Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([OH:21])=[C:16]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1.C(OCC)C>CN1C(=O)CCC1>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([O:21][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1)=[C:16]([C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[CH:15]=[CH:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1c(-c2ccc(F)cc2)ccc2cc(OCc3ccccc3)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: O=Cc1ccc(Oc2c(-c3ccc(F)cc3)ccc3cc(OCc4ccccc4)ccc23)cc1
Temperature: 165 °C
Yield: 70 %

Procedure:
Add sodium hydride (400 mg, 10 mmol) into a solution of 6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-ol in NMP (40 mL). Add the above alkoxide suspension into a solution of 4-fluorobenzaldehyde (2 mL, 19 mmol) in NMP (30 mL) at 165° C. Heat at 165° C. for 1 hour. Cool and add buffer solution (pH=7, 10 mL). Add diethyl ether (1 L). Separate the layers and wash the aqueous layer with diethyl ether (2×200 mL). Combine the organic layers, dry with magnesium sulfate and concentrate in vacuo. Chromatograph the residue on a biotage column eluting the material with a step gradient of methanol/dichloromethane (0 to 10%) to obtain 2.9 g (70%) of 4-[6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-yloxy]-benzaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12].Br[CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([CH2:14][CH2:15][OH:16])[C:5]2=[O:12]
Reactant: O=c1[nH]cnc2ccc(Br)cc12
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=c1c2cc(Br)ccc2ncn1CCO

Procedure:
6-Bromoquinazolin-4(3H)-one Compound 178-A (1.0 g), 2-bromoethanol (1.1 g), and potassium carbonate (610 mg) were heated in DMA (10 mL) at 80° C. for 16 h. Reaction was extracted with water and dichloromethane (3 times), combined organic layers washed with brine, over sodium sulphate and concentrated. Residue was triturated with acetonitrile to yield 6-bromo-3-(2-hydroxyethyl)quinazolin-4(3H)-one Compound 178-B (810 mg) as a white solid. MS m/z (ESI)=268.9 (base peak, 79Br-M+H+); 270.9 (81Br-M+H+); 290.9 (79Br-M+Na+); 292.9 (81Br-M+Na+).
Reaction SMILES: [CH:1]([N:3]([CH3:19])[CH:4]([C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:2].[CH3:20]C(C)([O-])C.[K+].COS(OC)(=O)=O>O1CCCC1>[CH:1]([N:3]([CH3:19])[CH:4]([C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:20])=[O:2]
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccsc1C(Cc1ccccc1O)N(C)C=O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: COc1ccccc1CC(c1sccc1C)N(C)C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
To an ice-water chilled solution of 5.10 g of N-formyl-2-hydroxy-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine and 100 ml of tetrahydrofuran, was added 2.24 g of potassium t-butoxide and then a solution of 2.52 g of dimethylsulfate and 25 ml of tetrahydrofuran dropwise, with stirring. The mixture was stirred at ice-bath temperature for 30 min, at room temperature for one hr, and at reflux for 30 mins. Additional dimethylsulfate and potassium t-butoxide were added and the mixture was refluxed for 20 min. The reaction mixture was decanted into 40 ml of water and basified with 10% sodium hydroxide solution. The mixture was extracted with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was combined with a previous sample. The combined residue Was purified by preparative H:PLC (Water Associates Prep LC/System 500, silica gel, material applied as a solution in dichloromethane, eluted with ethyl acetate-hexane (1:1,200 ml/min flow rate). The appropriate fractions were combined and concentrated. The residue crystallized during refrigerated storage. Recrystallization from cyclohexane afforded 3.5 g of the product, mp 80°-83° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Br:14])[CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[CH:10]2)=[O:4].[H-].[Na+].I[CH3:18]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Br:14])[CH:8]=[C:9]2[C:13]=1[N:12]([CH3:18])[CH:11]=[CH:10]2)=[O:4]
Reactant: CI
Reactant: COC(=O)c1cc(Br)cc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc2ccn(C)c12
Yield: 91.7 %

Procedure:
A solution of the 5-bromo-indole-7-carboxylic acid methyl ester (300 mg, 1.18 mmol) in DMF (15 mL) was cooled to 0° C. under nitrogen and treated with sodium hydride (60% in mineral oil) (56.6 gm, 1.4 mmol). After stirring for 15 minutes the iodomethane (0.08 mL, 1.3 mmol) was introduced and the cooling bath was removed (reaction became light purple). After 30 minutes the reaction was quenched with water (5 ml) and then concentrated to reduce the volume of DMF. The reaction was poured into water (1.6 L) and EtOAc (200 ml). The layers were separated and the aqueous phase was extracted with EtOAc (3×200 ml). The combined organics were washed with water (3×) and then dried (MgSO4). The solution was filtered and the filterate was concentrated. The residue was purfied by CombiFlash with 10% EtOAc in Hexane as the eluent to afford the desirable product 5-Bromo-1-methyl-1H-indole-7-carboxylic acid methyl ester (290 mg, 92%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[BH4-].[Na+].C(O)(=O)C(O)=O>CO.C(O)C>[OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(c2ccc(OCCCN3CCCCC3)cc2)CC1
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: OC1CCC(c2ccc(OCCCN3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.5 %

Procedure:
To a solution of 1-{3-[4-(4-oxocyclohexyl)phenoxy]propyl}piperidine (250 mg) in methanol (3 mL) is added sodium borohydride (15 mg). The mixture is stirred for two days at room temperature, then concentrated under reduced pressure and purified by column chromatography on silica gel (eluent dichloromethane/methanol/ammonia from 99.5/0.5/0.05 to 99/1/0.1) to give 179 mg of crude base which is dissolved in ethanol (2 mL). A solution of oxalic acid (50 g) in ethanol (1 mL) is added. A white precipitate appears which is filtered, rinsed with diethyl ether and dried under reduced pressure to give 127 mg of 1-{3-[4-(4-hydroxycyclohexyl)phenoxy]propyl}piperidine as a white solid
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11].C1(C)C=CC(S([N:34]=[N+:35]=[N-])(=O)=O)=CC=1>C(#N)C>[N+:34](=[C:9]([C:10](=[O:11])[CH3:12])[C:8]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)=[O:13])=[N-:35]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
35.0 ml (0.25 mol-1.8 equiv.) of triethylamine were added dropwise to a solution, cooled to 0° C., of 33.18 g (0.14 mol) of 4-nitrobenzyl acetoacetate and 30.40 g (0.15 mol) of p-toluenesulphonyl azide in 280 ml of anhydrous acetonitrile. The mixture was stirred at 0° C. for 2 hours, and the resultant precipitate was then filtered off under suction, washed with ether and dried in a high vacuum over P4O10. 20.3 g (55% of theory) of the title compound were obtained as colorless crystals, melting point: 132° C. A further 6.3 g (17% of theory) of the title compound were obtained by chromatography of the filtrate solution on 400 g of silica gel (toluene:ethyl acetate=9:1), Rf =0.35 (toluene:ethyl acetate=9:1).
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[F-:14].[Cs+].O.Cl>CS(C)=O>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([F:14])[NH:7][C:6]=2[CH:8]=1
Reactant: [F-]
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Agent: Cl
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=S1(=O)N=C(F)Nc2cc(Cl)sc21
Temperature: 155 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
A mixture of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (257 mg, 1.0 mmol) and cesium fluoride (456 mg, 3.0 mmol) in dry DMSO (1 ml) was stirred for 16 h at 155° C. in a sealed flask. Water (3 ml) was added to the cooled mixture followed by 4M hydrochloric acid to pH <2. The precipitated beige solid was isolated by filtration, washed with water and dried to give 193 mg (80%) of the title compound; 1H-NMR (DMSO-d6): δ7.09 (s, 1H), 7.34 (br s, 1H; MS: m/e 240/242 (M+).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:9]=[C:10]([C@@H:14]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:15]3[CH:27]=[CH:26][C:18]([C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:42][CH:43]1[CH2:45][CH2:44]1>C(#N)C>[CH:1]1([NH:7][C:8]2[CH:9]=[C:10]([C@@H:14]([N:28]3[CH2:33][CH2:32][N:31]([CH2:42][CH:43]4[CH2:45][CH2:44]4)[CH2:30][CH2:29]3)[C:15]3[CH:27]=[CH:26][C:18]([C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: BrCC1CC1
Reactant: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(NC3CCCCC3)c2)N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(NC3CCCCC3)c2)N2CCN(CC3CC3)CC2)cc1
Reaction time: 8 h
Yield: 81341 %

Procedure:
To a solution of COMPOUND 27 (250 mg; 0.56 mmol) in acetonitrile (8 mL) was added triethylamine (92.7 μL; 0.67 mmol). The solution was cooled to 0° C. than bromomethylcyclopropane (53.5 μL; 0.56 mmol) was added. Reaction mixture was stirred overnight then was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Column chromatography eluting with 5% methanol in dichloromethane gave COMPOUND 72 (229 g; 82% yield). Purity (HPLC-215 nm): >99%; Optical purity (Chiral HPLC-215 nm): >99%. 1H NMR (400 MHz, CD3OD) δ 0.34-0.40 (m, 2H), 0.65-0.71 (m, 2H), 0.99-1.04 (m, 3H), 1.14 (t, J=6.83 Hz, 3H), 1.30-1.35 (m, 6H), 1.61-1.64 (m, 1H), 1.75-1.78 (m, 2H), 1.85-1.90 (m, 2H), 2.46-2.54 (br s, 1H), 2.95-3.03 (br s, 6H), 3.10-3.18 (br s, 2H), 3.37-3.44 (br s, 5H), 3.54-3.60 (br s, 2H), 7.27-2.31 (m, 3H), 7.50-7.53 (m, 3H), 7.64-7.68 (m, 2H). Found: C, 59.91; H, 8.10; N, 10.28. C32H46N4O×3.2HCl×1.1H2O has C, 60.13; H, 8.10; N, 8.76%. [α]D16=+12.4 deg [c 0.51, MeOH].
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH3-]C#N.[Na+].Cl>CO>[CH2:13]([NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: NCC1CCc2ccccc2C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNCC2CCc3ccccc3C2)cc1
Reaction time: 16 h

Procedure:
A solution of 2-aminomethyl-1,2,3,4-tetrahydronaphthalene (XXXI) (14.5 g), benzaldehyde (9.7 g) and NaBH3CN (5.8 g) in methanol (150 ml) was cooled to 0°. Concentrated HCl was added dropwise until the apparent pH (litmus) was 3-4. The mixture was then stirred 16 hours at 0°. The solvent was evaporated, and the residue was dissolved in EtOAc, which was washed with saturated NaHCO3 solution, dried (MgSO4), and evaporated. The residual oil was dissolved in MeOH, and a slight excess of concentrated HCl was added. Adding EtOAc and boiling caused precipitation of Compound XXXIV.HCl, which was collected by filtration. Its NMR was consistent with the structure indicated, and it was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[S:19][CH:18]=[C:17]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.C1C[O:52][CH2:51]C1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[S:19][C:18]([CH:51]=[O:52])=[C:17]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:27][CH:28]=1
Reactant: COCCOCc1csc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: COCCOCc1c(C=O)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A mixture of 210 mg of N-(4-chlorobenzyl)-3-[(2-methoxyethoxy)methyl]-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide and 5.0 mL of dry THF is heated to boiling under argon to dissolve the solid, then is cooled to −78° C. Into this mixture is cannulated a solution of LDA in THF, prepared in the usual manner from 0.35 mL of diisopropylamine and 0.80 mL of 2.5 M (in hexane) butyllithium in 4.0 mL of THF. The resulting deep blue mixture is stirred at −78° C. for 15 min, then 0.25 mL of dry DMF is added and the mixture allowed to warm to ambient temperature. The mixture is then partitioned between CH2Cl2 and dil HCl, and the organic phase dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography on silica gel using 2% MeOH in CH2Cl2 provides 146 mg of the title compound as an orange solid. Recrystallization of a sample from EtOAc provides an analytical sample as a white solid.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:24]([CH3:36])[CH:23]=3)[C:12]3[C:13]([F:21])=[CH:14][C:15]([OH:20])=[C:16]([O:18][CH3:19])[C:17]=3[C:8]=2[C:7]([CH3:37])=[N:6]1)([CH3:4])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:49][CH:50]1[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]1)(=O)=O.O>CN(C=O)C>[CH3:4][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[C:24]([CH3:36])[CH:23]=3)[C:12]3[C:13]([F:21])=[CH:14][C:15]([O:20][CH2:49][CH:50]4[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:60])([CH3:62])[CH3:61])=[O:57])[CH2:52][CH2:51]4)=[C:16]([O:18][CH3:19])[C:17]=3[C:8]=2[C:7]([CH3:37])=[N:6]1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: COc1c(O)cc(F)c2c(-c3ccc(OCc4ccccc4)c(C)c3)nc3c(c(C)nn3C(C)(C)C)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(F)c2c(-c3ccc(OCc4ccccc4)c(C)c3)nc3c(c(C)nn3C(C)(C)C)c12
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 73.8 %

Procedure:
To a solution of 3-(1,1-dimethylethyl)-6-fluoro-1-methyl-9-(methyloxy)-5-{3-methyl-4-[(phenylmethyl)oxy]phenyl}-3H-pyrazolo[3,4-c]isoquinolin-8-ol (207 mg, 0.42 mmol) in DMF (2 mL) was added cesium carbonate (274 mg, 0.84 mmol) and tert-butyl 4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (135 mg, 0.46 mmol). The mixture was heated to 90° C. and stirred for 1.5 h. After cooling to rt, water was added and the resulting aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (gradient: 25% ethyl acetate in hexanes to 30% ethyl acetate in hexanes) to provide 1,1-dimethylethyl 4-{[(3-(1,1-dimethylethyl)-6-fluoro-1-methyl-9-(methyloxy)-5-{3-methyl-4-[(phenylmethyl)oxy]phenyl}-3H-pyrazolo[3,4-c]isoquinolin-8-yl)oxy]methyl}piperidine-1-carboxylate (214 mg, 0.31 mmol, 73% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.51-7.34 (m, 7H), 6.98 (d, 1H), 6.83 (d, 1H), 5.16 (s, 2H), 4.22 (br m, 2H), 3.98 (d, 2H), 3.91 (s, 3H), 2.89 (s, 3H), 2.80 (br m, 2H), 2.37 (s, 3H), 2.12 (m, 1H), 1.93-1.88 (m, 2H), 1.85 (s, 9H), 1.48 (s, 9H), 1.39-1.35 (m, 2H); MS (I) for C41H49FN4O5: 697 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.[H-].[Na+].FC(F)(F)S(O[CH2:25][C:26]([F:29])([F:28])[F:27])(=O)=O.O>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C2COCCN2c2nc(Cl)ncc2N1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
To a solution of 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (363 mg, 1.509 mmol) in DMF (6 ml) at 0° C. was added NaH (72.4 mg, 1.81 mmol). After 15 minutes of stirring at 0° C., a solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (525 mg, 2.26 mmol) in DMF (1 ml) was slowly added. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to give a crude oil. The crude residue was purified by silica gel chromatography (hexane/ethyl acetate, 19:1 to 1:1) to afford 2-chloro-5-(2,2,2-trifluoroethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (373 mg, 1.16 mmol, 77% yield) as a yellow solid. MS [M+H] found 323.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:28]1[N:33]=[CH:32][C:31](F)=[CH:30][N:29]=1>CN1C(=O)CCC1.C(OCC)(=O)C>[F:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: Cc1ncc(F)c(N2CCC(C3CCNCC3)CC2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ncc(F)c(N2CCC(C3CCN(c4ncccn4)CC3)CC2)n1
Temperature: 110 °C

Procedure:
1-(5-fluoro-2-methylpyrimidin-4-yl)-4,4′-bipiperidine (10 mg, 0.036 mmol) and cesium carbonate (35 mg, 0.11 mmol) were stirred in NMP (2 ml) and 2-chloro-5-fluoropyrimidine (8.2 mg, 0.72 mmol) was added. The mixture was heated at 110° C. for 2 h. The reaction was cooled down to r.t. and diluted with ethyl acetate (5 mL) and was washed with water 2 mL (×1) and brine 2 mL (×1). The organic phase was dried over magnesium sulfate, filtered, and concentrated on rotavapor. The crude material was purified by preparative TLC with 30% acetone: hexane to yield the titled compound.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([N:21]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(NC1CCCCC1)c1nn2cccc2c(=O)n1Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccccc1)N(C(=O)c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.7 %

Procedure:
3-Benzyl-2-(1-cyclohexylamino-propyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 28, 26.3 mg, 0.072 mmol) in CHCl3 (1.5 mL) at 25° C. was treated with benzoylchloride (34.9 mg, 0.248 mmol) and triethylamine (16.8 mg, 0.166 mmol). The resulting mixture was stirred at 25° C. for 18 h, then concentrated under vacuum and purified by preparative HPLC using a YMC S10 ODS 20×100 mm column affording the desired compound (8.0 mg, 23.7%) as a colorless film: LC/MS 94% at 4.42 min (ESI+) 469 (M++H).
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].O[C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][CH2:20][C:21]2=[O:26].CCN(CC)CC>C(Cl)Cl>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][CH2:20][C:21]2=[O:26])(=[O:3])=[O:2]
Reactant: O=C1CCc2c(O)cccc21
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCc2c(OS(=O)(=O)C(F)(F)F)cccc21
Temperature: 25 °C
Yield: 67 %

Procedure:
Triflic anhydride (152 g, 0.54 mol) was added dropwise to solution 80 g of compound 86 and 60 g of NEt3 in 1 L CH2Cl2 at 0° C. The resulting mixture was refluxed for 2 h, cooled to room temperature, filtered, washed with water (0.5 L), aqueous citric acid (50 g/0.5 L), brine (0.5 L), dried on Na2SO4, and evaporated to give about 100 g (67%) of compound 87 as dark liquid.
Reaction SMILES: [OH-].[K+].Br[CH2:4][CH:5]([CH3:7])[CH3:6].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1.O>CS(C)=O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][CH2:4][CH:5]([CH3:7])[CH3:6])=[CH:11][CH:10]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: CC(C)CBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)COCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Potassium hydroxide (1.32 g) and 1-bromo-2-methylpropane (1.04 mL) were added to a solution of 2-(4-bromophenyl)ethylalcohol (140 μL) in dimethyl sulfoxide (2 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was filtered through diatomaceous earth and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane only) to give the title compound as a colorless oil (180 mg, 70%).
Reaction SMILES: B#B.[F:3][C:4]([F:19])([F:18])[C:5]1[CH:6]=[CH:7][C:8]2[O:15][C:12]3([CH2:14][CH2:13]3)[C:11](=O)[NH:10][C:9]=2[CH:17]=1.O>O1CCCC1>[F:19][C:4]([F:3])([F:18])[C:5]1[CH:6]=[CH:7][C:8]2[O:15][C:12]3([CH2:13][CH2:14]3)[CH2:11][NH:10][C:9]=2[CH:17]=1
Reactant: O=C1Nc2cc(C(F)(F)F)ccc2OC12CC2
Agent: B#B
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc2c(c1)NCC1(CC1)O2
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
Under ice cooling, 1.1 ml of a 1M solution of diborane in tetrahydrofuran were added dropwise to a solution of 1.07 g of 3,4-dihydro-6-trifluoromethyl-3-oxo-2H-1,4-benzoxazine-2-spiro-cyclopropane in tetrahydrofuran, followed by stirring at room temperature for 4 hours. The reaction mixture was ice cooled, to which iced water was added, followed by stirring at room temperature for 15 minutes. The reaction mixture was extracted with ethyl ether and the extract was dried over magnesium sulfate. The ethyl ether was distilled off and the residue was purified by chromatography on a silica gel column, whereby 0.96 g of the title compound was obtained (yield: 95%).