Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:13][C:14]1[CH:15]=[C:16]([OH:22])[CH:17]=[C:18]([Cl:21])[C:19]=1[Cl:20].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:18]([Cl:21])[C:19]=1[Cl:20])[O:22][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Oc1cc(Cl)c(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1cc(Cl)c(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
In a 250 ml single-neck flask equipped with a magnetic stirrer and a reflux condenser fitted with a nitrogen bubbler were placed 8.68 g (0.0475 moles) of 2-chloro-5-nitrobenzonitrile 9.67 g (0.0489 moles) of 3,4,5-trichlorophenol, 6.75 g (0.0489 moles) of anhydrous K2CO3, and 75 ml of acetonitrile. The mixture was heated to reflux and held there for 3 hrs. The reaction mixture was cooled to room temperature and diluted with 150 ml of water. The product separated as a solid. The solid was filtered off, washed thoroughly with water, and air-dried. The air-dried solid was recrystallized from a mixture of 200 ml of absolute ethanol and 100 ml of acetone to give 11.62 g (71% yield) of purified 2-(3,4,5-trichlorophenoxy)-5-nitrobenzonitrile as small white crystals, mp 162°-164° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[Si:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(O)cn1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cn1

Procedure:
A solution of 10.9 g 5-hydroxypicoline, 8.85 g imidazole and 29.9 mL of t-butyldiphenylsilylchloride in 500 mL of CH2Cl2 was stirred for 4 days at 25° C. The mixture was washed with H2O, brine, dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica gel chromatography (EtOAc/Hexane 10:90) to afford the pure title compound as an oil.
Reaction SMILES: C([O:8][P:9]([O:36][CH2:37][CH2:38][NH:39][C:40](=[O:66])[CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][NH:55]C(OCC1C=CC=CC=1)=O)([O:11][CH2:12][CH:13]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:14][O:15][C:16](=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:10])C1C=CC=CC=1.CC(O)(C)C>[Pd].O>[NH2:55][CH2:54][CH2:53][O:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][C:40]([NH:39][CH2:38][CH2:37][O:36][P:9]([OH:10])([O:11][CH2:12][CH:13]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:14][O:15][C:16](=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])=[O:8])=[O:66]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)OCC(COP(=O)(OCCNC(=O)CCOCCOCCOCCOCCNC(=O)OCc1ccccc1)OCc1ccccc1)OC(C)(C)C
Agent: [Pd]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCCC(=O)OCC(COP(=O)(O)OCCNC(=O)CCOCCOCCOCCOCCN)OC(C)(C)C

Procedure:
A suspension of 9 (30.2 mg, 0.0313 mmol) and 10% Pd/C (11.3 mg) in 6:1 t-BuOH:H2O was shaken under an atmosphere of H2 (50 psi) for 5.5 hours. The reaction was filtered through a pad of Celite 545 and the pad was washed with 6:1 t-BuOH:H2O (10 mL) and EtOH (2×10 mL). The solvents were evaporated and the product was used in subsequent steps without further purification. RF=0.59 (10:5:1 CHCl3:MeOH:H2O); 6H(CD3OD): 4.16 (dt, 1H), 4.05 (dd, 1H), 3.80-4.02 (m, 5H), 3.71-3.79 (m, 4H), 3.59-3.71 (m, 13H), 3.45 (m, 2H), 3.14 (t, 2H), 3.02 (t, 2H), 2.50 (t, 2H), 2.30-2.39 (m, 2H), 1.63 (quin, 2H), 1.47 (quin, 2H), 1.43 (s, 9H), 1.28-1.28 (m, 2H), 1.22 (s, 9H); δP (CD3OD): 0.28; MALDI-MS: 732.4 ((M+H)+, 100.0).
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[CH3:5])[CH:2]=[CH2:3].F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:32]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:22]1[CH:21]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:15]=[CH:14]2)[CH3:5])[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCCCCc1ccc2[nH]ccc2c1
Reactant: Fc1ccccc1-c1ccccc1
Product: C=CCN(C)CCCCCc1ccc2c(ccn2-c2ccccc2-c2ccccc2)c1

Procedure:
In analogy to example 4.6, Allyl-[5-(1H-indol-5-yl)-pentyl]-methyl-amine and 2-fluoro-biphenyl were converted to yield Allyl-[5-(1-biphenyl-2-yl-1H-indol-5-yl)-pentyl]-methyl-amine as light yellow oil, MS: 409 (MH+).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4][CH2:3]1.O.[C:20](=O)(O)[O-].[Na+]>O1CCCC1>[CH2:17]([O:16][C:14](=[O:15])[C@@H:5]([NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH2:3][C:2](=[O:1])[CH3:20])[CH3:18]
Reactant: O=C([O-])O
Reactant: CCOC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CCC(C)=O)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of (S)-1-tert-butyl 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate (7.00 g, 27.4 mmol) in tetrahydrofuran (100 mL) was added methyl Grignard reagent (3M in diethyl ether, 9.60 mL, 28.8 mmol) dropwise for 20 minutes at −78° C., and stirred for 1 hour. After stiffing for 2 hours at 0° C., to the mixture was added saturated sodium bicarbonate water dropwise, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (7.60 g, 26.5 mmol, 97%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:18]=[C:19]([S:28](=[O:31])(=[O:30])[NH2:29])[C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[OH2:32].Cl.N1[CH:39]=[CH:38]C=CC=1>C(OC(=O)C)(=O)C>[CH2:11]([N:10]([CH2:9][C:8]1[CH:18]=[C:19]([S:28](=[O:31])(=[O:30])[NH2:29])[C:20]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=1)[C:38](=[O:32])[CH3:39])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O
Reactant: CCCCNc1cc(CNCc2ccccc2)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: c1ccncc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CCCCNc1cc(CN(Cc2ccccc2)C(C)=O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 3 h

Procedure:
To a solution of (3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)benzylamine (1.1 g; prepared as described in Example 136) in pyridine (6 ml), acetic anhydride (0.26 ml) is added and the mixture is left for 3 hours. Water (25 ml) is then added followed by concentrated hydrochloric acid (3 ml) to precipitate a semi-solid material. After recrystallization twice from aqueous ethanol, N-benzyl-N-(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)acetamide is obtained with a melting point of 75°-77° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[N:3]=1.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]1>>[ClH:1].[ClH:1].[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH:39][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)[N:3]=2)[CH2:35][CH2:34]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1cccc(C(F)(F)F)c1
Product: Cl
Product: N[C@H]1CC[C@H](Nc2nc(NCCNC(=O)c3cccc(C(F)(F)F)c3)c3ncn(C4CCCC4)c3n2)CC1
Temperature: 140 °C

Procedure:
290 mg of the product obtained in Stage 1 above and 365 mg of trans-1,4-diaminocyclohexane are mixed together and the reaction medium is heated to approximately 140° C. for 6 hours. After evaporating the solvent, chromatography on silica is carried out (eluent methylene chloride/methanol/ammonium hydroxide 85/15/1.5) followed by taking up in an ethanolic solution of hydrochloric acid, leaving to crystallize, separating, drying under reduced pressure and 206 mg of expected product is recovered.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[C:6]=2[CH:25]=1.CC1([CH2+])C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37](=[O:40])[NH:36][CH:35]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>O.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.C(O)C>[CH3:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:34]4[CH:39]=[CH:38][C:37](=[O:40])[NH:36][CH:35]=4)=[CH:25][C:6]=3[N:7]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH2:8][C@@H:9]([CH3:16])[C:10]2=[N:14][N:13]=1
Reactant: [CH2+]C1(C)OB(c2ccc(=O)[nH]c2)OC1(C)C
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(C#N)cc1)C[C@H]2C
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1nnc2n1-c1ccc(-c3ccc(=O)[nH]c3)cc1N(c1ccc(C#N)cc1)C[C@H]2C
Temperature: 100 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
A mixture of (R)-4-(8-bromo-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzonitrile (39.3 mg, 0.1 mmol), (4,5,5-trimethyl-2-(6-oxo-1,6-dihydropyridin-3-yl)-1,3,2-dioxaborolan-4-yl) methylium (66 mg, 0.3 mmol, tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol), cesium carbonate (65.2 mg, 0.2 mmol), toluene (2 mL), ethanol (1 mL) and water (3 drops) was stirred at 100° C. for 16 hours. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3*20 mL). The combined organic layers were washed with water (3*20 mL), brine (3*20 mL), dried over anhydrous sodium sulfate and filtered. The solvent was evaporated in vacuo, and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give (R)-4-(1,4-dimethyl-8-(6-oxo-1,6-dihydropyridin-3-yl)-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzonitrile as a white solid (20 mg, 49.0%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([C:14]2[S:21][C:20]([CH3:22])=[C:19]3[C:15]=2[CH2:16][C@H:17]2[C:23]([CH3:25])([CH3:24])[C@H:18]23)=[O:13])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].Br[CH2:27][CH2:28][CH2:29][OH:30]>C(O)(C)C.[OH-].[Na+]>[OH:30][CH2:29][CH2:28][CH2:27][O:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([CH2:10][CH2:11][C:12]([C:14]2[S:21][C:20]([CH3:22])=[C:19]3[C:15]=2[CH2:16][C@H:17]2[C:23]([CH3:25])([CH3:24])[C@H:18]23)=[O:13])=[CH:5][C:6]=1[CH3:9]
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1O
Reactant: OCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCCCO
Temperature: 70 °C
Reaction time: 5 h
Yield: 73.1 %

Procedure:
A solution of 3-(3,5-dimethyl-4-hydroxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (3.00 g, 8.46 mmol, Intermediate 10) in isopropanol (80 mL) and 2 N aq. NaOH (30 mL) is treated with 3-bromopropanol (2.35 g, 16.9 mmol). The dark red reaction mixture is stirred at 70° C. for 5 h. The solvent is removed under reduced pressure and the residue is dissolved in EA and washed twice with water. The organic layer is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 1:1 to give 3-[4-(3-hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-((1aS,5aR)-1,1,2-tri methyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (2.55 g) as a yellow oil; LC-MS: tR=1.10 min, [M+1]+=413.33; 1H NMR (CDCl3): δ 6.87 (s, 2H), 3.99-3.90 (m, 4H), 3.04-2.85 (m, 5H), 2.81 (d, J=18.8 Hz, 1H), 2.39 (s, 3H), 2.27 (s, 6H), 2.10-2.01 (m, 2H), 1.93-1.88 (m, 2H), 1.13 (s, 3H), 0.72 (s, 3H).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][CH2:17][N:18]([CH2:31][CH3:32])[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29])(=[O:21])=[O:20].[H-].[Na+].CCCCCC.C(OCC)(=O)C>CN(C=O)C>[CH:10]1[C:11]2[N:12]([CH2:15][CH2:16][CH2:17][N:18]([CH2:31][CH3:32])[S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:28]([O-:30])=[O:29])(=[O:20])=[O:21])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCN(CCCBr)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCN(CCCn1c2ccccc2c2ccccc21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 61.3 %

Procedure:
Carbazole (4.15 g, 24.8 mmol) and bromide 64 (9.7 g, 27.6 mmol) were dissolved in DMF (30 mL). NaH (2.0 g, 50.0 mmol, 2 eq) was added in portions, whereupon the temperature rose to 60° C. The reaction mixture was stirred for 1 h (TLC monitoring, hexane/ethyl acetate 3:2), poured into ice/water mixture, and extracted with ethyl acetate. The residue was triturated with ether. The yellow precipitate was filtered off and dried to afford 6.65 g (61%) of the product.
Reaction SMILES: C([O:3][C:4]([CH:6]1[O:20][C:9]2=[C:10]3[C:15](=[C:16]([CH3:18])[CH:17]=[C:8]2[CH2:7]1)[NH:14][C:13](=[O:19])[CH2:12][CH2:11]3)=O)C.[NH3:21].CO>C(Cl)(Cl)Cl>[NH2:21][C:4]([CH:6]1[O:20][C:9]2=[C:10]3[C:15](=[C:16]([CH3:18])[CH:17]=[C:8]2[CH2:7]1)[NH:14][C:13](=[O:19])[CH2:12][CH2:11]3)=[O:3]
Reactant: N
Reactant: CCOC(=O)C1Cc2cc(C)c3c(c2O1)CCC(=O)N3
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(C(N)=O)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The compound obtained in Example 258 (1 g, 3.63 mmol) was dissolved in chloroform (20 ml). To the solution, saturated ammonia--methanol solution (50 ml) was added. The vessel containing the mixture was sealed, and the content was stirred at room temperature for 24 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. 0.88 g of the title compound was obtained as a white solid (99%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14](=[S:16])[NH2:15])=[CH:4]1)[CH3:2].CO[CH:19](OC)[CH2:20]Br>C(COC)OC>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[S:16][CH:19]=[CH:20][N:15]=2)=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(N)=S)c2ccc(OC)cc21
Reactant: COC(CBr)OC
Solvent: COCCOC
Product: CCn1cc(-c2nccs2)c2ccc(OC)cc21
Temperature: 80 °C
Yield: 47.3 %

Procedure:
1-Ethyl-6-methoxy-1H-indole-3-thiocarboxamide (83 mg, 0.36 mmol), glyme (3.6 mL) and bromoacetaldehyde dimethyl acetal (220 μL, 1.86 mmol) are heated at 80° C. for 16 h. More bromoacetaldehyde dimethyl acetal (250 μL) is added. This is heated at 80° C. for 2 h. Addition of 250 μL more bromoacetaldehyde dimethyl acetal is followed by heating for another 2 hours. The reaction mixture is cooled to room temperature, absorbed onto silica and purified by silica gel chromatography (hexanes/EtOAc, 7/3) to afford 1-ethyl-6-methoxy-3-thiazol-2-yl-1H-indole as a brown oil (44 mg, 47%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=2[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])=[O:9])=[CH:4][C:3]=1[N+:26]([O-])=O.[CH2:29]([O:31][C:32]([N:34]=[C:35]=S)=[O:33])[CH3:30].C(Cl)CCl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[CH2:29]([O:31][C:32]([NH:34][C:35]1[O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:10]3[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=3[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[O:9])=[CH:4][C:3]=2[N:26]=1)=[O:33])[CH3:30]
Reactant: O=C(OCc1ccccc1)c1ccccc1C(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CCOC(=O)N=C=S
Agent: [Fe]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1nc2cc(C(=O)c3ccccc3C(=O)OCc3ccccc3)ccc2o1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A solution of phenylmethyl 2-[(4-hydroxy-3-nitrophenyl)carbonyl]benzoate (5.78 g, 15.3 mmol) in acetic acid (50 mL) was treated with iron powder (8.5 g, 153 mmol) at 50° C. for 30 min. After cooling to rt, the mixture was diluted with ethyl acetate, and the solids were removed by filtration though celite. The organic filtrate was washed with saturated sodium bicarbonate, which lead to further precipitation of solid contaminants. These solids were removed by filtration. The resulting organic filtrate was dried over magnesium sulfate, filtered, and concentrated to a brown foam. This material was taken up in DMF (30 mL). To this solution was added ethoxycarbonyl isothiocyanate (2.6 mL, 23 mmol). After stirring for 35 min, EDC (4.4 g, 23 mmol) was added to the reaction mixture. The mixture was stirred at rt for 35 min and then was stirred for a further 1 h at 65° C., and then it was cooled to rt. To the mixture was added 10% aqueous citric acid, and the resulting aqueous mixture was extracted twice with ethyl acetate. The organic extracts were combined, washed with brine, dried over magnesium sulfate, filtered, and concentrated to a brown solid. Contaminants were removed by trituration with methanol. Desired phenylmethyl 2-[(2-{[(ethyloxy)carbonyl]amino}-1,3-benzoxazol-5-yl)carbonyl]benzoate was isolated as a white solid (637 mg, 1.4 mmol, 9.4% yield). A sample was further purified by reverse phase HPLC. 1H NMR (400 MHz, CDCl3): 10.91 (br s, 1H), 8.12 (m 1H), 7.95 (br s, 1H), 7.67 (m, 1H), 7.63-7.52 (m, 3H), 7.47-7.38 (m, 2H), 7.26-7.13 (m, 5H), 5.08 (s, 2H), 4.29 (q, 2H), 1.38 (t, 3H); MS (EI) for C25H20N2O6: 445 (MH+).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:19]1)=[O:15])=O)C1C=CC=CC=1.[H][H]>CO.Cl.CO.[OH-].[Pd+2].[OH-].[C]>[NH2:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:19]1)=[O:15]
Reactant: O=C(CCNC(=O)OCc1ccccc1)NC[C@H]1CCCN(CC2CCCCC2)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: NCCC(=O)NC[C@H]1CCCN(CC2CCCCC2)C1
Reaction time: 44 h
Yield: 75 %

Procedure:
To a solution of 770 mg of 3-(benzyloxycarbonyl)amino-N-{((3R)-1-cyclohexylmethyl-3-piperidyl)methyl}propanamide in 12 ml of methanol, 0.5 ml of 10% hydrochloric acid-methanol and 15 mg of 20% palladium hydroxide-carbon catalyst were added, followed by 44 hours' stirring under 3 atmospheres of hydrogen. Filtering the catalyst off, the solvent was distilled off under reduced pressure, and the residue was rendered weakly basic with saturated aqueous sodium bicarbonate solution. The product was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by means of silica gel column chromatography (eluting solvent: chloroform-chloroform/methanol/28% aqueous ammonia=100/10/1) to provide 391 mg of the title compound.
Reaction SMILES: C(OC[N:10]1[C:15](=[O:16])[C:14]2[C:17]([CH3:28])=[CH:18][N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=2[CH:12]=[N:11]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH3:28][C:17]1[C:14]2[C:15](=[O:16])[NH:10][N:11]=[CH:12][C:13]=2[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[CH:18]=1
Reactant: Cc1cn(COCC[Si](C)(C)C)c2cnn(COCc3ccccc3)c(=O)c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cn(COCC[Si](C)(C)C)c2cn[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.7 %

Procedure:
To 380 ml of ethanol solution containing 25.3 g (65 mmol) of 5-benzyloxymethyl-3-methyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 24-(c) was added 25 g of 5% palladium-active carbon, and the mixture was stirred under 1 atm hydrogen atmosphere at room temperature for 2.5 hours. After completion of the reaction, insoluble material was removed from the reaction suspension by filtration, 100 ml of 28% aqueous ammonia was added to the obtained filtrate, and the mixture was stirred at room temperature for 5 hours. Then, the solution was concentrated under reduced pressure, 500 ml of water was added to the obtained concentrate, and precipitated solid was collected by filtration. The obtained solid was washed with water, and dried under reduced pressure to obtain 14.3 g of the title compound as a pale yellowish solid. (Yield: 79%)
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O-]CC.[Na+].C(Cl)(=O)C(Cl)=O.[Cl:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([S:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])=[O:39])[CH:32]=[CH:31]2>C1COCC1.ClCCl.N1C=CC=CC=1>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:12]([N:44]2[CH2:43][CH2:42][N:41]([S:38]([C:33]3[CH:32]=[CH:31][C:30]4[C:35](=[CH:36][CH:37]=[C:28]([Cl:27])[CH:29]=4)[CH:34]=3)(=[O:40])=[O:39])[CH2:46][CH2:45]2)=[O:14])[CH2:15][CH2:16]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: CC[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Yield: 69.4 %

Procedure:
To a stirring solution of N-Boc-isonipecotic acid (1.99 g, 8.7 mmol) in THF (50 mL) was added sodium ethoxide (0.592 g, 8.7 mmol) After 0.5 h, the solvent was removed in vacuo and the residue was suspended in dichloromethane (50 mL). To this mixture was added a couple drops of DMF, followed by oxalyl chloride (1.32 g, 10.4 mmol). After stirring for another hour, the solvent was removed in vacuo and the crude acid chloride resuspended in dichloromethane (25 mL). To this solution was added a solution of 1-(6-chloronaphthalen-2-ylsulfonyl)piperazine (1.8 g, 5.8 mmol) and pyridine (5 mL) in dichloromethane (25 mL) After stirring overnight, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed twice with 1 M citric acid, once with brine, twice with satd aq NaHCO3 and twice again with brine, then dried with MgSO4, filtered and concentrated in vacuo. The residue was then dissolved in a minimum amount of dichloromethane and chromatographed over silica gel, eluting with a step gradient of 35% ethyl acetate in hexanes through 75% ethyl acetate in hexanes. The product containing fractions were combined and concentrated in vacuo to give 2.1 g (69%) of a white foam.