Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.C[O:4][C:5]([C:7]1[N:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:19])([F:18])[CH3:17])[O:10][CH:11]=1)=[O:6].[OH-].[Na+]>C1COCC1.Cl>[F:19][C:16]([F:18])([CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12][C:9]1[O:10][CH:11]=[C:7]([C:5]([OH:6])=[O:4])[N:8]=1
Reactant: COC(=O)c1coc(CCCCC(C)(F)F)n1
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(F)(F)CCCCc1nc(C(=O)O)co1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(5,5-difluoro-hexyl)-oxazole-4-carboxylic acid methyl ester (320 mg, 1.29 mmol) in THF (13 mL) was treated at rt with 1N NaOH (6.5 mL, 6.5 mmol) and the reaction mixture was stirred for 1.5 h at rt. The reaction mixture was poured in 1N HCl (13 mL) and extracted twice with EA (2×20 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a brown solid. LC-MS-conditions 02: tR=0.84 min, [M+H]+=234.45.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][P:8]([CH3:12])(=[O:11])[O:9][CH3:10].C[O:14][C:15](=O)[CH2:16][CH2:17][CH:18]=[C:19]([Cl:21])[CH3:20].C(O)(=O)C>O1CCCC1>[CH3:6][O:7][P:8]([CH2:12][C:15](=[O:14])[CH2:16][CH2:17][CH:18]=[C:19]([Cl:21])[CH3:20])(=[O:11])[O:9][CH3:10]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)CCC=C(C)Cl
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CCC=C(C)Cl)OC
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
21.8 ml of n-butyllithium solution (2.2M in hexane) are added dropwise at -65° C. to a solution of 5.58 g of methanephosphonic acid dimethyl ester in 160 ml of absolute tetrahydrofuran and the mixture is stirred at that temperature for 15 minutes. A solution of 4.05 g of the methyl ester obtained in Example (6d) in 10 ml of tetrahydrofuran is then added and the mixture is stirred at -65° C. for 1 hour. The solution is heated to -10° C., 2.80 ml of acetic acid are added and the mixture is concentrated. The residue is partitioned between ethene and water, the ether phase is separated, dried over magnesium sulphate and concentrated in vacuo. The residue is then purified by ball-tube distillation. 4.23 g of the title compound are obtained (bath temperature 180°-185° C., 1.5 torr).
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Li][C:11](C)(C)[CH3:12].BrCC>C1COCC1.CCOC(C)=O>[CH2:11]([C:2]1[S:1][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1)[CH3:12]
Reactant: [Li]C(C)(C)C
Reactant: c1cnc2sccc2c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCBr
Product: CCc1cc2cccnc2s1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
To a solution of thieno[2,3-b]pyridine (0.35 g, 2.6 mmoles) prepared according to well known methods [see, Klemm, et al. (1969) J. Org. Chem., 34:347-354; see, also U.S. Pat. Nos. 5,026,700, 4,577,014, 4,406,898, 4,375,544, 4,311,845, and 4,161,599] in THF (10 ml) at -78° C. was added t-BuLi (1.7 M, 2.0 ml, 3.4 mmoles). The reaction solution was slowly warmed to -30° C. over a 45 minute period followed by the addition of bromoethane (0.25 ml, 3.4 mmoles). The solution was stirred 2 hours at ambient temperature then diluted with EtOAc (50 ml) and washed with H2O (75 ml). The organic phase was dried (MgSO4), filtered and concentrated to collect 0.41 g (97%) of the title compound as an orange-brown oil.
Reaction SMILES: [OH:1][C:2]1[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][C:3]=1[CH2:4][NH2:5].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH:18](=[N:5][CH2:4][C:3]1[CH:6]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=[C:9]([C:10]([CH3:11])([CH3:13])[CH3:12])[C:2]=1[OH:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)c1cc(CN)c(O)c(C(C)(C)C)c1
Solvent: CO
Product: CC(C)(C)c1cc(CN=Cc2ccccc2)c(O)c(C(C)(C)C)c1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-hydroxy-3,5,di-t-butylbenzylamine (prepared by the procedure described by G. E. Stokker, et al.; J. Med. Chem. 1980, 23, 1414; 2.35 g, 10.0 mmol) is prepared in 50 mL methanol. Benzaldehyde (1.06 g, 10.0 mmol) is added, and the resulting solution is stirred for 30 minutes. Product crystallizes upon cooling the solution to −40° C.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=S)[CH:2]=[CH2:3].[I-].ClC1C=CC=C[N+]=1C>C(N(CC)CC)C>[CH2:1]([N:4]=[C:5]=[N:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCNC(=S)Nc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Product: C=CCN=C=Nc1ccccc1

Procedure:
0.77 g of N-allyl-N'-phenylthiourea, 0.97 g of triethylamine und 1.2 g of 2-chloro-1-methylpyridinium iodide are reacted and worked up as described in Example 4. The product is obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH:3][CH:4]=[O:5].[OH-:14].[Na+]>C(O)C.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][C:2]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH:3][C:4]([OH:14])=[O:5]
Reactant: [OH-]
Reactant: CC(C=Cc1ccccc1)=CC=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C=Cc1ccccc1)=CC(=O)O
Reaction time: 5 h
Yield: 14.7 %

Procedure:
To a stirred solution of 3-methyl-5-phenyl-2,4-pentadienal (16.5 g) in ethanol (330 mL) was added dropwise a solution of silver nitrate (19.28 g) in water (160 mL) followed by dropwise addition of an aqueous sodium hydroxide (25 g, 80 mL) solution. The resulting mixture was allowed to stir for an additional five hours and then filtered. The solid was washed with ethanol. The combined filtrate was concentrated in vacuum. The residue was dissolved in water (200 mL). The aqueous solution was extracted with ether (300 mL) twice and acidified with 6 N hydrochloric acid (74 mL). The solid formed was filtered and recrystallized from methanol (40 mL) to yield 2.65 g of the desired 3-methyl-5-phenyl-2,4-pentadienoic acid. 1H NMR (acetone-d6, 300 MHz), δ(ppm) 7.60 (d, 2H), 7.35 (m, 3H), 7.06 (m, 2H), 6.02 (broad s, 1H), 2.50 (s, 3H).
Reaction SMILES: [CH2:1]([NH:5][CH3:6])[CH2:2][CH2:3][CH3:4].[Cl:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:1]([N:5]([CH3:6])[S:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][Cl:7])(=[O:15])=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC
Reactant: O=S(=O)(Cl)CCCCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCN(C)S(=O)(=O)CCCCCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.47 ml of N-butylmethylamine were added under an inert gas atmosphere to a solution of 410 mg of 5-chloropentane sulfonyl chloride in 10 ml of methylene chloride. The temperature rose from 13° C. to 26° C., and then after cooling to 0° to 5° C., 0.55 ml of triethylamine were added. The mixture was stirred at ambient temperature for 2 hours and the reaction medium was poured into an aqueous solution of 1M hydrochloric acid, extracted with methylene chloride, washed with water, then with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness under reduced pressure to obtain 486 mg of the expected product.
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:4][C:3]=1[CH2:12][C:13]1[C:14]([O:44][CH3:45])=[CH:15][C:16]([O:42][CH3:43])=[C:17]([C@@H:19]2[O:36][C@H:35]([CH2:37][O:38]COC)[C@@H:30]([O:31]COC)[C@H:25]([O:26]COC)[C@H:20]2[O:21]COC)[CH:18]=1.O>CO>[CH:2]1[C:11]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:4][C:3]=1[CH2:12][C:13]1[C:14]([O:44][CH3:45])=[CH:15][C:16]([O:42][CH3:43])=[C:17]([C@@H:19]2[O:36][C@H:35]([CH2:37][OH:38])[C@@H:30]([OH:31])[C@H:25]([OH:26])[C@H:20]2[OH:21])[CH:18]=1
Reactant: COCOC[C@H]1O[C@@H](c2cc(Cc3cc4cccccc-4c3)c(OC)cc2OC)[C@H](OCOC)[C@@H](OCOC)[C@@H]1OCOC
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1cc(OC)c([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1cc2cccccc-2c1
Yield: 31.1 %

Procedure:
10% aqueous solution of hydrochloric acid (0.5 ml) was added to a solution of (1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2,4-dimethoxyphenyl]-2,3,4,6-tetrakis-O-(methoxymethyl)-D-glucitol (0.09 g) in methanol (2.0 ml) and the mixture was refluxed with heating for 30 minutes. The reaction mixture was poured into ice-cooled water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain (1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2,4-dimethoxyphenyl]-D-glucitol (0.02 g).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[CH2:15][CH2:14]2.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[CH2:15][CH2:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1CCc2cc(O)ccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccc2c(c1)CCC2=O)c1ccccc1
Reaction time: 8 h

Procedure:
Benzoyl chloride (126.9 g, 0.900 mol) was added slowly to a stirred mixture of the product of Step A (121 g, 0.818 mol), triethylamine (99.1 g, 0.982 mol) and catalytic amount of DMAP (1 g, 8.18 mmol) in dichloromethane (1 L) at rt under nitrogen. The mixture was stirred overnight and diluted with dichloromethane (1 L). Then the solution was washed with water, hydrochloric acid (0.5 M, 2×1 L), and brine. The organic layer was dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The residue was dried in vacuo to give the compound. 1H-NMR (400 MHz, CDCl3): δ 8.19-8.22 (m, 2H), 7.83 (d, J=8.1 Hz, 1H), 7.65-7.69 (m, 1H), 7.52-7.55 (m, 2H), 7.37 (s, 1H), 7.22 (dd, J=8.1 Hz, J=2.0 Hz, 1H), 3.17-3.20 (m, 2H), 2.73-2.76 (m, 2H) ppm.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]1[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[C:4]1([CH3:16])[CH3:15].Cl>CO.[Pd]>[CH3:1][N:2]([CH3:17])[CH:3]1[CH2:7][CH2:6][NH:5][C:4]1([CH3:16])[CH3:15]
Reactant: CN(C)C1CCN(Cc2ccccc2)C1(C)C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)C1CCNC1(C)C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a solution of racemic N,N,2,2-tetramethyl-1-(phenylmethyl)-3-pyrrolidinamine (0.5637 g, 2.426 mmol) in MeOH (24 mL) was added 1 N aq. HCl (4.9 ml) and 10% Pd/C (50% water, 113 mg). The mixture was hydrogenated overnight, and then filtered through a 0.2 μM membrane. The resulting solution was concentrated in vacuo. The residue was diluted with 1 N aq. NaOH (20 mL) and extracted with DCM (2×100 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford crude, racemic N,N,2,2-tetramethyl-3-pyrrolidinamine (0.2930 g, 85% yield) as a pale yellow oil. LCMS: (M+H)+: 143.1.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[CH2:4][C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[C:10]([OH:16])[CH:9]=2.[I-].[N:24]1([C:34](N2C=C[N+](C)=C2)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[CH2:4][C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[C:10]([O:16][C:34]([N:24]1[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]1)=[O:35])[CH:9]=2
Reactant: Cc1c(Cc2c(Cl)cccc2Cl)c(=O)oc2cc(O)ccc12
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Agent: [I-]
Product: Cc1c(Cc2c(Cl)cccc2Cl)c(=O)oc2cc(OC(=O)N3CCCc4ccccc43)ccc12

Procedure:
The title compound was prepared from 3-(2,6-dichloro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=494 (M+1), Rt: 5.79 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][CH2:14][CH2:13][NH:12][C:11]2[N:16]([CH3:31])[N:17]=[C:18]([C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3C(OC(C)(C)C)=O)[C:10]1=2.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][CH2:14][CH2:13][NH:12][C:11]2[N:16]([CH3:31])[N:17]=[C:18]([C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)[C:10]1=2
Reactant: Cn1nc([C@@H]2CCCN2C(=O)OC(C)(C)C)c2c1NCCSC2c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc([C@@H]2CCCN2)c2c1NCCSC2c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.6 %

Procedure:
To tert-butyl (2S)-2-[4-(2,4-dichlorophenyl)-1-methyl-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-3-yl]pyrrolidine-1-carboxylate (0.31 g, 0.64 mmol), was added trifluoroacetic acid in DCM (1:4, 20 mL). The resulting mixture was stirred, for about 18 h, at rt. Subsequently, 5% aqueous sodium bicarbonate (100 mL) and DCM (200 mL) were added. The layers were separated and the organic layer was washed with water (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate/methanol (9:1) followed by 10% methanol in DCM) to afford 4-(2,4-dichlorophenyl)-1-methyl-3-[(2S)-pyrrolidin-2-yl]-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (38 mg, 0.1 mmol, 32%), as white solid: LC-MS (Table 1, Method a) Rt=1.38 min, m/z 383 (M+H)+; Major diastereomer; 1H NMR (400 MHz, CDCl3 and two drops of TFA) δ ppm 1.22-1.28 (1H, m) 1.85-2.35 (3H, m) 2.50-2.60 (1H, m) 2.68-2.83 (2H, m) 3.35-3.65 (3H, m) 3.75-3.85 (1H, m) 3.87 (3H, s) 4.60-4.70 (1H, br s) 5.32 (1H, s) 6.97 (1H, d, J=8.0 Hz) 7.16 (1H, dd, J=8.3, 2.2 Hz) 7.47 (1H, d, J=2.1 Hz) 9.65 (1H, br s). Minor diastereomer; 1H NMR (400 MHz, CDCl3 and two drops of TFA) δ ppm 1.22-1.28 (1H, m) 1.85-2.35 (4H, m) 2.68-2.83 (2H, m) 3.35-3.65 (3H, m) 3.75-3.85 (1H, m) 3.87 (3H, s) 4.60-4.70 (1H, br s) 5.31 (1H, s) 6.95 (1H, d, J=8.0 Hz) 7.10 (1H, dd, J=8.3, 2.2 Hz) 7.43 (1H, d, J=2.1 Hz) 9.25 (1H, br s).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11](=O)[CH2:12]Br)=[CH:9][CH:8]=1)#[N:6].[OH-].[Na+].O>C(O)C>[NH2:1][C:2]1[S:3][CH:12]=[C:11]([C:10]2[CH:15]=[CH:16][C:7]([C:5]#[N:6])=[CH:8][CH:9]=2)[N:4]=1
Reactant: NC(N)=S
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(-c2csc(N)n2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.3 %

Procedure:
Thiourea (0.76 g, 10 mmol) was added to 4-cyanophenacyl bromide (2.0 g, 8.9 mmol) in ethanol (20 mL), and the reaction heated under reflux. After 45 min, the mixture was cooled to room temperature, and poured into 2N NaOH (10 mL)/water (40 mL). The precipitate was collected and air-dried to give 4-(2-amino-thiazol-4-yl)benzonitrile (1.6 g, 90%), which was used without further characterization.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:17])[CH:14]([CH3:16])[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CC1CCCO1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([O:17][C:41]2[CH:42]=[CH:43][C:38]([Cl:37])=[CH:39][CH:40]=2)[CH:14]([CH3:15])[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Oc1ccc(Cl)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC1CCCO1
Product: CC(C)[C@H](Oc1ccc(Cl)cc1)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.8 %

Procedure:
(S)-3-((R)-1-hydroxy-2-methylpropyl)pyrrolidine-1-carboxylic acid t-butyl ester (35.0 g, 144 mmol, 1.0 eq.), triphenylphosphine (41.5 g, 158 mmol, 1.1 eq.), p-chlorophenol (37.0 g, 288 mmol, 2.0 eq.) and 2-methyl-tetrahydrofuran (300 mL) were combined and the vessel purged with nitrogen. Diisopropyl azodicarboxylate (31.2 mL, 1.1 eq.) was added slowly at room temperature over 2 hours. The mixture was then stirred at room temperature overnight. Hexanes (600 mL) were added and the resulting mixture was stirred at room temperature for 30 minutes. The phases were separated and the organic layer was washed with 1.0 M NaOH in water (600 mL), washed with diluted saturated aqueous NaCl (20 mL), then dried over Na2SO4 to yield the crude BOC-protected intermediate. Additional hexanes (50 mL) were added and the resulting mixture was stirred for 30 minutes. Solids were filtered off to yield the crude BOC-protected intermediate as a thick oil, which was then purified by silica gel chromatography (0-10-20% EtOAc in hexanes) to yield (S)-3-[(S)-1-(4-chlorophenoxy)-2-methylpropyl]pyrrolidine-1-carboxylic acid t-butyl ester (5.5 g).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].CI>CN(C)C=O>[CH3:1][O:22][C:21]([C@H:18]1[CH2:17][CH2:16][C@H:15]([NH:14][C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[CH2:20][CH2:19]1)=[O:23]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Potassium carbonate (877 mg, 6.34 mmol, 1.05 eq) is added at room temperature to a stirred solution of trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (1.50 g, 6.04 mmol, 1.0 eq) in N,N-dimethylformamide (30 mL), followed by methyl iodide (395 μL, 6.34 mmol, 1.05 eq). After 5 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3×30 mL) and water (30 mL). The combined organic layers are washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to afford trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid methyl ester as a yellow solid (1.60 g, 98% yield).
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@@H:8]([CH3:33])[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17](=[O:32])[NH:18][C@@H:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][C:25]([Br:31])=[CH:26][CH:27]=3)[N:22]=2)[CH3:20])[NH:12]1)=[O:10])(C)(C)C.Cl.[CH:36]1([CH:39]([OH:43])C(O)=O)[CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl.O1CCOCC1>[Br:31][C:25]1[CH:24]=[C:23]2[C:28]([CH:29]=[CH:30][C:21]([C@H:19]([NH:18][C:17]([C@@H:13]3[CH2:14][CH2:15][CH2:16][N:11]([C:9](=[O:10])[C@@H:8]([NH:7][C:6](=[O:5])[CH:39]([CH:36]4[CH2:38][CH2:37]4)[OH:43])[CH3:33])[NH:12]3)=[O:32])[CH3:20])=[N:22]2)=[CH:27][CH:26]=1
Reactant: O=C(O)C(O)C1CC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](NC(=O)C(O)C1CC1)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Temperature: 0 °C
Yield: 30.8 %

Procedure:
((S)-2-{(S)-3-[(R)-1-(7-Bromo-quinolin-2-yl)-ethylcarbamoyl]-tetrahydro-pyridazin-1-yl}-1-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester, (1.07 g, 2.00 mmol) was suspended in dichloromethane (20 mL) and the mixture was cooled to 0° C. with stirring. 4 M Hydrogen chloride in 1,4-dioxane (11 mL) was added and the reaction mixture stirred for 90 minutes and then evaporated. Residual water was azeotroped off with toluene and the residue was suspended in dichloromethane (20 mL) and cyclopropyl-hydroxy-acetic acid (255 mg, 2.20 mmol) was added. The mixture was cooled to 0° C. with stirring and N,N-diisopropylethylamine (775 mg, 1.05 mL, 6.00 mmol) was added followed by (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1.06 g, 2.40 mmol). The reaction was allowed to warm to ambient temperature and stirred for 18 h. 1M Hydrochloric acid was added and the organic layer was washed with saturated sodium bicarbonate solution, passed through a hydrophobic frit and evaporated. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate/methanol 1:0 to 9:1 to afford the title compound (328 mg) as a white foam. The original aqueous extracts were re-extracted with dichloromethane/methanol (9:1, 2×) and the organic extracts dried over anhydrous sodium sulfate, filtered and evaporated. The residue purified by silica gel chromatography eluting with a gradient of ethyl acetate/methanol 1:0 to 17:3 to afford the title compound (378 mg) as a white foam. The two foams were combined (706 mg, 66%). 1H NMR (300 MHz, CDCl3) δ 0.46-0.73 (m, 4H), 1.04-1.18 (m, 1H), 1.49-1.59 (m, 6H), 1.53-1.78 (m, 2H), 1.95-2.04 (m, 1H), 2.25-2.34 (m, 1H), 2.64-2.82 (m, 1H), 3.44-3.55 (m, 2H), 3.60-3.84 (m, 1H), 4.50-4.60 (m, 1H), 5.23-5.33 (m, 1H), 5.48-5.55 (m, 1H), 7.36-7.41 (m, 1H), 7.62-7.73 (m, 2H), 8.13-8.19 (m, 2H), 8.47-8.51 (m, 1H). LCMS (m/z) [M+H] 532.0, 534.0 Tr=2.07 min. LCMS (m/z) 532.0, 533.9 [M+H], Tr=2.12 min.
Reaction SMILES: [CH:1]1([C:4]2[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-])=O)[CH:5]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+]>CO.[Zn]>[CH:1]1([C:4]2[CH:5]=[C:6]([NH2:11])[C:7]([NH2:8])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(C2CC2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1ccc(C2CC2)cc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Cyclopropyl-2-nitroaniline (178 mg, 1 mmol) was dissolved in absolute methanol (6 mL), and zinc powder (200 mg, 3.1 mmol) and ammonium chloride (800 mg, 15 mmol) were added. The mixture was stirred at room temperature for 16 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The residue was partitioned between water (30 mL) and dichloromethane (30 mL). The organic layer was separated, and the aqueous layer was extracted twice with dichloromethane (15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give 4-cyclopropyl-benzene-1,2-diamine as a brown solid which was used without further purification (130 mg, 88%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:34])[C@H:7]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=1)[NH:8][S:9]([C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][N:18]([CH:22]([CH3:24])[CH3:23])[CH2:19]2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])C.Cl.CCOCC>O1CCOCC1>[CH3:24][CH:22]([N:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][C:12]([S:9]([NH:8][C@H:7]([C:6]([OH:34])=[O:5])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=3)(=[O:11])=[O:10])=[CH:13][CH:14]=2)[CH2:19]1)[CH3:23]
Reactant: CCOC(=O)[C@H](Cc1cccc(C#N)c1)NS(=O)(=O)c1ccc2c(c1)CN(C(C)C)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)N1CCc2ccc(S(=O)(=O)N[C@@H](Cc3cccc(C#N)c3)C(=O)O)cc2C1
Reaction time: 2.5 h
Yield: 83.3 %

Procedure:
1M Aqueous sodium hydroxide solution (6.0 ml, 6 mmol) was added to a stirred solution of N-[2-(2-propyl)-1,2,3,4-tetrahydroisoquinoline-7-sulphonyl]-3-cyano-(S)-phenylalanine ethyl ester (Preparation 25; 1.0 g, 2.19 mmol) in 1,4-dioxan (6.0 ml). After 2.5 hours at room temperature, the reaction mixture was neutralised using 1M hydrochloric acid (6.0 ml) and evaporated to dryness under reduced pressure. The residue was extracted successively with dichloromethane and a mixture of dichloromethane:2-propanol (9:1), then the combined extracts evaporated under reduced pressure to provide a material which, on trituration with ether, gave the title compound as a white powder (780 mg). Rf 0.06 (SS 3). m/e 428 (M+H)+.