. The crude was purified by chromatography to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:27][CH2:26][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([OH:25])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:28][C@H:29]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=2[N:41]2[CH:45]=[CH:44][C:43]([CH3:46])=[N:42]2)[C:30]([F:33])([F:32])[F:31])[N:3]=1.Cl.Cl[CH2:49][CH2:50][N:51]([CH3:53])[CH3:52].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH2:49][CH2:50][N:51]([CH3:53])[CH3:52])=[O:24])[CH2:12]3)[CH2:26][CH2:27]2)[CH:5]=[C:4]([O:28][C@H:29]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=2[N:41]2[CH:45]=[CH:44][C:43]([CH3:46])=[N:42]2)[C:30]([F:32])([F:31])[F:33])[N:3]=1
Reactant: CN(C)CCCl
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C4)nc(N)n2)C(F)(F)F)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCCN(C)C)N(C(=O)OC(C)(C)C)C4)nc(N)n2)C(F)(F)F)n1
Temperature: 65 °C

Procedure:
To a solution of (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-(tert-butoxycarbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (1.6 g, 2.45 mmol) in DMF (24 mL) were added (2-chloro-ethyl)-dimethyl-amine hydrochloride (535 mg, 3.7 mmol) and K2CO3 (1.0 g, 7.4 mmol), and the reaction mixture was heated at 65° C. for 16 h. Then the reaction was cooled to RT, partitioned between EtOAc and water, and extracted. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification via prep-HPLC column chromatography (CH2Cl2/MeOH/NH4OH) provided (S)-2-tert-butyl 3-(2-(dimethylamino)ethyl) 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Reaction SMILES: ClC1C(C(C)CC)=NC(C2C=NC=CC=2)=CN=1.[NH:18]([C:20]1[C:25]([CH:26]([CH3:29])[CH2:27][CH3:28])=[N:24][C:23]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:22][N:21]=1)[NH2:19].[C:36](OCC)(=O)[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>C(O)C.O>[CH3:29][CH:26]([C:25]1[C:20]2[N:21]([C:36]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[N:19][N:18]=2)[CH:22]=[C:23]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[N:24]=1)[CH2:27][CH3:28]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCC(C)c1nc(-c2cccnc2)cnc1NN
Agent: CCC(C)c1nc(-c2cccnc2)cnc1Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1nnc2c(C(C)CC)nc(-c3cccnc3)cn12

Procedure:
In a manner analogous to Example 1, by condensing 3-(2-amino-1,1-diethoxyethyl)pyridine with 3-methyl-2-oxopentanoic acid there is obtained rac-N-[2,2-diethoxy-2-(3-pyridyl)ethyl]-3-methyl-2-oxovaleramide as an amorphous, colorless solid. Subsequent acidic hydrolysis to rac-3-methyl-2-oxo-N-[(3-pyridylcarbonyl)methyl]valeramide hydrochloride (beige, crystalline solid, melting point 158°-159°) and ring closure gives rac-3-(1-methylpropyl)-5-(3-pyridyl)-2(1H)-pyrazinone as a yellow solid, melting point 146°-148° (from acetonitrile). The conversion into rac-2-chloro-3-(1-methylpropyl)-5-(3-pyridyl)pyrazine is also effected analogously to Example 1. Hydrazinolysis to rac-2-hydrazino-3-(1-methylpropyl)-5-(3-pyridyl)pyrazine in the form of beige crystals, melting point 166°-167° (from ethanol/water) and subsequent condensation with diethyl malonate gives ethyl rac-8-(1-methylpropyl)-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, MS: 335 (M)+, which is converted by saponification into the above acid, MS: 267 (M-CO 2)+.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:47]([NH:51][CH2:52][C:53]1[CH:67]=[CH:66][C:56]([O:57][C:58]([CH3:65])([CH3:64])[C:59]([O:61][CH2:62][CH3:63])=[O:60])=[C:55]([CH3:68])[CH:54]=1)[CH2:48][CH2:49][CH3:50].Br[C:70]1[CH:75]=[CH:74][CH:73]=[C:72]([C:76]2[CH:81]=[CH:80][C:79]([C:82]([F:85])([F:84])[F:83])=[CH:78][CH:77]=2)[N:71]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:47]([N:51]([CH2:52][C:53]1[CH:67]=[CH:66][C:56]([O:57][C:58]([CH3:65])([CH3:64])[C:59]([O:61][CH2:62][CH3:63])=[O:60])=[C:55]([CH3:68])[CH:54]=1)[C:70]1[CH:75]=[CH:74][CH:73]=[C:72]([C:76]2[CH:81]=[CH:80][C:79]([C:82]([F:83])([F:85])[F:84])=[CH:78][CH:77]=2)[N:71]=1)[CH2:48][CH2:49][CH3:50]
Reactant: CCCCNCc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Reactant: FC(F)(F)c1ccc(-c2cccc(Br)n2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCCN(Cc1ccc(OC(C)(C)C(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 80 °C
Yield: 42.6 %

Procedure:
Palladium (II) acetate (1.4 mg, 0.006 mmol) and (S)-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (5.9 mg, 0.0095 mmol) in anhydrous toluene (0.32 mL) were stirred together at 70° C. in a sealed reactivial for 30 minutes. The vial was then allowed to attain room temperature before the ethyl 2-{4-[(butylamino)methyl]-2-methylphenoxy}-2-methylpropanoate (29 mg, 0.095 mmol), 2-bromo-6-[4-(trifluoromethyl)phenyl]pyridine (24 mg, 0.08 mmol) and caesium carbonate (36 mg, 0.11 mmol) were added. The vial was then sealed and heated at 80° C. for 18 h, then allowed to cool to room temperature the reaction mixture filtered and the solvent removed in vacuo. Purification by SPE (Silica, 10 g) eluting with 99:1 cyclohexane:EtOAc afforded the title compound as a colourless oil (18 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]([OH:21])=O)[CH:10]=2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[CH2:26]([N:28]([CH2:29][CH3:30])[C:19]([C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[O:21])[CH3:27]
Reactant: CCNCC
Reactant: COc1ccc(-c2cc(C(=O)O)nc3ccccc23)cc1
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1cc(-c2ccc(OC)cc2)c2ccccc2n1

Procedure:
Operations are carried out as for Example 1, starting from 21 g of 4-(4-methoxy phenyl) quinoline 2-carboxylic acid, 64 ml of thionyl chloride and 39 ml of diethylamine. 2.2 g of N,N-diethyl 4-(4-methoxy phenyl) quinoline 2-carboxamide are obtained. After recrystallization in isopropyl ether the product melts at 91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:29])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH2:23][N:24]([CH3:26])[CH3:25])=[N:21][N:20]=[C:19]1[CH2:27]O.CS(Cl)(=O)=O.[CH2:35]([NH2:38])[C:36]#[CH:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:29])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH2:23][N:24]([CH3:26])[CH3:25])=[N:21][N:20]=[C:19]1[CH2:27][NH:38][CH2:35][C:36]#[CH:37]
Reactant: CN(C)Cc1nnc(CO)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Reactant: C#CCN
Agent: CS(=O)(=O)Cl
Product: C#CCNCc1nnc(CN(C)C)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 47, 2'-chloro-5-nitro-2-[3-(hydroxymethyl)-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone is treated first with methanesulfonyl chloride followed by propargylamine, to give 2'-chloro-5-nitro-2-[3-[[(2-propynyl)amino]methyl]-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)=O.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1>O1CCCC1.C(OCC)(=O)C.[Na].[Ti]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10](=[N:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: CN1CCC(N)CC1
Reactant: O=C(c1cc2ccccc2o1)c1nc2ccccc2s1
Agent: [Ti]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(N=C(c2cc3ccccc3o2)c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (benzofuran-2-yl)(benzothiazol-2-yl)methanone (1.4 g) and 4-amino-1-methylpiperidine (0.57 g) in tetrahydrofurane (8 mL) is added dropwise titanium tetraisopropoxyde (1.78 g). The suspension is stirred for 24 h at room temperature, diluted with ethyl acetate and 1N sodium hydroxyde. The precipitate is filtered over a clarcel pad and rinsed with ethyl acetate. The pooled filtrates are washed with saturated sodium chloride solution, dried and concentrated under reduced pressure. The residue is purified over silica gel (gradiant dichloromethane/methanol from 100/0 to 90/10) to afford [(benzofuran-2-yl)(benzothiazol-2-yl)methylene](1-methylpiperidin-4-yl)amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])=[S:10])=[C:4]([OH:20])[C:3]=1[S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22].[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].N1C=CN=C1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])=[S:10])=[C:4]([O:20][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C:3]=1[S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(Cl)c2Cl)c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(Cl)c2Cl)c1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To a solution of N-[4-chloro-2-hydroxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2,3dichlorophenyl)thiourea (440 mg, 1.07 mmol) in THF (20 mL), tert-butyldimethylsilyl chloride (730 mg, 4.85 mmol) and imidazole (132 mg, 1.94 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. Then it was partitioned between ethyl acetate and water. The combined organic phase was dried and concentrated. Chromatography of the residue on silica gel (30% Ethyl acetate/Hexane) gave desired product (270 mg, 50%). EI-MS m/z 570 (M+).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:15]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[C:30]([F:32])[C:29](Br)=[CH:28][C:27]=2[F:34])=[CH:22][CH:21]=1)[CH2:16][CH2:17][CH2:18][CH3:19].C(OC1(C2C=CC(CCCCC)=CC=2)C(F)=CC(C2C=CC=CC=2)=C(F)C1)CCCCC>>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:29]2[CH:28]=[C:27]([F:34])[C:26]([C:23]3[CH:24]=[CH:25][C:20]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:21][CH:22]=3)=[CH:31][C:30]=2[F:32])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2cc(F)c(Br)cc2F)cc1
Reactant: CCCCCc1ccc(B(O)O)cc1
Agent: CCCCCCOC1(c2ccc(CCCCC)cc2)CC(F)=C(c2ccccc2)C=C1F
Product: CCCCCc1ccc(-c2cc(F)c(-c3ccc(CCCCC)cc3)cc2F)cc1

Procedure:
The product from 2C is coupled with the product from 1F in an analogous manner as for 1G described to yield 4,4"-di-n-pentyl-2',5'-difluoro-p-terphenyl, K 65.0 N 86.0 I.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:53]=[CH:52][C:13]([CH2:14][O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[CH2:22][CH2:23][N:24]([CH2:40][CH2:41][C:42]4[CH:47]=[CH:46][C:45]([C:48]([O:50]C)=[O:49])=[CH:44][CH:43]=4)[CH:25]4[CH2:34][CH2:33][CH2:32][C:31]5[N:30]=[C:29]([C:35]([O:37]CC)=[O:36])[CH:28]=[CH:27][C:26]4=5)=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:54]=1.O.[OH-].[Li+]>C1COCC1.O>[C:48]([C:45]1[CH:46]=[CH:47][C:42]([CH2:41][CH2:40][N:24]([CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]2[CH:12]=[CH:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:54][C:6]=4[N:7]=3)=[CH:53][CH:52]=2)[CH:25]2[CH2:34][CH2:33][CH2:32][C:31]3[N:30]=[C:29]([C:35]([OH:37])=[O:36])[CH:28]=[CH:27][C:26]2=3)=[CH:43][CH:44]=1)([OH:50])=[O:49]
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccc(C(=O)OC)cc1)CCc1ccccc1OCc1ccc(-c2nc3cc(Cl)ccc3o2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(CCN(CCc2ccccc2OCc2ccc(-c3nc4cc(Cl)ccc4o3)cc2)C2CCCc3nc(C(=O)O)ccc32)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
68 mg (0.09 mmol) of ethyl 5-([2-(2-{[4-(5-chloro-1,3-benzoxazol-2-yl)benzyl]oxy}-phenyl)ethyl]-{2-[4-(methoxycarbonyl)phenyl]ethyl}amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 1, Example 63A) were taken up in 4 ml of THF and 2 ml of water, and 12 mg (0.27 mmol) of lithium hydroxide monohydrate were added. The reaction was stirred at 60° C. overnight. After the reaction had gone to completion, the THF was removed on a rotary evaporator and the mixture that remained was diluted with water. The mixture was then acidified to pH 4-5 using acetic acid and extracted repeatedly with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated to dryness. This gave 33 mg (0.04 mmol, 48% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][C:38]([S:42](Cl)(=[O:44])=[O:43])=[CH:39][CH:40]=2)[CH:35]=[CH:34]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:42]([C:38]1[CH:37]=[C:36]2[C:41](=[CH:40][CH:39]=1)[N:33]([CH3:32])[CH:34]=[CH:35]2)(=[O:43])=[O:44]
Reactant: Cn1ccc2cc(S(=O)(=O)Cl)ccc21
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1ccc2cc(S(=O)(=O)Nc3ccc(F)c(Nc4ncccc4-c4ncnc5c4ncn5C4CCCCO4)c3F)ccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 1-methyl-1H-indole-5-sulfonyl chloride (16 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]1[CH:29]=[CH:28][C:14]2[C:15]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][OH:27])[CH2:20][CH2:19]3)=[N:16][O:17][C:13]=2[CH:12]=1.[ClH:30]>C1(C)C=CC=CC=1.CCOCC>[ClH:30].[F:10][C:11]1[CH:29]=[CH:28][C:14]2[C:15]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][O:27][C:8](=[O:9])[NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:20][CH2:19]3)=[N:16][O:17][C:13]=2[CH:12]=1
Reactant: OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C

Procedure:
Phenylisocyanate (0.36 g, 3 mmol) and 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]propanol (0.3 g, 1.1 mmol) was refluxed in toluene (25 ml) for 6 h. The mixture was cooled to room temperature and hydrochloric acid in ether was added. The resulting precipitate was recrystallized from ethanol/ether and isopropanol/ether to give 180 mg of the title compound as white crystals. M.p. 204.5°-205.5° C. MS (70 eV): m/z 397 (39%, M+), 278 (4), 259 (26), 233 (50), 178 (28), 96 (100).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C@:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:17])[C@@H:13]([OH:25])[CH2:12]1)=O)C1C=CC=CC=1>CCO.[Pd]>[CH2:18]([C@:14]1([OH:17])[CH2:15][CH2:16][NH:11][CH2:12][C@@H:13]1[OH:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@@](O)(Cc2ccccc2)[C@@H](O)C1
Agent: [Pd]
Solvent: CCO
Product: O[C@H]1CNCC[C@@]1(O)Cc1ccccc1
Reaction time: 16 h

Procedure:
(3R,4R) and (3S,4S)-4-Benzyl-3,4-dihydroxy-piperidine-1-carboxylic acid benzyl ester 1.46 g (4.3 mmol) was dissolved in 30 ml EtOH and hydrogenated in the presence of 400 mg Pd/C (10%) under atmospheric pressure of H2 at r.t. After 16 hours the reaction was complete and the catalyst was filtered off and the solvent was removed under reduced pressure to give 796 mg (3.8 mmol, 89%) (3R,4R) and (3S,4S)-4-benzyl-3,4-dihydroxy-piperidine as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:6]([C:7](O)=[O:8])[CH:5]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:10]=[C:11]([Cl:13])[CH:12]=1
Reactant: COC(=O)c1cc(Cl)cc(C(=O)O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)cc(CO)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107 %

Procedure:
In a 3 liter 3-necked round-bottom flask equipped with mechanical stirrer and nitrogen inlet was placed 5-chloroisophthalic acid monomethyl ester (29.4 g). Borane tetrahydrofuran complex in tetrahydrofuran solution (1M, 280 ml) was then added to the flask dropwise at room temperature. The resulting solution was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous ammonium chloride solution (750 ml) and extracted with ethyl acetate (3×500 ml). The combined organic layers were agitated with 2% aqueous hydrochloric acid, washed with water, dried and the solvent eliminated in the rotavap yielding 29.4 g of 3-chloro-5-hydroxymethyl benzoic acid methyl ester as a clear oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10]C)(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].Br[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25]>C1COCC1>[CH3:25][O:24][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:14]=1[CH2:13][CH:4]([C:3]([O:9][CH3:10])=[O:8])[C:5](=[O:6])[CH3:7])[C:18]([O:20][CH3:21])=[O:19]
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(C(C)=O)C(=O)OC)c(OC)c1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
NaH (60% in mineral oil, 1.5 g) was added portion-wise over 10 mins to a solution of ethyl acetoacetate (4.4 mL) in THF (60 mL) at 0° C. The mixture was then stirred for 10 mins. Then, a solution of methyl 4-(bromomethyl)-3-methoxybenzoate (7.5 g) in THF (40 mL) was added and the mixture was warmed to 70° C. and stirred for 15 h. The mixture was then poured into ice/water (300 mL) and stirred for 30 mins. The resulting aqueous mixture was extracted with EtOAc. The organic extracts were combined, dried and concentrated in vacuo to provide crude product. The reaction was repeated on the same scale. The two batches of crude product were combined and purified by flash column chromatography on silica gel to give the sub-title compound (15 g) as a colourless oil; 1H NMR (300 MHz, CDCl3) δ=7.48 (1H, dd), 7.45 (1H, d), 7.24 (1H, d), 4.05 (2H, q), 3.95 (1H, dd), 3.86 (3H, s), 3.84 (3H, s), 3.10 (1H, dd), 3.00 (1H, dd), 2.17 (3H, s), 1.09 (3H, t).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=O)[CH3:10])[C:4]([CH3:12])=[N:3]1.[H-].[Na+].ClC1C=[C:20]([I:22])[C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=1.O.[OH-].[Li+]>CCOC(C)=O.O>[I:22][C:20]1[C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=[C:9]([NH:8][C:5]2[C:4]([CH3:12])=[N:3][N:2]([CH3:1])[C:6]=2[CH3:7])[CH:10]=1
Reactant: CC(=O)Nc1c(C)nn(C)c1C
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(C)c1Nc1cc(I)c(C(F)(F)F)cn1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
N-(1,3,5-trimethylpyrazol-4-yl)acetamide (1.142 g, 6.83 mmol) was added to sodium hydride (0.288 g, 6.83 mmol) suspended in nitrogen-degassed DMF (5 mL) under nitrogen. The resulting light suspension was stirred at 35° C. for 30 minutes then 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (1 g, 3.25 mmol) was added. The reaction mixture was allowed to cool to room temperature, stirred for 1 hour and quenched with water (20 mL). Lithium hydroxide hydrate (0.409 g, 9.76 mmol) was added, the mixture was stirred at room temperature for 1.5 hour and then diluted with EtOAc and water. The phases were separated and the organic phase was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel (40 g) eluting with 0 to 50% EtOAc in DCM to afford 4-iodo-5-(trifluoromethyl)-N-(1,3,5-trimethylpyrazol-4-yl)pyridin-2-amine (350 mg, 27.2%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:6]=1.C([O:17][CH:18]=[CH:19][C:20](OCC)=O)C.C1(C)C(C)=CC=CC=1>O>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][CH:20]=[CH:19][C:18](=[O:17])[N:6]2[N:5]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC=CC(=O)OCC
Reactant: Nc1nnc(SCc2ccccc2)s1
Solvent: O
Solvent: Cc1ccccc1C
Product: O=c1ccnc2sc(SCc3ccccc3)nn12
Reaction time: 0.5 h
Yield: 54 %

Procedure:
Fifteen point five (15.5) grams of 2-amino-5-benzylthio-1,3,4-thiadiazole, 10 g of ethyl 3-ethoxypropenoate, 15 g of polyphosphoric acid and 15 ml of xylene were mixed and vigorously stirred for 30 minutes. After the reaction was finished, the reaction mixture was cooled. Water was added to the reaction mixture and the mixture was extracted with toluene. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and water respectively and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was recrystallized from an ethanol/hexane mixture, and thus 10.3 g of 2-benzylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 54%.
Reaction SMILES: [CH2:1]([O:5][N:6]1[CH:13]=[C:12]([CH3:14])[C:10](=O)[NH:9][C:7]1=[O:8])[CH2:2][CH2:3][CH3:4].C(ONC(N)=O)CCC.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25]>>[CH2:1]([O:5][N:6]1[CH:13]=[C:12]([CH3:14])[C:10]([SH:25])=[N:9][C:7]1=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCCOn1cc(C)c(=O)[nH]c1=O
Agent: CCCCONC(N)=O
Product: CCCCOn1cc(C)c(S)nc1=O

Procedure:
In a manner analogous to that described in Example 1 25 g of 1-butoxy-5-methyl-uracil prepared by reacting of butoxyurea with β,β-diethoxy-α-methylpropionic acid ester was reacted with 50 g of phosphorus pentasulfide to give 1-butoxy-1,2-dihydro-4-mercapto-5-methyl-2-oxo-pyrimidine;