Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C(C)=C2C(C(=O)C(C3C=CC(OC)=CC=3)CO2)=CC=1.C(OC(=O)C)(=O)C.[C:29]([O:32][C:33]1[CH:54]=[CH:53][C:36]([C:37]2[C:46](=[O:47])[C:45]3[C:40](=[C:41]([CH3:52])[C:42]([O:48][C:49](=[O:51])[CH3:50])=[CH:43][CH:44]=3)[O:39][CH:38]=2)=[CH:35][CH:34]=1)(=O)C>N1C=CC=CC=1>[C:49]([O:48][C:42]1[C:41]([CH3:52])=[C:40]2[C:45]([C:46](=[O:47])[C:37]([C:36]3[CH:35]=[CH:34][C:33]([O:32][CH3:29])=[CH:54][CH:53]=3)=[CH:38][O:39]2)=[CH:44][CH:43]=1)(=[O:51])[CH3:50]
Reactant: CC(=O)Oc1ccc(-c2coc3c(C)c(OC(C)=O)ccc3c2=O)cc1
Agent: COc1ccc(C2COc3c(ccc(O)c3C)C2=O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(-c2coc3c(C)c(OC(C)=O)ccc3c2=O)cc1

Procedure:
7-Acetoxy-4′-methoxy-8-methylisoflavone was prepared from 7-hydroxy-4′-methoxy-8-methylisoflavanone (3.0 g, 10.6 mmol), acetic anhydride (10 ml) and pyridine (2.0 ml) as described for 4′,7-diacetoxy-8-methylisoflavone. Yield: (2.0 g, 58%) m.p. 190-192° C. 1H NMR (CDCl3): δ 2.31 (s, 3H, CH3), 2.38 (s, 3H, OCOCH3), 3.84 (s, 3H, OMe), 6.98 (d, 2H, J 8.7 Hz, ArH), 7.12 (d, 1H, J 8.6 Hz, H6), 7.52 (d, 2H, J 8.7 Hz, ArH), 8.03 (s, 1H, H2), 8.18 (d, 1H, J 8.6 Hz, H5). Mass spectrum: 325 (M+1, 13%); 324 (M, 58%); 282 (100); 281 (42).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1CCNCC(C)=CC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCC[C@H]1C(O)=O.COC1C=C(C=C(OC)C=1OC)C(O)=O>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=Cc1ccccc1)CNCCC1CCCN1C(=O)OC(C)(C)C
Agent: COc1cc(C(=O)O)cc(OC)c1OC
Agent: O=C(O)[C@@H]1CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of the compound 2-[2-(2-Methyl-3-phenyl-allylamino)-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared from racemic proline according to the scheme1), 0.6 g (2 mmol) and 3,4,5-trimethoxy benzoic acid 0.513 g (2.4 mmol) in dry dichloromethane 10 ml, triethyl amine 0.2 ml was added and stirred at room temperature for 20 min. Then was added O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyl uranium tetrafluoroborate 1.3 g (4 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and was washed with 10% NaHCO3 solution, water and brine, dried, concentrated and subjected to column chromatography silica gel using CHCl3/MeOH as eluent to obtain 1 g of 2-{2-[(2-Methyl-3-phenyl-allyl)-3,4,5-trimethoxy-benzoyl)-amino]-ethyl}-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.CC(=O)C.S(=O)(=O)(O)O.CO>O.[O-2].[O-2].[O-2].[Cr+6]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:8][CH2:9][C:10](=[O:13])[CH2:11][CH2:12]2)=[CH:14][CH:15]=1
Reactant: OC1CCC(Oc2ccc(F)cc2)CC1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: O=C1CCC(Oc2ccc(F)cc2)CC1
Reaction time: 3 h
Yield: 96.1 %

Procedure:
To a stirred and cooled mixture of 8.9 parts of 4-(4-fluorophenoxy)cyclohexanol and 160 parts of 2-propanone were added dropwise 13 parts of a solution of 26.7 parts of chromium trioxide in 42.3 parts of concentrate sulfuric acid diluted with water till a volume of 100 parts at a temperature below 5° C. Upon completion, stirring was continued for 3 hours at room temperature. After the addition of a few parts of methanol, the reaction mixture was poured onto water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 8.4 parts (96.1%) of 4-(4-fluorophenoxy)cyclohexanone as a residue (140).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].C([O-])(=O)C.[NH4+].[N+:16]([CH3:19])([O-:18])=[O:17].O>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:19][N+:16]([O-:18])=[O:17])=[CH:4][C:3]=1[F:10]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1ccc(Cl)c(F)c1
Yield: 65.9 %

Procedure:
4-Chloro-3-fluorobenzaldehyde (13 g, 82 mmol) and ammonium acetate (14.6 g, 189 mmol) were dissolved in acetic acid (150 ml) and nitromethane (12.6 ml, 234 mmol) was added. The solution was heated to reflux for 1.5 h. After cooling to RT water (120 ml) was added. A solid precipitated. The reaction was extracted three times with methylene chloride. The combined organic layers were washed with water and sat. aq. NaCl solution, dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The residue was purified by flash column chromatography (Ethyl acetate/cyclohexane:1/4). The crude product was suspended in heptane, filtered and dried to yield 1-chloro-2-fluoro-4-(2-nitro-vinyl)-benzene (10.9 g, 66%) as a light yellow solid. 1H NMR (CDCl3, 300 MHz): δ 7.29 (d, J=7.8 Hz, 1H), 7.33 (d, J=9.3 Hz, 1H), 7.50 (t, J=7.5H7, 1H), 7.54 (d, J=13.6 Hz, 1H), 7.92 (d, J=13.6 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.F[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=1.C(N(CC)CC)C>>[CH3:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]2)[CH:15]=1
Reactant: OCC1CCNCC1
Reactant: Cc1ccnc(F)c1
Solvent: CCN(CC)CC
Product: Cc1ccnc(N2CCC(CO)CC2)c1
Temperature: 150 °C

Procedure:
Piperidin-4-ylmethanol (8.68 mmol, 1 g), 2-fluoro-4-methylpyridine (26.0 mmol, 2.89 g) and triethylamine (26.0 mmol, 3.63 mL, 2.64 g) were combined and heated to 150° C. for 1 hour in the microwave. The solvent was removed at reduced pressure and the residue purified by silica chromatography eluting with DCM—2% MeOH/CM to afford (1-(4-methylpyridin-2-yl)piperidin-4-yl)methanol. (0.75 g) MS m/z 207.2 (M+H).
Reaction SMILES: [Cl-].[Li+].C([Mg]Cl)(C)C.I[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.[CH:20](=[O:24])[CH2:21][CH2:22][CH3:23]>O1CCCC1>[OH:24][CH:20]([C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CCCC=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(C(=O)OCC)cc1
Temperature: -40 °C
Reaction time: 0.67 h

Procedure:
At −40° C., isopropylmagnesium chloride lithium chloride (15.3 mL, 1.3 M in THF, 19.9 mmol) was added dropwise to a solution of ethyl 4-iodobenzoate (5000 mg, 18.11 mmol) in tetrahydrofuran (30 mL). The solution was stirred at −40° C. for 40 minutes. Butyraldehyde (1830 mg, 25.4 mmol) was added. The mixture was allowed to warm to room temperature over 3 hours. The reaction was quenched with 1N HCl and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give ethyl 4-(1-hydroxybutyl)benzoate. 1H NMR (400 MHz, CDCl3, δ): 8.02 (d, J=8.6 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H), 4.83-4.66 (m, 1H), 4.38 (q, J=7.2 Hz, 2H), 1.86 (d, J=3.7 Hz, 1H), 1.83-1.61 (m, 2H), 1.51-1.42 (m, 1H), 1.39 (t, J=7.2 Hz, 3H), 1.36-1.23 (m, 1H), 0.94 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[O:3]1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[OH-].[Na+]>C(O)C.[Cl-].[Na+].O>[CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH:5]=[C:4]([CH:8]=[CH:15][C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)[O:3]1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC1=CC(=O)C(C)(C)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)OC(C=Cc2ccc(F)cc2)=CC1=O
Temperature: 50 °C
Yield: 60.1 %

Procedure:
To a solution of 2,2,5-trimethyl-3(2H)-furanone (2.0 g, 15.9 mM) and 4-fluorobenzaldehyde (1.6 g, 13.2 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.6 mM). The reaction solution was heated at 50° C. for four hours. After the reaction solution was cooled to room temperature and diluted with saturated aqueous sodium chloride (200 mL) and water (200 mL), the aqueous solution was extracted with diethyl ether (2×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (25 mL), dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford a dark yellow crystalline solid. The crude product was recrystallized from hexane to give light yellow crystals (1.8 g, 45% yield), m.p. 55°-57° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([O:22][CH2:23][CH3:24])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13]CC2C=CC=CC=2)=[CH:8][C:7]=1[CH3:21]>[Pd]>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([O:22][CH2:23][CH3:24])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[CH3:21]
Reactant: CCO[C@@H](Cc1c(C)cc(OCc2ccccc2)cc1C)C(=O)OC
Agent: [Pd]
Product: CCO[C@@H](Cc1c(C)cc(O)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 d], (2S)-3-(4-benzyloxy-2,6-dimethyl-phenyl)-2-ethoxy-propionic acid methyl ester was hydrogenated over 10% palladium on charcoal to give (2S)-2-ethoxy-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Br.[O-:10][S:11]([O-:13])=[O:12].[Na+:14].[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:11]([O-:13])(=[O:12])=[O:10].[Na+:14]
Reactant: O=S([O-])[O-]
Reactant: BrCc1ccccc1Br
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=S(=O)([O-])Cc1ccccc1Br
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 155.6 %

Procedure:
A mixture of 1-bromo-2-(bromomethyl)benzene (20 g, 0.08 mol) and Na2SO3 (15 g, 0.12 mol) in methanol/H2O (100 mL/100 mL) was stirred at 85° Celsius for 2.5 hours, concentrated to dryness and dried to give sodium (2-bromophenyl)methanesulfonate (34 g, crude). 1H NMR (300 MHz, DMSO-d6) δ 7.54 (m, 2H), 7.27 (m, 1H), 7.12 (m, 1H), 3.91 (s, 2H).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]([CH3:13])([CH:10]([CH3:12])[CH3:11])[C:8]#[N:9].[OH-:14].[NH4+]>C1COCC1>[NH2:6][C:7]([CH3:13])([CH:10]([CH3:12])[CH3:11])[C:8]([NH2:9])=[O:14]
Reactant: [OH-]
Reactant: CC(C)C(C)(N)C#N
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(C)(N)C(N)=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To concentrated sulfuric acid (29.7 ml), cooled with stirring in an ice-acetone cooling bath, is added 11.8 g (-)-2-amino-2,3-dimethylbutyronitrile with [α]D25 =7.31° (c=0.0368 g/ml THF) at such arate that the temperature does not go above 25° C. After the addition, the temperature of the reaction mixture is slowly raised to 100° C. and held at that temperature for one hour. After cooling the mixture in an ice-acetone bath, 85 ml concentrated ammonium hydroxide is added at such a rate that the temperature does not exceed 75° C. The mixture is extracted five times with methylene chloride, the combined extracts dried and concentrated. This gives 11.95 g of white solid, mp 79°-81° C. and [α]D25 =+57.43° (c=0.0213 g/ml THF). This solid is recrystallized from methylene chloride-hexane to give 11.2 g of (+)-2-amino-2,3-dimethylbutyramide, mp 81°-82° C. [α ]D25 =+59.38° (c=0.0162 g/ml THF).
Reaction SMILES: Cl.Cl.[CH3:3][C@@:4]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][S:42](Cl)(=[O:44])=[O:43])=[CH:36][CH:35]=1>O>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][S:42]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][C@:4]3([CH3:3])[O:8][C:7]4=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]4[CH2:5]3)[CH2:21][CH2:20]2)(=[O:44])=[O:43])=[CH:38][CH:39]=1
Reactant: O=S(=O)(Cl)CCc1ccc(Cl)cc1
Reactant: C[C@]1(CN2CCNCC2)Cn2cc([N+](=O)[O-])nc2O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]1(CN2CCN(S(=O)(=O)CCc3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
A mixture of (S)-2-methyl-6-nitro-2-(piperazin-1-ylmethyl)-2,3-dihydroimidazo[2,1-b]oxazole dihydrochloride prepared in Example 408 (236 mg, 0.88 mmol) and DMF (3 ml) was added potassium carbonate (500 mg, 3.62 mmol) and 2-(4-chlorophenyl)ethanesulfonyl chloride (240 mg, 1 mmol) in this order followed by stirring at room temperature overnight. To the reaction mixture, water was added, and the solution was extracted with ethyl acetate. The organic phase was washed with water three times and saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford (S)-2-{4-[2-(4-chlorophenyl)ethanesulfonyl]piperazin-1-ylmethyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (100 mg, yield 26%) as a white powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[CH2:20][CH2:19][CH2:18][C:17]([C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:38])[CH:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:26][CH:25]=4)=[O:22])=[CH:16][C:15]=3[CH:39]=2)=[CH:7][CH:6]=1)=[O:4]>CO.C1COCC1.[OH-].[Na+]>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[CH2:20][CH2:19][CH2:18][C:17]([C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:38])[CH:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:26][CH:25]=4)=[O:22])=[CH:16][C:15]=3[CH:39]=2)=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(C(=O)O)cc4)ccc3CCC2)cc1)C1CCOCC1
Yield: 86.3 %

Procedure:
A mixture of 2-(4-methoxycarbonylphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-6,7-dihydro-5H-benzocyclohepten-8-carboxamide (0.25 g) in methanol (25 ml), THF (25 ml) and 1N NaOH (5 ml) was refluxed overnight. The reaction mixture was concentrated, and neutralized using 1N HCl. The precipitate was filtered, washed with water and dried to give 2-(4-carboxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-6,7-dihydro-5H-benzocyclohepten-8-carboxamide (0.21 g) as colorless amorphous.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30](O)=[O:31])=[CH:26][CH:25]=1>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:30](=[O:31])[CH2:29][O:28][C:27]3[CH:33]=[CH:34][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[S:14][C:9]=2[N:10]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3ccncc3)sc2n1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(-c3ccncc3)sc2n1
Yield: 43 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-4-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-chlorophenoxyacetic acid in a yield of 43%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([O:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]3)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[O:20]=[C:21]1[NH:26][C:25]2[CH:27]=[C:28]([CH:31]=O)[CH:29]=[CH:30][C:24]=2[O:23][CH2:22]1.[BH4-].[Na+]>ClCCCl.CO>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([O:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([NH:19][CH2:31][C:28]4[CH:29]=[CH:30][C:24]5[O:23][CH2:22][C:21](=[O:20])[NH:26][C:25]=5[CH:27]=4)[CH2:15][CH2:14]3)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2sc(O[C@H]3CC[C@H](N)CC3)nc12
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: COc1cccc2sc(O[C@H]3CC[C@H](NCc4ccc5c(c4)NC(=O)CO5)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
trans-4-(4-methoxy-benzothiazol-2-yloxy)-cyclohexylamine (0.5 mmol, intermediate 25.b) and 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (0.5 mmol) were dissolved in DCE (4 ml) and MeOH (4 ml). The mixture was stirred at RT overnight, NaBH4 (1 eq) was added and stirring continued for 1 h. The reaction mixture was partitioned between DCM and NH4OH. The organic layer was dried over MgSO4 and concentrated under reduced pressure. Purification by chromatography (EtOAc/MeOH 9:1 +1% NH4OH) and crystallisation from ether gave 36 mg (16%) of the title compound as a colourless solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[N:11]=[CH:12][N:13]3[CH:17]=[CH:16][S:15][C:14]=23)=[O:9])=[CH:4][CH:3]=1.[CH2:18]([Sn:22](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[N:11]=[CH:12][N:13]3[CH:17]=[C:16]([Sn:22]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH3:21])[S:15][C:14]=23)=[O:9])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1ccc(C(=O)c2ncn3ccsc23)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3ccc(C)nc3)c2s1

Procedure:
The title compound (606 mg) was prepared in substantially the same manner as in step c) of Synthesis Example 1, except that 447 mg of 7-(6-methylpyridin-3-yl)carbonylimidazo[5,1-b]thiazole, 0.552 ml of tri-n-butylstannyl chloride, and 3.2 ml of a 1.0 N lithium bis(trimethylsilyl)amide/THF solution were used as the starting materials.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([Br:12])=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8].CCN(C(C)C)C(C)C.[Cl:23][CH2:24][C:25](Cl)=[O:26].O>CC(C)=O>[Br:12][C:5]1[CH:4]=[C:3]([CH3:13])[C:2]([NH:1][C:25](=[O:26])[CH2:24][Cl:23])=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8]
Reactant: CNC(=O)c1cc(N)c(C)cc1Br
Reactant: O=C(Cl)CCl
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(NC(=O)CCl)c(C)cc1Br
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of 5-amino-2-bromo-N, 4-dimethylbenzamide (3A) (94 mg, 0.38 mmol) in acetone (4 mL) at 0° C. was added DIPEA (68 μL, 0.39 mmol) followed by 2-chloroacetylchloride (31 μL, 0.39 mmol). The solution was stirred for 60 minutes and another aliquot of 2-chloroacetylchloride (4 μL) was added. Water was added (94 mL) and the acetone removed in vacuo. The solids were stirred rapidly for 1 h, filtered and washed with water to give 104 mg (84% yield) of 2-bromo-5-(2-chloroacetamido)-N-methyl-4-methylbenzamide, 1H NMR: (CDCl3, 400 MHz) δ 8.28 (s, 1H), 8.03 (s, 1H), 7.44 (s, 1H), 6.01 (br s, 1H), 4.23 (s, 2H), 3.01 (d, J=5.0 Hz, 3H), 2.17 (s, 3H); LCMS 320.99 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]=2[CH:11]=1
Reactant: Cc1cc(C)c2oc(=O)[nH]c2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2oc(=O)n(CC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5,7-dimethyl-2-benzoxazolinone from Step A (200 mg, 1.23 mmol) in DMF (2 mL) was added sodium hydride (59 mg of a 60% dispersion in mineral oil, 1.47 mmol). The mixture was stirred at ambient temperature for 10 min, then tert-butyl bromoacetate (287 mg, 1.47 mmol) was added and stirring was continued for 2 h. The reaction mixture was quenched with H2O and purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=222 (M-C4H7).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][OH:13].C[N+]1([O-])CCOCC1>C(Cl)Cl.CC#N.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[CH:12]=[O:13]
Reactant: OCc1cc(C(F)(F)F)ccc1Br
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: O=Cc1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To (2-bromo-5-trifluoromethyl-phenyl)-methanol (2.216 g, 8.69 mmol) and N-methylmorpholine N-oxide (2.051 g, 17.38 mmol) in CH2Cl2 (44 mL) and MeCN (2.2 mL) was added tetrapropylammonium perruthenate (0.311 g, 0.87 mmol), and the reaction was stirred at room temperature for 20 minutes. Once no starting material was seen by analytical tlc, the mixture was concentrated and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[Cl:21][C:22]1[N:27]=[C:26](Cl)[CH:25]=[CH:24][N:23]=1.O>CC(N(C)C)=O>[Cl:21][C:22]1[N:27]=[C:26]([NH:13][C@H:10]2[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)[CH:25]=[CH:24][N:23]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccnc(Cl)n2)C1
Reaction time: 24 h
Yield: 89.7 %

Procedure:
(S)-(−)-1-Boc-3-aminopyrrolidine (0.375 g, 2.014 mmol) and triethylamine (0.561 mL, 4.028 mmol) were added to a solution of 2,4-dichloropyrimidine (0.300 g, 2.014 mmol) in DMA (12 mL) at 0° C. After 24 hours at room temperature, water (150 mL) was added and the aqueous phase was extracted with ethyl acetate (3×40 mL). The combined organic extracts were dried (MgSO4) and concentrated. The crude product was purified by silica gel chromatography (5% methanol in dichloromethane) to give the title compound as an oil (0.540 g, 90%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]#[N:12].[CH2:13]([Mg]Br)[CH3:14]>C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[CH2:10][C:11]1([NH2:12])[CH2:14][CH2:13]1
Reactant: CC[Mg]Br
Reactant: N#CCC1Cc2ccccc2C1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Product: NC1(CC2Cc3ccccc3C2)CC1
Yield: 66.2 %

Procedure:
By using 2,3-dihydro-1H-inden-2-yl acetonitrile (157 mg, 1.00 mmol) described in WO 1998/005651, ethyl magnesium bromide (3 M diethyl ether solution, 0.67 mL, 2.00 mmol), tetraisopropoxy titanium (0.33 mL, 1.10 mmol), and trifluoroborane-diethyl ether complex (0.25 mL, 2.00 mmol), the reaction was carried out in the same manner as the method described in J. Org. Chem. 2002, 67, 3965 to give the title compound as a white solid (124 mg, yield 66%).
Reaction SMILES: [C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)([CH3:4])([CH3:3])[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:14]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][CH:5]1[C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)C1Cc2ccccc2N1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N1c2ccccc2CC1C(C)(C)C
Reaction time: 2 h

Procedure:
2-t-Butylindoline (20.3 g, 116 mmol) (can be made according to the procedures described in J. Chem Soc. Chem. Commum. 1974, 677-678) and 4-dimethylaminopyridine (10 mg) are dissolved in pyridine (100 ml). Acetic anhydride (11.5 ml, 122 mmol) is added and the solution stirred for 2 hours. The mixture is poured into water (1 L) and the solid filtered and dried in vacuo. The title compound is obtained as white crystals (22.2 g, 88%): mp 75° C.