Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.Br[CH2:14][C@H:15]([CH3:25])[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>CCCCCCC.CCOC(C)=O>[Si:18]([O:17][CH2:16][C@@H:15]([CH3:25])[CH2:14][N:7]1[C:6]2[CH:12]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20]
Reactant: O=C1COc2ccc(F)cc2N1
Reactant: C[C@@H](CBr)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)CN1C(=O)COc2ccc(F)cc21
Yield: 76.1 %

Procedure:
6-Fluoro-4H-benzo[1,4]oxazin-3-one (95MF88) (2.54 g, 15.2 mmol), (R)-3-bromo-2-methylpropoxy-tert-butyldimethylsilane (4.07 g, 15.2 mmol) and Cs2CO3 (12.38 g, 38 mmol) were mixed according to GP7. CC (SiO2; Heptane/EtOAc 9:1) gave the title compound (111MF01) (4.09 g, 76%). 1H NMR (CDCl3) δ 6.93-6.87 (m, 1H), 6.92-6.88 (m, 1H), 6.68-6.63 (m, 1H), 4.56 (m, 2H), 4.01 (m, 1H), 3.78 (m, 1H), 3.58 (m, 1H), 3.45 (m, 1H), 2.11 (m, 1H), 0.92 (s, 12H), 0.06 (d, J=0.8 Hz, 6H); 13C NMR (CDCl3) δ 164.8, 158.5 (d, J=239.9 Hz), 141.6 (d, J=2.7 Hz), 130.1 (d, J=10.7 Hz), 117.6 (d, J=9.3 Hz), 109.6 (d, J=23.1 Hz), 103.6 (d, J=28.8 Hz), 67.8, 65.9, 44.2, 34.5, 26.0, 18.4, 14.9, −5.4, −5.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[S:11][CH:12]([CH3:14])[CH3:13]>[Ni].CO>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Sc1c(Cl)cccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CC(C)Sc1c(N)cccc1Cl
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 98.3 %

Procedure:
46.6 g of 2-chloro-6-nitrophenyl-isopropylsulfane, 160 ml of methanol and 5 g of Raney nickel 55 (water-moist, washed with methanol) were introduced into a steel autoclave. After flushing with nitrogen and hydrogen, the mixture was heated to 50° C., while stirring, and hydrogenation was carried out by forcing in hydrogen up to a maximum of 2 bar. After 2.5 hours, the uptake of hydrogen had ended. The mixture was then cooled to room temperature, the hydrogen was let down and the nickel catalyst was removed by filtration with suction and washed with methanol. After removal of the solvent, 39.9 g of 2-amino-6-chlorophenyl-isopropylsulfane were obtained in a purity of 97.8% (GC), which corresponds to 97% of theory. Only 0.2% of 2-aminophenylisopropylsulfane (formed by dehalogenation) was found as an impurity. Pure, colorless 2-amino-6-chlorophenyl-isopropylsulfane with a content of more than 99% was obtained by distillation at a boiling point of 144° C. at 11 mbar.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.O.[CH2:23](O)[CH3:24]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:23][CH3:24])=[O:17])=[CH:11][CH:10]=2)=[CH:19][CH:20]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CCO
Agent: Cl
Solvent: O
Product: CCOC(=O)Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A solution of 27.3 g of [p-(p-nitrophenoxy)phenyl]acetic acid in 270 ml of ethanol is cooled to 0° C. and saturated with dry HCl gas over 31/2 hours. The resulting deep red solution is heated to reflux and maintained at reflux overnight. A yellow crystalline solid separates on cooling. The entire mixture is poured into 500 ml of water and extracted with three 200 ml portions of benzene. The combined extracts are washed with two 150 ml portions of water, two 150 ml portions of saturated NaHCO3, 150 ml of saturated brine, and dried over MgSO4. Evaporation of the solvent at reduced pressure affords an oil which yields yellow crystals from 50 ml of ethanol, mp 70.5°-73° C. Recrystallization from ethanol affords yellow prisms, mp 70.5°-73° C.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:9]=2)[NH:4][CH:3]=1.C(N(CC)CC)C.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:24]1([S:30]([N:4]2[C:5]3=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=4)[CH:9]=[C:10]3[C:2]([I:1])=[CH:3]2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cn1cc(-c2cnc3[nH]cc(I)c3c2)cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccccc2)cn1
Reaction time: 2 h
Yield: 90 %

Procedure:
The 3-iodo-5-(1-methylpyrazol-4-yl)-7-azaindole prepared in accordance with WO 2008155000 (34 g) is suspended in 350 ml of dichloromethane, and 43.5 ml of triethylamine and 2.6 g of 4-(dimethylamino)pyridine are added. 17.5 ml of benzenesulfonyl chloride which has previously been diluted with 150 of dichloromethane are added to this mixture. After 2 h, the reaction is complete. The organic phase is extracted three times with water, and the organic phase is dried over sodium sulfate. After removal of the solvent, the residue is taken up in ethyl acetate, the precipitate is filtered off, rinsed with ethyl acetate, and the product is dried in air to give 44 g (90%) of beige crystals; (Rt: 2.467 min; M+H+: 464.9).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:14]([CH3:25])[CH2:13]2)=[N:4][N:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.[F-].[Cs+]>O1CCOCC1>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:14]([CH3:25])[CH2:13]3)=[N:4][N:3]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccccc23)CCN1C(=O)OC(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COc1ccc(-c2nnc(N3CCN(C(=O)OC(C)(C)C)[C@@H](C)C3)c3ccccc23)cc1
Temperature: 95 °C
Yield: 97 %

Procedure:
Treat a degassed mixture of (S)-tert-butyl 4-(4-chlorophthalazin-1-yl)-2-methylpiperazine-1-carboxylate (0.81 g, 2.23 mmol), 4-methoxybenzeneboronic acid (1.07 g, 7.05 mmol) and cesium fluoride (1.05 g, 6.94 mmol) in 1,4-dioxane (30 mL) with (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) chloride (0.27 g, 0.33 mmol). Heat the resulting mixture at 95° C. overnight. Partition the reaction mixture between water and EtOAc. Extract the aqueous layer with EtOAc. Wash the organic portion with water and brine, dry over Na2SO4, and concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (gradient of 15 to 70% EtOAc in hexanes) to provide the title compound (0.94 g, 96%). ES/MS m/z 435.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH2:30]([O:37][CH2:38][C@@H:39]([NH:44][CH3:45])[CH2:40][CH:41]([CH3:43])[CH3:42])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][CH2:38][C@@H:39]([N:44]([CH3:45])[C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([C:8]2[C:7]3[CH:26]=[C:27]([O:28][CH3:29])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=3[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][N:13]([CH3:16])[CH2:14]3)[N:9]=2)=[CH:25][CH:24]=1)[CH2:40][CH:41]([CH3:42])[CH3:43])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Reactant: CN[C@H](COCc1ccccc1)CC(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C)[C@H](COCc3ccccc3)CC(C)C)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)benzoic acid and N—((S)-1-benzyloxymethyl-3-methyl-butyl)-N-methyl-amine as described for example 1.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=2)[CH2:2]1.[CH3:15][N:16]=[C:17]=[O:18]>>[CH3:15][NH:16][C:17]([N:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:7]=[CH:8][C:9]([C:10]([NH2:12])=[O:11])=[CH:13][CH:14]=2)[CH2:2]1)=[O:18]
Reactant: NC(=O)c1ccc(OC2CNC2)cc1
Reactant: CN=C=O
Product: CNC(=O)N1CC(Oc2ccc(C(N)=O)cc2)C1

Procedure:
The compound was prepared from 4-(3-azetidinyloxy) benzamide and methylisocyanate as described in Example 7 of U.S. Pat. No. 4,226,861, m.p. 208°-210° C.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH2:15]([Cl:18])[CH:16]=[CH2:17]>C1C=CC=CC=1>[Cl:18][CH2:15][CH:16]1[CH:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH:13]([C:14]3[C:5]2=[CH:4][CH:3]=[CH:2][CH:1]=3)[CH2:17]1
Reactant: C=CCCl
Reactant: c1ccc2cc3ccccc3cc2c1
Solvent: c1ccccc1
Product: ClCC1CC2c3ccccc3C1c1ccccc12
Temperature: 220 °C

Procedure:
Anthracene (75 gm) was combined with allyl chloride (150 gm) and benzene (375 gm) in a Parr bomb and heated to 220° C. for 13 hours. The contents were filtered and the benzene was removed on a rotary evaporator. The residue was recrystallized from ethanol to provide the product as a white solid (mp=108°-111° C.).
Reaction SMILES: C([O:3][C:4](=[O:9])[C:5]([OH:8])([CH3:7])[CH3:6])C.[H-].[Na+].[CH2:12]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28]Cl)=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:12]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:3])=[O:9])=[N:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(C)(C)O
Reactant: ClCc1nn(Cc2ccccc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(OCc1nn(Cc2ccccc2)c2ccccc12)C(=O)O
Temperature: 90 °C

Procedure:
Ethyl-2-hydroxyisobutyrate (18.5 g, 140 mmol, 1.2 eq.), toluene (100 mL) and DMF (20 mL) were placed in a three-necked flask fitted with a mechanical stirrer and a reflux condenser under an inert atmosphere. A dispersion of 60% NaH (5.6 g, 140 mmol, 1.2 eq.) was added to the mixture in portions over a period of approximately 1.5 hours. A solution of 1-benzyl-3-chloromethyl-1H-indazole (30 g, 117 mmol, 1 eq.) in toluene (90 mL) and DMF (60 mL) was then added dropwise. The reaction mixture was heated to approximately 90° C. and kept at that temperature until the reaction was complete (checked by TLC, approximately 10 hours). After cooling to room temperature the mixture was washed with acidified water and water. The organic phase was concentrated under reduced pressure and the oily residue obtained was treated with 10 M NaOH (36 mL) at reflux temperature for at least 3 hours. The product, which was precipitated out by the addition of concentrated HCl, was filtered and dried. Yield: 32.3 g of white solid (85%).
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@H:7]([OH:8])[C@@H:6]([CH2:9][OH:10])[O:5][C@H:4]1[N:11]1[C:21]2[N:20]=[C:18]([NH2:19])[NH:17][C:15](=[O:16])[C:14]=2[N:13]=[CH:12]1.C[Si](Cl)(C)C.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29].[NH4+].[OH-]>N1C=CC=CC=1.O>[C:27]([NH:19][C:18]1[NH:17][C:15](=[O:16])[C:14]2[N:13]=[CH:12][N:11]([C:21]=2[N:20]=1)[C@@H:4]1[O:5][C@H:6]([CH2:9][OH:10])[C@@H:7]([OH:8])[C@H:3]1[O:2][CH3:1])(=[O:31])[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)C(=O)Cl
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Agent: C[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Reaction time: 0.33 h

Procedure:
2'-O-methylguanosine (3.5 g) in pyridine (100 ml) was treated with trimethylsilyl chloride (9 ml, 6 eq) and isobutyryl chloride (6.2 ml) at RT for 4 hr. The reaction mixture was cooled in an ice bath, H2O (20) was added and stirring continued for an additional 20 min. NH4OH (20 ml) was added and after stirring for 30 min the reaction mixture was evaporated. The residue was triturated with H2O, filtered and the filtrate evaporated and purified by silica gel chromatography as per the procedure of Example 4 to yield the product as an off white solid (1.5 g). 1H NMR (DMSO-d6) δ 1.1 [d, 6, CH(CH3)2 ], 2.77 [m, 1, CH(CH3)2 ], 3.33-3.6 (m, 5, OCH3, H-5'), 3.93 (m, 1, H-4'), 4.22 (m, 1), 4.3 (m, 1), 5.1 (t, 1, 5'-OH), 5.28 (d, 1, 3'-OH), 5.9 (d, 1, H-1'), 8.28 (s, 1, H-8) and 11.9 (br s, 1, NH).
Reaction SMILES: [Cl:1][CH:2]([CH2:7][C:8]([Cl:14])([Cl:13])[C:9]([Cl:12])([F:11])[F:10])[CH2:3][C:4](O)=[O:5].S(Cl)([Cl:17])=O>CN(C)C=O>[Cl:1][CH:2]([CH2:7][C:8]([Cl:14])([Cl:13])[C:9]([Cl:12])([F:11])[F:10])[CH2:3][C:4]([Cl:17])=[O:5]
Reactant: O=C(O)CC(Cl)CC(Cl)(Cl)C(F)(F)Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CC(Cl)CC(Cl)(Cl)C(F)(F)Cl

Procedure:
276 g of 2,4,4,5-tetrachloro-5,5-difluoropentane-1-carboxylic acid, 300 ml of thionyl chloride and 1 ml of N,N-dimethylformamide are mixed together, and the mixture is heated within 1 hour to 60° C. and finally refluxed for 1 hour. After the excess thionyl chloride has been distilled off, the residue is fractionally distilled to thus obtain 250.2 g (85% of theory) of 2,4,4,5-tetrachloro-5,5-di-fluoropentane-1-carboxylic acid chloride in the form of a clear liquid, which boils at 95°-97° C./2000 Pa.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([CH2:20][OH:21])=[CH:5][N:4]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([CH:20]=[O:21])=[CH:5][N:4]=1
Reactant: COc1ccc(CNc2nc(SC)ncc2CO)cc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2nc(SC)ncc2C=O)cc1Cl
Temperature: 25 °C

Procedure:
To a suspension of 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-hydroxymethylpyrimidine (prepared in the above (1)) 25.10 g in chloroform 150 ml is a manganese dioxide powder 37.6 g (one and a half of the starting material) and the mixture is vigorously stirred at room temperature for a day. Further the mixture is treated with a manganese dioxide powder 12.6 g (a half of the starting material) and the mixture is stirred for three nights. The insoluble materials are filtered off with Celite and the filtrate is concentrated in vacuo. The residue is suspended in ethyl acetate-isopropyl ether. The precipitate is filtered and washed with isopropyl ether and hexane in order, to give 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-formylpyrimidine as colorless crystals, 22.43 g. mp 124–125° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH2:6][CH:7]([OH:10])[CH2:8][OH:9])[CH3:2].[C:12]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH2:6][CH:7]([OH:10])[CH2:8][O:9][Si:16]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:18])[CH3:17])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)CCC(O)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC(O)CO[Si](C)(C)C(C)(C)C
Reaction time: 18 h

Procedure:
A solution of 4,5-dihydroxy-pentanoic acid ethyl ester, (7 g, 43.2 mmol) and 4-dimethylaminopyridine (0.2 g, 1.73 mmol) in dichloromethane (145 mL) at room temperature under nitrogen is treated with tert-butyl-dimethyl-silyl chloride (7.8 g, 51.85 mmol) and triethylamine (6.9 mL, 47.52 mmol) and stirred 18 h. The mixture is diluted with dichloromethane (100 mL), washed with water (100 mL), saturated ammonium chloride solution, and brine. The solution is filtered and concentrated in vacuo to yield the title compound, 11.85 g (99%), as a colorless oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:29][N:28]([CH3:30])[CH2:27][CH2:26][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.[NH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][C@@H:34]1[CH2:42][OH:43]>CS(C)=O>[CH3:30][N:28]1[CH2:27][CH2:26][C:9]2[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[CH:23][N:22]=[C:21]4[CH3:25])=[CH:16][CH:15]=3)[N:12]=[C:7]([N:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:35][C@@H:34]3[CH2:42][OH:43])[C:8]=2[CH2:29]1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C)CC3)cc1
Reactant: OC[C@H]1Cc2ccccc2N1
Solvent: CS(C)=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(N4c5ccccc5C[C@@H]4CO)n2)CN(C)CC3)cc1
Yield: 47.4 %

Procedure:
6-Methyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (65 mg, 0.14 mmol, Example 9a) and (R)-indolin-2-ylmethanol (20.70 mg, 0.14 mmol) in DMSO (3 mL) were heated to 80° C. in a microwave reactor for 2 h. The reaction mixture was filtered and purified by preparative HPLC, yielding (R)-(1-(6-methyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)indolin-2-yl)methanol (31.0 mg, 47.8%).
Reaction SMILES: O.[Na].[SH:3][C:4]1[N:8]([CH3:9])[N:7]=[N:6][N:5]=1.Cl[CH2:11][C:12](=[O:14])[CH3:13]>C(O)C>[CH3:9][N:8]1[C:4]([S:3][CH2:11][C:12]([CH3:13])=[O:14])=[N:5][N:6]=[N:7]1
Reactant: CC(=O)CCl
Reactant: Cn1nnnc1S
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC(=O)CSc1nnnn1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3.12 g (0.02 mol) of 5-mercapto-1-methyltetrazole sodium salt hydrate in 60 ml of absolute ethanol was added dropwise, 2.06 g (0.2 mol) of chloroacetone. After stirring for 20 hours at room temperature, the ethanol was evaporated in vacuo. The residue was dissolved in methylene chloride and was washed with water and then brine prior to drying over Na2SO4. Evaporation of the methylene chloride solution gave 1-methyl-5-acetonylthiotetrazole that was purified by flash chromatography on silica gel to yield 0.94 g of the 5-acetonylthio-1-methyltetrazole product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)#[N:2].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:48]2[CH:49]=[N:50][C:51]([F:54])=[CH:52][CH:53]=2)(N)[C@@H:44]([NH2:46])[CH3:45])=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]2[NH:46][C@@H:44]([CH3:45])[C:43]([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)([C:48]3[CH:49]=[N:50][C:51]([F:54])=[CH:52][CH:53]=3)[N:2]=2)[CH:8]=1)#[N:10]
Reactant: C[C@H](N)C(N)(c1ccc(F)cc1)c1ccc(F)nc1
Reactant: N#Cc1ccnc(C#N)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@@H]1NC(c2cc(C#N)ccn2)=NC1(c1ccc(F)cc1)c1ccc(F)nc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 78.4 %

Procedure:
2,4-Dicyanopyridine (46.5 mg) and ytterbium trifluoromethanesulfonate (24 mg) were added to a solution of the optical active (2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine (100 mg) described in Reference Example 5-1 in toluene (0.25 mL), and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate aqueous solution, water and saturated sodium chloride aqueous solution in this order, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was evaporated in vacuo. The obtained residue was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=2:3) to give the objective compound (106 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:15]([C:19](=[O:30])[NH:20][C@H:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][OH:23])=[C:16]([CH3:18])[N:17]=2)[CH:9]=[C:10]([C:12](O)=[O:13])[CH:11]=1.CN1CCOCC1.ClC(OCC(C)C)=O>C(COC)OC>[F:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:15]([C:19]([NH:20][C@H:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][OH:23])=[O:30])=[C:16]([CH3:18])[N:17]=2)[CH:9]=[C:10]([CH2:12][OH:13])[CH:11]=1
Reactant: Cc1nc2c(OCc3ccccc3F)cc(C(=O)O)cn2c1C(=O)N[C@@H](CO)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: COCCOC
Product: Cc1nc2c(OCc3ccccc3F)cc(CO)cn2c1C(=O)N[C@@H](CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
To a mixture of 100 mg of 8-[(2-fluorobenzyl)oxy]-3-{[(1R)-2-hydroxy-1-phenylethyl]carbamoyl}-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid, 28 μl of 4-methylmorpholine, and 0.7 ml of dimethoxyethane was added 34 μl of isobutyl chloroformate under ice-cooling, followed by stirring at room temperature overnight. The insoluble material was removed by filtration, and then to the filtrate were added 16 mg of sodium borohydride and 210 μl of methanol under ice-cooling, followed by stirring for 30 minutes under ice-cooling. To the reaction mixture were added a saturated aqueous ammonium chloride solution and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 21 mg of 8-[(2-fluorobenzyl)oxy]-6-(hydroxymethyl)-N-[(1R)-2-hydroxy-1-phenylethyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:4]=2[S:3]1.[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:14]1([C:11]([C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2](=[O:1])[S:3][C:4]=3[CH:10]=2)=[O:13])[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12
Reactant: O=C(O)c1ccc2[nH]c(=O)sc2c1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]c(=O)sc2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 74 %

Procedure:
The title compound is prepared from 2-oxo-2,3-dihydro-benzothiazole-6-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 74% of theory; LC (method 3): tR=2.28 min; Mass spectrum (ESI+): m/z=351 [m+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14]C)=[O:13])=[CH:9][C:8]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:7]([O:20]C)[CH:6]=2.Br>C(O)(=O)C.O>[OH:20][C:7]1[CH:6]=[C:5]2[C:10]([C:11]([C:12]([OH:14])=[O:13])=[C:2]([CH3:1])[C:3]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)=[N:4]2)=[CH:9][C:8]=1[S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(S(C)(=O)=O)cc12
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(S(C)(=O)=O)cc2c1C(=O)O
Temperature: 25 °C
Yield: 90.8 %

Procedure:
A solution of methyl 3-methyl-7-(methyloxy)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (4.95 g, 10.92 mmol) and hydrobromic acid (30 mL, 552 mmol) in acetic acid (30 mL) was heated to reflux for 5 days. The mixture was cooled to room temperature and diluted with water. The solid precipitate was collected by filtration, washed with water, and air dried to afford 7-hydroxy-3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (4.22 g, 91% yield). 1H NMR (400 MHz, DMSO-d6) δ14.51 (br. s., 1H), 11.77 (s, 1H), 8.32 (s, 1H), 7.95-8.00 (m, 2H), 7.90 (d, J=7.78 Hz, 1H), 7.78 (t, J=7.78 Hz, 1H), 7.54 (s, 1H), 3.41 (s, 3H), 2.36 (s, 3H); MS (m/z) 426.0 (M+H+).