Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=2)[CH2:5][N:4]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3([CH3:28])[CH2:27][CH2:26]3)=[O:24])[CH2:19][CH2:18]2)=[O:16])[CH2:3]1.[CH:29](=O)[CH3:30].C([BH3-])#N.[Na+]>C(O)C>[Cl:14][C:9]1[CH:8]=[C:7]([C@H:6]2[C@H:2]([NH:1][CH2:29][CH3:30])[CH2:3][N:4]([C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([C:25]4([CH3:28])[CH2:27][CH2:26]4)=[O:24])[CH2:19][CH2:18]3)=[O:16])[CH2:5]2)[CH:12]=[CH:11][C:10]=1[Cl:13]
Reactant: CC=O
Reactant: CC1(C(=O)N2CCC(C(=O)N3CC(N)C(c4ccc(Cl)c(Cl)c4)C3)CC2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCN[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.3 %

Procedure:
To a solution of rac-(3S,4R)-[3-Amino-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone (50 mg, 0.12 mmol) in ethanol (0.3 mL) were added acetaldehyde (10 uL, 0.18 mmol) and sodiumcyanoborohydride (15 mg, 0.24 mmol) and the reaction mixture was stirred at ambient temperature for 3 h. It was concentrated and the residue separated between water and ethylacetate. The organic layer was dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, dichloromethane:methanol=100:0 to 95:5) afforded the title compound (30 mg, 56%) as a light yellow oil. MS m/e: 452.3 [M]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[H-].[Na+].[Br:18][C:19]1[C:23]2[N:24]=[CH:25][N:26]=[C:27](Cl)[C:22]=2[N:21]([CH3:29])[CH:20]=1>CN(C=O)C>[Br:18][C:19]1[C:23]2[N:24]=[CH:25][N:26]=[C:27]([O:15][CH:12]3[CH2:11][CH2:10][N:9]([C:6]4[N:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][N:5]=4)[CH2:14][CH2:13]3)[C:22]=2[N:21]([CH3:29])[CH:20]=1
Reactant: CCc1cnc(N2CCC(O)CC2)nc1
Reactant: Cn1cc(Br)c2ncnc(Cl)c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(Oc3ncnc4c(Br)cn(C)c34)CC2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(5-ethylpyrimidin-2-yl)piperidin-4-ol (93 mg) was added to DMF (5 mL), and cooled to 0° C. Then, NaH (27 mg) was added thereto, and stirred for 30 min. 7-bromo-4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (100 mg) was added thereto, and stirred at room temperature for 12 hours. The reaction mixture was extracted with ethyl acetate and distilled water, and the organic layer thus obtained was washed with water and a saline solution. Subsequently, the washed organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([C:19](=O)[NH2:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([C:19](=[S:32])[NH2:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(N)=S
Reaction time: 3 h
Yield: 83 %

Procedure:
To a solution of [1-(S)-carbamoyl-2-(4-nitrophenyl)ethyl-carbamic acid tert-butyl ester, 1, (0.400 g, 1.29 mmol) in THF (10 mL) is added Lawesson's reagent (0.262 g. 0.65 mmol). The reaction mixture is stirred for 3 hours and concentrated to a residue which is purified over silica to provide 0.350 g (83%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 8.10 (d. J=8.4 Hz, 2H), 8.01 (s, 1H), 7.42 (d, J=8.4 Hz, 2H), 5.70 (d, J=7.2 Hz, 1H), 4.85 (d, J=7.2 Hz, 1H), 3.11-3.30 (m, 1H), 1.21 (s, 9H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].C([C:19](CC)(P(=O)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])C>O1CCCC1>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([CH:5]2[CH2:6][CH2:7][C:2](=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:3][CH2:4]2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(CC)(CC)P(=O)=O
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCC(c2ccc(O)cc2)CC1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
10 g of 4-(4-hydroxyphenyl)cyclohexanone (52.56 mmol, 1 eq.) are placed in 150 mL of tetrahydrofuran in a 250 mL round-bottomed flask under nitrogen. The solution is cooled to 4° C. on an ice bath and 2.523 g of 60% sodium hydride (63.08 mmol, 1.2 eq.) are added portionwise. 14.141 g of ethyl diethylphosphoacetate (63.08 mmol, 1.2 eq.) are placed in 150 mL of tetrahydrofuran in another 250 mL round-bottomed flask under nitrogen. This second solution is cooled on an ice bath and 2.523 g of 60% sodium hydride (63.08 mmol, 1.2 eq.) are added portionwise. The ice baths are removed and the media are stirred at room temperature for 30 minutes. The 4-(4-hydroxyphenyl)-cyclohexanone solution is added to the ethyl diethylphosphoacetate solution. The reaction medium is stirred for 1 hour 30 minutes. Saturated aqueous ammonium chloride solution is added and the reaction medium is extracted three times with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated to give 13.5 g of ethyl [4-(4-hydroxyphenyl)cyclohexylidene]acetate. M+H+=261.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([C:13]1[S:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[CH:14]=1)([CH3:12])[CH3:11].C([Li])CCC.[C:27](=[O:29])=[O:28].Cl>O1CCCC1>[S:17]1[C:13]([C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[C:27]([OH:29])=[O:28])([CH3:12])[CH3:11])=[CH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]1=2
Reactant: COc1ccc(Br)c(C(C)(C)c2cc3ccccc3s2)c1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c(C(C)(C)c2cc3ccccc3s2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
2-[1-(2-Bromo-5-methoxy-phenyl)-1-methylethyl]-benzo[b]thiophene (Compound Z3, 40 mg, 0.11 mmol) was dissolved in tetrahydrofuran (0.5 mL), cooled to −78° C., added with n-butyl lithium (1.57 M, hexane solution, 0.07 mL), and the mixture was stirred for 10 min. The reaction mixture was added with dry ice and then maintained for 1 hr. After that, the mixture was added with 0.5 N hydrochloric acid, extracted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate. The residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (22 mg, 55%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])#[N:2].Br[CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30])[CH2:20][CH2:19]1)=[O:17])#[N:2]
Reactant: N#CCCCCBr
Reactant: N#CCCCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCCCN1CCC(C(=O)c2nc3ccccc3n2CCCCC#N)CC1
Temperature: 90 °C

Procedure:
Mix 1-[(4-cyanobutyl)-1H-benzimidazol-2-yl][1-(4-piperidinyl)]methanone (4.0 g, 12.91 mmol), 5-bromovaleronitrile (2.5 g, 15.3 mmol), potassium carbonate (5.29 g, 38.25 mmol) and dimethylformamide (100 mL). Stir and heat at 90° C. overnight. Allow to cool to room temperature, dilute with water and extract with ethyl acetate (2×). Wash the combined organic phases with water (3×), then brine and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:23][CH2:24][CH2:25][CH3:26])[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:23][CH2:24][CH2:25][CH3:26])[C:13](=[O:14])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC1(C(O)c2ccc(Cl)c(Cl)c2)CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCCCC1(C(=O)c2ccc(Cl)c(Cl)c2)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
To a stirred solution of 2-butyl-2-[(3,4-dichloro-phenyl)-hydroxy-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.520 g, 1.29 mmol) in DCM (20 mL) at 0° C. under nitrogen was added DMP (0.658 g, 1.55 mmol) in a single portion. The reaction mixture was warmed to ambient temperature and stirred for 30 minutes, then diluted with DCM, washed with 1 N NaOH and brine, then dried (MgSO4), filtered and concentrated in vacuo to a yellow oil (0.62 g). Purification by chromatography (silica, 10-20% EtOAc in hexanes) gave 2-butyl-2-(3,4-dichloro-benzoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.441 g, 1.10 mmol, 85%) as a clear colourless gum.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([OH:18])[CH:8]=[CH:9][C:10]=1[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CS(O[CH:24]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1)(=O)=O.[OH-].[Na+]>CN(C=O)C.O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:10]=1[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[O:18][CH:24]1[CH2:25][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27]1
Reactant: COc1cc(O)ccc1CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1CN1CCOCC1
Temperature: 80 °C
Yield: 105.9 %

Procedure:
A mixture of NaH (55-65% disp. in oil, 0.30 g, 6.88 mmol) in dry DMF (5 mL) under nitrogen was cooled by a water-bath. A solution of 7A (1.17 g, 5.24 mmol) in DMF (10 mL) was added drop-wise over 15 minutes. The mixture was stirred for one h and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (1.7 g, 6.77 mmol) in DMF (10 mL) was added. The mixture was heated to 80° C. for 3 days and then cooled to RT. Water and some aqueous NaOH were added and the mixture was extracted three times with EtOAc. The combined organic solutions were dried (MgSO4) and evaporated. The residue was purified by column chromatography on SiO2 using 5% triethylamine in EtOAc as eluent. There was obtained 2.1 g (104%) of 7B as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 2.39-2.56 (m, 4H), 3.48 (s, 2H), 3.65-3.75 (m, 4H), 3.79 (s, 3H), 3.95-4.04 (m, 2H), 4.23-4.33 (m, 2H), 4.82-4.91 (m, 1H), 6.19 (d, 1H), 6.38 (s, 1H), 7.21 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][C:7]2=[O:12].C(O)(=[O:18])C.OO>[O-][W]([O-])(=O)=O.[Na+].[Na+].O>[CH3:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[S:10](=[O:18])[CH2:9][CH2:8][C:7]2=[O:12]
Reactant: Cc1c(C(=O)O)ccc2c1SCCC2=O
Reactant: CC(=O)O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: Cc1c(C(=O)O)ccc2c1S(=O)CCC2=O
Reaction time: 3 h

Procedure:
7.0 g (31.5 mmol) of 8-methylthiochroman-4-one-7-carboxylic acid are initially introduced into 70 ml of acetic acid together with a spatula tipful of sodium tungstate. 3.6 g (31.5 mmol) of 30% strength hydrogen peroxide solution are added dropwise at 50° C. and the reaction solution is subsequently stirred for 3 hours. It is then stirred into water and the product is extracted with ethyl acetate. The organic phase is dried and the solvent is removed. The product is purified by chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[C:9]([OH:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>[Cl:1][C:2]1[C:10]([O:11][C:4](=[O:5])[CH3:3])=[C:9]([O:12][C:10](=[O:11])[CH3:9])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(O)c(O)c1Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C(=O)O)c(Cl)c1OC(C)=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 192.4 %

Procedure:
To a suspension of 2-chloro-3,4-dihydroxybenzoic acid (12.0 g: 63.6 mMol.) in acetic anhydride (36.4 ml) under ice cooling is added concentrated sulfuric acid (1 drop), and the mixture is stirred for 90 minutes. The reaction mixture is diluted with ice water and resulting precipitate is collected by filtration, washed with water, and dried to give 2-chloro-3,4-diacetoxybenzoic acid (16.68 g). Yield: 96%.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:55][OH:56])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:58].[Na+].[Br-].[K+].Cl[O-].[Na+].Cl>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)=[CH:45][CH:46]=4)[CH:34]=3)[O:32][C@@:10]1([C:55]([OH:58])=[O:56])[CH2:11][O:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCc5ccccc5)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCc5ccccc5)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 101.3 %

Procedure:
To a solution of [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[3-[(4-benzyloxyphenyl)methyl]-4-chloro-phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 25l (0.45 g, 0.58 mmol) in tetrahydrofuran (20 mL) was added sodium bicarbonate (0.49 g, 5.8 mmol) at room temperature, and then potassium bromide (6.9 mg, 0.06 mmol), 2,2,6,6-tetramethylpiperidinooxy (9 mg, 0.06 mmol) and sodium hypochlorite (9 mL, available chlorine ≧5.5%) were added in turn at 0° C. The mixture was stirred at 0° C. for 40 min and acidified with aqueous HCl (1 N) till pH becomes 4. The resulting mixture was extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with water (20 mL×2) and saturated brine (20 mL×2) in turn, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 25m (0.46 g, 100%) as a white solid. This material was not further purified.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][O:9][CH:10]1[CH2:27][CH2:26][C:13]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH2:12][CH2:11]1.CCN(CC)CC>>[CH3:1][S:2]([O:6][CH2:7][CH2:8][O:9][CH:10]1[CH2:27][CH2:26][C:13]2([CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]2)[CH2:12][CH2:11]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(OCCO)CC2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CCC(OCCOS(C)(=O)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Methanesulfonyl chloride (5.43 mmol, 2.0 eq.) was added dropwise to a stirred solution of tert-butyl 9-(2-hydroxyethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (2.71 mmol, 1.0 eq.) and Et3N (9.485 mmol, 3.5 eq.) in MC (30 ml) at 0° C. and the resulting reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was diluted with MC (150 ml), washed with water (100 ml) and brine (100 ml) and dried over sodium sulfate. The solvent was evaporated under reduce pressure to give the crude product as a yellow sticky solid which was used in the next step reaction without further purification. Yield: 99%
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=O.[CH3:26][N:27]1[CH:31]=[CH:30][C:29]([NH2:32])=[N:28]1>>[CH3:26][N:27]1[CH:31]=[CH:30][C:29]([NH:32][C:3]([C:5]2[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:2])=[N:28]1
Reactant: Cn1ccc(N)n1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)nn1C
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)Nc2ccn(C)n2)n(C)n1
Yield: 48 %

Procedure:
As described for example 48c, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.29 mmol) was converted, using 1-methyl-1H-pyrazol-3-ylamine instead of N,N-dimethylhydrazine, to the title compound (58 mg, 48%) which was obtained as a yellow gum. MS: m/e=411.2 [M+H]+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl.N([O-])=O.[Na+].B(O)(O)O.[FH:30]>O>[F:30][C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: F
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(N)c1
Agent: Cl
Agent: O=N[O-]
Agent: OB(O)O
Solvent: O
Product: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 44.2 g. (0.15 moles) of ethyl 3-amino-4-cyclohexylphenylglyoxylate is added at 0° C. 44 ml. of 1.5 moles of concentrated hydrochloric acid. The reaction mixture is maintained at 0° C. and the diazonium salt is prepared with 23.2 g. (0.32 moles) of 95% sodium nitrite in 80 ml. of water. To this mixture is rapidly added a solution of 10.4 g. (0.17 moles) of boric acid dissolved in 22 g. (0.66 moles) of 60% hydrofluoric acid. The reaction mixture is then stirred for 1/2 hour and filtered, washed with 3×25 ml. of water, 2×25 ml. of methanol and 25 ml. of ether. The residual cake is then treated in vacuo. The treated cake is then placed in a distilling flask and heated to permit spontaneous decomposition. After the decomposition, the residue is then fractionally distilled to obtain ethyl 3-fluoro-4-cyclohexylphenylglyoxylate.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][C:6]=1[CH3:7].[CH:13](=O)[CH:14]([CH3:16])[CH3:15]>O>[CH3:1][C:2]1[NH:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]=1[CH3:7]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1cc(C)c(C)[nH]1
Solvent: O
Product: CCOC(=O)c1[nH]c(C)c(C)c1CC(C)C

Procedure:
As in Example 32 but using 2,3-dimethyl-5-carbethoxy-pyrrole and isobutyraldehyde, pouring the mixture into water after 3 hrs and extracting the product from the alkaline mixture with ether. It was distilled (70°, 1 × 10-4 mm) and crystallized from pentane as colourless prisms (45%), m.p. 109°-111°. Anal. Calc. for C13H21NO2 : C, 69.92; H, 9.48; N, 6.27. Found: C, 70.23; H, 9.79; N, 6.27.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])[N:19]=2)=[C:9]1[CH3:38])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][N:20]1[N:19]=[C:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:39])=[O:5])[C:9]=2[CH3:38])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21]1(=[O:29])=[O:28]
Reactant: Cc1c(C2=NN(Cc3ccccc3F)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2=NN(Cc3ccccc3F)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)O

Procedure:
{3-[2-(2-Fluoro-benzyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-acetic acid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 7.94 (d, 1H), 7.72 (t, 1H), 7.63 (t, 1H), 7.22 (d, 4H), 7.02 (m, 2H), 6.69 (dt, 1H), 6.38 (dd, 1H), 4.92 (bs, 2H), 4.51 (s, 2H), 1.86 (s, 3H) ppm. MS calculated for C25H19F2N3O4S—H: 494, observed: 494.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][C@@H:5]([CH3:13])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[Na+].Cl>C1COCC1.CO>[C:9]([O:8][C:6](=[O:7])[C@H:5]([CH3:13])[CH2:4][C:3]([OH:14])=[O:2])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)C[C@@H](C)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](CC(=O)O)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 2.55 g (9.89 mmol) of (R)-2-methyl-succinic acid 1-tert-butylester 4-methyl ester in 20 ml of THF/MeOH (1/1) are added at 0° C. 10 ml (20 mmol) of 2 M sodium hydroxide. The mixture is stirred for 4 h at 0° C. and then acidified to pH 2-3 by addition of 1 M HCl. The organic solvents are evaporated. The residual aq. solution is extracted with DCM (3×30 ml), and the combined organic layers are dried over sodium sulfate and concentrated to give the product in the form of a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][C@@H:9]1[C@@H:19]([OH:42])[C@H:20]([N:28]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][C@@H:9]1[C@@H:19]([OH:42])[C@H:20]([NH2:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)CCN1CCN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](Cc2ccccc2)N=C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)CCN1CCN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@H](N)Cc2ccccc2)C1

Procedure:
Dissolve 2-(R)-[2-(R)-(benzhydrylidene-amino)-1-(S)-hydroxy-3-phenylpropyl]-4-(3-methyl-butyl)-piperazine-1-carboxylic acid tert-butyl ester in methanol (3 mL) and add 10% palladium on carbon (29 mg). Stir under 1 atmosphere of hydrogen gas for 24 h and filter through a filtering agent, wash with methanol and concentrate to give the title compound which is used without further purification.
Reaction SMILES: [CH3:1][N:2]([O:15][CH3:16])[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6](F)[CH:5]=1.[CH:17]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]1.C(#N)C>Cl>[CH3:16][O:15][N:2]([CH3:1])[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([NH:22][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:5]=1
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: NC1CCCC1
Agent: Cl
Solvent: CC#N
Product: CON(C)C(=O)c1ccc([N+](=O)[O-])c(NC2CCCC2)c1
Yield: 92.1 %

Procedure:
Combine N-[methyl]N-[methoxy]3-fluoro-4-nitrobenzamide (2.3 g, 10 mmol), cyclopentylamine (12.3 mL, 100 mmol) and acetonitrile (50 mL) and stir at room temperature for 6 hours. Dilute with 1N HCl and extract with ethyl acetate. Wash the organic layer sequentially with water and saturated aqueous sodium chloride, then dry over magnesium sulfate. Concentrate under reduced pressure to provide the desired compound as an orange solid (2.7 g, 92%).