Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH:17]=O.[OH-].[Na+]>CO>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:2][C:1]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=2)=[O:3])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C(=O)C=Cc2ccc(Cl)c(Cl)c2)cc1
Reaction time: 19 h
Yield: 96 %

Procedure:
To a stirred suspension at room temperature of 4-acetylbenzoic acid (1.71 g, 10.44 mmol), 3,4-dichlorobenzaldehyde (2.05 g, 11.49 mmol) or aldehyde (1.1 equiv.) in MeOH (50 ml) was added a solution of NaOH (26.1 ml, 1N in H2O). After 19 h, the reaction mixture was filtered off, rinsed with MeOH and dried to afford the title compound IIa (3.22 g, 10.03 mmol, 96% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ(ppm): 8.35 (s, 1H), AB system (δA=8.13, δB=8.01, J=8.4 Hz, 4H), 8.12 (d, J=15.8 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.76 (d, J=8.3 Hz, 1H, 7.73 (d, 15.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][NH:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]3[C:23]4[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=4[N:21]=[C:20]3[C:29]([OH:32])([CH3:31])[CH3:30])[CH2:15][CH2:14]1)[CH2:5]2>C1CCCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]3[C:23]4[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=4[N:21]=[C:20]3[C:29]([OH:32])([CH3:30])[CH3:31])[CH2:15][CH2:14]1)[CH2:5]2
Reactant: Cc1ccc2c(c1)nc(C(C)(C)O)n2[C@H]1CC[C@@H](NCC2Cc3ccc(F)cc3C2)CC1
Solvent: C1CCCCC1
Product: Cc1ccc2c(c1)nc(C(C)(C)O)n2[C@H]1CC[C@H](NCC2Cc3ccc(F)cc3C2)CC1

Procedure:
This compound was isolated as the second and more polar product in the preparation of cis-2-(1-{4-[(5-fluoro-indan-2-ylmethyl)-amino]-cyclohexyl}-5-methyl-1H-benzoimidazol-2-yl)-propan-2-ol. The analysis of the 1H-NMR confirmed the trans-conformation of the cyclohexane. LC-MS showed a single peak, C27H34FN3O (m/e) calcd 435.2686, obsd 436.3 (M+H).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=[O:19])=[CH:10][CH:9]=1>C1COCC1>[CH3:7][N:6]1[C:2]([CH:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]=[CH:9][CH:10]=2)[OH:19])=[CH:3][N:4]=[CH:5]1
Reactant: Cn1cncc1Br
Reactant: O=Cc1ccnc2ccccc12
Solvent: C1CCOC1
Product: Cn1cncc1C(O)c1ccnc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Analogous to the general method described in J. Org. Chem. 2004, 69, 8115 and Chem. Pharm. Bull 1997, 1145. To a 2-necked flask containing 5-bromo-1-methyl-1H-imidazole (2.05 g, 12.7 mmol) was added THF (50 mL) and the solution was cooled to 0° C. To this clear homogeneous solution was added isopropyl magnesium chloride-LiCl complex (1.3 M, 10.5 mL, 13.6 mmol) which initially resulted in a white suspension, but became grayish once the addition of the Grignard reagent was complete. The reaction was stirred in an ice bath for 30 min, then a THF solution (20 mL) of quinoline-4-carbaldehyde (1.00 g, 6.36 mmol) was introduced and the reaction mixture became a greenish-grey color, and was subsequently allowed to warm to room temp. After 2 hours, the reaction mixture became brown in color and still remained heterogeneous. The reaction was quenched after 2 hours with saturated NH4Cl solution and the aqueous portion was extracted with EtOAc (4×75 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give an amber oil which solidified to a white solid upon standing. The crude material was triturated with DCM and then MeOH leaving behind the title compound as a white solid. The mother liquors were concentrated and chromatographed on silica gel (30% EtOAc-DCM increasing gradient to 10% MeOH-DCM) to provide more title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[O:34]=[C:35]([CH3:55])[CH2:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[NH:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:52]2[CH2:51][CH2:50][CH:49]([NH:48][C:40]3[N:39]([CH2:38][CH2:37][CH2:36][C:35](=[O:34])[CH3:55])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:54][CH2:53]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Reactant: CC(=O)CCCn1c(NC2CCNCC2)nc2ccccc21
Agent: I
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4CCCC(C)=O)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and (1-(4-oxopentyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH:19]3[CH:17]([C:18]3([C:22]3[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=3)[CH3:21])[CH2:16]1)=O)=[C:5]2[CH3:33].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][CH2:13][N:15]1[CH2:20][CH:19]3[CH:17]([C:18]3([C:22]3[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=3)[CH3:21])[CH2:16]1)=[C:5]2[CH3:33]
Reactant: Cc1c(CCC(=O)N2CC3C(C2)C3(C)c2cccc(NS(C)(=O)=O)c2)[nH]c2ccc(F)cc12
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(CCCN2CC3C(C2)C3(C)c2cccc(NS(C)(=O)=O)c2)[nH]c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
To a solution of N-(3-{3-[3-(5-fluoro-3-methyl-1H-indol-2-yl)propanoyl]-6-methyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide (Preparation 128, 100 mg, 0.213 mmol) in anhydrous tetrahydrofuran (2.5 ml) under a nitrogen atmosphere at 0° C. was added dropwise lithium aluminium hydride (1.0M solution in tetrahydrofuran, 0.42 ml, 0.42 mmol) and the reaction mixture was stirred at room temperature overnight. The rapidly stirred reaction mixture was treated sequentially with water (0.45 ml), sodium hydrogen carbonate (450 mg) and ethyl acetate (10 ml). After 5 min, the reaction mixture was filtered and concentrated in vacuo to afford 95 mg of a colourless oil. This was purified by chromatography using a Biotage Flash 12™ cartridge packed with silica gel (8 g) eluting with hexane:ethyl acetate (100:0 to 0:100 over 30 min) then ethyl acetate:methanol (100:0 to 0:100 over 15 min) to afford the title compound as a white foam (56 mg, 46%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=[O:11].[BH4-].[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][OH:11]
Reactant: O=Cc1cc2ccccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A cooled (0° C.) solution of commercially available benzofuran-2-carbaldehyde (1.000 g; 6.84 mmol) in anh. methanol (37 ml) was treated portionwise with NaBH4 (1.294 g; 34.21 mmol), and the resulting mixture was stirred at 0° C., under nitrogen, for 1 h 45. After concentration to dryness under reduced pressure, the resulting residue was treated with water (30 ml), and extracted with DCM (2×100 ml). The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, concentrated to dryness under reduced pressure, and the residue was further dried under HV affording benzofuran-2-ylmethanol as a slightly yellow oil. LC-MS (conditions D): tR=0.78 min.; no ionisation.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[C:18]([O:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])(=[O:29])=[O:28])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[ClH:36].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[C:18]([O:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])(=[O:28])=[O:29])[CH:17]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc(OS(=O)(=O)c3ccccc3Cl)cc3ccccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=S(=O)(Oc1cc(OCC2CCNCC2)c2ccccc2c1)c1ccccc1Cl
Reaction time: 1 h
Yield: 201.3 %

Procedure:
To a solution of 319 mg (0.596 mmol) of 2-chlorobenzenesulfonic acid 1-[[1-N-(tert-butoxycarbonyl)piperidin-4-yl]methoxy]naphthalen-3-yl ester, as prepared in the preceding step, in 2 mL of methylene chloride was added 1.5 mL (6 mmol) of 4 N HCl in dioxane. The reaction mixture was stirred for 1 h and triturated with diethyl ether to afford 281 mg of the title compound as a colorless powder. 1H-NMR (300 MHz, DMSO-d6) δ 8.94 (bd, 1 H, J=9 Hz), 8.68 (bd, 1 H, J=10 Hz), 8.6 (d, 1 H, J=8 Hz), 7.8-7.98 (m, 4 Hz), 7.50-7.6 (m, 3 H), 7.18 (d, 1 H, J=2 Hz), 6.69 (d, 1 H, J=2 H), 3.94 (d, 2 H, J=7 Hz), 2.93 (q, 2 H), 2.16 (bm, 1 H), 1.96 (d, 2 H), and 1.57-1.71 (m, 2 H). Mass spectrum (MALDI-TOF; gentisic acid matrix) calcd. for C22H22ClNO4S: 432.1 (M+H). Found: 431.5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([SH:8])[N:3]=1.[OH-].[Na+].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17]Cl>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)[N:3]=1
Reactant: Nc1ccnc(S)n1
Reactant: ClCc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccnc(SCc2ccccn2)n1
Temperature: 22 °C

Procedure:
4-Amino-2-mercaptopyrimidine (0.40 g, 3.15 mmol) is slurried in ethanol (2 ml) and 3.25 M NaOH (2.0 ml, 6.5 mmol) is added. The solution is heated to reflux for 10 minutes and after cooling to 22° C., 2-picolyl chloride*HCl (0.49 g, 2.98 mmol) is added. The solution is heated to reflux for an additional 15 minutes. The solution is cooled and concentrated in vacuo. The residue is dissolved in 1 N HCl and diluted with ethyl acetate. The mixture is neutralized with NaOH to pH 8 and the aqueous layer is separated and washed twice with ethyl acetate. The combined organic layers are washed with saturated NaHCO3, saturated NaCl, dried with MgSO4 and concentrated in uacuo, mp 133-134° C.
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:8]2[CH2:11][C:10](=[N:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[C:21]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)NN=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NNC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
To a stirred solution of tert-butyl 2-[1-(diphenylmethyl)azetidin-3-ylidene]hydrazinecarboxylate (Preparation 692, 15.8 g, 45 mmol) in acetic acid (126 ml) was added sodium cyanoborohydride (2.82 g, 45 mmol) portionwise at room temperature and stirred at room temperature for 4 hours. Then the reaction mixture was concentrated in vacuo. The pH was adjusted to 8-10 with 1M aqueous sodium hydroxide solution and extracted with dichloromethane (3×200 ml). The combined organic layer was washed with water (3×150 ml), saturated aqueous sodium chloride solution (150 ml), dried over anhydrous sodium sulphate and concentrated in vacuo. The crude product was triturated with diethyl ether to get 15 g (94%) of the title compound as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]([CH2:17]C(OCC)=O)[CH2:9][CH2:8]1.[OH2:23].[OH-].[Na+]>C1COCC1>[O:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]([CH2:17][OH:23])[CH2:9][CH2:8]1
Reactant: O
Reactant: CCOC(=O)CC1CCOc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of lithium aluminum hydride (3.45 g) in THF (400 ml) was added dropwise a solution of ethyl chroman-4-ylacetate (10.0 g) in THF (50 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added water (3.45 ml), 15% aqueous sodium hydroxide solution (3.45 ml) and water (10 ml), and the mixture was filtered, washed with ethyl acetate, and concentrated under reduced pressure to give chroman-4-ylmethanol (7.58 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.Cl.[OH:23][C:24]1[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:18]=[C:17]([C:19]([N:28]2[CH2:27][CH2:26][C:25]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:34])[C:24]=3[OH:23])[CH2:29]2)=[O:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: Cc1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2ccc(F)cc2F)nc2ccccc12
Agent: Cl
Product: Cc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(F)cc3F)nc3ccccc13)C2
Yield: 22 %

Procedure:
Reaction of 2-(2,4-difluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 61 (22% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.25 and 2.28 (2s, 3H), 2.82 and 3.04 (2t, 2H), 3.65 and 4.21 (2t, 2H), 4.54 and 5.08 (2s, 2H), 6.39 and 6.81 (2d, 1H), 6.90-7.08 (m, 3H), 7.63-7.73 (m, 1H), 7.99-8.11 (m, 2H), 8.22-8.28 (m, 2H); MS (ESI) m/z 432 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:9][C:6]1[N:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C)nc1[N+](=O)[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)nc1[N+](=O)[O-]

Procedure:
A mixture of 3-methoxy-6-methyl-2-nitropyridine (10.08 g, 60 mmol), NBS (9.79 g, 55 mmol), and benzoyl peroxide (2 g, 6 mmol) in CCl4 (250 mL) was refluxed for 56 hours under nitrogen atmosphere. The reaction mixture was added 100 mL 1M NaOH aq. and extracted using ethyl acetate (3×300 mL). The combined organic layer was dried over Mg2SO4 and filtered. The solvent was evaporated to yield a brown oily. 1H-NMR (CDCl3): δ 3.99 (s, 3H, OCH3), 4.51 (s, 2H, CH2), 7.55 (d, 1H, J=8.8 Hz, Py-H), 7.70 (d, 1H, J=8.4 Hz, Py-H). HR-MS (ESI+) m/z 246.9600 [M+1]+ C7H7BrN2O3 requires 245.9640.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[C:27]#[CH:28]>ClCCl>[CH2:31]([O:30][C:26](=[O:29])/[CH:27]=[CH:28]/[O:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1)[CH3:32]
Reactant: C#CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/O[C@@H]1C[C@@H]2C[C@H]1N(C(=O)OC(C)(C)C)[C@@H]2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a solution of 3-benzyl 2-tert-butyl (1R,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate obtained in Example 30-1 (593 mg) in dichloromethane (10 mL), were added ethyl propiolate (670 mg) and 4-methylmorphorine (190 mg). The mixture was stirred at room temperature for 3 hrs. The resulting mixture was evaporated in vacuo and the residue was chromatographed on silica gel eluting with hexane and ethyl acetate (4:1) to give the target compound (760 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.Cl.ClCC1N=C(NC2C=CC(OC)=C(F)C=2)C2C(=CC=CC=2)[N:28]=1.CI.[H-].[Na+]>C1COCC1>[NH2:28][CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1F
Reactant: COc1ccc(Nc2nc(CCl)nc3ccccc23)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(N(C)c2nc(CN)nc3ccccc23)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
(2-Chloromethyl-quinazolin-4-yl)-(3-fluoro-4-methoxy-phenyl)-methyl-amine: A suspension of (2-chloromethyl-quinazolin-4-yl)-(3-fluoro-4-methoxy-phenyl)-amine hydrochloride (497 mg, 1.4 mmol) and MeI (0.18 mL, 2.9 mmol) in THF (7 mL) was treated with NaH (60% disp., 158 mg, 3.95 mmol) and stirred for 2 h at rt. The reaction was quenched by the addition of MeOH, concentrated onto SiO2 and purified by gradient MPLC (SiO2, EtOAc/hexanes, 0-100%) to provide 281 mg (61%) of the title compound. 1H NMR (CDCl3) δ 7.85 (d, 1H), 7.61 (ddd, 1H), 6.97-7.13 (m, 3H), 6.86-6.97 (m, 2H), 4.75 (s, 2H), 3.93 (s, 3H), 3.62 (s, 3H); LC-MS (ESI+; 332 ([M+H]+)).
Reaction SMILES: BrBr.[Mg].[Br:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][N:6]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[C:19]1([CH2:25][C:26](=[O:28])[CH3:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Br:4][C:5]1[N:6]=[C:7]([C:26]([OH:28])([CH3:27])[CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: BrBr
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Product: CC(O)(Cc1ccccc1)c1cccc(Br)n1
Yield: 81 %

Procedure:
According to Example 2, the Grignard reagent 1d (freshly prepared via bromine-magnesium exchange[6] from 2,5-dibromopyridine (391 mg, 1.65 mmol; 1.10 equiv) and i-PrMgCl.LiCl (1.00 M in THF; 1.62 mL, 1.62 mmol, 1.08 equiv) at −10° C.) was reacted with 1-phenyl-propan-2-one (201 mg; 1.50 mmol) in the presence of LaCl3.2LiCl (0.33 M; 4.55 mL, 1.50 mmol, 1.00 equiv). The crude product was purified by flash column chromatography (silica; pentane:Et2O, 9:1, 0.2 vol-% NEt3) to give the desired product as colorless oil (355 mg, 81%).
Reaction SMILES: COC1C=CC(C)=CC=1C(C1C=CC=CC=1)=O.[CH2:18]([O:20][C:21](=[O:44])[C:22]1[CH:27]=[CH:26][C:25]([O:28]CC2C=CC=CC=2)=[C:24]([C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH2:37])[CH:23]=1)C>>[CH3:18][O:20][C:21](=[O:44])[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:36]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH2:37])[CH:23]=1
Reactant: C=C(c1ccccc1)c1cc(C(=O)OCC)ccc1OCc1ccccc1
Agent: COc1ccc(C)cc1C(=O)c1ccccc1
Product: C=C(c1ccccc1)c1cc(C(=O)OC)ccc1O

Procedure:
1H-NMR (400 MHz, CDCl3): δ [ppm]=3.84 (s, 3H, CH3), 5.42 (d, 2J=1.0 Hz, 1H, ═CH2), 5.88 (d, 2J=1.0 Hz, 1H, ═CH2), 6.97 (d, 3J=8.5 Hz, 1H, PhH), 7.32 (m, 5H, PhH), 7.88 (d, 4J=2.3 Hz, 1H, PhH), 7.94 (dd, 3J=8.5 Hz, 4J=2.3 Hz, 1H, PhH). 13C-NMR (100 MHz, CDCl3): δ [ppm]=51.9 (CH3), 115.8 (CHarom), 117.4 (═CH2), 122.4 (Cqarom), 126.8 (2×CHarom), 127.6 (Cqarom), 128.7 (CHarom), 128.7 (2×CHarom), 131.3 (CHarom), 132.4 (CHarom), 138.8 (Cqarom), 144.3 (Cqolefin), 157.3 (Cqarom), 166.8 (COOMe). MS (EI, 70EV): m/z [%]=254 (M+, 5), 253 (7), 239 (3), 223 (1), 165 (1), 152 (1), 131 (1), 120 (22), 105 (44), 91 (100), 77 (37), 65 (13), 59 (16), 51 (20), 45 (17).
Reaction SMILES: OO.[N:3]1([CH2:9][CH2:10][NH:11][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH2:21][CH2:22]4)=[CH:18][C:16]=3[N:17]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(O)(C(F)(F)F)=[O:27]>C(Cl)Cl.N>[N:3]1([CH2:9][CH2:10][NH:11][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH2:21][CH2:22]4)=[CH:18][C:16]=3[N+:17]=2[O-:27])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: [O-][n+]1nc(NCCN2CCCCC2)nc2cc3c(cc21)CCC3
Reactant: O=C(O)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Product: [O-][n+]1nc(NCCN2CCCCC2)[n+]([O-])c2cc3c(cc21)CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 56.3 %

Procedure:
H2O2 (70%, 0.63 mL, ca. 12.7 mmol) was added dropwise to a stirred solution of TFM (1.8 mL, 12.7 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 36 (397 mg, 1.3 mmol) and TFA (0.20 mL, 2.5 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 5° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 37 (241 mg, 57%) as a red solid: mp (MeOH/EtOAc) 165-168° C.; 1H NMR δ 8.11 (s, 1H, H-9), 8.08 (s, 1H, H-5), 7.43 (br s, 1H, NH), 3.60-3.64 (m, 2H, CH2N), 3.03-3.11 (m, 4H, H-6, H-8), 2.62 (t, J=6.0 Hz, 2H, CH2N), 2.42-2.47 (m, 4H, 2×CH2), 2.15-2.22 (m, 2H, H-7), 1.57-1.63 (m, 4H, 2×CH2), 1.41-1.47 (m, 2H, CH2); 13C NMR δ 155.6, 149.5, 145.7, 138.0, 129.7, 115.8, 111.6, 56.9, 54.4 (2), 38.2, 33.4, 32.4, 25.9 (2), 25.6, 24.3. Anal. calcd for C17H23N5O2.¼H2O: C, 61.2; H, 7.1; N, 21.0. Found: C, 60.7; H, 7.0; N, 21.0%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[C:23]3[C:18](=[C:19]([CH3:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:27]3[S:28][CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:31]=3)[CH:15]=2)[CH2:10][C@H:9]1[C:36](O)=[O:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:72][NH:73][CH2:74][CH2:75][CH2:76][CH2:77][CH:78]=[CH:79]C.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:74]([N:73]([CH3:72])[C:36]([C@@H:9]1[CH2:10][C@H:11]([O:13][C:14]2[C:23]3[C:18](=[C:19]([CH3:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:27]3[S:28][CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:31]=3)[CH:15]=2)[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:37])[CH2:75][CH2:76][CH2:77][CH:78]=[CH2:79]
Reactant: COc1ccc2c(O[C@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-c3nc(C(F)(F)F)cs3)nc2c1C
Reactant: CC=CCCCCNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CN1C(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
Compound 125 (21.33 g) was dissolved in anhydrous DMF (48 mL) at room temperature. O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.25 eq.) was added at room temperature and the reaction mixture was stirred for 10 min. Compound 32b (1.1 eq.) was added and the reaction mixture was stirred for additional 10-15 min. After cooling to 5° C., diisopropylethylamine (3 eq.) was added. After warming to room temperature for 1 hr, the reaction mixture was diluted with ethyl acetate, washed with brine and ammonium chloride, dried over Na2SO4, and concentrated under vacuum to give crude 126 (22.09 g) as an orange foam. The crude product was crystallized from ethyl acetate and heptane to give compound 126 (20.8 g) as an off-white powder in 90% yield and 99% purity.