Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.[O:10]=[C:11]1[NH:16][CH2:15][C@@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>O1CCOCC1.[Cu]I>[Cl:9][C:4]1[N:3]=[C:2]([N:16]2[C:11](=[O:10])[CH2:12][CH2:13][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:15]2)[C:7]([CH3:8])=[CH:6][CH:5]=1
Reactant: Cc1ccc(Cl)nc1Br
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC(=O)NC1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccc(Cl)nc1N1C[C@@H](NC(=O)OC(C)(C)C)CCC1=O
Temperature: 110 °C
Yield: 55.1 %

Procedure:
A solution containing 2-bromo-6-chloro-3-methylpyridine (487 mg, 2.24 mmol), tert-butyl N-[(3S)-6-oxo-3-piperidyl]carbamate (400 mg, 1.87 mmol), Copper(I) iodide (356 mg, 1.87 mmol), Potassium carbonate (310 mg, 2.24 mmol) and N,N′-Dimethylethylenediamine (329 mg, 3.73 mmol) in dioxane 12 mL was stirred at 110° C. 18 h. The reaction was filtered through celite and concentrated. The crude product was purified by flash chromatography (EtOAc/Heptane eluted at 50% EtOAc) to give the desired product 350 mg 38% yield. MS (ESI) m/z: 340.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[C:8](=[O:11])[C:7]1[C:12]([OH:20])=[C:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[CH:15][C:6]=1[O:5]2.[CH3:21][N:22]([CH3:27])[S:23](Cl)(=[O:25])=[O:24]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:21][N:22]([CH3:27])[S:23](=[O:25])(=[O:24])[O:16][C:14]1[C:13]([CH2:17][CH2:18][CH3:19])=[C:12]([OH:20])[C:7]2[C:8](=[O:11])[N:9]3[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:5][C:6]=2[CH:15]=1
Reactant: CCCc1c(O)cc2oc3cc(Cl)cn3c(=O)c2c1O
Reactant: CN(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(OS(=O)(=O)N(C)C)cc2oc3cc(Cl)cn3c(=O)c2c1O
Temperature: 85 °C
Yield: 71.1 %

Procedure:
To 80 mg (0.27 mmol) of 2-chloro-6,8-dihydroxy-7-propyl-9H-pyrrolo [2,1-b][1,3]benzoxazin-9-one in 3 mL of toluene was added 0.3 mL (2.77 mmol) of dimethylsulfamylchloride and 0.066 g (0.54 mmol) of 4-dimethylaminopyridine (DMAP). The mixture was heated to 85° C. for 2 hr. It was cooled, diluted with ethyl acetate and extracted two times with 1N HCl. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by preparative TLC (hexane: CH2Cl2 ; 1:1) to give 77 mg of the title compound mp 159-160° C.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.[Cl:10][C:11]1[CH:27]=[CH:26][C:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:18][CH2:19][C:13]=2[C:12]=1[NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=O)[CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:32][CH:31]=1>C(O)C>[Cl:10][C:11]1[CH:27]=[CH:26][C:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:25])[C:21]([F:23])([F:24])[F:22])[CH2:18][CH2:19][C:13]=2[C:12]=1[NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[N:2][OH:3])[CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:32][CH:31]=1
Reactant: NO
Reactant: CC(C)CC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)CC(=NO)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 43.6 %

Procedure:
Add hydroxylamine hydrochloride (6.3 mg, 0.091 mmol) and pyridine (15 uL, 0.182 mmol) to a solution of 7-chloro-6-[4-(3-methyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (42 mg, 0.091 mmol) in ethanol (1 mL). Heat the mixture to reflux for 18 h. Remove the solvent in vacuo and partition the residue between DCM and 0.1N aqueous HCl. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (95:5 to 1:1 gradient over 30 min). Concentrate in vacuo to obtain 7-chloro-6-[4-(1-hydroxyimino-3-methyl-butyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an off-white solid (19.1 mg, 44%). MS (ES+) m/z: 482 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][C:4]2[CH:19]=[CH:20][C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:3]1=2.[BH4-].[Na+].Cl>CO>[OH:1][CH:2]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:11]=2)[CH:6]=[CH:5][C:4]2[CH:19]=[CH:20][C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:3]1=2
Reactant: CS(=O)(=O)Nc1ccc2ccc3ncc(-c4ccccc4)cc3c(=O)c2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc2c(c1)C(O)c1cc(-c3ccccc3)cnc1C=C2
Reaction time: 0.5 h

Procedure:
To a stirred slurry of N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide (0.50 g, 1.3 mmol) in MeOH (30 mL) was added NaBH4 (100 mg, 2.6 mmol). The reaction mixture was left to stir for 30 min, treated with 1 N HCl and then 1 N NaOH, and concentrated. The residue was diluted with EtOAc and washed with brine. The organic layer was dried (Na2SO4), concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CD3OD) δ 8.66 (d, 1H); 8.38 (d, 1H); 7.15-7.71 (m, 10H); 5.28 (s, 1H); 2.96 (s, 3H). LRMS (APCI) calc'd for (C21H19N2O3S) [M+H]+, 379.1; found 379.1.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([CH3:20])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]([CH3:19])[C:10]=2[CH2:9][CH2:8][O:7]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O1CCCC1>O1CCCC1>[CH3:20][C:6]1([CH2:5][CH2:4][OH:3])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]([CH3:19])[C:10]=2[CH2:9][CH2:8][O:7]1
Reactant: CCOC(=O)CC1(C)OCCc2c1c1ccccc1n2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c2c(c3ccccc31)C(C)(CCO)OCC2

Procedure:
A solution of 1,5-dimethyl-1,3,4,5-tetrahydropyrano[4,3-b]indole-1-acetic acid ethyl ester (17.0 g), described in Example 916, in tetrahydrofuran (200 ml) is added dropwise to a suspension of lithium aluminium hydride (5.0 g) in tetrahydrofuran (150 ml). The mixture is heated at reflux for 2.5 hr. and then cooled and treated with a mixture of water-tetrahydrofuran (30 ml - 150 ml). The mixture is filtered through celite and the filtrate is evaporated. The residue is purified by chromatography on silica gel. Elution with chloroform gives 1,5-dimethyl-1,3,4,5-tetrahydropyrano[4,3-b]indole-1-ethanol.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[N:24]=[C:25]=[S:26])(=[O:3])[CH3:2].[NH2:27][CH2:28][CH:29]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[NH:24][C:25]([NH:27][CH2:28][CH:29]([NH:40][C:41]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[S:26])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](N=C=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCCCCCCCCC(CN)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC(CNC(=S)N[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O)NC(=O)OC(C)(C)C
Yield: 98.7 %

Procedure:
2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate 37 (25.0 mg, 0.0617 mmol), tert-butyl N-[1-(R/S)-(aminomethyl)-undecyl]carbamate (27.8 mg, 0.0927 mmol) and triethylamine (12.5 mg, 0.0124 mmol) were dissolved in abs. CH2Cl2 (5 ml) and stirred at room temperature for 1 hour. Following evaporation, the residue was purified by column chromatography to give 65 (42.0 mg, 94%)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH2:12][C:13]([O:15]C)=[O:14])=[N:8][C:7]=2[CH:29]=1)#[N:2].[OH-].[Na+]>C1COCC1.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH2:12][C:13]([OH:15])=[O:14])=[N:8][C:7]=2[CH:29]=1)#[N:2]
Reactant: COC(=O)CC(c1nc2cc(C#N)ccc2o1)c1c(OC)cc(C)c2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c2[nH]ccc2c1C(CC(=O)O)c1nc2cc(C#N)ccc2o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (+) or (−)-methyl 3-(5-cyanobenzo[d]oxazol-2-yl)-3-(5-methoxy-7-methyl-1H-indol-4-yl)propanoate (tr=3.8 min) (74 mg, 0.190 mmol) in THF (475 μl) and water (475 μl) was added NaOH (950 μl, 0.950 mmol) and the reaction stirred at room temperature for 4 hours. The reaction was directly purified via preparative HPLC (HC-B) to obtain the title compound. 1H NMR as in Example 148-B. HRMS calcd. for C21H17N3O4 (M+H)+ 376.1297. found 376.1290.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:14][CH2:13][C:12]([CH3:18])([CH:15]([CH3:17])[OH:16])[CH2:11][O:10]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:28])[CH3:27].O>C1C=CC=CC=1>[C:26]([O:16][CH:15]([CH3:17])[C:12]1([CH3:18])[CH2:11][O:10][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:19])[CH3:1])=[CH:8][CH:7]=2)[O:14][CH2:13]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC(O)C1(C)COC(c2ccc(N(C)C)cc2)OC1
Solvent: O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC(C)C1(C)COC(c2ccc(N(C)C)cc2)OC1

Procedure:
2-[4-(Dimethylamino)phenyl]-α,5-dimethyl-1,3-dioxan-5-methanol (195 mg), dry pyridine (2.0 ml), and acetyl chloride (1.0 ml), in benzene (10 ml) were refluxed for 3 hrs. The cooled mixture was poured into water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4), and evaporated. The residue was purified by preparative layer chromatography on silica gel (eluting with benzeneethyl acetate 5:1) and distilled to give an oil, b.p. 155°-160°/0.05 torr.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([C:30]1[CH:35]=[C:34]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]([F:22])([F:23])[F:21])[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: CS(=O)(=O)c1cccc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)c1

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 3-methylsulfonylphenylboronic acid to give 148. MS (ESI+) 507.0. 1H NMR (400 MHz, DMSO) δ 8.44 (d, J=8.3, 1H), 8.31 (s, 1H), 8.25 (s, 1H), 8.14 (d, J=8.0, 1H), 7.93 (d, J=7.8, 1H), 7.75 (t, J=7.8, 1H), 7.67 (dd, J=8.3, 1.7, 1H), 7.55 (d, J=1.7, 1H), 5.88 (q, J=8.6, 2H), 4.45 (t, J=4.9, 2H), 3.52 (t, J=4.9, 2H), 3.32 (s, 3H)
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][CH2:16][O:17][C:18]3[CH:33]=[CH:32][C:21]([CH2:22][CH:23]([C:28]([O:30]C)=[O:29])[C:24]([O:26]C)=[O:25])=[CH:20][CH:19]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CO.O1CCCC1>[CH3:1][C:2]1([CH3:34])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:22][CH:23]([C:24]([OH:26])=[O:25])[C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(OCCOc3ccc(CC(C(=O)O)C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of dimethyl 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoxy)ethoxy]benzylmalonate (1.50 g, 3.21 mmol) in a mixture of methanol (12.9 ml) and tetrahydrofuran (6.4 ml) is added a 2 mol/L aqueous solution of sodium hydroxide (8.01 ml, 16.03 mmol). The mixture is stirred for 2 hours at room temperature, and then the solvent was removed under a vacuum. The residue is dissolved in water and washed with ethyl acetate (10 ml). The aqueous solution is acidified to pH 2–3 with dilute hydrochloric acid and extracted with ethyl acetate (3×15 ml). The combined extracts are washed with water (20 ml) and brine (20 ml), dried over sodium sulfate, and concentrated. The residue is crystallized from ethyl acetate to give the title compound (1.38 g, 98%). HRMS calcd for C26H32O6: 440.5365. Found: 440.5363. MA calcd for C26H32O6: C, 70.89%; H, 7.32%. Found: C, 70.72%; H, 7.36%.
Reaction SMILES: [F:1][CH2:2][CH:3]([NH:8]C(OC(C)(C)C)=O)[CH2:4][C:5]([OH:7])=[O:6].[ClH:16]>CCOCC>[ClH:16].[F:1][CH2:2][CH:3]([CH2:4][C:5]([OH:7])=[O:6])[NH2:8]
Reactant: CC(C)(C)OC(=O)NC(CF)CC(=O)O
Agent: Cl
Solvent: CCOCC
Product: NC(CF)CC(=O)O
Yield: 68 %

Procedure:
4-Fluoro-3-tert-butoxycarbonylamino-1-butanoic acid (545 mg, 2.46 mmoles) is dissolved in dry ether (20 ml) saturated with hydrogen chloride gas. After a few minutes, the solution becomes turbid and white crystals start to precipitate. Recrystallization from ethanol/ether afford beta-monofluoromethyl beta-alanine hydrochloride (265 mg, 68%), m.p. 152°-153° C. (dec).
Reaction SMILES: O[Li].O.[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:19][CH:20]3[O:24]C(=O)[N:22]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:21]3)[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([Br:18])=[CH:12][CH:11]=3>C1COCC1.O>[Br:18][C:13]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:19][CH:20]([OH:24])[CH2:21][NH:22][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:8]3[C:16]([C:15]=2[CH:14]=1)=[CH:17][C:5]([Br:4])=[CH:6][CH:7]=3
Reactant: O=C1OC(Cn2c3ccc(Br)cc3c3cc(Br)ccc32)CN1c1cccnc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: OC(CNc1cccnc1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 168 h
Yield: 79.3 %

Procedure:
The title compound of Example 40 was prepared as follows. LiOH.H2O (0.0097 g, 0.231 mmol) was added to 5-((3,6-dibromo-9H-carbazol-9-yl)methyl)-3-(pyridin-3-yl)oxazolidin-2-one (0.0116 g, 0.0231 mmol) in a mixture of 265 μL THF and 29 μL H2O (v/v=9:1). The mixture was stirred at room temperature for 7 days. The reaction mixture purified by silica gel chromatography using CHCl3/MeOH as elute to afford 0.0087 g white solid as product, yield 79.3%.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=S)[NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1)=[O:3].N>OO>[O:3]=[C:2]1[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:10][C:11]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[N:1]1
Reactant: Cc1cccc(C(=O)NC(=S)Nc2ccccc2C(N)=O)c1
Agent: N
Agent: OO
Product: Cc1cccc(C(=O)Nc2nc(=O)c3ccccc3[nH]2)c1
Reaction time: 48 h
Yield: 27.7 %

Procedure:
To a stirred mixture of 9.3 g of the above benzamide and 200 ml of methanolic ammonia was added dropwise, 10 ml of 30% hydrogen peroxide over 3 minutes. An exotherm required cooling in an ice bath. A 15 ml portion of 30% hydrogen peroxide was added, the mixture was stirred 48 hours, the solid collected, and mixed with 100 ml of hot water. This solid was collected, mixed with 400 ml of hot acetonitrile and filtered. The filtrate was chilled, giving 2.3 g of the desired product as off-white crystals, mp 211°-213° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH3:21])([CH3:20])[C:9](=[O:19])[N:10](COCC[Si](C)(C)C)[C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=O.N1CCNCC1.O>C(Cl)Cl.C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH3:21])([CH3:20])[C:9](=[O:19])[NH:10][C:4]=2[CH:3]=1
Reactant: CC1(C)C(=O)N(COCC[Si](C)(C)C)c2cc(Cl)ncc21
Agent: C1CNCCN1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)Nc2cc(Cl)ncc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
To a solution of 6-chloro-3,3-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one (7.25 g, 22.2 mmol) in DCM (50 mL) was added TFA (50 mL) and resulting mixture was stirred at 20° C. for 1 h. The solution was evaporated in vacuo and the residue dissolved in MeOH and solvent re-evaporated to give a solid. To an aliquot of this material (2.40 g) in THF (53 mL) was added piperazine (4.56 g, 52.9 mmol). After stirring for 1 h, water (30 mL) and EtOAc (30 mL) were added and the organic layer separated. The organic layer was washed with water (30 mL×2) and brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. Chromatography on silica gel (gradient elution, 0-100% EtOAc/petrol), gave the title compound (1.4 g, 67%) as a colourless solid. 1H NMR (Me-d3-OD): 8.12 (1H, s), 6.99 (1H, s), 1.41 (6H, s).
Reaction SMILES: [C:1]([CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])#[N:2].Br[CH2:13][CH2:14]Br.C1OCCOCCOCCOCCOCCOC1.[F-].[K+]>ClCCl>[C:4]([C:3]1([C:1]#[N:2])[CH2:14][CH2:13]1)(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCCBr
Reactant: N#CCC(=O)c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: N#CC1(C(=O)c2ccccc2)CC1
Yield: 20.9 %

Procedure:
1 g (7 mmol) of α-cyanoacetophenone, 8 g (43 mmol) of 1,2-dibromoethane, 0.1 g (0.4 mmol) of 18-crown-6 and 4 g (69 mmol) of potassium fluoride are heated under reflux for 18 h as a heterogeneous system in 10 ml of dichloromethane. After cooling, the mixture is filtered, the organic phase is washed with H2O and the solvent is evaporated in vacuo after drying over Na2SO4. The residue is chromatographed on a silica gel using CH2Cl2. 0.25 g (20% of theory) of 1-benzoyl-1-cyanocyclopropane are obtained in this manner as a colorless oil,
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Br:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>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.COCCOC.O>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccccc1I
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: [K+]
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1ccccc1-c1ccc(Br)cc1

Procedure:
o-iodonitrobenzene (9.42 g, 37.84 mmol), 4-bromobenzeneboronic acid (7.6 g, 37.84 mmol), potassium carbonate (21 g, 151.36 mmol) was added to 190 mL DME/water (3:2) solution and degassed for 30 minutes. Pd(PPh3)4 (437 mg, 0.38 mmol) was added to the slurry under nitrogen and the slurry was degassed for another 5 minutes. The reaction was refluxed under nitrogen for 6 h. Content of the flask was filtered through a pad of celite and partitioned in ethyl acetate and brine. Organic phase was dried over anhydrous Na2SO4 and evaporated under vacuum. Crude yellow oil was flashed over silica gel using 5% ethylacetate/hexane. Final compound was isolated as colorless oil (9.8 g, 35.4 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:12]3[CH2:18][C:17]4[CH:19]=[C:20]([C:23]5[CH:24]=[C:25]([NH2:30])[C:26]([NH2:29])=[N:27][CH:28]=5)[CH:21]=[CH:22][C:16]=4[O:15][CH2:14][CH2:13]3)[C:4]=2[CH2:3]1.[CH3:32][O:33][C:34]([NH:36][C:37](=NC(OC)=O)SC)=[O:35]>C(O)(=O)C>[CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:12]3[CH2:18][C:17]4[CH:19]=[C:20]([C:23]5[CH:24]=[C:25]6[NH:30][C:37]([NH:36][C:34](=[O:35])[O:33][CH3:32])=[N:29][C:26]6=[N:27][CH:28]=5)[CH:21]=[CH:22][C:16]=4[O:15][CH2:14][CH2:13]3)[C:4]=2[CH2:3]1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(N)c(N)c5)cc4C3)c2C1
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ncc(-c3ccc4c(c3)CN(c3ncnc5c3CC(C)(C)CC5)CCO4)cc2[nH]1
Temperature: 80 °C
Reaction time: 10 h
Yield: 51 %

Procedure:
A mixture of 5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]pyridine-2,3-diamine (174 mg, 0.42 mmol) and 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (86 mg, 0.42 mmol) in acetic acid (5 mL) was stirred at 80° C. for 10 h. After cooling to room temperature the mixture was concentrated, methanol (10 mL) was added, the precipitate was filtered off, and lyophilized from a mixture of acetonitrile (2 mL), water (6 mL), and 1N hydrochloric acid (0.25 mL) to give the hydrochloride salt of the title Compound (107 mg, 48% yield) as a yellow solid. 1H NMR (400 MHz, methanol-d4): 8.53 (m, 2H), 8.35 (s, 1H), 7.78 (s, 1H), 7.58 (d, 1H), 7.10 (d, 1H), 5.18 (s, 2H), 4.49 (m, 2H), 4.34 (m, 2H), 3.93 (s, 3H), 2.86 (m, 2H), 2.61 (s, 2H), 1.71 (m, 2H), 0.95 (s, 6H); MS (EI) for C27H29N7O3: 500 (MH+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C:8]1[C:13]([C:14]([O-])=[O:15])=[CH:12][N:11]=[C:10]([CH2:17][CH3:18])[N:9]=1>C1COCC1>[NH2:7][C:8]1[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[C:10]([CH2:17][CH3:18])[N:9]=1
Reactant: CCc1ncc(C(=O)[O-])c(N)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ncc(CO)c(N)n1
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To a 100 ml flask equipped with constant pressure dropping funnel and drying pipe, 3.8 g (0.1 mol) of LiAlH4 and 20 ml of THF were charged, cooled with ice bath. 7.8 g (0.04 mol) of 4-amino-2-ethylpyrimidine-5-carboxylate in the 20 ml of THF was dropped into the flask slowly. After the addition was finished, the reaction was stirred for 1-2 h. The reaction was quenched with water and the solid was removed by filtration. The filtrate was concentrated. To the residue, 20 ml of ethyl acetate and 120 ml of petroleum ether were added. After shaking and standing, large amount of white solids precipitated. 4.59 g of aim product was obtained by filtration (yield 75%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:18][C@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([S:29][C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=3)[C:33]([OH:35])=[O:34])[CH:25]=2)[O:20]1)[CH2:9][C@H:10]([OH:17])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][Si](C=[N+]=[N-])(C)C>CO.C(OCC)(=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:18][C@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([S:29][C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=3)[C:33]([O:35][CH3:39])=[O:34])[CH:25]=2)[O:20]1)[CH2:9][C@H:10]([OH:17])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(Sc3cccc(C(=O)O)c3)ccc2O1)C[C@H](O)c1cccnc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Sc2ccc3c(c2)CC[C@H](CN(C[C@H](O)c2cccnc2)C(=O)OC(C)(C)C)O3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
To 650 mg (1.25 mmol) of 3-{[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]sulfanyl}benzoic acid (Example 173) dissolved in 10 mL 1:1 methanol/ethyl acetate, was added 3 mL of 2M trimethylsilyl diazomethane dropwise. The resulting solution was then allowed to stir at room temperature for 16 hours. The solution was then diluted with ethyl acetate, washed with water and brine, and concentrated in vacuo. The crude mixture was purified by Biotage with 75% ethyl acetate/hexanes to obtain 223 mg (33% yield) of product; MH+ 551.2.