Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[OH:11][N:12]=[C:13]([C:18](=O)[CH3:19])[CH2:14][N:15]([CH3:17])[CH3:16].[OH-].[NH4+:22]>CO>[OH:11][N:12]1[C:13]([CH2:14][N:15]([CH3:17])[CH3:16])=[C:18]([CH3:19])[N:22]=[C:6]1[C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: CC(=O)C(CN(C)C)=NO
Reactant: Cc1ccc(C=O)cc1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2nc(C)c(CN(C)C)n2O)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-methylbenzaldehyde (12.6 g, 0.105 moles) in methanol (300 ml), ammonium hydroxide (sp. gr.=0.9, 180 ml) is added, followed by 2-hydroxyimino-1-dimethylamino-3-butanone hydrochloride (17.4 g, 0.0965 moles, described in Example 1). After standing overnight the mixture is evaporated to give a residue of the title compound. The residue is dissolved in methanol and a solution of hydrogen chloride in diethyl ether is added. The solution is treated with charcoal and filtered. The filtrate is evaporated and crystallized from methanol-diethyl ether to give the dihydrochloride salt of the title compound (23.99 g), mp 222°-224° C. Two recrystallizations from the latter solvent raised the melting point to 223°-226° C.; nmr (DMSO-d6) δ 2.4(s), 2.52(s), 2.83(s), 4.6(s), 7.35(s), 8.2(s) and 12.2(broad); and anal. Calc'd. for C14H19N3O.2HCl: C, 53.00; H, 6.62; N, 13.20% and Found: C, 52.55; H, 6.72; N, 13.34%.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11]/[C:12](=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]([C:34]([F:37])([F:36])[F:35])([C:30]([F:33])([F:32])[F:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)/[CH2:13][OH:14].C(N(CC)CC)C>ClCCl>[F:11]/[C:12](=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]([C:30]([F:31])([F:32])[F:33])([C:34]([F:37])([F:35])[F:36])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)/[CH:13]=[O:14]
Reactant: OC/C(F)=C/CCCCCCOC(c1ccccc1)(C(F)(F)F)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C/C(F)=C/CCCCCCOC(c1ccccc1)(C(F)(F)F)C(F)(F)F
Reaction time: 1 h

Procedure:
Dimethyl sulphoxide (293 mg) in dry dichloromethane (3 ml) was added to oxalyl chloride (162 mg) in dichloromethane (14 ml) at -60° C. After 10 minutes the above alcohol (0.73 g) in dichloromethane (3 ml) was added and the mixture kept at -60° C. for 1 hour. Triethylamine (1.01 ml) was added and the whole allowed to reach 0° C. gradually. Conventional work-up gave (Z)-2-fluoro-9-(bistrifluoromethylbenzyloxy)non-2-ene-1-al.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20].[CH3:29][N:30]([CH3:34])[C:31](Cl)=[O:32].N12CCCN=C1CCCCC2>C1COCC1>[O:28]=[C:22]1[CH:21]([N:14]2[CH2:13][C:12]3[C:16](=[CH:17][CH:18]=[CH:19][C:11]=3[CH2:10][NH:9][C:31](=[O:32])[N:30]([CH3:34])[CH3:29])[C:15]2=[O:20])[CH2:26][CH2:25][C:24](=[O:27])[NH:23]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)C(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
Triethylamine (0.6 g, 5.9 mmol) was added slowly to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and dimethylcarbamoyl chloride (0.3 g, 3.2 mmol) in THF (100 mL). The mixture was stirred at room temperature overnight. Another portion of dimethylcarbamoyl chloride (0.3 g) and 1,8-diazabicyclo[5,4,0]-undec-7-ene (0.6 g) was added and stirred for another day. The mixture was concentrated, and the residue was stirred with 1N HCl (15 mL). The mixture was filtered, and the solid was slurried with hot methanol (10 mL) to give 3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1,1-dimethyl-urea (0.3 g, 46%) as a white solid: mp 169-171° C.; 1H NMR (DMSO-d6) δ 1.99-2.04 (m, 1H), 2.32-2.64 (m, 2H), 2.80 (s, 6H, 2CH3), 2.85-3.00 (m, 1H), 4.27 (d, J=5.6 Hz, 2H, CH2), 4.40 (d, J=17.3 Hz, 1H), 4.47 (d, J=17.3 Hz, 1H), 5.10-5.17 (dd, J=5.0 and 13.2 Hz, 1H, CH), 6.94 (t, J=5.6 Hz, 1H, NH), 7.44-7.64 (m, 3H, Ar), 11.02 (s, 1H); 13C NMR (DMSO-d6) δ 22.58, 31.18, 35.88, 46.20, 51.55, 121.20, 128.08, 130.38, 131.39, 136.35, 139.77, 158.08, 168.15, 171.00, 172.83; Anal. calcd. for C17H20N4O4: C, 59.29; H, 5.85; N, 16.27. Found: C, 59.05; H, 5.91; N, 15.92.
Reaction SMILES: [NH:1]1[C:9]2C(=CC=CC=2)C[CH2:2]1.Cl[C:11]1C2C(=CC=CC=2)N=CN=1.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]([CH2:40][C:41]([O:43][CH2:44]C)=[O:42])[CH2:32]2)=[N:23][CH:22]=1>>[CH3:2][N:1]([CH3:9])[C:36]1[CH:35]=[C:34]2[C:39](=[CH:38][CH:37]=1)[N:31]([C:24]1[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]=[CH:22][N:23]=1)[CH:32]([CH3:11])[CH:33]2[CH2:40][C:41]([O:43][CH3:44])=[O:42]
Reactant: Clc1ncnc2ccccc12
Reactant: c1ccc2c(c1)CCN2
Reactant: CCOC(=O)CC1CN(c2ncnc3ccccc23)c2ccccc21
Product: COC(=O)CC1c2cc(N(C)C)ccc2N(c2ncnc3ccccc23)C1C

Procedure:
This indoline derivative was then reacted with 4-chloroquinazoline in a similar manner to that described in Example 4 for the preparation of ethyl 1-quinazolin-4-ylindolin-3-ylacetate, and there was obtained methyl 5-dimethylamino-2-methyl-1-quinazolin-4-ylindolin-3-ylacetate, as a syrup which was shown to be pure by TLC (systems A and B).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](#[N:13])[CH2:10][C:11]#[N:12].C(N(CC)CC)C.[CH3:21][N:22]1[C:26](=[O:27])[CH2:25][C:24]([CH3:28])=[N:23]1>C(O)C>[NH2:12][C:11]1[O:27][C:26]2[N:22]([CH3:21])[N:23]=[C:24]([CH3:28])[C:25]=2[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[C:9]#[N:13]
Reactant: CC1=NN(C)C(=O)C1
Reactant: O=Cc1ccccc1
Reactant: N#CCC#N
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nn(C)c2c1C(c1ccccc1)C(C#N)=C(N)O2
Reaction time: 0.02 h
Yield: 34.4 %

Procedure:
A mixture of benzaldehyde (290 μL, 2.87 mmol, 1.0 equ.), malononitrile (190 mg, 2.87 mmol, 1.0 equ.) and triethylamine (400 μL, 2.87 mmol, 1.0 equ.) in ethanol (10 mL) was stirred for 1 min, followed by the addition of 1,3-dimethyl-1H-pyrazol-5(4H)-one (322 mg, 2.87 mmol, 1 equiv.). The reaction mixture was concentrated after 19 h and washed with ethanol and hexanes. The crude material was purified by column chromatography on SiO2 (25% ethyl acetate in n-hexanes to 100% ethyl acetate) and then re-crystallized from ethanol to give 6-amino-1,3-dimethyl-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitril (263 mg, 0.988 mmol, 34%) as a yellow powder. 1H-NMR (400 MHz) DMSO: 7.34-7.32 (m, 2H), 7.25-7.23 (t, 1H), 7.19-7.17 (d, 2H), 7.05 (s, 2H), 4.57 (s, 1H), 3.60 (s, 3H), 1.66 (s, 3H), 13C-NMR (100 MHz) DMSO: 159.9, 144.6, 144.4, 142.9, 128.8, 128.0, 127.3, 120.6, 96.5, 58.7, 37.5, 33.8, 12.8; LC/MS-MS: 267.0→201.3 m/z; GS1 and GS2 at 30, DP=61, CE=29, CXP=12, tR=3.74 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Cl)[CH:3]=1.Cl.[CH3:11][O:12][C:13]([CH:15]1[CH2:19][CH:18]([OH:20])[CH2:17][NH:16]1)=[O:14].C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[CH3:11][O:12][C:13]([C@@H:15]1[CH2:19][C@@H:18]([OH:20])[CH2:17][N:16]1[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:14]
Reactant: ClCc1cccc(Cl)c1
Reactant: COC(=O)C1CC(O)CN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](O)CN1Cc1cccc(Cl)c1
Yield: 64.9 %

Procedure:
Chloro-3-chloromethyl-benzene (15.2 ml, 120 mmol) was added to the mixture of 4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester hydrochloride (14.5 g, 80 mmol) and triethylamine (18.6 g, 180 mmol) in dichloromethane (120 ml). The reaction mixture was refluxed overnight. After cooling, 1M aqueous sodium hydroxide was added, and the mixture was extracted with dichloromethane. The extract was washed with brine, dried over sodium sulfate, concentrated and purified by chromatography on silica gel (hex/EA=5:1 to hex/EA=31) to give 14 g title product as yellow oil in 65% yield.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[Cl:8][C:9]1[CH:10]=[C:11]([C:15]([OH:44])([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[C:16]([N:18]2[CH2:37][CH2:36][CH2:35][C@H:19]2[C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH:34]=[N:33][N:32]=[N:31]2)=[O:21])=[O:17])[CH:12]=[CH:13][CH:14]=1.C(=O)(O)[O-:46].[Na+].ClC1C=C(C=CC=1)C(OO)=O>ClCCl.CCOC(C)=O>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[Cl:8][C:9]1[CH:10]=[C:11]([C:15]([OH:44])([C:38]2[CH:39]=[N+:40]([O-:46])[CH:41]=[CH:42][CH:43]=2)[C:16]([N:18]2[CH2:37][CH2:36][CH2:35][C@H:19]2[C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH:34]=[N:33][N:32]=[N:31]2)=[O:21])=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C([O-])O
Reactant: O=C(NCc1ccccc1-n1cnnn1)[C@@H]1CCCN1C(=O)C(O)(c1cccnc1)c1cccc(Cl)c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccccc1-n1cnnn1)[C@@H]1CCCN1C(=O)C(O)(c1cccc(Cl)c1)c1ccc[n+]([O-])c1
Reaction time: 2 h

Procedure:
The TFA salt of the polar isomer of 1-[(3-chlorophenyl)(hydroxy)pyridin-3-ylacetyl]-N-[2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (0.01 g, 0.02 mmol) was partitioned between EtOAc and saturated sodium bicarbonate solution and extracted with EtOAc to retrieve the free base. To a stirred solution of the dried free base of 1-[(3-chlorophenyl)(hydroxy)pyridin-3-ylacetyl]-N-[2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (0.009 g, 0.017 mmol) in dichloromethane (1 mL), cooled to 0° C., was added 3-chloroperoxybenzoic acid 70% (0.006 g, 0.026 mmol). After 2 hours, the reaction was evaporated in vacuo and purified on a Gilson Preparative HPLC. Pure fractions were combined, freeze dried and lyophilized to yield the solid TFA salt of 1-[(3-chlorophenyl)(hydroxy)(1-oxidopyridin-3-yl)acetyl]-N-[2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (0.003 g, HPLC RT=2.70 min, Method A; LCMS m/z=534).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7](=[O:13])[NH:8][C:9](=[O:12])[C:10]=2[N:11]=1.[C:14]([OH:17])(=[O:16])[CH3:15]>>[C:14]([O:17][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7](=[O:13])[NH:8][C:9](=[O:12])[C:10]=2[N:11]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)O
Reactant: Cc1ccc2[nH]c(=O)[nH]c(=O)c2n1
Product: CC(=O)OCc1ccc2[nH]c(=O)[nH]c(=O)c2n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 5000-mL 4-necked round-bottom flask was placed a solution of 6-methylpyrido[3,2-d]pyrimidine-2,4(1H,3H)-dione 2 (120 g, 677.97 mmol, 1.00 equiv) in acetic acid (2400 mL). This was followed by the addition of m-CBPA (608 g, 3.51 mol, 5.18 equiv) in several batches. The resulting solution was stirred overnight at 100° C. The resulting mixture was cooled and concentrated under vacuum. The residue was washed with 2×1500 mL of ether and 2×500 mL of DCM, then it was dissolved in HOAc (1200 mL) and acetic anhydride (500 mL). The resulting solution was stirred for 0.5 h at 110° C. The reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum. The residue was washed with 2×500 ml of ether and dried. This resulted in 80 g (50%) of (2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-6-yl)methyl acetate 3 as a brown solid.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([O:11][P:12]([C:19]1[CH:20]=[C:21]([C:37]2[S:38][C:39]([Sn](CCCC)(CCCC)CCCC)=[C:40]([P:42]([O:49][CH2:50][CH2:51][CH2:52][CH3:53])([O:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:43])[CH:41]=2)[S:22][C:23]=1[Sn:24]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:29]CCC)[CH2:25][CH2:26][CH2:27][CH3:28])([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])[CH2:8][CH2:9][CH3:10].[F-].[K+].[C:69]1(C)[CH:74]=CC=C[CH:70]=1>>[CH2:45]([O:44][P:42]([C:40]1[CH:41]=[C:37]([C:21]2[S:22][C:23]([Sn:24]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:29][CH2:70][CH2:69][CH3:74])=[C:19]([P:12]([O:11][CH2:7][CH2:8][CH2:9][CH3:10])([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])[CH:20]=2)[S:38][C:39]=1[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1)([O:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:43])[CH2:46][CH2:47][CH3:48]
Reactant: Cc1ccccc1
Reactant: Ic1cccs1
Reactant: CCCCOP(=O)(OCCCC)c1cc(-c2cc(P(=O)(OCCCC)OCCCC)c([Sn](CCCC)(CCCC)CCCC)s2)sc1[Sn](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Product: CCCCOP(=O)(OCCCC)c1cc(-c2cc(P(=O)(OCCCC)OCCCC)c([Sn](CCCC)(CCCC)CCCC)s2)sc1-c1cccs1
Yield: 53 %

Procedure:
At room temperature, 0.1285 g (0.44 mmols) of 2-iodothiophene and 0.0092 g (0.008 mmols) of commercially available tetrakistriphenylphosphine palladium were dissolved in toluene, to which 0.1961 g (0.200 mmols) of 4,4′-bis(dibutoxyphosphoryl)-5,5′-bis(tributylstannyl)-[2,2′]-bithiophene was added at room temperature. Thereafter, the reaction mixture was heated and stirred under reflux for 2 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a potassium fluoride aqueous solution was added, followed by stirring for 1 hour. Thereafter, the solid was removed by celite filtration and the filtrate was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a silica gel column to obtain the specified substance in the form of a red solid at a yield of 0.0634 g (yield: 53%). The thus obtained substance was used as it is for reaction in Example 12(26).
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[S:15][C:14](=[S:16])[NH:13][N:12]=1.[OH-].[Na+].I[CH3:20]>CO>[CH3:20][S:16][C:14]1[S:15][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:12][N:13]=1
Reactant: S=c1[nH]nc(-c2ccc3ccccc3c2)s1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1nnc(-c2ccc3ccccc3c2)s1
Reaction time: 2 h

Procedure:
To a solution of 5-naphthalen-2-yl-3H-[1,3,4]thiadiazole-2-thione (2.8 g, 11.5 mmol) in methanol (100 ml) was added dropwise 1 N sodium hydroxide (12 ml, 12 mmol) at 0° C. After stirred for 10 min. at 0° C. iodomethane (2.0 g, 13.8 mmol) was added dropwise and stirring was continued at 0° C. for 5 min. and at room temperature for 2 h. The volatiles were evaporated in vacuo and to the residue was added water (100 ml). The precipitate was filtered off and dried in vacuo at 50° C. The dried compound (2.4 g) was recrystallised from ethyl acetate (60 ml) affording after drying in vacuo at 50° C. 0.7 g (23%) of the title compound as a solid.
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:40]=[CH:39][C:10]([CH2:11][C:12]2[S:16][C:15]([C:17]3[C:22]([Br:23])=[CH:21][N:20]=[C:19]([NH:24][CH2:25][CH2:26][N:27]4[C:31]([CH3:33])([CH3:32])[C:30](=[O:34])[NH:29][C:28]4=[O:35])[N:18]=3)=[CH:14][C:13]=2[CH2:36][CH2:37]O)=[CH:9][CH:8]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+].[NH:52]1[CH2:56][CH2:55][CH2:54][C@H:53]1[CH2:57][OH:58]>ClCCl.O>[F:6][C:7]1[CH:40]=[CH:39][C:10]([CH2:11][C:12]2[S:16][C:15]([C:17]3[C:22]([Br:23])=[CH:21][N:20]=[C:19]([NH:24][CH2:25][CH2:26][N:27]4[C:31]([CH3:32])([CH3:33])[C:30](=[O:34])[NH:29][C:28]4=[O:35])[N:18]=3)=[CH:14][C:13]=2[CH2:36][CH2:37][N:52]2[CH2:56][CH2:55][CH2:54][C@H:53]2[CH2:57][OH:58])=[CH:9][CH:8]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc(CCO)c(Cc3ccc(F)cc3)s2)n1
Reactant: OC[C@@H]1CCCN1
Agent: CS(=O)(=O)Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc(CCN3CCC[C@H]3CO)c(Cc3ccc(F)cc3)s2)n1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Methanesulfonyl chloride (82 mg, 0.72 mmol) was added to a mixture of 1-(2-(4-(5-(4-fluorobenzyl)-4-(2-hydroxyethyl)thiophen-2-yl)-5-bromopyrimidin-2-ylamino)ethyl)-5,5-dimethylimidazolidine-2,4-dione (200 mg, 0.36 mmol) and diisopropylethylamine (93 mg, 0.72 mmol) in dichloromethane (10 mL) at 0° C. After stirring at 0° C. for 5 h, the solvent was removed in vacuo and 5 mL of N-methylpyrrolidine, a catalytic amount of sodium iodide and (S)-pyrrolidin-2-ylmethanol (0.3 g, 2.97 mmol) were added. The mixture was heated at 100° C. for 15 h and then cooled to rt. 50 mL of water was added and the mixture extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the product purified by flash chromatography eluting with methanol (1M, ammonia)/dichloromethane (1:20) to give the title compound as a slightly yellow solid (105 mg, 46%). MS (M+H)+ 645/647.
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[CH:6][N:7](C)C)C.[NH:16]([C:18]1[N:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:27][CH:26]([OH:28])[CH2:25]2)[CH:19]=1)N.C1COCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[OH:28][CH:26]1[CH2:27][N:24]([C:20]2[N:21]=[CH:22][N:23]=[C:18]([N:16]3[C:4](=[O:15])[C:5]([N:10]4[CH:14]=[CH:13][N:12]=[N:11]4)=[CH:6][NH:7]3)[CH:19]=2)[CH2:25]1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Reactant: NNc1cc(N2CC(O)C2)ncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(N2CC(O)C2)ncn1
Temperature: 25 °C

Procedure:
348 mg (1.7 mmol) of the compound from Example 3A and 300 mg (1.7 mmol) of the compound from Example 11A are initially introduced into a mixture of 6 ml THF and 6 ml ethanol. 63 mg (0.3 mmol) p-toluenesulfonic acid monohydrate are added and the mixture is reacted in a single mode microwave (CEM Explorer) at 130° C. for 1.5 h. The mixture is allowed to cool to RT, a further 50 mg of the compound from Example 3A and a spatula-tip of p-toluenesulfonic acid monohydrate are added and the mixture is heated at 150° C. for 1 h. It is allowed to cool to room temperature and is decanted off from the solid and the solid is washed several times with THF (solid batch 1). The supernatant decanted off and the wash solution are combined, the mixture is concentrated and 5 ml ethanol and 5 ml THF and a spatula-tip of p-toluenesulfonic acid monohydrate are added to the residue obtained. The mixture is reacted again in a single mode microwave (CEM Explorer) at 150° C. for 2 h. It is allowed to cool to RT and the solid formed is filtered off (solid batch 2). The filtrate is concentrated, 3 ml DMSO are added to the residue and purification is carried out by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions are combined and concentrated. The residue is dissolved in ethanol, a little THF is added and the mixture is concentrated, with formation of a precipitate. The solid is filtered off and washed with THF (solid batch 3). The three solid batches obtained are combined and the mixture is dried under a high vacuum.
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:12]([F:13])=[CH:11][C:10]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[N:24]=[CH:23][CH:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:9][C:8]=2[F:26])[CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:28].[Na+]>CO.C(OCC)(=O)C.O>[F:13][C:12]1[CH:11]=[C:10]([N:14]2[CH2:18][C@H:17]([CH2:19][N:20]3[N:24]=[CH:23][CH:22]=[N:21]3)[O:16][C:15]2=[O:25])[CH:9]=[C:8]([F:26])[C:7]=1[C:4]1[CH2:5][CH2:6][S:1](=[O:28])[CH2:2][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C1O[C@@H](Cn2nccn2)CN1c1cc(F)c(C2=CCSCC2)c(F)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=C1O[C@@H](Cn2nccn2)CN1c1cc(F)c(C2=CCS(=O)CC2)c(F)c1
Reaction time: 3 h
Yield: 74.1 %

Procedure:
(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-(1,2,3-triazol-2-ylmethyl)oxazolidin-2-one (Example 88; 0.48 g, 1.3 mmol) was stirred in a mixture of methanol and ethyl acetate (1:1, 20 ml) at ambient temperature. Sodium periodate (0.28 g, 1.4 mmol) in water (10 ml) was added dropwise, and the mixture stirred for 3 hours. Precipitated salts were removed by filtration and washed with ethyl acetate. The filtrate was washed with brine, dried over magnesium sulfate and concentrated to dryness. Crystallisation from dichloromethane gave the title compound (0.38 g). MS (ESP): 395 (MH+) for C17H16F2N4O3S
Reaction SMILES: [CH:1]1[C:6](O)=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:23]([N:25](CC)CC)[CH3:24]>[Pt]>[N:25]1[C:3]2[C:2](=[CH:1][CH:6]=[CH:5][CH:4]=2)[CH:8]=[CH:24][CH:23]=1
Reactant: CCN(CC)CC
Reactant: Cc1cccc(O)c1
Agent: [Pt]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: c1ccc2ncccc2c1

Procedure:
A 5-inch platinum wire was coated with a thin film of the polymer of Example 1, by dipping the wire into a 5% solution of the polymer in a m-cresol/P2O5 mixture. The film-coated wire was neutralized by dipping into a 10% triethylamine--90% ethanol solution and dried in a vacuum oven at 60° C.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:12]([C@@H:21]([CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:22])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:33][NH2:34]>CO>[NH:33]([C:10]([C@@H:9]([C@@H:12]([C@@H:21]([CH2:23][O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[OH:22])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11])[NH2:34]
Reactant: NN
Reactant: O=C[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Solvent: O
Solvent: CO
Product: NNC(=O)[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Reaction time: 24 h

Procedure:
18.1 g (43 mmoles) of 2,3,5-tri-O-benzyl-D-ribose are dissolved in 18 ml of absolute methanol and, while cooling and stirring 21.5 g (43.0 mmoles) of 100% hydrazine hydrate (dissolved in 20 ml of absolute methanol) are added to the solution. After a few minutes the ice bath is removed and stirring is carried out for 24 hours at room temperature. The excess hydrazine hydrate is drawn off (oil pump) together with the methanol in a rotary evaporator at room temperature. A viscous yellow oil remains which is dried further using an oil pump. Yield: 17.9 g (96%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
To the solution of 1-tert-butoxycarbonylpiperazine (1.86 g, 10.0 mmol) and triethylamine (1.67 mL, 12.0 mmol) in dichloromethane (30 mL) was added 4-fluorobenzenesulfonyl chloride (2.34 g, 12.0 mmol), and the mixture was stirred at room temperature for 24 hours. To the mixture was added water (30 mL). and the mixture was concentrated under reduced pressure. To the concentrate was added ethyl acetate (70 mL). The organic layer was washed with water (30 mL), 1N-hydrochloric acid (10 mL×3), a saturated aqueous solution of sodium hydrogencarbonate (10 mL×3), saturated sodium chloride solution (10 mL), successively, dried over magnesium sulfate and concentrated under reduced pressure. To the concentrate was added diisopropyl ether, and the resulting precipitates were collected by filtration. The precipitates were washed with diisopropyl ether, and dried under reduced pressure to give the titled compound (1.94 g, 5.6 mmol, Yield 56%) as white crystals.