Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([N:14]1[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([C:24]([NH:26][O:27]C4CCCCO4)=[O:25])=[CH:19][CH:20]=3)[CH2:15]1)=[O:13])=[CH:6]2>CO.Cl>[OH:27][NH:26][C:24]([C:18]1[CH:17]=[C:16]2[C:21]([CH2:22][CH2:23][N:14]([C:12]([C:7]3[NH:8][C:9]4[C:5]([CH:6]=3)=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=4)=[O:13])[CH2:15]2)=[CH:20][CH:19]=1)=[O:25]
Reactant: COc1ccc2[nH]c(C(=O)N3CCc4ccc(C(=O)NOC5CCCCO5)cc4C3)cc2c1
Agent: Cl
Solvent: CO
Product: COc1ccc2[nH]c(C(=O)N3CCc4ccc(C(=O)NO)cc4C3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.6 %

Procedure:
A mixture of 207 mg 2-[(5-methoxy-1H-indol-2-yl)carbonyl]-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide in 6 ml methanol and 6 ml 0.1 N aqueous hydrochloric acid is stirred overnight at ambient temperature. Subsequently, the reaction mixture is evaporated. The residue is treated with 10 ml methanol at 60° C. for 1 h. The resulting solid is collected and dried. 43 mg of the title compound are obtained as colorless solid. MH+=365.0
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=1[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][C:22]=2[CH3:28])[CH:18]=[CH:19][CH:20]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[CH3:46][CH:47]([CH3:50])[CH:48]=[O:49]>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=1[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH:48]([OH:49])[CH:47]([CH3:50])[CH3:46])=[CH:23][C:22]=2[CH3:28])[CH:18]=[CH:19][CH:20]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1cc(Br)ccc1-c1cccc(OCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Reactant: CC(C)C=O
Agent: [Li]CCCC
Product: Cc1cc(C(O)C(C)C)ccc1-c1cccc(OCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1

Procedure:
In a manner similar to that of Example 27(f), by reaction of 2 g (3.1 mmol) of 3′-[3,4-bis-(tert-butyldimethylsilanyloxymethyl)benzyloxy]-4-bromo-2-methylbiphenyl with 1.4 mL (3.5 mmol) of 2.5 M butyllithium and 400 μl (37 mmol) of 2-methylpropionaldehyde, the desired product is obtained in the form of a colourless oil (m=1.1 g; Y=56%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.[C:18]([C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[N:24][CH:25]=1)#[CH:19]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:19]=[CH:18]/[C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: C#Cc1ccc(C)nc1
Product: Cc1ccc2c(c1)c1c(n2/C=C/c2ccc(C)nc2)C2CCN(CC2)C1

Procedure:
The coupling of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (453 mg, 2.0 mmol; Example 2B) and 5-ethynyl-2-methylpyridine (937 mg, 8.0 mmol; prepared as described in International Publication No. WO2005090333) was performed according to the procedure described in Example 20 to afford the title compound as the minor isomer: 1H NMR (300 MHz, methanol-d4) δ ppm 2.05-2.19 (m, 4H), 2.41 (s, 3H), 2.53 (s, 3H), 3.00-3.14 (m, 2H), 3.17-3.28 (m, 2H), 3.39-3.47 (m, 1H), 4.22 (s, 2H), 6.74 (d, J=15 Hz, 1H), 7.03 (dd, J=8, 2 Hz, 1H), 7.12-7.19 (m, 1H), 7.29 (d, J=8 Hz, 1H), 7.54 (d, J=8 Hz, 1H), 7.69 (d, J=14 Hz, 1H), 7.95 (dd, J=8, 2 Hz, 1H), 8.51 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 344 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].CC[O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:18]([O:17][C:15]([C:14]1[CH:20]=[N:5][C:4]2[C:6]([C:13]=1[OH:12])=[CH:7][C:8]([F:9])=[C:2]([Cl:1])[CH:3]=2)=[O:16])[CH3:19]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(Cl)c(F)cc2c1O

Procedure:
A mixture of 3-chloro-4-fluoroaniline (1) (87.3 g) and diethyl ethoxymethylene malonate (129.7 g) and Dowtherm (700 mL) (diphenyl ether) was refluxed for 4 h. It was cooled and the resulting solid was removed by filtration. The solid was recrystallized from DMF to give 55.O g (4). m.p.=>300° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]=[CH:14][S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:11]=2)[C:6]([CH2:24][C@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[CH3:30])=[CH:5]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[C:18]1([S:15]([CH:14]=[CH:13][C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[NH:4][CH:5]=[C:6]3[CH2:24][C@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[CH3:30])(=[O:17])=[O:16])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)n1cc(C[C@H]2CCCN2C)c2cc(C=CS(=O)(=O)c3ccccc3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(C=CS(=O)(=O)c3ccccc3)cc12
Temperature: 25 °C
Yield: 74.9 %

Procedure:
A suspension of (R)-1-acetyl-5-(benzenesulfonylethenyl)-3-(N-methyl-pyrrolidin-2-ylmethyl)-1H-indole (220.8 g) in methanol (2.21 L) was treated with potassium carbonate (72.23 g) and stirred at ambient temperature. After about one hour active carbon (22.1 g) was added to the solution then water (660 mL) added slowly. The mixture was filtered and the filtrate heated to reflux and water (660 mL) added dropwise. The mixture was allowed to cool and crystallize, then further water was added slowly (3.31 l). The resulting solid was filtered, washed with 1:2 methanol:water mixture (2×200 mL) then dried in vacuo to give the title compound (149 g): mp, 84°-87° C. IR (KBr) 1600, 1450, 1290, 1145, 1085 cm-1 : 1H NMR (CDCl3) 8.4 (b, 1H), S.0 (d, 2H), 7.8 (d, 1H), 7.7 (s, 1H), 7.6-7.5 (m, 3H), 7.3 (s, 2H), 7.05 (b, 1H), 6.75 (d, 1H), 3.15 (m, 2H), 2.6 (m, 1H), 2.45 (s, 3H), 2.4 (s, 1H), 2.2 (m, 1H), 2.0-.5 (m, 4H); LRMS (TSP), m/z 381, 165, 133, 119.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[C:17]([C:19]3[C:23]4[CH2:24][C:25]([CH3:30])([CH3:29])[CH2:26][C:27](=[O:28])[C:22]=4[S:21][C:20]=3[N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:16]=[CH:15][N:14]=2)[CH:8]=1)(=O)=O.C(OC([NH:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)=O)(C)(C)C.CC(C)([O-])C.[K+]>O1CCOCC1.CC(O)=O.CC(P(C(C)(C)C)C1C(C2[C-]=CC=CC=2)=CC=CC=1)(C)C.[Pd]>[NH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[C:17]([C:19]4[C:23]5[CH2:24][C:25]([CH3:30])([CH3:29])[CH2:26][C:27](=[O:28])[C:22]=5[S:21][C:20]=4[N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)[CH:16]=[CH:15][N:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:49][CH2:48]1
Reactant: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3ccnc(-c4cccc(OS(=O)(=O)C(F)(F)F)c4)c3)c2C1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1[c-]cccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3ccnc(-c4cccc(N5CCC(N)CC5)c4)c3)c2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.5 %

Procedure:
A mixture of Example 360 (150 mg, 0.27 mmol), 4-(tert-butoxycarbonylamino)-piperidine (105 mg, 0.52 mmol), potassium tert-butoxide (45 mg, 0.37 mmol) and acetato(2′-di-tert-butylphosphino-1,1′-biphenyl-2-yl)palladium(II) (20 mg, 0.043 mmol) in 1,4-dioxane (6.0 mL) was heated in a sealed tube at 100° C., under microwave irradiation, for 30 minutes. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 0-100% EtOAc/heptane). A sample of the obtained solid (43 mg) was taken up in DCM (8.0 mL), treated with trifluoroacetic acid (2.0 mL) and stirred at room temperature for 4 h. The reaction mixture was partitioned between DCM (20 mL) and saturated aqueous sodium hydrogencarbonate solution (20 mL). The organic phase was dried (magnesium sulfate), the solvent was removed in vacuo and the residue was purified by column chromatography (0-20% MeOH/DCM, 1% NH4OH) to give the title compound (23 mg, 33%) as a clear glass. δH (CD3OD) 8.68 (1H, d, J 5.1 Hz), 7.91 (1H, s), 7.64-7.59 (1H, m), 7.46-7.33 (3H, m), 7.15-7.06 (1H, m), 3.87-3.77 (2H, m), 3.72-3.64 (4H, m), 3.10-3.00 (4H, m), 2.92-2.75 (3H, m), 2.63 (2H, s), 2.46 (2H, s), 2.01-1.90 (2H, m), 1.63-1.47 (2H, m), 1.04 (6H, s). LCMS (ES+) 517.3 (M+H)+.
Reaction SMILES: [C:1](O)(=[O:3])C.[C:5]([O:9][C:10](=[O:32])[N:11]([C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([CH2:30][NH2:31])[N:24]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[O:21][CH3:22])([CH3:8])([CH3:7])[CH3:6].C(N(CC)C(C)C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[C:5]([O:9][C:10](=[O:32])[N:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[O:21][CH3:22])[C:23]1[CH:28]=[CH:27][C:26]2[NH:29][C:1](=[O:3])[NH:31][CH2:30][C:25]=2[N:24]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(N)c(CN)n2)c(OC)c1
Reactant: CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CNC(=O)N3)c(OC)c1
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To a solution of (5-amino-6-aminomethyl-pyridin-2-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester acetate salt (1.3 g, 2.56 mmol) and N,N-diisopropylethylamine (890 μL, 5.12 mmol, 2 equiv) in THF (20 mL) was added a solution of 1,1′-carbonyldiimidazole (622 mg, 3.84 mmol, 1.5 equiv) and the reaction mixture was stirred overnight. The solvent was evaporated and the crude material was purified by column chromatography (SiO2, eluted with petrol—EtOAc 50-100%) to afford (2,4-dimethoxy-benzyl)-(2-oxo-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl)-carbamic acid tert-butyl ester (464 mg). MS: [M+H]+=415
Reaction SMILES: CC1[N:3]([C:8]2[CH:12]=[C:11]([I:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[N:9]=2)C(C)=CC=1.[Cl-].O[NH3+].C(N(CC)CC)C>CCCCCC.C(OCC)(=O)C>[F:20][C:16]1[CH:15]=[C:14]([N:10]2[C:11]([I:13])=[CH:12][C:8]([NH2:3])=[N:9]2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc(C)n1-c1cc(I)n(-c2cccc(F)c2)n1
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1cc(I)n(-c2cccc(F)c2)n1
Temperature: 95 °C
Reaction time: 17 h
Yield: 89.4 %

Procedure:
To a solution of 3-(2,5-dimethylpyrrol-1-yl)-1-(3-fluorophenyl)-5-iodo-1H-pyrazole (4.5 g) in ethanol/water (2/1, 81 ml) were sequentially added hydroxylammonium chloride (16.3 g) and triethylamine (3.3 ml), and the mixture was stirred at 95° C. for 17 hours. This reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the resulting residue was added an 8M aqueous solution of sodium hydroxide, and the mixture was extracted with ethyl acetate. This organic layer was sequentially washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to give the titled compound (3.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:18])[S:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:38]1([N:44]=[C:45]=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[NH:44]([C:45]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[O:18])[S:10][N:9]=2)=[CH:6][CH:7]=1)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC(=O)c1c(-c2ccc(N)cc2)nsc1NC(=O)NCCCN1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1c(-c2ccc(NC(=O)Nc3ccccc3)cc2)nsc1NC(=O)NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 76.4 %

Procedure:
A mixture of 3-(4-aminophenyl)-5-(3-(3-morpholinopropyl)ureido)isothiazole-4-carboxamide (12 mg, 0.030 mmol), N,N-diisopropylethylamine (0.021 mL, 0.120 mmol), and phenyl isocyanate (0.0056 mL, 0.051 mmol) in 1.0 mL THF was stirred at rt for 19 hours. The reaction was quenched with 0.2 mL aqueous Na2CO3 solution, stirred 5 min at rt, and then partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated to a white solid. The solid was chromatographed eluting with CHCl3, then gradient 2.5% to 10% MeOH in CHCl3. The resulting solid was subjected to an EtOAc/NaHCO3 work-up to remove the presence of any silica gel impurity. Upon evaporation of the EtOAc layer the title compound was obtained as a white solid (12 mg, 77%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13]CC)=[O:12])=[C:4]2[CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cnn2ccc(C)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccn2ncc(C(=O)O)c2c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
To a solution of ethyl 5-methylpyrazolo[1,5-a]pyridine-3-carboxylate (2.73 g) in THF/EtOH (30/15 mL) was added 1N aqueous sodium hydroxide solution (20 mL), and the mixture was stirred at 80° C. for 4 hr. To the reaction mixture was added 1N hydrochloric acid at 0° C., and the mixture was extracted with THF/EtOAc. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with cooled hexane/IPE to give the title compound (2.11 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][C:8]=2[CH:11]([CH3:13])[CH3:12])[CH:3]1O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[C:8]([CH:11]([CH3:12])[CH3:13])[CH:7]=[CH:6][C:5]=2[CH3:14]
Reactant: Cc1ccc(C(C)C)c2c1C(O)C(C)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC1=Cc2c(C(C)C)ccc(C)c2C1
Yield: 78 %

Procedure:
In a 1-liter egg-plant flask were charged about 40 g (0.20 mol) of 2,7-dimethyl-4-isopropyl-indanol, 500 ml of benzene, and p-toluenesulfonic acid monohydrate and the mixture was stirred under reflux for 1 hour. The reaction mixture was poured in an aqueous sodium hydrogen carbonate solution and extracted with diethyl ether. The organic layer was washed with water and with saline and dried over sodium sulfate. Sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure (69 to 74° C./0.5 mmHg) to obtain 29.06 g (0.156 mol) of 2,7-dimethyl-4-isopropylindene as a colorless liquid.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH3:13])=[O:11])(OCC)=O)C.[H-].[Na+].[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[CH:26]=O>C1COCC1>[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1/[CH:26]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-(diethoxyphosphoryl)acetate (4.41 g, 20.9 mmol) in THF (8 mL) was added NaH (0.91 g, 22 mmol) and the resultant solution was stirred for 20 min. The reaction mixture was cooled to 0° C. and quinoline-2-carbaldehyde (3.0 g, 19 mmol) in THF (4 mL) was added via syringe. The reaction was allowed to warm to room temperature and stirred for 3 h. The reaction was quenched with saturated sodium bicarbonate (10 mL) and the resulting mixture was extracted with DCM (100 mL). The DCM layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue obtained was purified by flash column chromatography on silica gel (0-30% EtOAc-heptane) to afford compound 79a. Mass spectrum (LCMS, ESI pos.) Calcd. For C13H11NO2 214.1 (M+H). found 214.1.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:18]=[CH2:19])[C:11]=2[OH:25])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCCCCC>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:18][CH3:19])[C:11]=2[OH:25])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: C=CC(CCCCC)c1cc(C)cc(-n2nc3ccccc3n2)c1O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCCCCC
Product: CCCCCC(CC)c1cc(C)cc(-n2nc3ccccc3n2)c1O

Procedure:
0.5 g of 2-(benzotriazole-2-yl)-4-methyl-6-(1-octen-3-yl)-phenol and a trace of “Lindlar catalyst” (Fluka) in 20 ml of hexane was hydrogenated for 4 hours under normal hydrogen pressure. Then the reaction mixture was filtered and concentrated to yield (quantitatively) 2-(benzotriazole-2-yl)-4-methyl-6-(3-octyl)-phenol as a yellow liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[CH:24]=[CH:23][C:17]([O:18][CH2:19][C@@H:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[CH:24]=[CH:23][C:17]([O:18][CH2:19][C@@H:20]([NH:22][C:27](=[O:29])[CH3:28])[CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N)COc1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N[C@@H](C)COc1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1

Procedure:
(S)-2-[4-(4-Benzyloxyphenoxy)phenoxy]-1-methylethylamine (195 mg, 0.56 mmol) was reacted with acetic anhydride in analogy to example 2a. Yield: 218 mg (100%), M+H+: 392.18.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([C:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH:9]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([C:8]2[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1C1=CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)cnc1C1=CCC(=O)CC1
Yield: 45.6 %

Procedure:
5-Bromo-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-3-methylpyridine (21.1 g) described in Reference Example 105 was dissolved in concentrated hydrochloric acid (64.5 ml) and water (64.5 ml), and stirred at room temperature. After completion of the reaction, the reaction solution was ice-cooled, 10% sodium carbonate aqueous solution was added thereto to adjust the solution to pH 8, the precipitated solid was collected by filtration, washed with water, and then dried under air blow. The obtained solid was dissolved in ethanol, and the solvent was evaporated. This procedure was repeated twice, then to the obtained residue were added n-hexane and a small amount of ethyl acetate, washed, collected by filtration, and heat-dried in vacuo to give 4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-one (8.26 g) as a pale yellow solid. MS (ESI) m/z: 266, 268 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:6]=2[CH:17]=1.[O:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[ClH:52]>ClCCl.CO>[ClH:52].[CH3:1][C:2]1[C:3]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:12][CH2:13][N:14]([CH:25]4[CH2:26][CH2:27][O:22][CH2:23][CH2:24]4)[CH2:15][CH2:16]3)[C:6]=2[CH:17]=1
Reactant: Cc1cc2c(cc1OC(C)C)[nH]c(=O)n2C1CCNCC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1OC(C)C)[nH]c(=O)n2C1CCN(C2CCOCC2)CC1
Reaction time: 3 h

Procedure:
A solution of 6-methyl-5-[(1-methylethyl)oxy]-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one (D77) (assumed 0.14 mmol—crude material) in dichloromethane (2 mL) was treated with tetrahydro-4H-pyran-4-one (1.4 mmol, 140 mg, 10 eq) and triethylamine (1.4 mmol, 141.7 mg, 10 eq) at room temperature under argon, then sodium triacetoxyborohydride (1.4 mmol, 296.8 mg, 10 eq) was added and the mixture was allowed to stir for 3 h and to stand overnight. The mixture was diluted with dichloromethane and treated with aqueous sodium hydroxide so that the pH was maintained around 12. The aqueous phase was extracted, the organics were combined, washed with aqueous sodium hydroxide solution (pH˜12), dried and concentrated under reduced pressure. The residue was purified by chromatography (methanol/dichloromethane, 0-10% 5CV) to give a gum, which was dissolved in dichloromethane and methanol, treated with ethereal hydrogen chloride, then concentrated under reduced pressure to give the title compound as its hydrochloride salt-white solid (0.071 mmol, 29 mg, 51% yield). M+H 374.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18](SC)[N:17]=3)=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[NH3:25]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH2:25])[N:17]=3)=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: N
Reactant: COc1ccc(Nc2nccnc2-c2nc(C)nc(SC)n2)cn1
Solvent: C1COCCO1
Product: COc1ccc(Nc2nccnc2-c2nc(C)nc(N)n2)cn1
Temperature: 100 °C
Yield: 85 %

Procedure:
A glass microwave reaction vessel was charged with N-(6-methoxypyridin-3-yl)-3-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrazin-2-amine (44 mg, 0.129 mmol) and ammonia (1 mL, 37% in water) in dioxane (1 mL). The reaction mixture was stirred and heated at 100° C. for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 10% MeOH/EtOAc to give 4-(3-(6-methoxypyridin-3-ylamino)pyrazin-2-yl)-6-methyl-1,3,5-triazin-2-amine (34 mg, 0.110 mmol, 85% yield) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 11.83 (s, 1H); 8.37 (d, J=2.05 Hz, 1H); 8.24 (s, 1H); 8.20 (s, 1H); 8.04 (dd, J=8.92, 2.48 Hz, 1H); 6.80 (d, J=8.77 Hz, 1H); 5.71 (s, 2H); 3.95 (s, 3H); 2.62 (s, 3H). m/z (ESI, +ve ion) 311.0 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:13]=2[CH3:22])[C:7]2[CH:23]=[CH:24][C:25]([C:27]#[N:28])=[CH:26][C:6]=2[N:5]([C:29](=[O:35])[CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[C@H:4]1[CH3:36].[C:37]([O:41][C:42]([N:44]([CH2:50][CH3:51])[C@@H:45]([CH3:49])[C:46](O)=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:27]([C:25]1[CH:24]=[CH:23][C:7]2[N:8]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][C:13]=3[CH3:22])[C:9](=[O:10])[C@@H:3]([NH:2][C:46](=[O:47])[C@@H:45]([N:44]([CH2:50][CH3:51])[C:42](=[O:43])[O:41][C:37]([CH3:38])([CH3:40])[CH3:39])[CH3:49])[C@H:4]([CH3:36])[N:5]([C:29](=[O:35])[CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:6]=2[CH:26]=1)#[N:28]
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H](C)C(=O)O
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](N)[C@H](C)N(C(=O)CS(C)(=O)=O)c2cc(C#N)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C)ccc3ccccc23)c2ccc(C#N)cc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To a rt solution of (3S,4S)-3-amino-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (100 mg, 190 μmol) in DMF (632 μl) was added (S)-2-(tert-butoxycarbonyl(ethyl)amino)propanoic acid (45.3 mg, 209 μmol), N,N-diisopropylethylamine (131 μl, 759 μmol), and HBTU (79.2 mg, 209 μmol). The reaction was stirred at rt for 30 min, then purified by reverse phase preparative HPLC to provide tert-butyl(S)-1-((3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(ethyl)carbamate (105 mg, 80%) as a white solid. MS m/z 712 (MNa)+.