Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10]C(=O)C)=[N:7][CH:8]=1)#[N:2].[OH-].[Li+]>O1CCCC1.O.C(OCC)(=O)C>[OH:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=1
Reactant: CC(=O)OCc1ccc(C#N)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of Example 31A (180 mg, 1.02 mmol) is dissolved in tetrahydrofuran (8 ml). Lithium hydroxide (48.94 mg, 2.04 mmol) is dissolved in water (5 ml) and added to the THF solution. The reaction is stirred for 2 hours at room temperature. The mixture is diluted with water and ethyl acetate. The aqueous phase is extracted three times with ethyl acetate. The organic phases are combined and washed with brine, dried with magnesium sulphate monohydrate, filtered and concentrated in vacuo. The residue is used without further purification.
Reaction SMILES: [NH2:1][C:2]([CH3:14])([CH3:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:12])[CH3:11])=[CH:6][CH:5]=1.[C:15]([O:19][C:20]1[CH:21]=[C:22]([C@H:33]([OH:40])[CH2:34]OS(C)(=O)=O)[C:23]2[S:27][C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[N:25][C:24]=2[CH:32]=1)([CH3:18])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[C:15]([O:19][C:20]1[CH:21]=[C:22]([C@H:33]([OH:40])[CH2:34][NH:1][C:2]([CH3:14])([CH3:13])[CH2:3][C:4]2[CH:9]=[CH:8][C:7]([N:10]([CH3:11])[CH3:12])=[CH:6][CH:5]=2)[C:23]2[S:27][C:26]([O:28][CH:29]([CH3:30])[CH3:31])=[N:25][C:24]=2[CH:32]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CN(C)c1ccc(CC(C)(C)N)cc1
Reactant: CC(C)Oc1nc2cc(OC(C)(C)C)cc([C@H](O)COS(C)(=O)=O)c2s1
Solvent: Cc1ccccc1
Product: CC(C)Oc1nc2cc(OC(C)(C)C)cc([C@H](O)CNC(C)(C)Cc3ccc(N(C)C)cc3)c2s1
Temperature: 80 °C

Procedure:
[4-(2-Amino-2-methyl-propyl)-phenyl]-dimethyl-amine (210 mg) and Methanesulfonic acid (S)-2-(5-tert-butoxy-2-isopropoxy-benzothiazol-7-yl)-2-hydroxy-ethyl ester (120 mg) are dissolved in toluene (2 ml). The reaction mixture is heated to 80° C. for 20 hours. The solvent is removed by vacuo to give (S)-1-(5-tert-Butoxy-2-isopropoxy-benzothiazol-7-yl)-2-[2-(4-dimethylamino-phenyl)-1,1-dimethyl-ethylamino]-ethanol. MS (ES+) m/e. 500
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[N:15]1[C:19]([NH:20][C:21]([CH2:23][O:24]C(C)=O)=[O:22])=[C:18]([N+:28]([O-:30])=[O:29])[CH:17]=[N:16]1.[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[N:15]1[C:19]([NH:20][C:21]([CH2:23][OH:24])=[O:22])=[C:18]([N+:28]([O-:30])=[O:29])[CH:17]=[N:16]1
Reactant: CC(=O)OCC(=O)Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(CO)Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.8 %

Procedure:
A mixture of 1.5 grams (0.0034 mole) of 1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-5-methylcarbonyloxymethylcarbonylamino -4-nitropyrazole, 2.63 mL of a 2N aqueous sodium hydroxide solution, 1.5 mL of ethanol, and 4.7 mL of water was stirred at room temperature for 15 minutes. After the pH was adjusted to 5.0 with dilute hydrochloric acid, ethanol was removed from the mixture by distillation under reduced pressure. The remaining aqueous phase was extracted with methylene chloride, and the extract was washed with water. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 0.75 gram of 1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-5 -hydroxymethylcarbonylamino-4-nitropyrazole as a solid (compound 19 of Table 1). The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH:57]2[CH2:59][O:58]2)=[CH:51][CH:50]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:20][C:18]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:59][C@H:57]([OH:58])[CH2:56][O:55][C:52]4[CH:53]=[CH:54][C:49]([OH:48])=[CH:50][CH:51]=4)=[CH:30][CH:29]=3)[CH2:17][CH2:16]2)=[O:19])=[CH:27][CH:26]=1
Reactant: NCCc1ccc(NC2CCN(C(=O)OCc3ccc(F)cc3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: O=C(OCc1ccc(F)cc1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 29.3 %

Procedure:
4-Fluorobenzyl 4-[4-(2-aminoethyl)anilino]-1-piperidinecarboxylate formate (0.33 g, 0.792 ) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.32 g, 0.792 mmol) according to the method described in Procedure G to give the title compound (0.18 g, 0.232 mmol).
Reaction SMILES: [CH2:1]([N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]([C:8]1[C:12]([Cl:13])=[CH:11][NH:10][N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].F[C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][C:20]=1[C:30]([N:32]1[CH2:41][CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33]1)=[O:31]>>[Cl:13][C:12]1[C:8]([C:6](=[O:7])[N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][N:10]([C:19]2[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][C:20]=2[C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[CH:11]=1
Reactant: CCOC(=O)c1ccc(F)c(C(=O)N2CCc3ccccc3C2)c1
Reactant: CCCCN(CCCC)C(=O)c1n[nH]cc1Cl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)OCC)cc2C(=O)N2CCc3ccccc3C2)cc1Cl
Yield: 70.8 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1E, N,N-dibutyl-4-chloro-1H-pyrazole-3-carboxamide (100 mg, 0.39 mmol) and ethyl 4-fluoro-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (Intermediate 1D, 140 mg, 0.43 mmol) were converted to the title compound (156 mg, 71%). 1H NMR (CDCl3, mixture of amide rotamers) δ 8.23-8.16 (m, 1H), 8.12-8.06 (m, 1H), 7.98-7.85 (m, 1H), 7.71-7.58 (m, 1H), 7.26-7.04 (m, 3.5H), 6.78 (d, J=7.5 Hz, 0.5H), 4.99-4.70 (m, 1H), 4.45-4.24 (m, 2.5H), 4.17-4.01 (m, 1H), 3.79-3.73 (m, 0.5H), 3.57-3.15 (m, 5H), 3.11-2.87 (m, 1H), 2.74 (t, J=5.8 Hz, 1H), 1.67-1.06 (m, 10.5H), 1.00-0.86 (m, 3.5H), 0.86-0.73 (m, 3H); MS(ESI+) m/z 565.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:16]([OH:18])=[O:17])[CH3:15])[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1.[CH3:26]NN=NC1C=CC(C)=CC=1>C(Cl)(Cl)Cl.CCOCC.CCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:16]([O:18][CH3:26])=[O:17])[CH3:15])[CH2:9][N:8]=[C:7]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:6]=2[CH:25]=1
Reactant: CC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)C(=O)O
Reactant: CNN=Nc1ccc(C)cc1
Solvent: CCCCC
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COC(=O)C(C)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
To a solution of 0.39 g. (0.001 mole) of 7-chloro-2-[(1-carboxyethylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine is added 0.164 g. (0.0011 mole) of 3-methyl-1-p-tolyltriazene. After standing at room temperature (22°-25° C.) overnight, the solution is concentrated, then diluted with ether, filtered and evaporated to give a solid. This solid is redissolved in chloroform, diluted with ether and pentane to give .17 g. of 7-chloro-2-[[1-(merhoxycarbonyl)ethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([P:21](=[O:30])([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24])([P:11](=[O:20])([O:16][CH:17]([CH3:19])[CH3:18])[O:12][CH:13]([CH3:15])[CH3:14])[F:10])[CH:5]=[N:6][CH:7]=1.[CH3:31][C:32]1[C:36](B(O)O)=[C:35]([CH3:40])[O:34][N:33]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[CH3:31][C:32]1[C:36]([C:2]2[CH:3]=[C:4]([CH2:8][C:9]([P:21](=[O:30])([O:22][CH:23]([CH3:24])[CH3:25])[O:26][CH:27]([CH3:29])[CH3:28])([P:11](=[O:20])([O:16][CH:17]([CH3:18])[CH3:19])[O:12][CH:13]([CH3:15])[CH3:14])[F:10])[CH:5]=[N:6][CH:7]=2)=[C:35]([CH3:40])[O:34][N:33]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC(C)OP(=O)(OC(C)C)C(F)(Cc1cncc(Br)c1)P(=O)(OC(C)C)OC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1noc(C)c1-c1cncc(CC(F)(P(=O)(OC(C)C)OC(C)C)P(=O)(OC(C)C)OC(C)C)c1
Temperature: 80 °C
Reaction time: 36 h
Yield: 46.7 %

Procedure:
A sample of tetraisopropyl (2-(5-bromopyridin-3-yl)-1-fluoroethane-1,1-diyl)bis(phosphonate) (85 mg; 0.16 mmol), Pd(Ph3)4 (36.9 mg; 0.032 mmol) and (3,5-dimethylisoxazol-4-yl)boronic acid (34 mg; 0.24 mmol) are added in a vial, the vial is capped with a septum and added DME (4 mL) is added. The mixture is immediately flushed with argon, potassium carbonate solution (2.5 eq.) is added and flushed again with argon. The reaction mixture is stirred at 80° C. for 36 h under argon. The mixture is cooled, diluted with EtOAc and filtered through Celite™, the Celite™ is rinsed 3× with EtOAc/MeOH (1:1). The combined filtrate is concentrated under vacuum and deposited on silica gel. Purification by column chromatography on silica gel (pre washed with 1% NEt3 in hexanes) using a solvent gradient from hexanes to EtOAc, and then to 50% MeOH in EtOAc lead to the isolation of the product as a brown oil (41 mg; 47% yield).
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([C:11]([CH2:13][OH:14])=[O:12])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:15][CH2:16][C:17]3[C@@:23]([CH3:24])([C@H:5]1[CH2:4][CH2:3]2)[CH2:22][CH2:21][C:19](=[O:20])[CH:18]=3.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.[OH-].[K+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:14][CH2:13][C:11]([CH:10]1[C:2]2([CH3:1])[CH:7]([CH:6]3[CH:5]([CH2:4][CH2:3]2)[C:23]2([CH3:24])[C:17](=[CH:18][C:19](=[O:20])[CH2:21][CH2:22]2)[CH2:16][CH2:15]3)[CH2:8][CH2:9]1)=[O:12]
Reactant: BrCCCCCBr
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CC12CCC(=O)C=C1CCC1C2CCC2(C)C(C(=O)COCCCCCBr)CCC12
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
A mixture of 21-hydroxyprogesterone (200 mg, 0.605 mmol), 1,5-dibromopentane (1.65 mL, 12.1 mmol), 40% KOH (300 μL), and tetrabutylammonium hydroxide (60 μL) was stirred for 16 h at room temperature. The reaction mixture was diluted in dichloromethane and washed with water three times. The organic layer was dried over sodium sulfate and concentrated by rotary evaporation. The crude residue was purified by flash chromatography with hexanes/ethyl acetate (2:1) as the eluent to afford 7 as a colorless oil (125 mg, 43%). 1H NMR (500 MHz, CDCl3) δ 5.67 (s, 1H), 3.96 (q, J=17.2 Hz, 2H), 3.41 (t, J=6.4 Hz, 2H), 3.38-3.31 (m, 2H), 2.56 (t, J=9.1 Hz, 1H), 2.40-2.09 (m, 6H), 1.96 (m, 1H), 1.90-1.74 (m, 5H), 1.72-1.16 (m, 14H), 1.12 (s, 3H), 1.05-0.86 (m, 2H), 0.65-0.58 (m, 3H). 13C NMR (125 MHz, CDCl3) δ 207.55, 198.50, 169.94, 122.92, 75.79, 70.34, 61.56, 57.43, 55.12, 52.51, 43.53, 37.54, 34.61, 32.85, 31.74, 31.47, 30.82, 28.69, 27.74, 23.77, 23.47, 21.81, 19.97, 16.34, 12.55. ESI-MS m/z [M+H]+ observed: 481.1, calculated: 481.2.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[CH3:12][O:13][C:14]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:15]=1[C:16]([Cl:18])=[O:17].C(=O)([O-])[O-].[Na+].[Na+].O>C(Cl)(Cl)Cl>[ClH:18].[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:14]=1[O:13][CH3:12])[CH2:5]2
Reactant: NC1CN2CCC1CC2
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(C(=O)NC2CN3CCC2CC3)c(OC)c1
Yield: 23.7 %

Procedure:
A mixture of 3-aminoquinuclidine dihydrochloride, 6.95 g, (0.0349), 2,4-dimethoxybenzoyl chloride, 700 g, (0.0349 mole), anhydrous sodium carbonate, 36.99 g, (0.349 mole), 175 ml water, and 175 ml chloroform was stirred rapidly to achieve good mixing of the 2 layers for 20 hrs. The chloroform layer was then separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated to an impure oil. The oil was triturated twice with 20 ml portions of petroleum ether to remove some impurities. The oil was then dissolved in ether and filtered to remove a small amount of insoluble material. The filtrate was treated with ethereal hydrogen chloride and the resulting salt collected to yield 2.70 g (23.7% yield) white solid. The salt was recrystallized from ethanol-isopropyl ether. Further recrystallization from methanol-ethyl ether yielded a white solid, m.p. 211°-212° C. The NMR analysis was satisfactory.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:14][C:13]([NH2:15])=[N:12][C:11]2[C:7]=1[N:8]=[CH:9][N:10]=2.C([O-])([O-])=O.[K+].[K+].[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24]>CN(C=O)C.CCOC(C)=O>[NH2:15][C:13]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[CH2:24][CH2:23][C:22]([O:26][CH3:27])=[O:25])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:14]=1
Reactant: C=CC(=O)OC
Reactant: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCn1cnc2c(-c3ccco3)nc(N)nc21
Reaction time: 40 h
Yield: 11.4 %

Procedure:
A solution of 6-(2-furyl)-1H-purine-2-amine (0.70 g, 3.48 mmol) and K2CO3 (0.48 g, 3.48 mmol) in DMF (20 mL) was treated with methyl acrylate (3.3 g, 38.3 mmol), stirred for 40 h, diluted with EtOAc, filtered to remove polymeric acrylate, washed with water, dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2: EtOAc-heptane, (4:1)] to give the title compound (114 mg, 11%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11][CH:12]=[CH2:13])=[C:9]([OH:14])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].I[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:33]=[CH:32][C:23]2[CH2:24][CH2:25][CH:26]([C:28]([O:30][CH3:31])=[O:29])[O:27][C:22]=2[C:21]=1[CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[NH2:6][C:4]([C:3]1[CH:7]=[CH:8][C:9]([O:14][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:33]=[CH:32][C:23]3[CH2:24][CH2:25][CH:26]([C:28]([O:30][CH3:31])=[O:29])[O:27][C:22]=3[C:21]=2[CH2:34][CH2:35][CH3:36])=[C:10]([CH2:11][CH:12]=[CH2:13])[C:2]=1[OH:1])=[O:5]
Reactant: CCCc1c(OCCCI)ccc2c1OC(C(=O)OC)CC2
Reactant: C=CCc1c(O)ccc(C(N)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCc1c(OCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(C(N)=O)c1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound of Example 20 (550 mg, 2.89 mmol), the compound of Example 23 (1.21 g, 2.89 mmol), and potassium carbonate (800 mg, 5.78 mmol) were added to about 25 to 30 ml of DMF. The reaction mixture as stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and concentrated under vacuum. The crude material was chromatographed on silica gel with 30% ethyl acetate/hexane as eluant. The fractions containing the product were collected and the solvent was removed under vacuum to give the product as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[O:5][C:6]1[CH:7]([CH2:20][CH:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)[NH:8][C:9](=[O:19])[C:10]=1[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[CH3:18])[CH3:2].[NH2:28][C:29]#[N:30].C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C>C(Cl)Cl.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:1]([O:3][C:4](=[O:27])[O:5][C:6]1[CH:7]([CH2:20][CH:21]2[CH2:26][CH2:25][S:24](=[N:30][C:29]#[N:28])[CH2:23][CH2:22]2)[NH:8][C:9](=[O:19])[C:10]=1[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[CH3:18])[CH3:2]
Reactant: N#CN
Reactant: CCOC(=O)OC1=C(c2cc(C)ccc2C)C(=O)NC1CC1CCSCC1
Agent: [Rh+3]
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)OC1=C(c2cc(C)ccc2C)C(=O)NC1CC1CCS(=NC#N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of carbonic acid 4-(2,5-dimethyl-phenyl)-5-oxo-2-(tetrahydro-thiopyran-4-ylmethyl)-2,5-dihydro-1H-pyrrol-3-yl ester ethyl ester (compound P1.2) (184 mg, 0.47 mmol), NH2CN (40 mg, 0.95 mmol), (diacetoxyiodo)benzene (247 mg, 0.76 mmol), MgO (75 mg, 1.87 mmol) and rhodium acetate (10 mg, 0.02 mmol) in 10 ml of CH2Cl2 was stirred at room temperature for 2 h. Then, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by chromatography on silica gel. Yield: 110 mg of carbonic acid 2-(1-cyanoimino-hexahydro-1λ4-thiopyran-4-ylmethyl)-4-(2,5-dimethyl-phenyl)-5-oxo-2,5-dihydro-1H-pyrrol-3-yl ester ethyl ester (title compound P1.9) as a solid, mp 103-105° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:8][C:9]2[CH:10]=[C:11]([O:31][C:32]3[C:33]([CH3:38])=[N:34][CH:35]=[CH:36][CH:37]=3)[C:12]([NH:15][C:16]3[S:20][N:19]=[C:18]([C@H:21]4[CH2:25][O:24]C5(CCCCC5)[O:22]4)[N:17]=3)=[N:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[ClH:39]>C(O)C>[ClH:39].[CH3:1][C:2]1[C:3]([S:8][C:9]2[CH:10]=[C:11]([O:31][C:32]3[C:33]([CH3:38])=[N:34][CH:35]=[CH:36][CH:37]=3)[C:12]([NH:15][C:16]3[S:20][N:19]=[C:18]([C@H:21]([OH:22])[CH2:25][OH:24])[N:17]=3)=[N:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1Sc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Agent: Cl
Solvent: CCO
Product: Cc1cccnc1Sc1cnc(Nc2nc([C@H](O)CO)ns2)c(Oc2cccnc2C)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a solution of (S)—N-(5-(3-methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.565 g, 1.03 mmol) in ethanol (25 mL) was added an aqueous solution of 6N HCl (2 mL) The reaction was heated at 80° C. for 2 hours, cooled to ambient temperature, stirred for 30 minutes, then cooled at 0° C. for an hour. The reaction was filtered, washed with cold ethanol, hexanes, and dried to afford (S)-1-(5-(5-(3-methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol hydrochloride (0.450 g, 0.891 mmol, 86.5% yield) as white crystals. Mass Spectrum (apci) m/z=469.1 (M+H−HCl).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[CH3:11][C@@H:12]([NH:22][CH2:23][C@H:24]([OH:35])[C:25]1[CH:26]=[CH:27][C:28]([OH:34])=[C:29]([NH:31][CH:32]=[O:33])[CH:30]=1)[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1.NC1C=C([C@@H](O)CN[C@H](C)CC2C=CC(OC)=CC=2)C=CC=1O>CO>[CH3:11][C@@H:12]([NH:22][CH2:23][C@H:24]([OH:35])[C:25]1[CH:26]=[CH:27][C:28]([OH:34])=[C:29]([NH:31][CH:32]=[O:33])[CH:30]=1)[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1.[C:6]([C@@H:4]([C@H:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([O-:8])=[O:7]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: COc1ccc(C[C@@H](C)NC[C@H](O)c2ccc(O)c(N)c2)cc1
Agent: COc1ccc(C[C@@H](C)NC[C@H](O)c2ccc(O)c(NC=O)c2)cc1
Solvent: CO
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A solution containing 3.9 g (26 mmol) of L-tartaric acid and 36 mL of methanol was added to a solution of 9 g (26 mmol) of arformoterol base and 144 mL methanol at 23° C. Afterwards, the resulting mixture was seeded with form D and stirred at 23° C. for 1 hour. It was then further cooled to 0-5° C. for 1 hour and the product collected by filtration and dried under inlet air (atmospheric pressure) for 16 hours to provide 11.1 g (86% yield) (99.7% chemical purity, containing 0.14% of the degradation impurity (R)-1-(3-amino-4-hydroxyphenyl)-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethanol) of (R,R)-formoterol L-tartrate form D, as an off white powder. 1H-NMR (200 MHz, d6-DMSO) δ: 1.03 (d, 3H); 2.50-2.67 (m, 5H); 3.72 (s, 3H); 3.99 (s, 2H); 4.65-4.85 (m, 1H); 6.82-7.15 (m, 5H); 8.02 (s, 1H); 8.28 (s, 1H); 9.60 (s, NH). No residual solvent was detected (1H-NMR).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][S:18]([NH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([S:32](Cl)(=[O:34])=[O:33])[CH:30]=2)[C:25]([N:36]=[N:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]#[N:45])=[CH:24][CH:23]=1)(=[O:20])=[O:19].Cl>O.CC(C)=O>[CH3:17][S:18]([NH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([S:32](=[O:34])(=[O:33])[NH:1][C:2]3[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][CH:3]=3)[CH:30]=2)[C:25]([N:36]=[N:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]#[N:45])=[CH:24][CH:23]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Nc1ccc(N=Nc2ccccc2C#N)c2ccc(S(=O)(=O)Cl)cc12
Reactant: Nc1ccc(S(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CS(=O)(=O)Nc1ccc(N=Nc2ccccc2C#N)c2ccc(S(=O)(=O)Nc3ccc(S(=O)O)cc3)cc12
Reaction time: 1 h

Procedure:
To a solution of 52.5 g of p-aminobenzene sulphinic acid and 96 g of potassium carbonate in 850 ml of water first 1 l of acetone was added and then portionwise 157 g of compound P with stirring. Thereupon, the mixture was stirred for 1 h, poured into 2.5 l of water and acidified with 100 ml of concentrated hydrochloric acid. The precipitate formed was sucked off, washed with methanol and dried. Yield: 160 g.
Reaction SMILES: [NH:1]([CH:19]=O)[C@H:2]([C:15]([O:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.CO.Br.C(O)(=O)C.C([O-])(O)=O.[Na+]>C1COCC1>[NH:1]([CH3:19])[C@H:2]([C:15]([O:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:5]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)NC=O
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CN[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)OC
Reaction time: 0.33 h
Yield: 89.7 %

Procedure:
To a solution of N-formyl-Tyr(3-tBu)-OMe (23.8 g, 85.3 mmol) in THF (400 ml), 1.0M borane-THF complex (170 ml) was added dropwise under cooling with ice over 30 min. The mixture was stirred for 20 min., mixed with methanol (50 ml) and further stirred for 30 min. The reaction mixture was mixed with 33% hydrobromic acid/acetic acid (31 ml) and stirred for 2 hours. The mixture was neutralized by saturated aqueous NaHCO3 under cooling with ice and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol=20:1), giving N-Me-Tyr(3-tBu)-OMe (20.3 g, 90%).