Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:13])[CH2:8]2.[Li+].[CH3:15][CH:16]([N-]C(C)C)[CH3:17].[CH2:22](Br)[CH:23]=[CH2:24]>C1COCC1.C1CCCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:13])[C:8]2([CH2:24][CH:23]=[CH2:22])[CH2:17][CH:16]=[CH2:15]
Reactant: COc1cccc2c1CCC(=O)C2
Reactant: CC(C)[N-]C(C)C
Reactant: C=CCBr
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: C=CCC1(CC=C)C(=O)CCc2c(OC)cccc21
Reaction time: 5 h
Yield: 32.5 %

Procedure:
To a solution of 5.3 g (30 mmol) 5-methoxy-2-tetralone in 45 mL THF in a three-neck round-bottomed flask, equipped with a gas inlet and septum, was added 22 mL LDA (33 mmol, 1.5M in cyclohexane, at -30° C. under a nitrogen atmosphere. The solution was allowed to warm to 0° C. over a thirty-minute period and 3.4 mL (39 mmol) allylbromide was added. TLC analysis was used to monitor the reaction. After five hours of stirring, the reaction mixture was quenched with 10% sodium bisulfate to pH 2-3. After removal of THF under reduced pressure, the mixture was extracted with ethyl acetate (2×1 L) and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting oil was purified by liquid chromatography on 800 g of silica gel 60 (230-400 m), eluting with 1 L of hexane and 5 L of hexane-ethyl acetate (19:1), and collecting 40 mL fractions. Fractions 45-87 gave 2.5 g (32.5%) of pure 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1,1-di-(2-propenyl)-naphthalene as a near colorless oil and fractions 88-140 gave 1.07 g (16.5%) of pure 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-(2-propenyl)naphthalene as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH:18]1([N:23]2[CH2:28][CH2:27][CH:26](OS(C)(=O)=O)[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C.CC(OC)(C)C.O.[OH-].[Na+]>[CH:18]1([N:23]2[CH2:28][CH2:27][CH:26]([O:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)=[CH:4][CH:3]=3)[CH2:25][CH2:24]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CS(=O)(=O)OC1CCN(C2CCCC2)CC1
Reactant: N#CC1(c2ccc(O)cc2)CCOCC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: COC(C)(C)C
Product: N#CC1(c2ccc(OC3CCN(C4CCCC4)CC3)cc2)CCOCC1
Temperature: 75 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (459 mg, 2.26 mmol) in DMF (2 ml) was added to a solution of NaH (100 mg, 2.5 mmol) in DMF (2 ml) at room temperature under N2. The reaction was stirred for 1 hr and a solution of methanesulfonic acid 1-cyclopentyl-piperidin-4-yl ester (447 mg, 1.81 mmol) in DMF (1.3 ml) was slowly added. The reaction was heated to 75° C. and stirred for 6 hrs. The reaction was allowed to cool to room temperature and diluted with TBME (20 ml), water (10 ml) and 5M NaOH solution (10 ml). The organic layer was washed with 2.5M NaOH (2×20 ml), brine (2×20 ml), dried over MgSO4, filtered and concentrated in vacuo. The crude reaction was purified by successive column chromatography, eluting with DCM:MeOH:NH3 (98:1:1) to give the title compound as a pale yellow solid (81 mg, 13%). 1H NMR (400 MHz, CDCl3) δ 7.37 (d, 2H), 6.93 (d, 2H), 4.36 (m, 1H), 4.11-4.04 (m, 2H), 3.89 (td, 2H), 2.91-2.77 (m, 2H), 2.67-2.25 (m, 2H), 2.15-1.99 (m, 7H), 1.95-1.81 (m, 4H), 1.78-1.64 (m, 2H), 1.62-1.39 (m, 4H).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[NH3:6]>[Ni].[H][H]>[CH:1](=[N:6][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC=O
Reactant: N
Reactant: [H][H]
Agent: [Ni]
Product: CCCC=NCCCC

Procedure:
1000 g n-butyraldehyde are reacted in the presence of 80 g of a commercially available nickel containing carrier catalyst (containing about 52 to 53% by weight nickel, and employing chromium (3)-oxide as activator) at 115° C with ammonia and hydrogen (volume ratio 1 : 1) in a flask equipped as described in Example 1. Altogether 260 l ammonia and 260 l hydrogen are introduced into the aldehyde-catalyst-suspension over a period of 4 hours. After termination of the reaction, the catalyst is separated from the reaction mixture. 840 g butylidene-butylamine are obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)(=[O:4])=[O:3].Br[C:15]1[N:16]=[C:17]([O:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[S:18][CH:19]=1>>[C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][CH:21]([O:20][C:17]2[S:18][CH:19]=[C:15]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH:8]=[CH:9]3)[N:16]=2)[CH2:26][CH2:25]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nc(Br)cs2)CC1
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc(-n3ccc4cc(S(C)(=O)=O)ccc43)cs2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using 5-(methylsulfonyl)-1H-indole (intermediate 21) and tert-butyl 4-((4-bromothiazol-2-yl)oxy)piperidine-1-carboxylate (intermediate 46) (0.007 g, 5%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C:26]2([CH3:34])[CH2:31][O:30]C(C)(C)[O:28][CH2:27]2)[N:12]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C:26]([CH2:31][OH:30])([CH3:34])[CH2:27][OH:28])[N:12]=1
Reactant: CC1(Oc2cc(NS(=O)(=O)N3CCC3)nc(SCc3cccc(F)c3F)n2)COC(C)(C)OC1
Agent: Cl[Fe](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(CO)(CO)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2,2,5-trimethyl-1,3-dioxan-5-yl)oxy]-4-pyrimidinyl]-1-azetidinesulfonamide (the product from step (0.46 g) in DCM (15 mL) was added iron (III) chloride hexahydrate (0.85 g) and the mixture was stirred and ambient temperature for 30 min. A saturated solution of sodium hydrogencarbonate was added and then extracted with DCM (×4). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using a MeOH/DCM (99:1 to 98:2 gradient) as eluent to give the title compound as a white foam. Yield: 100 mg
Reaction SMILES: [Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12]([C:16](=[O:18])[NH2:17])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7](C(OCC)=O)=[CH:8][C:9]=1[NH:10]2.[CH3:24][Li].CC[O:28][CH2:29][CH3:30].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:29]([OH:28])([CH3:30])[CH3:24])=[CH:6][CH:5]=3)[NH:10][C:11]=2[C:12]([C:16]([NH2:17])=[O:18])=[CH:13][C:14]=1[CH3:15]
Reactant: CCOCC
Reactant: [Li]C
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(C)c(Br)c12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(N)=O)c2[nH]c3cc(C(C)(C)O)ccc3c2c1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution of ethyl 5-bromo-8-carbamoyl-6-methyl-9H-carbazole-2-carboxylate (0.500 g, 1.33 mmol) in THF (12 mL) at −78° C. was treated dropwise over 10 min with 1.6 M methyllithium in ether (2.50 mL, 4.00 mmol). The mixture was stirred at −78° C. for 30 min, then was treated with additional methyllithium solution (1.67 mL, 2.67 mmol). After 30 min more, additional methyllithium solution (1.67 mL, 2.67 mmol) was added and stirring was continued for 45 min. The mixture was then treated with saturated aqueous NH4Cl and allowed to warm to room temperature. The mixture was diluted with EtOAc and washed sequentially with water and brine. The aqueous layers were extracted with EtOAc, and the combined organic layers were dried and concentrated to provide an off-white solid. The solid was triturated and sonicated with MeOH and collected by filtration. The filtrate was purified by reverse-phase preparative HPLC. The appropriate fractions were treated with saturated aqueous NaHCO3 and concentrated. The residue was partitioned between EtOAc and water. The organic phase was washed with brine, and the aqueous layers were extracted with EtOAc. The combined organic layers were dried and concentrated, and the residue was combined with the first solid to give 4-bromo-7-(2-hydroxypropan-2-yl)-3-methyl-9H-carbazole-1-carboxamide as a tan solid (0.409 g, 85% yield). Mass spectrum m/z 343, 345 (M+H—H2O)+. 1H NMR (500 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.56 (d, J=8.6 Hz, 1H), 8.12 (br. s., 1H), 7.91-7.89 (m, 2H), 7.48 (br. s., 1H), 7.36 (dd, J=8.3, 1.7 Hz, 1H), 5.06 (s, 1H), 2.53 (s, 3H), and 1.51 (s, 6H).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][NH:6][CH:5]([C:9]([NH:11][C@H:12]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH3:13])=[O:10])[CH2:4]2)[CH2:2]1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:6]2[CH2:7][CH2:8][C:3]3([CH2:2][CH2:1]3)[CH2:4][CH:5]2[C:9]([NH:11][C@H:12]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[CH3:13])=[O:10])=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)C2CC3(CCN2)CC3)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)C2CC3(CCN2Cc2ccc(F)cc2)CC3)cc1

Procedure:
The title compound (D126) (30 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((1S)-1-(6-azaspiro[2.5]octane-5-carboxamido)ethyl)benzoate (D91) (60 mg) and 4-Fluorobenzylbromide (0.074 ml). (Na2CO3: 2.5 eq; reaction time: 4 hrs; 60° C.)
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:13][C:14](=[O:30])[CH2:15][N:16]=[C:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:12].C(=O)=O.C[C:35]([CH3:37])=O.I[CH2:39][CH3:40]>O1CCCC1>[C:18]1([C:17](=[N:16][C:15]([CH2:35][CH3:37])([CH2:39][CH3:40])[C:14]([O:13][CH2:11][CH3:12])=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCI
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: CC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)(CC)N=C(c1ccccc1)c1ccccc1
Reaction time: 3.5 h
Yield: 97 %

Procedure:
A solution of potassium bis(trimethylsilyl)amide (15.02 g, 75.3 mmol) in 80 mL of anhydrous tetrahydrofuran was added under nitrogen dropwise over 30 min to a solution of N-(diphenylmethylene)glycine ethyl ester (18.34 g, 68.6 mmol) in 300 mL of anhydrous tetrahydrofuran at dry ice-acetone temperature. After the addition, the reaction was stirred at dry ice-acetone temperature for 1 h. Iodoethane (6.60 mL, 82.5 mmol) was added over 2 min. The cooling bath was removed and the stirring continued for 3.5 h. Reaction cooled to dry ice-acetone temperature. A solution of potassium bis(trimethylsilyl)amide (15.02 g, 75.3 mmol) in 100 mL of anhydrous tetrahydrofuran was added dropwise over 30 min. After the addition, the reaction was stirred at dry ice-acetone temperature for 1 h. Iodoethane (6.60 mL, 82.5 mmol) was added over 2 min. The cooling bath was removed and the reaction stirred for 17 h. The reaction was concentrated under reduced pressure to remove most of the tetrahydrofuran. The residue was partitioned between methylene chloride and water. The organic layer was separated and the aqueous layer extracted three times with methylene chloride. The combined extracts were washed with saturated sodium chloride, dried (anhydrous MgSO4), filtered and the solvent removed under reduced pressure to give ethyl 2-[(diphenylmethylene)amino]-2-ethylbutanoate (21.50 g, 97%) as a yellow oil, MS (ESI) m/z 324 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].FC(F)(F)C([N:12]([C:27]1[CH:42]=[CH:41][C:30]([C:31](ON2C(=O)CCC2=O)=[O:32])=[CH:29][CH:28]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=O.[OH-].[Na+].Cl>O.C(O)C.C(N(CC)CC)C>[CH:21]1([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:27]2[CH:42]=[CH:41][C:30]([C:31]([NH:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])=[O:32])=[CH:29][CH:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(N(CCCCCCCCC2CCCCC2)C(=O)C(F)(F)F)cc1
Reactant: NCCS(=O)(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: O=C(NCCS(=O)(=O)O)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of 2.50 g. of taurine and 5.6 ml. of triethylamine in 22.5 ml. of water is added 5.55 g. of N-{p-[2,2,2-trifluoro-N-(8-cyclohexyloctyl)acetamido]benzoyloxy}succinimide as a solution in 45 ml. of ethanol. After 24 hours, the mixture is treated with 20 ml. of 2.0 M sodium hydroxide and 25 ml. of water. After stirring for 10 min., the mixture is acidified with dilute hydrochloric acid, and the crude product is collected by filtration. Recrystallization affords the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C:43]([OH:45])=[O:44])[CH2:10]2)=[CH:5][CH:4]=1.[N+](=[CH2:48])=[N-].S([O-])([O-])(=O)=O.[Mg+2]>CO.CCOCC>[CH3:48][O:44][C:43](=[O:45])[CH2:42][C@H:11]1[CH2:10][C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=3[CH:31]=2)[CH2:13][N:12]1[S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:33])=[O:34]
Reactant: C=[N+]=[N-]
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: CCOCC
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)OC)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
To a solution of 2.03 g of [(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetic acid (from example 25f) in 50 ml of methanol at 0° C. is added a 0.1M solution of diazomethane in ether until the conversion to the methyl ester is complete. The reaction mixture is treated with magnesium sulfate to destroy the excess of diazomethane. The solids are removed by filtration and the organic layer is concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow oil. Rf=0.24 (EtOAc-heptane 1:1); Rt=5.24.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si](C(C)(C)C)(C)C)[CH:46]([O:58][CH2:59][CH:60]=[CH2:61])[CH2:45]2)[CH:7]([CH3:63])[CH2:6][CH2:5][C:4]1=[O:64])[CH3:2]>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:58][CH2:59][CH:60]=[CH2:61])[CH2:45]2)[CH:7]([CH3:63])[CH2:6][CH2:5][C:4]1=[O:64])[CH3:2]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O[Si](C)(C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.7 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (115 mg) (STEP 31A) in acetonitrile (2.5 ml) was added a solution of 2% HF in aqueous acetonitrile (40 μl), and the mixture was stirred at room temperature. After 4 hours, the solution was diluted with ethyl acetate and quenched with saturated sodium bicarbonate. The layers were separated, and the organic layer was washed with brine and dried over magnesium sulfate. Purification of the concentrate-by flash chromatography on silica gel (ethyl acetate:hexane (1:2)) gave the title compound (42 mg). 1H NMR consistent with the desired structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=3[CH:17]=2)=[CH:21][CH:20]=1
Reactant: Brc1ccc(I)cc1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3ccc(Br)cc3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 1-bromo-4-iodobenzene according to the procedure described in example 2. 1H NMR (DMSO-d6): δ 8.25 (s, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.11 (dd, J=8.7, 2.3 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H), 6.92 (d, J=8.9 Hz, 2H), 6.87 (d, J=2.3 Hz, 1H), 3.26 (s, 3H), 1.95 (m, 4H), 0.82 (t, J=7.3 Hz, 6H); MS (ESI) m/z 389/391 ([M+H]+); MS (ESI) m/z 387/389 ([M−H]−); Anal. calcd for C19H21BrN2O2: C, 58.62; H, 5.44 N, 7.20. Found: C, 58.59; H, 5.29; N, 7.03.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[CH2:9]([NH2:11])[CH3:10].C(O)(=O)C.[OH-].[Na+]>O.CO>[CH2:9]([NH:11][CH2:2][CH2:1][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)[CH3:10]
Reactant: C=Cc1cnccn1
Reactant: CCN
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCNCCc1cnccn1
Temperature: 70 °C
Yield: 81 %

Procedure:
A mixture of 21.2 g (0.2 mole) of vinylpyrazine, 18.0 g (0.4 mole) of ethylamine, 6.0 g (0.1 mole) of acetic acid and 60 ml methanol was placed in a pressure bottle and heated at 70° C. for 24 hours. After removing the methanol, the residue was made basic with 8.0 g (0.2 mole) of sodium hydroxide in 80 ml of water and extracted with several portions of chloroform. After removing the chloroform, the residue was distilled to give 24.5 g of β-ethylaminoethylpyrazine, b.p. 70°-72° C. at 0.5 mm Hg, nD25 =1.5103.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[N+:18]([O-])=O.O.O.Cl[Sn]Cl>CCO>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[NH2:18]
Reactant: COC(=O)c1ccccc1Sc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccccc1Sc1ccc(Cl)cc1N
Temperature: 80 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
To a mixture of 2-(4-chloro-2-nitro-phenylsulfanyl)-benzoic acid methyl ester (189JO09) (232 mg, 0.72 mmol) in EtOH (5 mL) was added SnCl2.2H2O (812 mg, 3.6 mmol) and the resulting mixture was stirred at 80° C. for 2 h and then concentrated. The residue was treated with ice, and then Na2CO3 was added until a pH of 10 was reached. EtOAc was added and the slurry was filtered through celite. The EtOAc-phase was washed with water and brine, dried (Na2SO4) and concentrated to give 149 mg (70%) of the title compound (189JO11). 1H NMR (CDCl3) δ 8.02 (dd, 1H, J=1.6, 7.8 Hz), 7.39 (d, 1H, J=8.2 Hz), 7.29 (m, 1H), 7.15 (dt, 1H, J=1.2, 7.8 Hz), 6.87 (d, 1H, J=2.2 Hz), 6.80 (dd, 1H, J=2.2, 8.2 Hz), 6.76 (dd, 1H, J=1.2, 8.0 Hz), 3.96 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:8][CH:7]=1)=[O:5])C.[OH-].[K+].C(OCC)C>C(O)C>[C:4]([C:6]1[S:10][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:8][CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)s2)CC1
Temperature: 40 °C
Yield: 56.4 %

Procedure:
5.33 g (15.6 mmol) of tert-butyl 4-(5-ethoxycarbonylthiazol-2-yl)piperazine-1-carboxylate [Precursor BBB60] were dissolved in ethanol together with 0.96 g (17.1 mmol) of KOH (100 ml) and stirred at 40° C. 4 h. The resulting precipitate was filtered off and dissolved in water. After this, the solution was adjusted to a pH<2 with 10% strength hydrochloric acid and extracted with chloroform. The organic phase was washed with water and a satd aq. NaCl soln and dried over MgSO4. After filtration and concentration in vacuo, 2.77 g (8.8 mmol, 56%) of tert-butyl 4-(5-carboxythiazol-2-yl)piperazine-1-carboxylate were obtained from the residue by recrystallization from diethyl ether.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([O:14][CH3:15])=[C:12](Cl)[N:11]=[CH:10][N:9]=1.[H][H]>O.[Pd]>[CH3:15][O:14][C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[N:11][CH:12]=1
Reactant: C1CNCCN1
Reactant: COc1c(Cl)ncnc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: COc1cncnc1N1CCNCC1
Yield: 61.4 %

Procedure:
Piperazine (20 g, 0.233 mol, 8.33 eq) is dissolved in water (100 ml), and to this solution is added 4,6-dichloro-5-methoxypyrimidine (5.00 g, 41.9 mmol, 1.0 eq). The mixture is stirred vigorously at room temperature for 2.0 h, during which 4,6-dichloro-5-methoxypyrimidine is gradually dissolved. The reaction solution is loaded into hydrogenation reactor and added with 10% Pd/C (0.66 g), and the mixture is stirred under 60 psi (0.4 Mpa) hydrogen atmosphere for 3.0 h. The mixture is filtered, extracted with CH2Cl2 (60 ml*3) for the products in the aqueous phase. Extracts are combined, dried over anhydrous sodium sulfate and filtered by vacuum filtration, and concentrated to give a crude product (5.0 g). The crude product is left to precipitate a white solid (yield: 92.6%).