Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[OH:12][C:13]([C@H:16]1[CH2:20][CH2:19][NH:18][C@H:17]1[CH3:21])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Li+].[Li+]>>[OH:12][C:13]([C@H:16]1[CH2:20][CH2:19][N:18]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[O:10][CH3:11])[C@H:17]1[CH3:21])([CH3:15])[CH3:14]
Reactant: COc1cc(C#N)ccc1F
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: COc1cc(C#N)ccc1N1CC[C@H](C(C)(C)O)[C@@H]1C

Procedure:
Using 4-fluoro-3-methoxybenzonitrile (232 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (390 mg) and lithium carbonate (153 mg), the title compound was obtained as a white solid (yield: 42 mg) by an operation similar to that in Example 3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8].[Li+].CC([N-]C(C)C)C.[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Br)[CH3:19].CC(O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[CH2:8][CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:24]
Reactant: Cc1c(Br)cncc1Br
Reactant: CCOC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)CCc1c(Br)cncc1Br
Temperature: 25 °C
Yield: 33.4 %

Procedure:
A solution of 3,5-dibromo-4-methylpyridine (20 g, 0.08 mol) in THF (50 mL) was added over a period of 1 hour to a solution of LDA (0.088 mol) [generated from N,N-diisopropylamine (8.9 g, 0.088 mol) and n-butyllithium (35 mL, 0.088 mol, 2.5 M in hexane) in 400 mL THF] at −78° C. The resulting dark red solution was stirred at −78° C. for 30 min before ethylbromoacetate (33.4 g, 0.2 mol) in THF (50 mL) was added over a period of 30 min. The reaction mixture was stirred for an additional 2.5 hour at −78° C. before 10% AcOH was added (resulting in a pH=4-5). The reaction mixture was then allowed to warm up to room temperature. After evaporation of the solvents, the residue was poured into satd. aq. NaHCO3 solution and extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhy. Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound (9 g, 33.5%) as a yellow solid. MS: 337.7 (M+H+, 2Br).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[NH2:11][N:12]1[C:17]2[C:18]([CH2:29]O)=[CH:19][CH:20]=[C:21]([C:22]3[C:23]([CH3:28])=[N:24][O:25][C:26]=3[CH3:27])[C:16]=2[O:15][CH2:14][CH:13]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:28][C:23]1[C:22]([C:21]2[C:16]3[O:15][CH2:14][CH:13]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:12]4[C:17]=3[C:18]([CH:29]=[N:11]4)=[CH:19][CH:20]=2)=[C:26]([CH3:27])[O:25][N:24]=1
Reactant: Cc1noc(C)c1-c1ccc(CO)c2c1OCC(c1ccccc1)N2N
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(C)c1-c1ccc2cnn3c2c1OCC3c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 31.9 %

Procedure:
A solution of 2.0 M oxalyl chloride in methylene chloride (0.132 mL) at −78° C. was treated with methylene chloride (0.363 mL) followed by dimethyl sulfoxide (0.025 mL, 0.353 mmol) dropwise. The reaction mixture was stirred at −78° C. for 20 min and treated with a solution of [4-amino-8-(3,5-dimethylisoxazol-4-yl)-3-phenyl-3,4-dihydro-2H-1,4-benzoxazin-5-yl]methanol (0.062 g, 0.18 mmol) in methylene chloride (1.50 mL) dropwise. The reaction mixture was stirred at −78° C. for 1 h and treated with triethylamine (0.0984 mL, 0.706 mmol) dropwise. The reaction mixture was stirred at −78° C. for 1 h and warmed to 25° C. The reaction mixture was quenched with water (2 mL) and diluted with methylene chloride (30 mL) and saturated ammonium chloride solution (10 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated to give a tan foam. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired product (19 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.39-7.30 (m, 3H), 7.13-7.06 (m, 2H), 7.03 (d, J=8.3 Hz, 1H), 5.90 (dd, J=3.9 Hz, 1H), 4.79 (dd, J=11.6, 3.4 Hz, 1H), 4.69 (dd, J=11.6, 4.6 Hz, 1H), 2.32 (s, 3H), 2.16 (s, 3H). LCMS calculated for C20H18N3O2 (M+H)+: m/z=332.1. found: 332.1.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[O:3].[Na+].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>[OH-].[Na+]>[CH:8](=[CH:4][C:2](=[O:3])[C:1]([OH:6])=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)C(=O)[O-]
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(=O)C=Cc1ccccc1
Reaction time: 4 h
Yield: 75 %

Procedure:
Sodium pyruvate (60.5 g, 0.55 mol) was first added to a cold (0° C.) 1N aqueous solution of sodium hydroxide (550 ml). Benzaldehyde (53 g, 0.55 mol) was then added at such a rate that the temperature was maintained below 5° C. The reaction mixture was then aged four hours at 0° C. with good agitation. Following the age period, the mixture was acidified to pH 1.0 with 6N HCl maintaining a temperature of 0°-5° C. After acidification, the benzalpyruvic acid product was extracted with 500 ml ethyl acetate. Yield: 75-77% by HPLC analysis. Anal. Calcd. for C10H7O3K: C, 56.08; H, 3.30; K, 18.21. Found: C, 56.11; H, 3.31; K, 18.20. 1H NMR (acetone-d6) δ: 7.2 (d, 1H), 7.8 (d, 1H), 7.5 (s, 5H). IR (KBr) cm-1 : 3500sb, 3050-2900s, 1740s, 1695s, 1230s, 1020s.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([NH2:11])[C:5]=2[N:4]=[CH:3][CH:2]=1.[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[CH2:23][CH2:24][CH2:25][CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([NH:11][CH2:26][CH2:25][CH2:24][CH2:23][N:14]3[C:15](=[O:22])[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:13]3=[O:12])[C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: NC1CCCc2nccnc21
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2nccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of 5,6,7,8-tetrahydroquinoxalin-5-ylamine (313 mg, 2.09 mmol) in CH2Cl2 (20 mL) at room temperature under inert atmosphere was added 4-(1,3,-dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (227.8 mg, 1.05 mmol) followed by sodium triacetoxyborohydride (444 mg, 2.10 mmol). The reaction mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution (10 mL) was added and the mixture was extracted with dichloromethane (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated. The resultant material was purified by column chromatography on silica gel (10:1:0.5 CH2Cl2:MeOH:NH4OH) to provide the product as a clear oil (298 mg, 81%): 1H NMR (CDCl3): δ 1.56-1.66 (m, 2H), 1.70-1.95 (m, 4H), 2.04-2.22 (m, 4H), 2.71-2.85 (m, 2H), 2.87-3.05 (m, 2H), 7.69-7.73 (m, 2H), 7.80-7.85 (m, 2H), 8.34 (br s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([Cl:17])[CH:12]=1)=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([Cl:17])[CH:12]=2)=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccnc(Cl)c1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccnc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 133 mg of (2-Amino-5-chloro-phenyl)-(2-chloro-pyridin-4-yl)-methanone and 116 mg of 4-tert-Butyl-benzenesulfonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[N:15]=[C:10]3[CH:9]=[C:8]2[C:20](=[S:22])[NH2:21])=[CH:4][CH:3]=1.CO[CH:27](OC)[CH2:28]Br.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([S:16]([CH3:19])(=[O:17])=[O:18])[N:15]=[C:10]3[CH:9]=[C:8]2[C:20]2[S:22][CH:27]=[CH:28][N:21]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1cnc2c(cc(C(N)=S)n2Cc2ccc(F)cc2)n1
Reactant: COC(CBr)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cnc2c(cc(-c3nccs3)n2Cc2ccc(F)cc2)n1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5-(4-fluorobenzyl)-2-methanesulfonyl-5H-pyrrolo[2,3-b]pyrazine-6-thioamide (90 mg), bromoacetaldehyde dimethylacetal (0.06 ml), p-toluenesulfonic acid (4 mg) and acetic acid (1 ml) was stirred at 100° C. for 1.5 hours. The reaction solution was separated using silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the desired product (30 mg).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8]N(C)C=O>>[C:4]1(=[O:5])[O:6][C:1](=[O:7])[CH:2]=[CH:3]1.[CH2:8]=[C:3]([CH3:2])[CH3:4]
Reactant: CN(C)C=O
Reactant: O=C1CCC(=O)O1
Product: C=C(C)C
Product: O=C1C=CC(=O)O1

Procedure:
The formed particulate matter was collected by centrifugation and dried to obtain 4.4 kg of realistic anhydride/isobutene copolymer. The resulting copolymer contained 50 mole % of succinic anhydride units according to elemental analysis, and had relative solution viscosity of 2.0 (measured in N,N-dimethylformamide solvent at 23° C. with an Ubbelohde viscometer).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]#[N:9])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[F:11][C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[CH:14]=[N+:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.FC1C=CC=CC=1C=O.N1CCCCC1>>[F:11][C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[CH:14]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:2]1[N:1]([CH2:6][CH2:7][C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCn1cccc1
Reactant: Fc1ccccc1C=[N+]1CCCCC1
Agent: O=Cc1ccccc1F
Agent: [Cl-]
Solvent: C1CCNCC1
Product: N#CCCn1cccc1C(c1ccccc1F)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 3-pyrrol-1-yl-propionitrile and 1-(2-fluoro-benzylidene)-piperidinium chloride, which had been prepared in accordance with example 3 from 2-fluorobenzaldehyde and piperidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].C(=O)([O-])[O-].[Na+].[Na+].[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1B(O)O>C1(C)C=CC=CC=1.C(O)C.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>[CH3:20][O:19][C:18]1[C:17]([O:21][CH3:22])=[CH:16][C:4]([CH:5]=[C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])=[C:3]([C:31]2[CH:30]=[CH:29][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[CH:2]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: COc1cc(C=C2C(=O)Nc3ccccc32)cc(Br)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc(C=C2C(=O)Nc3ccccc32)c(-c2ccc3ccccc3c2)cc1OC
Reaction time: 12 h
Yield: 30.9 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.02 g) was added to a solution of 3-(3-bromo-4,5-dimethoxybenzylidene)-1,3-dihydroindol-2-one (0.20 g) in toluene (1 ml) and ethanol (1 ml) followed by addition of 2M aqueous sodium carbonate (1.1 ml). To this mixture was added naphthalene-2-boronic acid (0.11 g), and the mixture was held at 100° C. in a sealed tube for 12 hours. The precipitate which formed was filtered, washed with ethanol and then dissolved in 20% methanol/toluene, filtered and concentrated. The resulting solid was triturated with hexanes and dried to afford 0.07 g (29%) of 3-(4,5-dimethoxy-2-naphthalen-2-ylbenzylidene)-1,3-dihydroindol-2-one as an orange solid.
Reaction SMILES: [C:1]([O:24][CH:25]1[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]1)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]1)=[O:11].[C:35]([O:39]O)([CH3:38])([CH3:37])C>[Mo](=O)(=O)=O.C1CCCCC1>[C:1]([O:24][CH:25]1[CH2:30][C:29]([CH3:32])([CH3:31])[N:28]([O:39][CH:35]2[CH2:38][CH2:6][CH2:5][CH2:4][CH2:37]2)[C:27]([CH3:34])([CH3:33])[CH2:26]1)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:18][C:17]([CH3:19])([CH3:20])[N:16]([O:39][CH:35]2[CH2:38][CH2:3][CH2:2][CH2:1][CH2:37]2)[C:15]([CH3:21])([CH3:22])[CH2:14]1)=[O:11]
Reactant: CC(C)(C)OO
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: O=[Mo](=O)=O
Solvent: C1CCCCC1
Product: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Temperature: 140 °C
Reaction time: 2 h
Yield: 126.4 %

Procedure:
A mixture of 20.0 g (41.6 mmol) of di-(2,2,6,6-tetramethylpiperidin-4-yl) sebacate, 43 g (334 mmol) of 70% aqueous t-butyl hydroperoxide, 1.3 g (9.0 mmol) of molybdenum trioxide, and 125 ml of cyclohexane is heated at reflux for 2.3 hours. Water is collected in a Dean-Stark trap. The red reaction mixture is cooled and transferred to a Fischer-Porter bottle. Fresh cyclohexane (25 ml) is used to thoroughly rinse the flask, and the rinsings are added to the pressure bottle. The pressure bottle is immersed in an oil bath (140° C.) for 3 hours whereupon the colorless reaction mixture is cooled to room temperature and filtered. The filtrate is stirred with 10 g of sodium sulfite in 90 ml of water for 2 hours to decompose unreacted hydroperoxide, then diluted with ethyl acetate (200 ml) and water (100 ml). The organic layer is washed with 10% sodium sulfite (100 ml), water (100 ml), saturated sodium chloride (100 ml), then dried over magnesium sulfate and concentrated at reduced pressure. The crude product is purified by flash chromatography (silica gel, 100:2 heptane:ethyl acetate) to afford 17.8 g (63% yield) of a white solid, m.p. 56°-9° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]([C@:14]1([C:20]([N:22]2[CH2:27][C:26]3[CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=[CH:31][C:25]=3[O:24][CH2:23]2)=[O:21])[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15]1)([CH3:13])[CH3:12].C(N(CC)CC)C.Cl>C(Cl)Cl>[CH:11]([C@:14]1([C:20]([N:22]2[CH2:27][C:26]3[CH:28]=[C:29]([C:32]([F:34])([F:35])[F:33])[CH:30]=[CH:31][C:25]=3[O:24][CH2:23]2)=[O:21])[CH2:18][CH2:17][C:16](=[O:19])[CH2:15]1)([CH3:13])[CH3:12]
Reactant: CC(C)[C@]1(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)CCC(O)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@]1(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)CCC(=O)C1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of DMSO (0.656 mL, 9.24 mmol) in 7 mL of DCM was added dropwise to a cooled (−78° C.) solution of oxalyl chloride (0.403 mL, 4.62 mmol) in 30 mL of DCM. After 5 min, a solution of (3S)-3-isopropyl-3-{[6-(trifluoromethyl)-2H-1,3-benzoxazin-3(4H)-yl]carbonyl}cyclopentanol (826 mg, 2.31 mmol) in 8 mL of DCM was added dropwise. The reaction mixture was stirred at −78° C. for 25 min, then was treated dropwise with neat triethylamine (2.58 mL, 18.5 mmol). After stirring at −78° C. for an additional 10 min, the reaction mixture was allowed to warm to rt and stir for 1.5 h. The mixture was then poured into 1N HCl solution and extracted with DCM. The organic layer was washed with more 1N HCl solution, then with saturated NaHCO3 solution and brine. The organic layer was then dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by MPLC (silica, 75% ethyl acetate/hexanes) to provide (3S)-3-isopropyl-3-{[6-(trifluoromethyl)-2H-1,3-benzoxazin-3(4H)-yl]carbonyl}cyclopentanone.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[C:14]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:14]([CH:22]1[CH2:27][CH2:26][N:25]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:24][CH2:23]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: O=C(c1ccccc1)C1CCNCC1
Product: N#Cc1ccc(N2CCC(C(=O)c3ccccc3)CC2)c2ccccc12
Yield: 7.5 %

Procedure:
The title compound (3 mg, 8% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and 4-benzoylpiperidine (89 mg, 0.468 mmol).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4]Br.[C:6](=[O:9])([O-])[O-].[K+].[K+].[CH:12]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13].O>CN(C)C=O>[CH:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:2][CH2:3][CH2:4][N:14]2[CH2:19][CH2:18][N:17]([CH:6]=[O:9])[CH2:16][CH2:15]2)[CH2:16][CH2:15]1)=[O:13]
Reactant: BrCCCBr
Reactant: O=CN1CCNCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=CN1CCN(CCCN2CCN(C=O)CC2)CC1
Reaction time: 20 h
Yield: 80.2 %

Procedure:
1,3-Dibromopropane (1.0 ml; 9.9 mmol) and potassium carbonate (2.0 g; 15 mmol) were added to a solution of 1-formylpiperazine (2.5 g; 22 mmol) in dimethylformamide (5 ml), and the mixture was stirred for 20 hours in a bath controlled at 60° C. Water was added to the reaction mixture to conduct extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 2.13 g (yield: 81%) of 1,3-bis(4-formyl-1-piperazinyl)propane as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=O)OC(C)(C)C)=[C:6]([CH3:17])[CH:5]=[C:4]([CH3:18])[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1.C(OCC)(=O)C>[CH3:17][C:6]1[CH:5]=[C:4]([CH3:18])[N:3]=[C:2]([OH:1])[C:7]=1[CH2:8][NH:9][CH3:10]
Reactant: Cc1cc(C)c(CNC(=O)OC(C)(C)C)c(O)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CNCc1c(C)cc(C)nc1O
Temperature: 70 °C
Yield: 86.6 %

Procedure:
To a solution of tert-butyl (2-hydroxy-4,6-dimethylpyridin-3-yl)methylcarbamate (700 mg, 2.78 mmol) in tetrahydrofuran (25 mL), lithium aluminum hydride (1 g, 26.3 mmol) was added in portions at room temperature. Then the mixture was heated at 70° C. for 15 hours with stirring. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (20 mL). And then water (20 mL) was added to the reaction mixture dropwise. The organic phase was separated and concentrated to provide 4,6-dimethyl-3-((methylamino)methyl)pyridin-2-ol as a pale yellow solid (0.4 g, 87%). LRMS (M+H+) m/z: calcd 166.1. found 166.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH:10]=[CH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[N:9]=1.[Cl-:17].[NH4+:18]>>[ClH:17].[S:13]1[CH:14]=[CH:15][N:16]=[C:12]1[CH:11]=[CH:10][CH:8]1[NH:9][C:3](=[NH:18])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: [Cl-]
Reactant: COC1=NC(C=Cc2nccs2)CCCC1
Reactant: [NH4+]
Product: Cl
Product: N=C1CCCCC(C=Cc2nccs2)N1

Procedure:
The product of Example 182 is reacted with ammonium chloride by the method of Example 5 to generate the title compound.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:19])=[N+]=[N-]>CO.[H][H]>[NH2:1][CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:19]
Reactant: [H][H]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O

Procedure:
The thus-obtained 5′-azido-5′-deoxythymidine was then dissolved in methanol and reduced with hydrogen using 10% palladium/carbon as a catalyst, whereby 5′-amino-5′-deoxythymidine was obtained. Yield 1.734 g, 71.6%.
Reaction SMILES: [O:1]1[CH2:27][CH:2]1[CH2:3][O:4][C:5]1[CH:26]=[CH:25][C:8]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[Cl:24])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:35][CH2:36][C:37]#[N:38].O>CS(C)=O>[O:1]1[CH2:27][CH:2]1[CH2:3][O:4][C:5]1[CH:26]=[CH:25][C:8]([NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH2:35][CH2:36][C:37]#[N:38])[C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[Cl:24])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1
Reactant: N#CCCBr
Reactant: Clc1ccc(Cl)c(Nc2cc(Nc3ccc(OCC4CO4)cc3)ncn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCN(c1cc(Nc2ccc(OCC3CO3)cc2)ncn1)c1cc(Cl)ccc1Cl
Reaction time: 20 h
Yield: 26 %

Procedure:
To a solution of 4-{4-[2,3-epoxypropoxy]anilino}-6-(2,5-dichloroanilino)pyrimidine (Reference Example 9, 1.4 g) in DMSO (3.75 ml) was added K2CO3 (1.1 g) and 3-bromopropionitrile (0.66 ml) and the reaction stirred for 20 hours. The mixture was poured into water and extracted with EtOAc. The organic extract was dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with DCM:MeOH; 99:1 to give the product (436 mg, 26%) as a colourless oil. NMR: 2.66 (1H, t), 2.78-2.92 (3H, m), 3.76 (1H, dd), 3.82-4.36 (3H, m), 5.28 (1H, s), 6.82 (2H, d), 7.38 (2H, d), 7.57 (1H, dd), 7.72 (1H, m), 8.25 (1H, s), 8.89 (1H, s); m/z 456(MH+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C:6]2[C:8]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:18][N:15]1[CH2:14][CH2:13][N:12]([C:8]2[C:6]3[CH2:7][C@H:2]([NH:1][C:31]([C:27]4[O:26][CH:30]=[CH:29][CH:28]=4)=[O:32])[CH2:3][O:4][C:5]=3[CH:11]=[CH:10][CH:9]=2)[CH2:17][CH2:16]1
Reactant: O=C(Cl)c1ccco1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccco2)CO3)CC1
Temperature: 0 °C
Yield: 78.4 %

Procedure:
To an ice-cooled stirred solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (230 mg, 0.930 mmol) and triethylamine (194 μL, 1.39 mmol) in anhydrous methylene chloride (10 mL) was added 2-furoyl chloride (101 μL, 1.02 mmol) under nitrogen. The ice-bath was removed, and the reaction mixture was allowed to reach room temperature. The mixture was washed with a 2 M NH3 solution, dried (MgSO4), and the solvent was removed in vacuo. The remains was purified on a chromatotron (accelerated thin layer chromatography, eluent: chloroform/ethanol; 92:8+0.5% conc. NH3) affording 249 mg (79% yield) of the title compound as a white solid: mp sinters >50° C.; [α]21D−83° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 341 (52, M+).