Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:15]=O>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH3:15])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Reactant: C=O
Solvent: O=CO
Product: CN1CCC(O)(c2cc(F)cc(F)c2)C1
Reaction time: 5 h

Procedure:
Preparation according to Example 11: Enantiomer E2 of 3-(3,5-difluorophenyl)-pyrrolidin-3-ol (0.29 g, 1.45 mmol), formic acid (3.8 mL), aqueous formaldehyde (40%, 3.4 mL). 65° C. for 5 h. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 10:1). Yield: 0.19 g. [α]D=−22.8° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 134-135° C.; MS m/z (relative intensity, 70 eV) 213 (M+, 15), 57.1 (bp), 58.1 (31), 113 (13), 127 (11), 141 (11).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:29][C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[CH:27][C:26](=O)[O:25]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:37]=[CH:36][CH:35]=[C:32]([C:33]#[N:34])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as a light yellow foam (239 mg).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[SH:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>CCO>[S:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[S:16][CH2:3][C@H:2]([OH:1])[CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1CO1
Reactant: Sc1nc2ccccc2s1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1C[C@@H](O)CSc1nc2ccccc2s1
Yield: 58.4 %

Procedure:
A suspension of compound N-[(2R)-oxiran-2-ylmethyl]-phthalimide (21.1 g, 104 mmol) and 2-mercaptobenzothiazole (17.4 g, 104 mmol) in EtOH (600 mL) was heated to reflux for 16.5 h. The reaction was then cooled and concentrated under reduced pressure. The crude mixture was crystallized from ethanol and filtered to provide N-[(2R)-3-(1,3-benzothiazol-2-ylthio)-2-hydroxypropyl]-phthalimide (22.5 g, 59%) as a yellow solid. Data for N-[(2R)-3-(1,3-benzothiazol-2-ylthio)-2-hydroxypropyl]-phthalimide: 1H NMR (300 MHz, CDCl3) δ 7.88 (m, 2H), 7.75 (m, 4H), 7.45-7.26 (m, 2H), 5.18 (m, 1H), 4.42 (m, 1H), 4.08-3.88 (m, 2H), 3.61 (m, 1H), 3.42 (m, 1H).
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1.C[O-:25].[Na+].Cl>CO.O>[O:25]=[C:3]1[NH:8][C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]=2[N:5]=[N:4]1
Reactant: C[O-]
Reactant: CCCOc1ccccc1-c1nc2nc(SC)nnc2c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCOc1ccccc1-c1nc2[nH]c(=O)nnc2c(=O)[nH]1
Yield: 92.4 %

Procedure:
A stirred mixture of 3-methylthio-8-oxo-6-(2-propoxyphenyl)-7,8-dihydropyrimido[4,5-e][1,2,4]triazine (0.5 g) and sodium methoxide (prepared from sodium, 0.17 g. and methanol) in methanol (50 ml) was heated under reflux for 3 hours. The cooled reaction mixture was evaporated under reduced pressure to afford a yellow solid which was dissolved in water and acidified with 2 Normal hydrochloric acid to yield a yellow solid (420 mg) which was recrystallized from dimethylformamide to afford the title compound, 0.16 g, m.p. 296-299° C.
Reaction SMILES: C([O:5][C:6](=[O:30])[C@@H:7]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:20]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:10]1=[O:29])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:28][C:27]1[C:20]2[C:19]([CH2:18][N:11]3[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:9]([C@@H:7]([CH3:8])[C:6]([OH:30])=[O:5])[C:10]3=[O:29])=[CH:23][S:22][C:21]=2[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1cccc2scc(Cn3c(=O)n([C@@H](C)C(=O)OC(C)(C)C)c4ccccc43)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2scc(Cn3c(=O)n([C@@H](C)C(=O)O)c4ccccc43)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
To a solution of (S)-2-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid tert-butyl ester (0.12 g, 0.28 mmol) in CH2Cl2 (5 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 3 h. When the reaction was complete, the reaction mixture was diluted with CH2Cl2 and washed with water. The organic phase was dried over Na2SO4 and concentrated. When a small amount of CH2Cl2 (˜3 mL) was added to the resulting residue, a white solid came out of the solution. This solid was filtered and dried to afford 69 mg (66%) of the titled compound. LCMS (ESMS): m/z 367.23 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>CCO>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C1CCNC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(N2CCCC2)nc1
Temperature: 70 °C
Yield: 78.1 %

Procedure:
To a slurry of 2-chloro-5-nitropyridine (10 g, 63.1 mmol) in EtOH (100 mL) at room temperature was added pyrrolidine (15.72 mL, 189 mmol) and the mixture was heated at 70° C. for 18 hours. The cooled solution was concentrated in vacuo and the residue partitioned between CH2Cl2 and 1 M NaOH. The organic layer was dried (Na2SO4), filtered and solvent removed in vacuo to give title compound (9.52 g, 78%). MS (ESI) m/z 194 (M+H)+.
Reaction SMILES: C(O)(=O)C.I[CH:6]([CH2:17][C:18]([F:30])([F:29])[C:19]([F:28])([F:27])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16]>C(O)C.[Zn]>[F:25][C:20]([F:26])([C:21]([F:22])([F:23])[F:24])[C:19]([F:27])([F:28])[C:18]([F:30])([F:29])[CH2:17][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16]
Reactant: OCCCCCCCCCC(I)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: OCCCCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
To a slurry of 130.0 g of zinc powder in 500 mL of ethanol was added 5.0 g of acetic acid. A solution of 230.0 g of the crude 10-iodo-11-(nonafluorobutyl)-1-undecanol prepared above in 100 mL of ethanol was added dropwise with stirring over 1 hr. Then, the reaction mixture was heated at 50° C. for 4 hr. The mixture was filtered, and the filtrate was concentrated to a viscous, light yellow liquid. Bulb-to-bulb distillation of the liquid, in several portions, provided 97.3 g of 11-(nonafluorobutyl)-1-undecanol as a colorless solid, b.p. 160-200° C. at 0.05 torr (7 Pa).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:15]([O-])=O)=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH4+].[Cl-]>CO.O.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[NH2:15]
Reactant: O=[N+]([O-])c1c(Cl)cccc1Nc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1c(Cl)cccc1Nc1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of (3-chloro-2-nitrophenyl)phenylamine (0.0109 mol) in MeOH (150 mL) and water (50 mL) were added NH4Cl (3.51 g, 0.0656 mol) and iron powder (2.45 g, 0.0438 mol) and the reaction mixture was heated to reflux temperature for 3 h. After cooling to RT, the solid was filtered through a pad of Celite® and washed with additional MeOH. The filtrate was concentrated in vacuo and then partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo affording 3-Chloro-N1-phenylbenzene-1,2-diamine as a light brown solid (2.61 g, quantitative). LCMS: RT 3.72 min [M+H]+ 219.0
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2Br)[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1B(O)O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(COC)OC.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>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:33]2[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:32]=2[O:31][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=1)[CH3:2]
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Reactant: CCOC(=O)c1cccc(C2=C(Br)CCC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)c1cccc(C2=C(c3cc(Cl)ccc3OCc3ccccc3)CCC2)c1
Yield: 39.3 %

Procedure:
3-(2-Bromocyclopent-1-enyl)-benzoic acid ethyl ester (148 mg, 0.5 mmol), tetrakis(triphenylphosphine)palladium (0) (30 mg), potassium carbonate (0.20 g) and (2-benzyloxy-5-chlorophenyl) boronic acid (150 mg, 0.5 mmol) in dimethoxyethane (5 mL) were refluxed for 17 h under nitrogen. The reaction mixture was then filtered through Kieselguhr and evaporated down to an oil. Purification was carried out on a Water's separation pack (10 g) with dichloromethane/iso-hexane to give the product (85 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C@@H:8]([NH:11][C:12]([C:14]2[C:15]3[CH:22]=[N:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:16]=3[CH:17]=[N:18][CH:19]=2)=[O:13])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:2]2[CH:7]=[C:6]([C@@H:8]([NH:11][C:12]([C:14]3[C:15]4[CH:22]=[N:21][N:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[C:16]=4[CH:17]=[N:18][CH:19]=3)=[O:13])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=2)[CH2:33][CH2:32]1
Reactant: CN1CCNCC1
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(Br)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(N2CCN(C)CC2)c1
Reaction time: 4 h

Procedure:
A microwave vessel charged with 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-bromopyridin-4-yl)-propyl]-amide (0.05 g, 0.11 mmol), 1-methylpiperazine (33.1 mg, 0.33 mmol) and DIPEA (115 μL, 0.66 mmol) in 1-butanol (1.5 mL) was irradiated at 200° C. After 4 hours, the reaction was cooled, evaporated to dryness and the residue was purified with reverse phase liquid chromatography to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@@H:5]1[C@:22]2([CH3:23])[C:8]([C:9]3[CH2:10][CH2:11][CH:12]4[C@:17]([C:19]=3[CH2:20][CH2:21]2)([CH3:18])[CH2:16][CH2:15][C@H:14]([OH:24])[C:13]4([CH3:26])[CH3:25])=[CH:7][CH2:6]1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].N1C=CN=C1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@@H:5]1[C@:22]2([CH3:23])[C:8]([C:9]3[CH2:10][CH2:11][CH:12]4[C@:17]([C:19]=3[CH2:20][CH2:21]2)([CH3:18])[CH2:16][CH2:15][C@H:14]([O:24][Si:28]([CH3:30])([CH3:29])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:13]4([CH3:26])[CH3:25])=[CH:7][CH2:6]1
Reactant: COC(=O)C[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)C[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)C1CC3
Temperature: 0 °C
Yield: 103.8 %

Procedure:
92 g of 4,4-dimethyl-3β-hydroxypregna-8,14-dien-21-oic acid methyl ester is stirred with 0.75 liter of N,N-dimethylformamide, 51 g of tert-butyldimethylsilyl chloride and 27.8 g of imidazole for 18 hours at 70° C. After cooling, it is poured into 10 liters of an ice-cold 0.5 molar aqueous hydrochloric acid and filtered. The filter cake is taken up in ethyl acetate, washed neutral with 1N sodium hydroxide solution, dried on sodium sulfate, filtered and concentrated by evaporation. 124.8 g of 4,4-dimethyl-3β-[[dimethyl(1,1-dimethylethyl)silyl]oxy]pregna-8,14-dien-21-oic acid methyl ester is obtained, which is further used without purification.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][C:4]([C:6]1[N:7]=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=12)=[O:5].[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][C:4]([C:6]1[N:7]=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]=12)=[O:5].[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]
Reactant: CC(C)(C)CC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC(=O)c1nc(-c2ccccc2)n2c1CNCC2
Reaction time: 2 h

Procedure:
Intermediate 26B (0.08 g, 0.20 mmol) was dissolved in DCM and TFA was added. The resulting mixture was stirred for 2 hours. The mixture was concentrated, diluted with water and acetonitrile and lyophilized to produce the desired product as a TFA salt. The residue was dissolved in methanol and filtered through a SPE SCX tube column, eluting with 2N ammonia in methanol to provide Compound 291 (0.055 g, 90%) as a free base. 1H-NMR (400 MHz, CD3OD) δ: 1.05 (s, 9H), 2.87 (s, 2H), 3.15 (t, 2H), 4.07 (t, 2H), 4.35 (s, 2H), 7.52 (m, 3H), 7.67 9 m, 2H); LCMS (+ESI) m/z 298.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[Mg].[C:11]([N:18]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[Cl-].[NH4+]>O1CCCC1>[F:9][C:4]1[CH:3]=[C:2]([C:20]2([OH:23])[CH2:21][CH2:22][N:18]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:19]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)cc(F)c2)C1
Temperature: 25 °C
Yield: 104.6 %

Procedure:
To a solution of 1-bromo-3,5-difluorobenzene (3.13 g, 16.2 mmol) in dry tetrahydro-furan (40 mL), under nitrogen, was added magnesium turnings (0.39 g, 16.2 mmol). The mixture was refluxed for 1 h, cooled to ambient temperature and a solution of 1-N-boc-3-pyrrolidinone (2.0 g, 10.8 mmol) in dry tetrahydrofuran (10 mL) was added drop wise. The resulting mixture was refluxed 1 h, cooled to ambient temperature, aqueous saturated ammonium chloride solution (40 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phase was dried (MgSO4), filtered and evaporated to give the title compound (3.38 g). MS m/z (rel. intensity, 70 eV) 299 (M+, 1), 243 (42), 198 (49), 168 (31), 127 (28), 57 (bp).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:22](=[O:23])[C:21]3[S:24][CH:25]=[CH:26][C:20]=3[NH:19][C:18]2=[O:27])[CH2:11][CH2:10]1.Br[CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C)C=O>[CH2:36]([O:35][C:33]([CH2:32][CH2:31][CH2:30][CH2:29][N:19]1[C:20]2[CH:26]=[CH:25][S:24][C:21]=2[C:22](=[O:23])[N:17]([CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:14][CH2:13]2)[C:18]1=[O:27])=[O:34])[CH3:37]
Reactant: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3ccsc3c2=O)CC1
Reactant: CCOC(=O)CCCCBr
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCn1c(=O)n(CCN2CCN(c3ccccc3OC)CC2)c(=O)c2sccc21
Yield: 82 %

Procedure:
The title compound was produced following the procedure of Example 13 using dimethylformamide as solvent, the thienopyrimidine-2,4-dione (3.0 g, 7.76 mmol) from Example 19, and ethyl 5-bromovalerate was used as the alkylating agent. The title compound was isolated in 82% yield (3.3 g), after recrystallization from EtOH, mp 118°-119° C.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:8]=2[C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][O:17][C:18]1[CH:32]=[CH:31][C:21]([CH2:22][N:23]2[C:27]([C:28](Cl)=[O:29])=[N:26][N:25]=[N:24]2)=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:9]([C:8]1[C:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:14][CH:13]=[CH:12][C:11]=1[NH:15][C:28]([C:27]1[N:23]([CH2:22][C:21]2[CH:31]=[CH:32][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[N:24]=[N:25][N:26]=1)=[O:29])#[N:10]
Reactant: N#Cc1c(N)cccc1N1CCCCC1
Reactant: COc1ccc(Cn2nnnc2C(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(Cn2nnnc2C(=O)Nc2cccc(N3CCCCC3)c2C#N)cc1

Procedure:
The N-[2-cyano-3-(1-piperidinyl)phenyl]-1-(4-methoxyphenylmethyl)-1H-tetrazole-5-carboxamide was prepared in the usual manner as illustrated in Example I from 2-(1-piperidinyl)-6-aminobenzonitrile and 1-p-methoxybenzyl-5-tetrazolecarbonylchloride in the presence of pyridine. The product was recrystallized from acetonitrile, m.p. 166°-168° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:5](=[N:16][N:17]([CH3:19])[N:18]=2)[NH:6][C:7]2[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:8]=2[N:9]=1.CS(C)=O.[CH3:24][N:25]1[CH2:30][CH2:29]N[CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[Cl:14][C:12]1[C:11]([Cl:15])=[CH:10][C:8]2[N:9]=[C:3]([N:2]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[C:4]3[C:5](=[N:16][N:17]([CH3:19])[N:18]=3)[NH:6][C:7]=2[CH:13]=1
Reactant: Cn1nc2c(n1)C(N)=Nc1cc(Cl)c(Cl)cc1N2
Reactant: CN1CCNCC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CN1CCN(C2=Nc3cc(Cl)c(Cl)cc3Nc3nn(C)nc32)CC1
Temperature: 125 °C

Procedure:
10-Amino-6,7-dichloro-2-methyl-2,4-dihydro-1,2,3-triazolo[4,5-b][1,5]benzodiazepine hydrochloride (0.84 g) was added to a mixture of dry dimethylsulphoxide (5 ml), toluene (5 m) and N-methylpiperazine (1 ml), which had been purged with nitrogen for 20 minutes. The stirred solution was then heated at 125° C. (oil bath) under nitrogen for 16 hours, cooled to room temperature, and distilled water (10 ml) added, keeping the temperature below 25° C. After stirring at 5° C. for half an hour, the suspension obtained was filtered off and dried at 70° C. under reduced pressure to leave a yellow-brown solid which was recrystallised from ethyl acetate/n-hexane to give a yellow crystalline solid, melting point 217.5°-218.5° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6]C)=O.[CH3:10][O:11][CH2:12][CH2:13][NH2:14]>>[OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([NH:14][CH2:13][CH2:12][O:11][CH3:10])=[O:6]
Reactant: COC(=O)C(C)(C)CO
Reactant: COCCN
Product: COCCNC(=O)C(C)(C)CO
Yield: 100 %

Procedure:
Prepared as in Example 197d (Method A) from methyl 3-hydroxy-2,2-dimethylpropanoate and 2-methoxyethanamine in 100% yield. MS 30 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:12][CH2:13][CH2:14][O:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[N:10][CH:11]=1.C(N(CC)CC)C>ClCCl>[C:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([S:12][CH2:13][CH2:14][O:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[N:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(SCCOC(=O)c2cccc(Cl)c2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(SCCOC(=O)c2cccc(Cl)c2)nc1
Reaction time: 16 h

Procedure:
A mixture of 2-[(5-nitro-2-pyridinyl)thio]ethyl 3-chlorobenzoate (5) (0.24 g, 0.71 mmol) and 10% Pd/C (0.10 g) in toluene or methanol was agitated under a hydrogen atmosphere (40 PSI) for 1 h. The reaction mixture was filtered through Celite® and concentrated to give 2-[(5-amino-2-pyridinyl)thio]ethyl-3-chlorobenzoate (51), LCMS: purity: 99%; MS (m/e): 309 (MH+), which was used without further purification. Acetyl chloride (4.6 μL, 0.064 mmol) was added to a room temperature solution of 2-[(5-amino-2-pyridinyl)thio]ethyl-3-chlorobenzoate (51) (18.9 mg, 0.061 mmol) and triethylamine (18 μL, 0.13 mmol) in anhydrous dichloromethane (1.0 mL), After 16 h, the reaction mixture was diluted with dichloromethane and washed with 1N HCl and brine and then dried over anhydrous MgSO4. Purification by silica gel chromatography provided 2-[(5-acetylamino-2-pyridinyl)thio]ethyl-3-chlorobenzoate (52), LCMS: purity: 99%; MS (m/e): 351 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][C@@H:19]([CH3:21])[C@@H:18](CS([O-])(=O)=O)[C@@H:17]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:42]=[N+:43]=[N-:44].[Na+]>CN(C=O)C>[N:42]([C@H:18]1[C@@H:19]([CH3:21])[CH2:20][N:15]([C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:8]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:16][C@H:17]1[NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
To a solution of (3R,4R,5S)-1-(3-(bis(tert-butoxycarbonyl)amino)pyridin-4-yl)-3-((tert-butoxycarbonyl)amino)-5-methylpiperidin-4-ylmethanesulfonate (1.0 equiv.) in DMF (0.13 M) was added NaN3 (5.0 equiv.). The solution was submerged in an 80° C. oil bath and left stirring under Ar for 24 hrs. The solution was cooled to rt and left stirring under Ar overnight. The solution was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat.), NaCl(sat.), dried over MgSO4, filtered, concentrated to yield tert-butyl (4-((3R,4S,5S)-4-azido-3-((tert-butoxycarbonyl)amino)-5-methylpiperidin-1-yl)pyridin-3-yl)(tert-butoxycarbonyl)carbamate in 60% yield. LC/MS (m/z)=548.4 (MH+), Rt=0.94 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 0.97-1.13 (m, 3H), 1.33-1.52 (m, 30H), 2.03-2.19 (m, 1H), 2.66-2.87 (m, 2H), 3.16 (dd, J=12.72, 2.15 Hz, 1H), 3.22-3.32 (m, 1H), 3.81-4.01 (m, 2H), 4.78 (d, J=9.00 Hz, 1H), 6.76-6.88 (m, 1H), 8.05-8.18 (m, 1H), 8.26-8.37 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[C:18]4[NH:22][C:21](=[O:23])[NH:20][C:19]4=[O:24])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[H][H]>O.C(O)C.[Pd]>[O:23]=[C:21]1[NH:22][CH:18]([CH2:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][CH:9]=[C:8]3[CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[C:19](=[O:24])[NH:20]1
Reactant: [H][H]
Reactant: CN1CC=C(c2c[nH]c3ccc(C=C4NC(=O)NC4=O)cc23)CC1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CN1CCC(c2c[nH]c3ccc(CC4NC(=O)NC4=O)cc23)CC1
Yield: 98.8 %

Procedure:
The product from step (c) (2.4 g) was suspended in a mixture of water (100 ml) and ethanol (200 ml) and 10% w/w Pd/C (0.25 g) added. The mixture was stirred under 1 atmos. pressure of hydrogen for 17 hours when uptake was complete. The mixture was filtered through Hyflo and the filtrate evaporated in vacuo to give the desired product as a colourless solid (2.4 g).