Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[CH2:11]([C:18]1([N:25]([CH3:27])[CH3:26])[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:11]([C:18]1([N:25]([CH3:26])[CH3:27])[CH2:23][CH2:22][CH:21]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][CH2:6][CH2:5]3)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Reactant: Nc1ccc2c(c1)CCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C)C1(Cc2ccccc2)CCC(Nc2ccc3c(c2)CCC3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
266 mg 5-aminoindane and 462 mg 4-benzyl-4-dimethylamino-cyclohexanone (see example 3) were dissolved in dry 1,2-dichloroethane under argon and the solution was stirred with 2 g sodium sulfate for 24 hours at RT. 600 mg sodium triacetoxyborohydride were added to this mixture and the mixture was stirred for two hours at RT. For working up, the reaction mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product was chromatographed over silica gel with ethyl acetate. 440 mg 1-benzyl-N′-indan-5-yl-N,N-dimethyl-cyclohexane-1,4-diamine were obtained as a colorless oil. For preparation of the hydrochloride, the base was dissolved in 2-butanone (8 ml), and 1.85 M ethanolic hydrochloric acid (1.75 ml) was added. The solid which had precipitated out was filtered off with suction and dried. 280 mg 1-benzyl-N′-indan-5-yl-N,N-dimethyl-cyclohexane-1,4-diamine hydrochloride were obtained as a white solid (m.p. 200-203° C.)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[CH3:9][S:10][C:11]1[NH:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I.CCOC(C)=O.O>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=[C:11]2[S:10][CH3:9])=[CH:3][CH:4]=1
Reactant: CCOC(=O)c1c[nH]c(SC)n1
Reactant: Ic1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cn(-c2ccc(I)cc2)c(SC)n1
Temperature: 130 °C
Yield: 10.4 %

Procedure:
A mixture of 1,4-diiodobenzene 1-1 (4.00 g, 12.1 mmol), ethyl 2-(methylthio)-1H-imidazole-4-carboxylate (2.26 g, 12.1 mmol), 8-hydroxyquinoline (270 mg, 1.86 mmol) and K2CO3 (3.40 g, 24.6 mmol) in DMSO (12 mL) was degassed with Ar before being charged with CuI (345 mg, 1.82 mmol). The mixture in a sealed tube was heated at 130° C. for 3 days. After cooling down, H2O and EtOAc were added. After being filtered through celite, the organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, eluted with EtOAc in hexane (10-35% EtOAc) to give ethyl 1-(4-iodophenyl)-2-(methylthio)-1H-imidazole-4-carboxylate (0.49 g).
Reaction SMILES: [C:1]([N:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[C:25](OC)=[O:26])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[C:1]([N:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:25][OH:26])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC1CCCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 22 °C
Yield: 91.3 %

Procedure:
A solution of 5.00 g (13.4 mmol) of the above ester in 50 mL of diethyl ether is added dropwise to a mixture of 0.509 g (13.4 mmol) of solid lithium aluminum hydride in 10 mL of ether while stirring under nitrogen. The mixture is brought to a gentle reflux and an additional 6.7 mL (6.7 mmol) of a 1M solution of lithium aluminum hydride in ether is injected by syringe. After refluxing for 2 hrs the reaction is cooled to 22° C. and quenched with 10 mL of methanol. The mixture is partitioned between 100 mL of 0.5M NaOH and 50 mL of ether and then stirred vigorously for 25 minutes and filtered. The ether layer is separated, washed with brine (30 mL), dried (MgSO4) and evaporated to give 4.20 g of (1-tritylpyrrolidin-2-yl)methanol as a white foam. By the method described in preparation 2, this material is used to prepare the title compound which is recrystallized from ethyl acetate/hexane.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][N:18]=1>>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:19][N:18]=1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: BrCc1ccc(Br)nc1
Product: N#Cc1ccc(N(Cc2ccc(Br)nc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-Cyanophenyl) amino]pyrimidine and 2-bromo-5-(bromomethyl)pyridine
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][NH2:19].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C.CCCCCC>[C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH3:11])[N:19]=1)([CH3:9])([CH3:8])[CH3:1]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: Cc1ccccc1NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCCCCC
Product: Cc1ccccc1-n1nc(C(C)(C)C)cc1N
Yield: 92.5 %

Procedure:
4,4-Dimethyl-3-oxopentanenitrile (36.7 g, 0.29 mol), (2-methylphenyl)hydrazine hydrochloride (47.7 g, 0.29 mol), and glacial acetic acid (7.03 g, 6.7 mL, 0.12 mol) were dissolved in abs ethanol (585 mL) and heated under reflux for 18 h. After removal of the solvent under reduced pressure, EtOAc and water (500 mL each) were added, then sodium bicarbonate (42 g, 0.50 mol) was carefully added. After addition of hexane (500 mL), the organic phase was separated, washed with brine (500 mL), and dried over Na2SO4. The mixture was then filtered through a pad of silica gel (500 g) on a sintered glass funnel. The pad was eluted with hexanes/EtOAc (1:1, v/v), and the filtrate was concentrated under reduced pressure. The resulting solid was triturated with hexanes/EtOAc (9:1, v/v), filtered, washed and dried in vacuo to afford a colorless solid (61.5 g, 93%). 1H NMR (400 MHz, CD2Cl2) δ 1.29 (s, 9H), 2.12 (s, 3H), 3.56 (br, 2H), 5.48 (s, 1H), 7.28 (m, 2H), 7.31 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[N:4]=[C:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].[C:21]([O-:24])(O)=O.[Na+].C(Cl)(Cl)Cl>C(O)(=O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[C:9]([CH:21]=[O:24])=[CH:10][CH:5]=[CH:6][CH:7]=3)[C:5]=2[N:4]=[C:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19]
Reactant: O=C([O-])O
Reactant: Cc1cccc2c1nc(-c1ccccc1[N+](=O)[O-])n2C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cn1c(-c2ccccc2[N+](=O)[O-])nc2c(-c3ccccc3C=O)cccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 42 %

Procedure:
A solution of ceric ammonium nitrate (2.19 g, 4.0 mmol) in acetic acid (10 mL, 50%) was added to a stirred solution of N-methyl-4-methyl-2-(2-nitrophenyl)-benzimidazole (0.27 g, 1.0 mmol) in same acid (5.0 mL, 50%) dropwise at 90° C. and the mixture was stirred for 6 hours. The mixture was then cooled to room temperature, neutralized with saturated NaHCO3 to PH=7-8,extracted with CHCl3 and the extract dried over Na2SO4. Concentration using a rotary evaporator and subsequent column chromatography on silica gel using hexane/ethyl acetate (1:3) as the eluent to give N-methyl-2-(2-nitrophenyl)-benzimidazole-4-benzaldehyde (115 mg, 42%) as a light-yellow solid. Rf=0.28 (hexane/ethyl acetate=1:3); 1H NMR (250 MHz, CDCl3) δ 3.68 (s, 3H), 7.47 (t, J=7.8 Hz, 1H), 7.66-7.74 (m, 2H), 7.77-7.86 (m, 2H), 7.90 (d, J=7.6 Hz, 1H), 8.28 (dd, J,=7.9 Hz, J2 =1.5 Hz, 1H), 10.81 (s, 1H). HRMS: Calcd for C15H11N3O3 281.0800, found 281.0814.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[Br:11]Br>C(O)(=O)C>[Br:11][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: BrBr
Reactant: Clc1ccc2nccn2n1
Solvent: CC(=O)O
Product: Clc1ccc2ncc(Br)n2n1
Yield: 60 %

Procedure:
The 6-Chloro-imidazo[1,2-b]pyridazine (4) (500 mg, 0.0032 mol) was taken in glacial acetic acid (5 ml) and bromine (0.4 ml) was added slowly at room temperature. After 20 mins solid precipitated out which was filtered. The solid was washed with ether (3×15 ml) and dried under air to furnish 3-Bromo-6-chloro-imidazo[1,2-b]pyridazine (5) (400 mg, yield=60%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].O[N:27]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])[NH2:29].CCN(C(C)C)C(C)C>>[CH3:13][CH:10]1[CH2:11][CH2:12][CH:8]([CH3:7])[N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]2[O:20][N:29]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])[N:27]=2)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]
Reactant: COc1ccccc1C(N)=NO
Reactant: CC1CCC(C)N1c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(N3C(C)CCC3C)c([N+](=O)[O-])c2)n1

Procedure:
Oxalyl chloride (152 mg; 1.2 mmol; 3 eq.), Intermediate 25 (106 mg; 0.4 mmol; 1 eq.), Intermediate 1 (66 mg; 0.4 mmol, 1 eq.) and DIEA (155 mg; 1.2 mmol; 3 eq.) were reacted according to general procedure 2. Purification by precipitation from Et2O/n-pentane afforded the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([S:8][CH3:9])[S:5][C:4]=1[C:10]1[NH:11][C:12]2[C:13]([N:18]=1)=[N:14][CH:15]=[CH:16][CH:17]=2.[OH:19]O>>[CH3:1][O:2][C:3]1[CH:7]=[C:6]([S:8]([CH3:9])=[O:19])[S:5][C:4]=1[C:10]1[NH:11][C:12]2[C:13]([N:18]=1)=[N:14][CH:15]=[CH:16][CH:17]=2
Reactant: COc1cc(SC)sc1-c1nc2ncccc2[nH]1
Reactant: OO
Product: COc1cc(S(C)=O)sc1-c1nc2ncccc2[nH]1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
3.80 g (13.7 mmoles) of the 2-(3-methoxy-5-methylthio-2-thienyl)-1H-imidazo[4,5-b]pyridine, obtained in Example 1, are dissolved in 80 ml of glacial acid, 1.63 g (14.4 mmoles) of 30% aqueous solution of hydrogen peroxide are added and stirred at room temperature for 30 hours. The solution is concentrated in vacuo, the residue is dissolved in a small amount of water, neutralized with a saturated solution of sodium hydrogen carbonate, and the precipitating crystals are aspirated and dried. Yield: 3.95 g (98%), m.p. (ethanol) 233°-235° C. (dec.).
Reaction SMILES: O1CCOCC1.FC(F)(F)C1C=CC([N+]([O-])=O)=CC=1N.[N+](C1C=CC(C(F)(F)F)=CC=1N)([O-])=O.C[O:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=1>O>[C:37]([OH:44])(=[O:36])[C:38]1[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=1
Reactant: COC(=O)c1cccnc1
Agent: Nc1cc(C(F)(F)F)ccc1[N+](=O)[O-]
Agent: Nc1cc([N+](=O)[O-])ccc1C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccnc1
Yield: 46.4 %

Procedure:
Add 20 ml of dioxan and 10 g of 2-trifluoromethyl-5-nitroaniline or 2-nitro-5-trifluoromethyl-aniline to 12 g of nicotinic acid methyl ester. Reflux for 60 hours; then pour the reaction mass into water. Filter the resulting solid and recrystallize several times from ethanol. 5 g of (I) or (III) are thus obtained with the same melting-point values as the products of Examples 1 and 3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:17]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18]1.O(C(C)(C)C)[Na].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[S:13]1[CH:14]=[CH:15][N:16]=[C:12]1[NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: O=C(O)C1CCNC1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: O=C(O)C1CCN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)C1
Temperature: 100 °C
Yield: 43.5 %

Procedure:
Prepared using general procedure 31. A mixture of 4-bromo-N-(thiazol-2-yl)benzenesulfonamide (4.70 g, 14.7 mmol), pyrrolidine-3-carboxylic acid (3.66 g, 22.1 mmol, 1.5 eq.), NaO-t-Bu (7.62 g, 79.3 mmol, 5.4 eq.), 2-(dicyclohexylphosphino)-2′, 6′-dimethoxybiphenyl (0.722 g, 1.76 mmol, 12 mol %) and tris(dibenzylideneacetone)-dipalladium (0.40 g, 3 mol %) in toluene (45 mL) was heated at 100° C. for 20 hours. The brown suspension was cooled to room temperature. Purification via silica gel chromatography using 1-10% MeOH in CH2Cl2 gave 1-(4-(N-thiazol-2-ylsulfamoyl)-phenyl)pyrrolidine-3-carboxylic acid (2.26 g, 43%). 1H NMR (300 MHz, DMSO-d6): δ 7.55 (d, J=8 Hz, 2H); 7.17 (dd, J=4.7, 1.1 Hz, 1H); 6.73 (dd, J=4.7, 1.1 Hz, 1H); 6.55 (d, J=8 Hz, 2H); 3.50-3.23 (m, 4H, partly obscured by water from DMSO-d6); 3.20-3.15 (m, 1H); 2.23-2.09 (m, 2H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1>FC(F)(F)C(O)=O>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCSc2nc3ccccc3[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2[nH]c(SCCN3CCNCC3)nc2c1
Reaction time: 0.5 h
Yield: 152.3 %

Procedure:
1-[2-(benzimidazol-2-ylthio)ethyl]-4-tert-butoxycarbonyl piperazine (13.83 g, 38.15 mmol) was dissolved in trifluoroacetic acid (75 mL) in an ice bath, and the mixture was stirred at the same temperature for 30 minutes, and after elevating the temperature to room temperature, the mixture was stirred for another 40 minutes. The reaction solution was concentrated under reduced pressure, and the resulting crystals were recrystallized from methanol-diethyether to give 15.24 g of 1-[2-(benzimidazole-2-ylthio)ethyl]piperazine.3 trifluoroacetate (66%) as pale yellow powdery crystals.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[CH3:27][O:28][CH2:29][C:30]1[N:31]2[CH:37]=[N:36][CH:35]=[C:32]2[S:33][CH:34]=1>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:36]3[CH:35]=[C:32]4[S:33][CH:34]=[C:30]([CH2:29][O:28][CH3:27])[N+:31]4=[CH:37]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: COCc1csc2cncn12
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: COCc1csc2cn(CC3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)c[n+]12
Yield: 10.3 %

Procedure:
The same procedure as in Example 1 was repeated except that 76 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 53 mg of 3-methoxymethylimidazo[5,1-b]thiazole were used, thereby obtaining 8.4 mg of the title compound.
Reaction SMILES: S([O-])([O-])(=O)=O.[NH4+].[NH4+].[Cl:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[NH:11][CH:12]=[N:13]2.C[Si](C)(C)N[Si](C)(C)C.C(O[CH:31]1[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:49])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:37][C@H:32]1[O:33][C:34](=[O:36])[CH3:35])(=O)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+]>>[C:34]([O:33][C@@H:32]1[CH2:37][C@@H:38]([CH2:40][O:41][C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:49])[O:39][C@H:31]1[N:13]1[CH:12]=[N:11][C:10]2[C:14]1=[N:15][CH:16]=[N:17][C:9]=2[Cl:8])(=[O:36])[CH3:35]
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)C[C@H]1OC(C)=O
Reactant: Clc1ncnc2nc[nH]c12
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Product: CC(=O)O[C@@H]1C[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)ncnc21
Reaction time: 0.17 h

Procedure:
A catalytic amount of ammonium sulfate was added to a mixture of 6-chloropurine (0.56 grams, 3.62 mmol) and hexamethyldisilazane (15 mL), and the mixture was refluxed for 3 hours. The solvent was evaporated under reduced pressure, and the residue was co-evaporated with dry toluene (3×10 mL). The white solid residue was dissolved in dry methylene chloride (40 mL) and 1,2-di-O-acetyl-5-O-benzoyl-3-deoxy-ribofuranose, (1.00 g, 3.10 mmol) was added. After 10 minutes of stirring, trimethylsilyl triflate (0.8 mL) was added, and the solution stirred at room temperature for an additional 3 hours. A solution of cold, saturated sodium bicarbonate was added. After 5 minutes stirring, the organic layer was separated and the aqueous solution extracted with methylene chloride (2×30 mL). The organic layers were combined and dried over sodium sulfate, to give (5S,2R,3R)-2-(6-chloropurin-9-yl)-5-(phenylcarbonyloxymethyl)oxolan-3-yl acetate, which was purified by crystallization from methanol. The mother liquor was chromatographed on a Chromatotron, to provide additional product.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[C:9]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:26])=[C:21](F)[C:22]=3[Cl:24])[C:17](=[O:27])[C:16]([C:28]([OH:30])=[O:29])=[CH:15]2)[N:8]=1.Cl.Cl.[NH2:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:33][CH:34]1[CH2:37][N:36]([C:21]2[C:22]([Cl:24])=[C:23]3[C:18]([C:17](=[O:27])[C:16]([C:28]([OH:30])=[O:29])=[CH:15][N:14]3[C:9]3[N:8]=[C:7]([NH2:6])[C:12]([F:13])=[CH:11][N:10]=3)=[CH:19][C:20]=2[F:26])[CH2:35]1
Reactant: NC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ncc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)ncc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
To 100 mg of N,N-dimethylformamide were added 25 mg of 1-(4-amino-5-fluoropyrimidine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 20 mg of 3-aminoazetidine dihydrochloride, and 50 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour. After adding 0.2 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 10 mg of the title compound as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=3[S:17][C:15]=2[N:16]=1>>[Cl:10][C:11]1[N:12]=[C:13]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=3[S:17][C:15]=2[N:16]=1
Reactant: NCc1ccc(F)cc1
Reactant: Clc1nc(Cl)c2c3c(sc2n1)CCCC3
Product: Fc1ccc(CNc2nc(Cl)nc3sc4c(c23)CCCC4)cc1

Procedure:
Following the procedure of Example 1, the reaction of 4-fluorobenzylamine with 2,4-dichloro-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidine yields 2-chloro-5,6-,7,8-tetrahydro-4-(4-fluorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:11][CH3:12])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[C:13]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:11][CH3:12])[C:8]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[CH:30]=3)[CH2:25][CH2:24]2)=[O:9])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CCC(C(=O)O)(c1ccccc1)c1ccccc1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(CC)(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 15 was prepared from 2,2-diphenylbutanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.43–7.38 (m, 1H), 7.37–7.29 (m, 9H), 7.28–7.21 (m, 4H), 6.90 (d, 1H, J=8.2 Hz), 6.43 (t, 1H, J=4.1), 3.32 (q, 2H, J=6.5 Hz), 2.95–2.89 (m, 2H), 2.45 (q, 2H, J=7.9 Hz), 2.43–2.35 (m, 3H), 2.27 (t, 2H, J=6.5 Hz), 2.01–1.92 (m, 2H), 1.78–1.59 (m, 6H), 1.24 (t, 3H, J=7.9 Hz), 0.79 (t, 3H, J=6.5 Hz); ESMS m/e: 512.3 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH3:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:32]O)=[N:24]1>C(#N)C>[CH3:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:32][Br:20])=[N:24]1
Reactant: Cn1nc(CO)c2ccccc21
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Cn1nc(CBr)c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.5 %

Procedure:
To a stirring solution of 692 mg (2.64 mmol, 1.3 equiv) of triphenylphosphine in 10 mL of acetonitrile at 0° C. is added 125 μL (2.44 mmol, 1.2 equiv) of Br2. The resulting orange-yellow suspension is stirred 10 min at 0° C., then a solution of 330 mg (2.03 mmol) of (1-Methyl-1H-indazol-3-yl) methanol, prepared as in Intermediate 24, in 5 mL of acetonitrile is added over 2 min. The resulting solution is stirred 1.5 h at RT, and the solvent is removed in vacuo. Purification of the residue by silica gel flash column chromatography using hexane/EtOAc 5/1 as eluent afforded 185 mg of the title compound as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ7.82 (d, 1H), 7.40 (m, 2H), 7.22 (m, 1H), 4.82 (s, 2H), 4.03 (s, 3H); Rf =0.87 in hexane/EtOAc 1/1.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:31])[CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:47]1([CH2:53][C:54]([N:56]=[C:57]=[S:58])=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(OCC)C>C(O)C.C1(C)C=CC=CC=1.CCCCCC>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:57]([NH:56][C:54](=[O:55])[CH2:53][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[S:58])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ncn3)CC2)CC1
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)ncn3)CC2)CC1
Reaction time: 0.08 h
Yield: 15.6 %

Procedure:
4-(1-Methylpiperidin-4-yl)piperazine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (110 mg) was dissolved in ethanol (1 ml), and then (S)-(+)-10-camphorsulfonic acid (60 mg) was added thereto, followed by stirring for 5 min. A 0.25 M solution of 2-phenylacetyl isothiocyanate in toluene (1.54 ml) was added thereto, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (30 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (20 ml), water (20 ml), brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; heptane:ethyl acetate=1:5 to 1:10, then ethyl acetate). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (1.5 ml) and hexane (3.0 ml) were then added to suspend. The solid was filtered off, and dried under aeration to provide the titled compound (24.3 mg, 15.6%) as white powder.