Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[O:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:31]([CH2:30][CH:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)=[N:15][C:14]=2[CH:16]=1
Reactant: O=CCC1CCOCC1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2oc(-c3ccc4c(c3)nc(CC3CCOCC3)n4C3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (250 mg, 0.808 mmol) in dimethylformamide (3 mL) was added (4-tetrahydropyranyl)acetaldehyde (114 mg, 0.889 mmol) and oxone (323 mg, 0.525 mmol), and this was stirred at room temperature for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (197 mg, 58% yield) as light brown crystals.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][CH:8]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[C:9]([OH:11])=O)=[CH:5][CH:4]=1)#[N:2].[CH3:19][O:20][C:21]([C@@H:23]([NH2:30])[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22].Cl.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:19][O:20][C:21](=[O:22])[C@@H:23]([NH:30][C:9](=[O:11])[CH:8]([C:12](=[O:13])[N:14]([CH3:16])[CH3:15])[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:18][CH:17]=1)[CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COC(=O)[C@@H](N)C1CCCCC1
Reactant: CN(C)C(=O)C(Cc1ccc(C#N)cc1)C(=O)O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C#N)cc1)C(=O)N(C)C)C1CCCCC1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
2-(R,S)-(4-Cyano-benzyl)-N,N-dimethyl-malonamic acid (10 g, 40.6 mmol) and L-cyclohexylglycine methylester hydrochloride (8.3 g, 40 mmol) were dissolved in dimethylformamide (500 ml). After cooling to −10° C. TOTU (13.1 g, 40 mmol) and diisopropylethylamine (10.34 g, 80 mmol) were added. The mixture was stirred for 1 hour and then allowed to warm to room temperature. After evaporation ethyl acetate was added to the residue and the organic layer was extracted with aqueous sodium hydogen carbonate solution, potassium hydrogen sulfate solution and water. The organic layer was evaporated. Yield: 14.53 g (90%); MS m/z: 400.3 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Br:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>>[Br:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cccc(Br)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(Br)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-Bromo-benzoic Acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]([C:29]3[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=3)[NH:21][C:20]2=[O:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1C(=O)NC(c2ccncc2)c2ccccc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NC(c2ccncc2)c2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-1-(pyrid-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-one (Example 5-B), the title compound was prepared as a solid having a melting point of 100° C.
Reaction SMILES: [I:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=O)=[C:6]2[CH:5]=[C:4]([CH3:14])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[C@H:47]12[CH2:53][C@H:50]([NH:51][CH2:52]1)[CH2:49][O:48]2>CN(C=O)C.O>[C@H:47]12[CH2:53][C@H:50]([N:51]([C:11]([C:10]3[CH:9]=[N:8][N:7]4[C:2]([I:1])=[CH:3][C:4]([CH3:14])=[CH:5][C:6]=34)=[O:13])[CH2:52]1)[CH2:49][O:48]2
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: Cc1cc(I)n2ncc(C(=O)O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(I)n2ncc(C(=O)N3C[C@@H]4C[C@H]3CO4)c2c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 47.3 %

Procedure:
To a solution of 7-iodo-5-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid (500 mg) in DMF (10 mL) were added HATU (755 mg) and triethylamine (0.531 mL), and the mixture was stirred at room temperature for 3 min. To the reaction mixture was added (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (247 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (300 mg).
Reaction SMILES: O.[N+:2]([CH:5]([CH:8]=O)[CH:6]=O)([O-:4])=[O:3].[Na].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)=O>CN(C=O)C.O>[CH2:11](/[N:18]=[CH:6]/[CH:5]([N+:2]([O-:4])=[O:3])/[CH:8]=[N:18]/[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: NCc1ccccc1
Agent: [Na]
Solvent: O=CO
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])C(/C=N/Cc1ccccc1)/C=N/Cc1ccccc1
Reaction time: 24 h
Yield: 10.2 %

Procedure:
A turbid, yellow-orange solution of sodium nitromalonaldehyde monohydrate (15.7 mg, 0.10 mmol) in DMF (275 uL) and water (25 uL) was added dropwise over a 2 min period to a solution of benzylamine (27.4 uL, 0.25 mmol) in DMF (165 uL), water (15 uL) and 96% formic acid (0.94 uL, 0.025 mmol) and was stirred at room-temperature for 24 h. A few drops of the reaction mixture were added to ˜1 mL water giving a white, opaque emulsion that was extracted with EtOAc twice. The combined organics were dried over Na2SO4, evaporated under N2 and dried in vacuo at room-temperature to give 3.0 mg of the crude title compound (I1) as a pale-pink residue (3.0 mg, 10% crude yield); HRMS calcd for C17H18N3O2 (M+H+) 296.13990, obsd 296.13733 (100%); 1H NMR (300 MHz, DMSO-d6) δ 4.719 (s, 4H), 7.274-7.304 (m, 10H), 8.898 (s, 2H), ˜11.7 (br s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:9][C:10]1[CH:39]=[CH:38][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][C:25]3[N:30]=[C:29]([C:31]4[CH:32]=[N+:33]([O-:37])[CH:34]=[CH:35][CH:36]=4)[CH:28]=[CH:27][N:26]=3)[CH:18]=2)=[O:15])=[CH:12][CH:11]=1.C(OCC)(=O)C>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][C:25]4[N:30]=[C:29]([C:31]5[CH:32]=[N+:33]([O-:37])[CH:34]=[CH:35][CH:36]=5)[CH:28]=[CH:27][N:26]=4)[CH:18]=3)=[O:15])=[CH:38][CH:39]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2ccc[n+]([O-])c2)n1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2ccc[n+]([O-])c2)n1
Temperature: 10 °C
Reaction time: 15 h

Procedure:
N-Methylpiperazine (99 mg, 1.0 mmol) is added to a stirred suspension of 4-chloromethyl-N-[4-methyl-3-[[4-(1-oxido-3-pyridinyl)-2-pyrimidinyl]-amino]-phenyl]-benzamide (220 mg, 0.49 mmol) In ethanol (5 mL). The mixture is then stirred at 10° C. for 15 h to give a solution, which is then cooled to RT and treated with ethyl acetate (200 mL). The resulting solution is washed with aqueous sodium hydroxide (100 mL of 2M) and saturated aqueous sodium chloride solution (100 mL), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 25% aqueous ammonia-methanol-dichloromethane (0.5:10:90) to give the title compound as a yellow crystalline solid, m.p. 232-235° C.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[F:24][C:25]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28].C(Cl)Cl.CO>O1CCCC1>[F:24][C:25]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:26]=1[C:27]([N:17]1[C:9]2=[N:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:12][C:11](=[O:13])[N:10]2[CH2:14][CH2:15][C@H:16]1[C:18]([F:20])([F:21])[F:19])=[O:28]
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1F)N1c2nc(N3CCOCC3)cc(=O)n2CC[C@H]1C(F)(F)F
Yield: 5.5 %

Procedure:
The product is prepared according to the procedure described in Example 18, using 300 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 47 mg of sodium hydride and 174 mg of 2,4-difluorobenzoyl chloride in 4 ml of tetrahydrofuran. After two successive purifications by silica chromatography (eluent: CH2Cl2/MeOH, gradient of 100/0 to 98/02 then 99/01), 24 mg of (8S)-9-[(2,4-difluorophenyl)carbonyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetra-hydro-4 H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of a colourless lacquer, the characteristics of which are the following:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.F[P-](F)(F)(F)(F)F.CN(C(ON1C2=NC=CC=C2N=N1)=[N+](C)C)C.[NH:33]1[C:41]2[C:36](=[C:37]([C:42]3[CH:43]=[C:44]([NH2:57])[C:45]4[C:49]([CH:50]=3)=[N:48][N:47](C3CCCCO3)[CH:46]=4)[CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34]1>CN(C=O)C.CCN(C(C)C)C(C)C>[NH:33]1[C:41]2[C:36](=[C:37]([C:42]3[CH:50]=[C:49]4[C:45]([CH:46]=[N:47][NH:48]4)=[C:44]([NH:57][C:6]([C:4]4[N:3]=[CH:2][NH:1][CH:5]=4)=[O:8])[CH:43]=3)[CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: O=C(O)c1c[nH]cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1c[nH]cn1
Reaction time: 0.08 h

Procedure:
1H-Imidazole-4-carboxylic acid (7 mg) in DMF (0.2 ml) was treated with N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (27 mg) in DMF (0.2 ml) and DIPEA (0.03 ml). The reaction mixture was shaken for five min prior to treatment with 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (20 mg) in DMF (0.2 ml). The reaction mixture was shaken for five min and left to stand at 22° C. for 18 h. Solvent was removed in vacuo and the product re-dissolved in methanol (0.5 ml) prior to application on to an SCX SPE cartridge (1 g). The product was eluted after 1 h with 2M ammonia in methanol (2×3 ml), the fractions were combined and concentrated under a stream of nitrogen using blow down apparatus. Purification by mass directed preparative HPLC (Method C) gave the title compound.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][NH2:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([CH:30]=2)[C:27](O)=[O:28])[N:18]=1>>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][NH:14][C:27](=[O:28])[C:26]3[CH:30]=[C:22]([C:19]4[N:18]=[C:17]([C:16]([F:32])([F:31])[F:15])[O:21][N:20]=4)[CH:23]=[N:24][CH:25]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCc1coc(-c2ccccc2)n1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCc1coc(-c2ccccc2)n1)c1cncc(-c2noc(C(F)(F)F)n2)c1
Yield: 32 %

Procedure:
This compound was synthesized from 2-(2-phenyloxazol-4-yl)ethanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (42 mgs, yield 32%). 1H NMR (CDCl3) δ 9.46 (d, J=2.1 Hz, 1H), 9.32 (d, J=2.1 Hz, 1H), 8.87 (t, J=2.7 Hz, 1H), 8.06-7.96 (m, 3H), 7.57-7.44 (m, 3H), 3.85 (m, 2H), 2.93 (t, J=6.3 Hz, 2H). MS (ESI) m/z: Calculated for C20H14F3N5O3: 429.10. found: 430.1 (M+H)+.
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][C@@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9][O:10][CH3:11].CCN(CC)CC.[N-:27]=[N+:28]=[N-:29].[Na+]>C(Cl)Cl.CCOC(C)=O>[N:27]([CH2:7][C@@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9][O:10][CH3:11])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: COC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
Methanesulfonyl chloride (4.0 g, 35 mmol) in DCM (50 mL) was slowly added to a solution of (R)-tert-butyl 1-hydroxy-3-methoxypropan-2-ylcarbamate (6.0 g, 29 mmol) and Et3N (3.64 g, 36 mmol) in DCM (150 mL) at 0° C. The reaction mixture was stirred at RT for 2 h. The organic phase was washed with water and saturated aq NaHCO3, concentrated, and dissolved in DMF. Sodium azide (2.34 g, 36.0 mmol) was added, and the reaction mixture was stirred at 75° C. for 4 h. The reaction mixture was diluted by EtOAc and washed with water. The crude product was purified by column chromatography on silica gel eluting with EtOAc and petroleum ether (EtOAc/PE=2/1) to give the title compound (4.3 g, 64%). 1H NMR (400 MHz, CDCl3) δ ppm 4.92 (s, 1 H), 3.91 (m, 1 H), 3.53-3.48 (m, 2 H), 3.45-3.40 (m, 2 H), 3.38 (s, 3 H), 1.47 (s, 9 H).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[CH3:15])C>ClC1C=CC=CC=1.O>[CH3:15][C:8]1[C:7]2[S:6][CH:5]=[CH:4][C:12]=2[CH:11]=[C:10]([O:13][CH3:14])[CH:9]=1
Reactant: CCOC(CSc1ccc(OC)cc1C)OCC
Solvent: O
Solvent: Clc1ccccc1
Product: COc1cc(C)c2sccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
To the hot (130° C.) solution of polyphosphoric acid (20 mL) in chlorobenzene (50 mL) was added dropwise a solution of 1-(2,2-diethoxy-ethylsulfanyl)-4-methoxy-2-methyl-benzene from step 2 (6.8 g, 0.025 mol) in chlorobenzene (25 mL) over a period of 2 h and stirred for 2 h at same temperature. The reaction mixture was cooled to room temperature and stirred for 12 h. The mixture was then cooled and diluted with water and the layers were separated. The aqueous layer was extracted in ethyl acetate. The combined organic layers were washed with water, dried and concentrated. The crude material was purified by chromatography (silica gel: hexane:ethyl acetate/4:1) to provide 2 g of 7-methyl-5-methoxy benzothiophene. MS m/z 178 (M+).
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[CH:10]=[C:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([CH2:21][CH:22]=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37])=[CH:25]1>>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[C:10]([CH:22]([C:25]2[NH:24][C:32]3[C:27]([C:26]=2[CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37])=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)NCCc1c[nH]c2ccccc12
Reactant: O=CCc1ccccc1
Reactant: O=C1C=C(O)C(Cc2ccccc2)O1
Product: CC(=O)NCCc1c(C(Cc2ccccc2)C2=C(O)C(Cc3ccccc3)OC2=O)[nH]c2ccccc12

Procedure:
Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) was reacted with phenyl-acetaldehyde and N-[2-(1H-indol-3-yl)-ethyl]-acetamide) to give the title compound as a white solid. MS: 493.0 ([M−H]−).
Reaction SMILES: CC1(C)[C@@H]2CC[C@@]1(CSSCC13C(C)(C)C(CC1)CC3N1CCOCC1)[C@H](N1CCOCC1)C2.C([Zn][CH2:38][CH3:39])C.[CH:40](=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:41]1([C@H:40]([OH:47])[CH2:38][CH3:39])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC[Zn]CC
Reactant: O=Cc1ccccc1
Agent: CC1(C)C2CCC1(CSSC[C@]13CC[C@H](C[C@H]1N1CCOCC1)C3(C)C)C(N1CCOCC1)C2
Product: CC[C@@H](O)c1ccccc1

Procedure:
After stirring a mixture of (1S,2R,4R)-1,2-bis((7,7-dimethyl-2-morpholinobicyclo[2.2.1]heptan-1-yl)methyl)disulfane (IIIa) (51 mg, 0.10 mmol) and diethylzinc (3.2 mmol, 1.0 M in hexanes) at ambient temperature for 30 minutes, neat benzaldehyde (200 μL, 2.0 mmol) was added in one portion. Upon complete consumption of benzaldehyde as judged by TLC, sat. aq. NH4Cl (3 mL) was slowly added to the reaction product mixture followed by ethyl acetate (20 mL). The mixture was washed twice with 1 N aq. HCl (20 mL each) and brine (5 mL), dried over solid Na2SO4, and concentrated to give a colorless oil which was purified by silica gel column chromatography (1:10 ethyl acetate/n-heptane) to give (R)-1-phenyl-propanol as a colorless oil (221 mg; 81%; 95.2% e.e.).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:7])[CH:3]=[C:4](Br)Br.Cl[C:17]([O:19][CH3:20])=[O:18].CC(C1C=CC(OC)=CC=1)(C)C#CC>>[CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:7])[C:3]#[C:4][C:17]([O:19][CH3:20])=[O:18]
Reactant: COc1ccc(C(C)(C)C=C(Br)Br)cc1
Reactant: COC(=O)Cl
Agent: CC#CC(C)(C)c1ccc(OC)cc1
Product: COC(=O)C#CC(C)(C)c1ccc(OC)cc1

Procedure:
This compound was prepared from Compound 53 and ClCO2Me in the same manner of Compound 54.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([CH2:23][CH2:24][N:25]=3)[C:8]([NH:14][C:15]([C:17]3[CH:18]=[N:19][CH:20]=N[CH:22]=3)=[O:16])=[N:9][C:10]=2[C:11]=1[O:12][CH3:13].[C:26](=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].Br[CH2:35][CH2:36][CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42]>CN(C)C=O.O>[C:41]([O:40][C:39](=[O:45])[NH:38][CH2:37][CH2:36][CH2:35][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([CH2:23][CH2:24][N:25]=3)[C:8]([NH:14][C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:26][CH:22]=3)=[O:16])=[N:9][C:10]=2[C:11]=1[O:12][CH3:13])([CH3:44])([CH3:43])[CH3:42]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: COc1c(O)ccc2c1N=C(NC(=O)c1cncnc1)N1CCN=C21
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(OCCCNC(=O)OC(C)(C)C)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 100 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
N-(8-Hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide (Intermediate B, 1.5 g, 4.4 mmol) was diluted in dimethylformamide (50 mL) containing a few drops of water. Cesium carbonate (7.24 g, 22.2 mmol) and sodium iodide (0.80 g, 5.3 mmol) were added, followed by tert-butyl (3-bromopropyl)carbamate (3.18 g, 13.3 mmol). The mixture was stirred at 100° C. overnight. After cooling to rt, the solvent was removed in vacuo. The residue was diluted in 10% methanol in dichloromethane, and solids were removed by filtration. The filtrate was concentrated and purified by silica gel flash column chromatography, eluting with 0-10% methanol in dichloromethane, to afford the title compound (1.13 g, 51%). 1H NMR (DMSO-d6+2 drops TFA-d) δ: 1.37 (9H, s), 1.94 (2H, m), 3.15 (2H, t), 4.03 (3H, s), 4.26 (4H, m), 4.57 (2H, m), 6.96 (1H, br t), 7.47 (1H, d), 7.82 (1H, m), 8.03 (1H, d), 8.79 (1H, m), 8.91 (1H, m), 9.46 (1H, m).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: N#Cc1ccc(F)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc(C#N)cc2)CC1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 4-fluorobenzonitrile and 1-methylpiperazine.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[CH2:17][C@@:16]([C:28](=[O:31])[NH:29][CH3:30])([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[O:15][C:13]1=[O:14])=O)C1C=CC=CC=1.[H][H].C[OH:35]>[Pd]>[NH2:11][C@H:12]([CH2:17][C@@:16]([OH:15])([C:28](=[O:31])[NH:29][CH3:30])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[C:13]([OH:14])=[O:35]
Reactant: CO
Reactant: CNC(=O)[C@@]1(Cc2c[nH]c3ccccc23)C[C@@H](NC(=O)OCc2ccccc2)C(=O)O1
Reactant: [H][H]
Agent: [Pd]
Product: CNC(=O)[C@@](O)(Cc1c[nH]c2ccccc12)C[C@@H](N)C(=O)O

Procedure:
The aforementioned (2R,4R)-2-benzyloxycarbonylamino-4-methylcarbamoyl-4-(3-indolylmethyl)-γ-butyrolactone in an amount of 897 mg was dissolved in 40 ml of methanol, and 400 mg of 10% Pd—C was added thereto. Reduction was performed at room temperature in an atmosphere of hydrogen at ordinary pressure for 1 hour. After removing the catalyst by filtration, the reaction solution was vacuum concentrated. The residue was dissolved in 15 ml of ethanol, and 1.9 ml of a 2 N sodium hydroxide solution was added followed by stirring for a while. The reaction solution was vacuum concentrated and the residue was dissolved in 5 ml of water. The pH of the resulting solution was adjusted with a 2 N hydrochloric acid solution to be slightly acidic. Ethanol was then added and the deposited crystals were filtered resulting in 360 mg of (2R,4R)-2-amino-4-hydroxy-4-methylcarbamoyl-4-(3-indolylmethyl)butyric acid (1.18 mmol) as a crystal (Compound No. 7 in Table 1).
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[N:7][N:8]=2)[CH2:3][CH2:2]1.[Li]CCCC.[Mg+2].[Br-].[Br-].O(CC)CC.[C:22]([O:26][C:27](=[O:34])[NH:28][CH:29]([CH:32]=[O:33])[CH2:30][CH3:31])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27](=[O:34])[NH:28][CH:29]([CH:32]([C:6]1[O:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:8][N:7]=1)[OH:33])[CH2:30][CH3:31])([CH3:23])([CH3:24])[CH3:25]
Reactant: c1nnc(C2CC2)o1
Reactant: CCC(C=O)NC(=O)OC(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(NC(=O)OC(C)(C)C)C(O)c1nnc(C2CC2)o1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 48.6 %

Procedure:
A solution of 2-cyclopropyl-[1,3,4]oxadiazole (2.16 g, 19.6 mmol) in dry THF (100 mL) is cooled to −78° C. nBuLi (1.6M in hexanes, 12.3 mL, 19.6 mmol) is added dropwise. The reaction mixture is stirred at −78° C. for 40 min. MgBr2.OEt2 (5.0692 g, 19.6 mmol) is added. The reaction mixture is allowed to warm up to −45° C. and stirred at that temperature for 1.5 hr. A solution of (1-formyl-propyl)-carbamic acid tert-butyl ester (3.7 g, 19.6 mmol) in THF (40 mL) is added. The reaction mixture is allowed to warm up to −20° C. and stirred at that temperature for 3.5 hrs. The reaction mixture is quenched with a solution of saturated NH4Cl solution and extracted with ethyl acetate. Combined organic extracts is washed with saturated NaCl solution and dried over MgSO4. The solvent is evaporated under reduced pressure and the crude is purified by column chromatography eluting with ethyl acetate and heptane mixture to give {1-[(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-propyl}-carbamic acid tert-butyl ester (2.83 g, 49%).