Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([N:17]4C=CN=C4)=[O:16])=[C:10]3[C@@H:9]3[CH2:22][CH2:23][CH2:24][N:8]3[C:7](=[O:25])[C:6]=2[CH:26]=1.N>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([NH2:17])=[O:16])=[C:10]3[C@@H:9]3[CH2:22][CH2:23][CH2:24][N:8]3[C:7](=[O:25])[C:6]=2[CH:26]=1
Reactant: O=C1c2cc(F)ccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1cc(F)ccc1-2

Procedure:
20 g (57 mmol) of 1-[[(S)-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole are suspended in 55 ml of N,N-dimethylformamide, the suspension is treated with 9.9 ml of 25 percent ammonia solution in water, the mixture is stirred for a half hour and then poured into 300 ml of water. The precipitated product is filtered off under suction, washed with water and dried at 80° for 48 hours in a water-jet vacuum. There is obtained (S)-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamide of melting point 239°-240°.
Reaction SMILES: [C:1]([C:3]1([NH:9][C:10](=[O:40])[C@@H:11]([NH:20][C@@H:21]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:22]([F:32])([F:31])[O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:12][S:13]([CH2:16][CH:17]2[CH2:19][CH2:18]2)(=[O:15])=[O:14])[CH2:8][CH2:7]S[CH2:5][CH2:4]1)#[N:2].OO[S:43]([O-:45])=[O:44].[K+]>CO.O>[C:1]([C:3]1([NH:9][C:10](=[O:40])[C@@H:11]([NH:20][C@@H:21]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:22]([F:32])([F:31])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:12][S:13]([CH2:16][CH:17]2[CH2:19][CH2:18]2)(=[O:15])=[O:14])[CH2:4][CH2:5][S:43](=[O:45])(=[O:44])[CH2:7][CH2:8]1)#[N:2]
Reactant: O=S([O-])OO
Reactant: N#CC1(NC(=O)[C@H](CS(=O)(=O)CC2CC2)N[C@@H](c2ccc(F)cc2)C(F)(F)Oc2ccc(F)cc2)CCSCC1
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#CC1(NC(=O)[C@H](CS(=O)(=O)CC2CC2)N[C@@H](c2ccc(F)cc2)C(F)(F)Oc2ccc(F)cc2)CCS(=O)(=O)CC1
Temperature: 45 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a solution of N-(4-cyanotetrahydrothiopyran-4-yl)-3-cyclopropylmethanesulfonyl-2(R)-[2,2-difluoro-2-(4-fluorophenoxy)-1(S)-(4-fluorophenyl)ethylamino]propionamide (0.063 g, 0.1 mmol) in MeOH (10 ml) at 45° C., a solution of OXONE (0.3 mmol) in water (1 ml) was added. After stirring for 3 h at 45° C., the solvent was evaporated under vacuum and the residue was partitioned between DCM (15 ml) and water (15 ml). The organic phase was separated and the aqueous solution was extracted with DCM. The combined organic layers were washed with brine and dried over sodium sulfate. After removal of the solvent under vacuum, the crude was purified by preparative TLC, using ethyl acetate/hexanes (1/1) as mobile phase to give the title compound as a white solid (55%). 1HNMR (DMSO-d6): δ 8.82 (1H, s), 7.47 (2H, dd), 7.17 (6H, m), 4.32 (1H, q), 3.96 (1H, m), 3.40 (1H, m), 3.37 (4H, m), 3.00 (2H, m), 2.37 (2H), 1.15 (2H, m), 0.59 (3H, m), 0.30 (3H, m). LC/MS, M+1: 632.5; M−1: 630.6.
Reaction SMILES: C([O:8][CH2:9][C@@:10]1([O:24][CH3:25])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@H:11]1[F:23])C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[F:23][C@H:11]1[C@:10]([CH2:9][OH:8])([O:24][CH3:25])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]1
Reactant: [H][H]
Reactant: CO[C@]1(COCc2ccccc2)CCN(C(=O)OC(C)(C)C)C[C@H]1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CO[C@]1(CO)CCN(C(=O)OC(C)(C)C)C[C@H]1F
Yield: 110.6 %

Procedure:
20% palladium hydroxide on carbon powder (102 mg) was suspended in a MeOH (29 ml) solution of tert-butyl rel-(3R,4S)-4-[(benzyloxy)methyl]-3-fluoro-4-methoxypiperidine-1-carboxylate (971 mg), and stirring was performed at room temperature under a flow of hydrogen gas for 4 hours. After filtration through Celite, the filtrate was concentrated to obtain tert-butyl rel-(3R,4S)-3-fluoro-4-(hydroxymethyl)-4-methoxypiperidine-1-carboxylate (800 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
13.8 g (0.1 mol) 2,4-dihydroxybenzaldehyde are dissolved in 150 ml acetone, 17.1 g (0.1 mol) benzylbromide and 13.8 g (0.1 mol) potassium carbonate are added, and the mixture is stirred at room temperature for 3 d. After filtration, the solvent is removed in vacuo and the residual crude product further purified by column chromatography on silica gel using dichloromethane as eluent.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]4[CH:26]=[CH:27][N:28]=[C:24]4[CH:23]=[C:22]([C:29]4[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=4)[N:21]=3)=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].C(Cl)[Cl:36].Cl.O1CCOCC1>>[ClH:36].[CH3:34][N:32]1[CH:33]=[C:29]([C:22]2[N:21]=[C:20]([C:17]3[CH:18]=[CH:19][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:7][NH:6][CH2:5]4)[N:16]=3)[N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[CH:23]=2)[CH:30]=[N:31]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3ccn(C4(CC#N)CN(C(=O)OC(C)(C)C)C4)n3)n2)cn1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc3nccn3c(-c3ccn(C4(CC#N)CNC4)n3)n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
Tert-butyl 3-(cyanomethyl)-3-(3-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (Example 129; 28.3 mg, 0.0616 mmol) was dissolved in DCM (308 μL, 0.0616 mmol) and treated with 4N HCl in dioxane (308 μL, 1.23 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, then concentrated in vacuo to afford 2-(3-(3-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (14.3 mg, 53.7% yield) as a white solid. MS (apci) m/z=360.2 (M+H).
Reaction SMILES: Cl.[C:2]1([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:17]=[C:18]=[O:19].[K+]>O.C(O)C>[C:18]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)(=[O:19])[NH2:17]
Reactant: c1ccc(C2CNc3ccccc32)cc1
Reactant: [N-]=C=O
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(=O)N1CC(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture comprising 2.3 g of 3-phenyl indoline hydrochloride in 23 ml of water and 0.81 g of potassium isocyanate in 23 ml of ethanol was stirred for 15 minutes at room temperature. The precipitate which resulted was filtered off, washed with water and recrystallized from dilute ethanol. The yield of N-carbamoyl-3-phenylindoline was 0.9 g and the product had a melting point of 144°-145° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[C:16]1([CH:21]=O)[CH2:20][CH2:19][CH2:18][CH:17]=1.N1CCCC1>CO>[C:16]1([CH:21]=[C:3]2[C:2](=[O:1])[C:11]3[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=3)[O:5][CH2:4]2)[CH2:20][CH2:19][CH2:18][CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)OCCC2=O
Reactant: O=CC1=CCCC1
Solvent: C1CCNC1
Solvent: CO
Product: COC(=O)c1ccc2c(c1)OCC(=CC1=CCCC1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
To a solution of methyl 4-oxochroman-7-carboxylate (500 mg, 2.4 mmol) in methanol (5 mL) was added cyclopent-1-enecarbaldehyde (465 mg, 4.8 mmol) and pyrrolidine (0.40 mL, 4.8 mmol). The solution was stirred for one hour at ambient temperature. The resulting brown precipitate was collected by vacuum filtration and dried to give methyl 3-(cyclopentenylmethylene)-4-oxochroman-7-carboxylate (444 mg, 64% yield). LC/MS on 4.6×50 mm C-18 column, tR=6.49 minutes (10 to 90% acetonitrile/water over 8 minutes at 2 mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 285 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.88-1.99 (m, 2H), 2.43 (d, J=13.16 Hz, 2H), 2.63 (t, J=6.98 Hz, 2H), 3.85 (s, 3H), 5.36 (s, 2H), 6.45 (br. s., 1H), 7.37 (s, 1H), 7.49 (d, J=1.34 Hz, 1H), 7.60 (dd, J=8.06, 1.61 Hz, 1H), 7.93 (d, J=8.32 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CN(C)C(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:5]#[N:6]
Reactant: C1CNCCN1
Reactant: N#Cc1ccc(F)c(F)c1
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1ccc(N2CCNCC2)c(F)c1
Temperature: 120 °C
Yield: 95.4 %

Procedure:
3,4-Difluorobenzonitrile (2.0 g, 14.3 mmol) and piperazine (6.19 g, 71.8 mmol) were dissolved in N,N-dimethylacetamide (10 mL) and the solution was heated to 120° C. for 1.5 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to get 3-fluoro-4-(piperazin-1-yl)benzonitrile (2.8 g, yield 95%), which was carried through without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.69-7.65 (dd, J=13.6 Hz, 2.0 Hz, 1H), 7.56-7.53 (dd, J=8.5 Hz, 1.8 Hz, 1H), 7.12-7.07 (d, J=8.7 Hz, 1H), 3.08-3.05 (m, 4H), 2.83-2.80 (m, 4H). MS (ESI) m/z: Calculated for C11H12FN3: 205.10. found: 205.9 (M+H)+
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:33])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21](Br)[N:22]=3)[N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2].[Cl:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]2[CH:41]=[C:42]([Sn](CCCC)(CCCC)CCCC)[S:43][C:36]=12.CCOC(C)=O>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:33])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:42]4[S:43][C:36]5[C:37](=[N:38][CH:39]=[CH:40][C:35]=5[Cl:34])[CH:41]=4)[N:22]=3)[N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(Br)cnc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cc4nccc(Cl)c4s3)cnc21
Temperature: 90 °C
Reaction time: 16 h
Yield: 85.1 %

Procedure:
To a solution of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (180 mg, 0.34 mmol) and 7-chloro-2-tributylstannanyl-thieno[3,2-b]pyridine (162 mg, 0.35 mmol) in DMF (3 mL) were added copper(I) iodide (13.5 mg, 0.071 mmol) and tetrakis(triphenylphosphine)palladium(0) (20.4 mg, 0.018 mmol) under argon atmosphere. The reaction mixture was stirred for 16 h at 90° C. then poured into EtOAc (25 mL) and washed with water (4×30 mL). The organic extracts were dried over Na2SO4 and evaporated under vacuum. The crude residue was purified by column chromatography (SiO2, 11 g, CH2Cl2 100% to CH2Cl2:EtOAc 4:6 in 25 min) to afford 180 mg (82%) of 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:6]=1[N:15]1[C:37](=[O:38])[C:34]2[C:35]3[C:36]4[C:31](=[CH:32][CH:33]=2)[C:30]2[C:39]5[C:26]([CH:27]=[CH:28][CH:29]=2)=[CH:25][CH:24]=[CH:23][C:22]=5[C:21]=4[CH:20]=[CH:19][C:18]=3[C:16]1=[O:17])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:46]Br>ClC1C=CC=CC=1>[Br:46][C:27]1[C:26]2[C:39]3[C:30]([C:31]4[C:36]5[C:35]6=[C:18]([C:16]([N:15]([C:6]7[CH:7]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:9]=[CH:10][C:5]=7[C:1]([CH3:2])([CH3:3])[CH3:4])[C:37](=[O:38])[C:34]6=[CH:33][CH:32]=4)=[O:17])[CH:19]=[CH:20][C:21]=5[C:22]=3[CH:23]=[CH:24][CH:25]=2)=[CH:29][CH:28]=1
Reactant: BrBr
Reactant: CC(C)(C)c1ccc(C(C)(C)C)c(N2C(=O)c3ccc4c5cccc6cccc(c7ccc(c3c47)C2=O)c65)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: CC(C)(C)c1ccc(C(C)(C)C)c(N2C(=O)c3ccc4c5cccc6c(Br)ccc(c7ccc(c3c47)C2=O)c65)c1
Reaction time: 2 h

Procedure:
650 mg (1.28 mmol) of N-(2,5-di-tert-butylphenyl)perylene-3,4-dicarboximide (2b) are dissolved in 100 ml of chlorobenzene, the red solution is mixed with 650 mg of anhydrous potassium carbonate, and 0.30 ml of bromine in 10 ml of chlorobenzene is then added dropwise to the mixture. The reaction mixture is stirred at 40°-50° C. for 2 h, the temperature is then increased to 50°-60° C. and maintained there for another 5 h, and the chlorobenzene is then evaporated off on a rotary evaporator, during which substantial amounts of bromine are also removed. A thin-layer chromatogram (toluene/silica gel) shows that no more starting material is present in the residue obtained, which could only be removed with difficulty. Several separations by column chromatography on silica gel using chloroform afford 610 mg of an orange powder which is recrystallized by extraction with ethyl acetate. Yield 570 mg (77%) of orange-coloured small needles having a slight solid fluorescence, m.p. >320° C. Rf (CHCl3 /silica gel)=0.43. UV (CHCl3): λmax (ε)=511 nm (36058), 486 (35564), 357 (3430). Fluorescence (CHCl3): λmax (Irel)=542 nm (1), 572. The position of the bromine substituent could be determined by comparison with the spectrum of 9-bromo-N-(1-hexylheptyl)perylene-3,4-dicarboximide and 1H spectra. The substitution pattern of the comparison substance was determined by a combination of COSY and NOESY spectra.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].NCCCNCC[CH2:20][N:21]([CH2:29][CH:30]1[CH2:35][CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[O:31]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[O:31]1[C:32]2[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=2[CH2:34][CH2:35][CH:30]1[CH2:29][N:21]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:20][CH2:11][CH2:12][N:8]1[CH2:9][CH2:6][CH2:7][NH:3][C:1]1=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCCNCCCN(Cc1ccccc1)CC1CCc2ccccc2O1
Solvent: C1CCOC1
Product: O=C1NCCCN1CCCN(Cc1ccccc1)CC1CCc2ccccc2O1
Temperature: 25 °C
Reaction time: 17 h
Yield: 42 %

Procedure:
1,1′-Carbonylbis-1H-imidazole (0.02 mol) was added to a solution of (±)-N-(3-aminopropyl)-N′-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N′-(phenylmethyl)-1,3-propanediamine (0.0(2 mol) in THF (100 ml). The reaction solution was stirred for 17 hours at room temperature. The solvent was evaporated. Water was added to the residue and the mixture was extracted with toluene. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was crystallized from ethyl acetate (50 ml). The precipitate was filtered off and dried, yielding 3.3 g (42%) of (±)-1-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl](phenylmethyl)amino]propyl]-tetrahydro-2(1H)-pyrimidinone (comp. 13): mp. 94.7° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:25])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([CH2:19][NH:20][CH2:21][CH3:22])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC[O:28][C:29]([C@H:31](OS(C(F)(F)F)(=O)=O)[CH3:32])=[O:30]>>[Cl:1][C:2]1[C:3]([F:25])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([CH2:19][N:20]([CH2:21][CH3:22])[C@H:31]([C:29]([OH:28])=[O:30])[CH3:32])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCNCc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC
Reactant: CCOC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Product: CCN(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)[C@@H](C)C(=O)O

Procedure:
N-(3-Chloro-2-fluorophenyl)-6-[(ethylamino)methyl]-7-methoxyquinazolin-4-amine was coupled with ethyl O-trifluoromethanesulfonyl-D-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-ethyl-L-alanine; 1H NMR Spectrum: (DMSO-d6) 1.03 (t, 3H); 1.29 (d, 3H); 2.71 (q, 2H); 3.56 (q, 1H); 3.86 (d, 1H); 3.94 (m, 4H); 7.19 (s, 1H); 7.28 (t, 1H); 7.48 (m, 1H); 7.56 (m, 1H); 8.41 (m, 2H); 9.76 (brs, 1H); Mass Spectrum: (M+H)+ 433.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1.[H][H]>[C].[Pd].CC(O)C>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]([CH3:12])[CH2:3]1
Reactant: [H][H]
Reactant: C[C@@H]1CC(C)(C)c2cccc(N)c21
Agent: [Pd]
Solvent: CC(C)O
Product: CC1CC(C)(C)c2cccc(N)c21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into a reaction vessel were charged 6.00 parts by weight of (3R)-1,1,3-trimethyl-4-aminoindane (optical purity of 96.5% ee), 0.81 parts by weight of 5% palladium-carbon (STD-type, manufactured by N. E. Chemcat Corporation), and 12 parts by weight of 2-propanol, thereby obtaining a mixture. The reaction vessel was sealed and the gas inside the reaction vessel was replaced with nitrogen. While stirring the mixture at room temperature, to the reaction vessel was charged hydrogen until the internal pressure of hydrogen in the reaction vessel reached 0.5 MPa. After 15 minutes, the gas in the reaction vessel was replaced with nitrogen, and the mixture was stirred at an internal temperature of 150° C. and an internal pressure of 0.8 MPa for 7 hours to obtain a reaction mixture. The obtained reaction mixture was cooled and filtered. The obtained solid was washed with 20 parts by weight of 2-propanol. The washing liquid recovered after washing and the filtrate obtained by filtration were combined. The combined mixture was concentrated under reduced pressure to obtain 5.82 parts by weight of 1,1,3-trimethyl-4-aminoindane. The obtained 1,1,3-trimethyl-4-aminoindane had an optical purity of 1.2% ee and a recovery rate of 97.0%.
Reaction SMILES: [K+].[OH:2][CH2:3][CH2:4][C:5]([CH3:10])([CH3:9])[C:6]([O-:8])=[O:7].[C:11]1([CH2:17]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C=O)C>[C:11]1([CH2:17][O:7][C:6](=[O:8])[C:5]([CH3:10])([CH3:9])[CH2:4][CH2:3][OH:2])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(CCO)C(=O)[O-]
Reactant: BrCc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(CCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.3 %

Procedure:
A mixture of 4-hydroxy-2,2-dimethylbutyric acid monopotassium salt (10.6 g,62.35 mmol) and phenylmethyl bromide (11.63 g, 68 mmol) in 100 ml of DMF was stirred at room temperature for 24 hours and then the mixture was poured into ice/water. The mixture was extracted with ether (3×) and the organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (silica, 12-66% of ethyl acetate/hexane) to afford 10.02 g (72%) of 4-hydroxy-2,2-dimethylbutyric acid phenylmethyl ester.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]#[N:12])=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl.[NH2:14][OH:15].C(N(CC)CC)C>CO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([NH:14][OH:15])=[NH:12])=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: NO
Reactant: N#CNc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: N=C(NO)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 56.4 %

Procedure:
In 150 ml of methanol was dissolved 6.56 g of 4-carboxyphenyl cyanamide produced in Reference Example 26. To the solution were added, while stirring at room temperature, 6.1 g of hydroxylamine hydrochloride and 8.88 g of triethylamine. The mixture was stirred for two hours. The resulting crystalline precipitate was collected by filtration to afford 4.45 g of the title compound as a colorless crystalline product.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[C:15]([O:22][CH3:23])(=[O:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18].[H-].[Na+]>C1COCC1.CCOC(C)=O>[N+:8]([C:7]1[C:2]([CH:16]([C:15]([O:22][CH3:23])=[O:21])[C:17]([O:19][CH3:20])=[O:18])=[N:3][CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)c1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 56.2 %

Procedure:
A solution of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine from Example B16 (400 mg, 1.766 mmol) in THF (5 mL) was treated sequentially with dimethyl malonate (250 μl, 2.187 mmol) and sodium hydride (60%, 85 mg, 2.119 mmol). The resultant mixture was stirred at RT overnight. The mixture was diluted with EtOAc and washed with 0.1 M aq HCl, water, and brine, dried (MgSO4), concentrated in vacuo and purified by silica gel chromatography to provide dimethyl 2-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)malonate (320 mg, 56% yield) of sufficient purity for the next step. MS (ESI) m/z: 323.0 (M+H+).
Reaction SMILES: [CH:1](/[C:9]1[CH:10]=[CH:11][C:12]2[O:13][CH2:14][C:15](=[O:19])[NH:16][C:17]=2[N:18]=1)=C\C1C=CC=CC=1.CSC.C(Cl)Cl.C[OH:27]>>[O:19]=[C:15]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]([CH:1]=[O:27])=[N:18][C:17]=2[NH:16]1
Reactant: O=C1COc2ccc(/C=C/c3ccccc3)nc2N1
Reactant: CO
Solvent: ClCCl
Solvent: CSC
Product: O=Cc1ccc2c(n1)NC(=O)CO2
Temperature: -78 °C
Yield: 77 %

Procedure:
6-((E)-Styryl)-4H-pyrido[3,2-b][1,4]oxazin-3-one (6.2 g, 27 mmole) was dissolved in 5:1 CH2Cl2/MeOH (500 mL) and the solution was cooled to −78° C. Ozone was bubbled through the solution with stirring until a pale blue color appeared, then the excess ozone was removed by bubbling oxygen through the solution for 15 min. Dimethylsulfide (9.9 mL, 135 mmole) was added to the solution, and the reaction was stirred at −78° C. for 3 hr, then at room temperature overnight. The solvent was removed in vacuo, and the residue was triturated and stirred with Et2O (150 mL). The solid was collected by suction filtration, washed with additional Et2O, and dried to afford the title compound (3.4 g, 77%): LC-MS (ES) m/e 179 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:33]([F:34])=[C:32]([F:35])[C:31]([F:36])=[C:30]([F:37])[C:3]=1[O:4][S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1C(OC(C)(C)C)=O)=[N:13][CH:12]=[CH:11]2)(=[O:7])=[O:6].[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[NH:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[C:14]1[C:15]2[C:10](=[CH:9][C:8]([S:5]([O:4][C:3]3[C:2]([F:1])=[C:33]([F:34])[C:32]([F:35])=[C:31]([F:36])[C:30]=3[F:37])(=[O:6])=[O:7])=[CH:17][CH:16]=2)[CH:11]=[CH:12][N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(C3CCCN3)nccc2c1
Reaction time: 2 h

Procedure:
A round-bottom flask was charged with tert-butyl 2-(6-((perfluorophenoxy)sulfonyl)isoquinolin-1-yl)pyrrolidine-1-carboxylate (1.02 g, 1.873 mmol) and DCM (5.0 mL) to give a light yellow solution. TFA (1.443 ml, 18.73 mmol) was added in one portion to give a yellow solution. The reaction was stirred for two hours. The reaction was concentrated, dissolved in diethyl ether, and sonicated until a fine white solid triturated out of solution. The solids were filtered, washed with diethyl ether, and vacuum dried overnight to afford perfluorophenyl 1-(pyrrolidin-2-yl)isoquinoline-6-sulfonate 2,2,2-trifluoroacetate as a white solid. (ESI) 445.3 (M+H)+.