Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][CH2:8][C@:9]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:10]1[C@@H:11]1[C@@:24]([CH3:27])([CH2:25][CH2:26]2)[C@@:23]2([CH3:28])[C@@H:14]([C@:15]3([CH3:44])[C@@H:20]([CH2:21][CH2:22]2)[C:19]([CH3:30])([CH3:29])[C:18]([C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37]C(C)(C)C)=[O:36])=[CH:33][CH:32]=2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([NH:4][CH2:5][CH2:6][NH:7][CH2:8][C@:9]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:10]1[C@@H:11]1[C@@:24]([CH3:27])([CH2:25][CH2:26]2)[C@@:23]2([CH3:28])[C@@H:14]([C@:15]3([CH3:44])[C@@H:20]([CH2:21][CH2:22]2)[C:19]([CH3:30])([CH3:29])[C:18]([C:31]2[CH:43]=[CH:42][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)(=[O:3])[CH3:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCNC(C)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(CNCCNC(C)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 38.9 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-acetamidoethylamino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (114 mg, 0.167 mmol) in DCM (1 ml) was added TFA (0.4 ml, 5.19 mmol). The mixture was stirred at rt for 3.5 h then was concentrated under reduced pressure. The residue was dissolved in dioxane and MeOH and was purified by pre. HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure to afford the title compound as an off-white solid (40.7 mg, 0.065 mmol, 38.8% yield). LCMS: m/e 629.5 (M+H)+, 2.17 min (method 6). 1H NMR (500 MHz, Acetic) δ ppm 8.03 (d, J=8.24 Hz, 2H),7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.58 Hz, 1H), 4.79 (s, 1H), 4.68 (s, 1H), 3.61-3.70 (m, 2H), 3.40-3.53 (m, 2H), 3.37 (d, J=13.12 Hz, 1H), 2.98 (d, J=12.82 Hz, 1H), 2.49-2.57 (m, 1H), 2.09 (s, 3H), 1.75 (s, 3H), 1.19 (s, 3H), 1.14-2.24 (m, 22H), 1.10 (s, 3H), 1.07 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]([C:11]1[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH:18]([CH3:20])[CH3:19])[N:12]=1)=O.[NH2:22]/[C:23](=[C:26](\[NH2:29])/[C:27]#[N:28])/[C:24]#[N:25].CS(C)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:22]=[C:23]([C:24]#[N:25])[C:26]([C:27]#[N:28])=[N:29][C:9]=1[C:11]1[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH:18]([CH3:20])[CH3:19])[N:12]=1
Reactant: CC(C)n1nc(C(=O)C(=O)c2ccccc2Br)ccc1=O
Reactant: N#C/C(N)=C(/N)C#N
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CC(C)n1nc(-c2nc(C#N)c(C#N)nc2-c2ccccc2Br)ccc1=O
Yield: 56 %

Procedure:
A mixture of 1-(2-bromophenyl)-2-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-1,2-ethanedione (5.30 g) and (2Z)-2,3-diamino-2-butenedinitrile (1.65 g) in a solution of DMSO (0.25 ml) and toluene (25 ml) was refluxed for 8 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (85:15 v/v) to give 5-(2-bromophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2,3-pyrazinedicarbonitrile as a solid (3.58 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][C:6]2=[CH:5][C:4]=1[NH:12][C:13](=[O:21])OC1C=CC=CC=1.[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[C:27]([CH3:29])[CH:28]=1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][C:6]2=[CH:5][C:4]=1[NH:12][C:13]([N:33]1[CH2:34][CH2:35][N:30]([C:25]2[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([CH3:22])[CH:24]=2)[CH2:31][CH2:32]1)=[O:21]
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: COc1nc2c(cc1NC(=O)Oc1ccccc1)CCC2
Product: COc1nc2c(cc1NC(=O)N1CCN(c3cc(C)cc(C)c3)CC1)CCC2
Yield: 55 %

Procedure:
Phenyl N-(2-methoxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[CH3:26].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([C:21]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[C:10]([O:11][CH3:12])[CH:9]=[CH:8][CH:7]=3)[N:1]=2)=[CH:19][C:18]=1[CH3:26]
Reactant: COc1cccc(C(N)=O)c1N
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cccc2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc12
Temperature: 115 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-3-methoxy-benzamide (700 mg, 4.22 mmol) and 4-(2-hydroxyethoxy)-3,5-dimethyl benzaldehyde (823 mg, 4.22 mmol) in N,N-dimethyl acetamide (10 mL) were added NaHSO3 (58.5 wt %, 841 mg, 4.64 mmol) and p-TSA (160 mg, 0.84 mmol). The reaction mixture was heated at 115° C. for 16 hours, then cooled to room temperature. Solvent was removed under reduced pressure. Water (100 mL) was added and stirred for 1 hour at room temperature. The solid separated was filtered and dried. The solid was further washed with diethyl ether to give crude product 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-8-methoxy-3H-quinazolin-4-one as an off-white solid. Yield: 1.2 g (84%).
Reaction SMILES: [BH4-].[Na+].CC([N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:27]3[C:22](=[C:23]([C:28](=[O:30])[CH3:29])[CH:24]=[CH:25][CH:26]=3)[C:21]([NH:31][S:32]([C:35]3[S:36][C:37]([Cl:40])=[CH:38][CH:39]=3)(=[O:34])=[O:33])=[N:20]2)[CH:13]=1)C(=O)[O-])(C)C.Cl.O1CCOCC1>CO>[NH2:7][CH2:11][C:12]1[CH:13]=[C:14]([CH2:18][N:19]2[C:27]3[C:22](=[C:23]([CH:28]([OH:30])[CH3:29])[CH:24]=[CH:25][CH:26]=3)[C:21]([NH:31][S:32]([C:35]3[S:36][C:37]([Cl:40])=[CH:38][CH:39]=3)(=[O:34])=[O:33])=[N:20]2)[CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)c1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN(C(=O)[O-])C(C)(C)C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CC(O)c1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (20.52 mg, 0.543 mmol) was added to a stirring solution of 1,1-dimethylethyl({3-[(4-acetyl-3-{[(5-chloro-2-thienyl)sulfonyl]amino}-1H-indazol-1-yl)methyl]phenyl}methyl)carbamate (for a preparation see Intermediate 75) (260 mg, 0.452 mmol) in MeOH (5 mL) at 25° C. under N2. The reaction mixture was stirred at room temp for 2 h. About ˜⅔ of the methanol was evaporated in vacuo and the residue was treated slowly with 1M HCl (5 mL). The product was extracted with EtOAc (2×40 mL) and the combined organic layers were dried by passing through a hydrophobic frit and concentrated to afford a yellow oil. 4N HCl in Dioxane (2 mL, 8.00 mmol) was added to the residue at 25° C. and the reaction mixture was stirred for 30 min. The crude sample was loaded straight on to a pre-washed (MeOH) SPE sulphonic acid (SCX-2) cartridge (20 g). The SCX cartridge was washed with 2 column volumes of MeOH and the product was collected by washing with 3 column volumes of 2N Ammonia in MeOH. The appropriate fractions were combined and evaporated in vacuo to give the title compound (235 mg, 91)%. LCMS (System A) RT=0.77 min, ES+ve m/z 477/479 (M+H)+.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([C:18]2[CH:31]=[CH:30][C:21]3[O:22][C:23]([CH3:29])([CH3:28])[C@@:24]4([CH3:27])[O:26][C@H:25]4[C:20]=3[CH:19]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[OH:32][C:33]1[N:34]=[N:35][C:36]([OH:39])=[CH:37][CH:38]=1.N1C=CC=CC=1>C(O)C>[OH:26][C@:24]1([CH3:27])[C:23]([CH3:28])([CH3:29])[O:22][C:21]2[CH:30]=[CH:31][C:18]([S:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)(=[O:17])=[O:16])=[CH:19][C:20]=2[C@H:25]1[O:39][C:36]1[N:35]=[N:34][C:33]([OH:32])=[CH:38][CH:37]=1
Reactant: CC1(C)Oc2ccc(S(=O)(=O)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc2[C@@H]2O[C@@]21C
Reactant: Oc1ccc(O)nn1
Solvent: c1ccncc1
Solvent: CCO
Product: CC1(C)Oc2ccc(S(=O)(=O)c3ccc(O)cc3)cc2[C@@H](Oc2ccc(O)nn2)[C@]1(C)O
Yield: 44.5 %

Procedure:
(3S,4S)-6-(4-tert-Butyldimethylsilyloxyphenyl)sulphonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo[b]pyran (0.35 g) (see Preparation 14) and 3,6-dihydroxypyridazine (0.273 g) were suspended in absolute ethanol (3 ml), dry pyridine (0.065 ml) was added and the mixture was heated under reflux for 4 days. The solvent was then removed under reduced pressure and the residue chromatographed on silica with 1:99 methanol:ethyl acetate as the eluent to yield (3S,4R)-3,4-dihydro-3-hydroxy-6-(4-hydroxyphenyl)sulphonyl-4-(3-hydroxypyridazin-6-yl)oxy-2,2,3-trimethyl-2H-benzo[b]pyran (0.155 g) as a white solid, m.p. >200° C. Found: C,57.54; H,5.35; N,5.57. C22H22N2O7S, 0.20 ethyl acetate requires C,57.50; H,4.99; N,5.88%.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][C:10](O)=[O:11].S(Cl)([Cl:16])=O>CN(C)C=O>[CH3:1][C:2]1([CH3:13])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][C:10]([Cl:16])=[O:11]
Reactant: CC1(C)[C@H]2CC[C@@H](CC(=O)O)[C@@H]1C2
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@@H](CC(=O)Cl)[C@@H]1C2
Temperature: 22 °C
Reaction time: 2 h

Procedure:
To a mixture of the product from Example 4B (300 mg, 1.65 mmol) and thionyl chloride (901 μL, 12.4 mmol) was added a drop of dimethylformamide. The reaction was stirred at 22° C. for 2 hours. The excess of thionyl chloride was evaporated and the residue was dried under vacuum to afford the title compound.
Reaction SMILES: CO[C:3](=[O:17])[CH2:4][C@:5]([NH2:16])([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH3:6].[CH3:18][NH:19][C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=S>>[C:25]([O:24][C:23](=[O:29])[NH:22][C:20]1[N:19]([CH3:18])[C:3](=[O:17])[CH2:4][C@@:5]([CH3:6])([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:16]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)C[C@](C)(N)c1cccc([N+](=O)[O-])c1
Reactant: CNC(=S)NC(=O)OC(C)(C)C
Product: CN1C(=O)C[C@@](C)(c2cccc([N+](=O)[O-])c2)N=C1NC(=O)OC(C)(C)C

Procedure:
Starting from (S)-3-amino-3-(3-nitro-phenyl)-butyric acid methyl ester and tert-butyl [(methylamino)carbonothioyl]carbamate, the product [(S)-1,4-dimethyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester was obtained as white solid. MS (ESI): m/z=361.4 [M−H]−.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[NH:17][N:18]=[CH:19][CH:20]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:20]=[CH:19][N:18]([CH2:29][CH2:28][O:27][C:26]3[CH:31]=[CH:32][C:23]([F:22])=[CH:24][CH:25]=3)[N:17]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(OCCBr)cc1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccn(CCOc3ccc(F)cc3)n2)sc1C(=O)NCc1ccccc1
Temperature: 90 °C
Yield: 26.7 %

Procedure:
A solution of 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid benzylamide (0.2 g, 0.61 mmol) in dimethyl sulfoxide (5 mL) was treated with 4-fluorophenoxyethyl bromide (0.14 g, 0.67 mmol) and potassium carbonate (0.30 g, 2.0 mmol), and the reaction mixture was heated to 90° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with brine (2×50 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel (methylene chloride:methanol, 95:5) to provide 2-{1-[2-(4-fluoro-phenoxy)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid benzylamide (0.071 g, 51% yield) as a white solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=2)=[N:5][N:6]=1.[F:21][C:22]1[CH:23]=[C:24](/[CH:39]=[CH:40]/[O:41][CH3:42])[C:25]([O:37][CH3:38])=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.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>[F:21][C:22]1[CH:23]=[C:24](/[CH:39]=[CH:40]/[O:41][CH3:42])[C:25]([O:37][CH3:38])=[C:26]([C:2]2[S:3][C:4]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=3)=[N:5][N:6]=2)[CH:27]=1
Reactant: CO/C=C/c1cc(F)cc(B2OC(C)(C)C(C)(C)O2)c1OC
Reactant: CC(C)Oc1ccc(-c2nnc(Br)s2)cc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/C=C/c1cc(F)cc(-c2nnc(-c3ccc(OC(C)C)c(C(F)(F)F)c3)s2)c1OC
Temperature: 120 °C
Yield: 33.9 %

Procedure:
To a suspension of 2-bromo-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazole (D4) (393 mg), 2-{5-fluoro-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (495 mg) and tripotassium phosphate (568 mg) in N,N-dimethylformamide (DMF) (8 mL) and water (2 mL) under nitrogen was added Pd(Ph3P)4 (61.8 mg). The reaction vessel was sealed and heated under microwave at 120° C. for 10 min. Water was added. The reaction mixture was extracted with EA for 3 times, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, the dried solution was concentrated, and purified by column chromatography to afford 2-{5-fluoro-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazole (D34) (170 mg) as a yellow solid. MS (ES): C22H20F4N2O3S requires 468. found 469.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>[Ni].CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: CCN1CCN(c2ccc([N+](=O)[O-])c(Cl)c2)CC1
Agent: [Ni]
Solvent: CO
Product: CCN1CCN(c2ccc(N)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 1-(3-chloro-4-nitro-phenyl)-4-ethyl-piperazine (1 g, 3.7 mmol) and Raney Nickel (0.1 g) in MeOH (20 mL) is stirred for 8 h at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 95:5) to afford the title compound as an off-white solid: ESI-MS: 240.1/242.1 [MH]+; tR=0.90 min (system 1), TLC: Rf=0.46 (DCM/MeOH+1% NH3aq, 95:5).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[C:29]([CH3:37])[CH:28]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:33]([C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][C:29]=4[CH3:37])(=[O:34])=[O:35])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: Cc1cc(F)ccc1S(=O)(=O)Cl
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(F)cc4C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 4-fluoro-2-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:26]1([N:32]([CH2:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][NH:36]2)[CH3:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:36]1[CH2:37][CH2:38][CH2:39][CH2:40][CH:35]1[CH2:34][N:32]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH3:33])=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CN(CC1CCCCN1)C1CCCCC1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCCC2CN(C)C2CCCCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 2-(N-cyclohexyl-N-methylaminomethyl)piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.25 minutes; C30H37Cl2N5O2 (570.56); mass spectrum: (M−H)−=570/572/574 (chlorine isotope).
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1)C1C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[CH3:15][C:12]1([CH3:16])[O:11][C@@H:10]([CH2:9][OH:8])[CH2:14][O:13]1
Reactant: CC1(C)OC[C@H](COCc2ccccc2)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@H](CO)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
10% Palladium-carbon (2.7 g) was added to thus obtained (S)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (16.228 g, 73.02 mmol) in ethyl acetate(270 ml) and the mixture was stirred for 3 hours at 25° C. under an atmosphere of hydrogen. After the reaction was over, palladium-carbon was filtered off and the solvent was condensed in vacuo. The crude product was distilled to give 8.78 g of (S)-2,2-dimethyl-1,3-dioxolane-4-methanol (yield 91%, b.p. 70° C. at 6 mmHg, optical purity 97.2% e.e., specific rotation [α]D20 +10.76°(c=1,MeOH))).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])[CH:8]=1)([O-])=O>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])[CH:8]=1
Reactant: CC(=O)NCCn1cc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NCCn1cc(N)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 110.1 %

Procedure:
To a solution of N-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)acetamide (610 mg) obtained in Step C of Example 348 in ethanol (20 mL) was added 10% palladium-carbon (160 mg), and the mixture was stirred at room temperature for 3 hr under hydrogen atmosphere (at normal pressures). The palladium carbon was removed by filtration through Celite, and the solvent was evaporated under reduced pressure to give the title compound (570 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8].[CH3:13][NH:14][CH3:15]>CO>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:14]([CH3:15])[CH3:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CNC
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Solvent: CO
Product: CN(C)S(=O)(=O)c1cnc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.4 %

Procedure:
5-Bromo-6-chloropyridine-3-sulfonyl chloride (1.455 g, 5 mmol) in methanol (20 mL) was treated with 2.0 N dimethylamine (6.25 mL, 12.50 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The solvent was removed, and the solid was washed with water several times. The solid was then purified by chromatography on silica gel eluting with 15% ethyl acetate in hexanes to give 0.8 g of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[C:7]1(C)[CH:12]=CC(S(O)(=O)=O)=C[CH:8]=1>C(OC(C)=O)C.Cl.COC(OC)(C)C>[CH3:8][C:7]1([CH3:12])[O:6][CH:3]([CH2:2][NH2:1])[CH2:4][O:5]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NCC(O)CO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: COC(C)(C)OC
Product: CC1(C)OCC(CN)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 533.6 %

Procedure:
3-Aminopropane-1,2-diol (400 mg, 4.4 mmol) was dissolved in EtOAc—HCl (20 mL). And the reaction mixture was stirred at r.t. for 30 min. The reaction mixture was concentrated in vacuo to get to the white solid. The white solid was added in 2,2-dimethoxy-propane (10 mL) and toluene-4-sulfonic acid (86 mg, 0.5 mmol) was added into the mixture. The reaction mixture was stirred at 60 for 12 h. The reaction mixture was concentrated in vacuo, washed by acetone to give (2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (350 mg, yield: 46%). 1HNMR (DMSO-d6, 400 MHz): δ8.08 (s, 2H), 4.32 (s, 1H), 4.05 (q, J=4.8 Hz, 1H), 3.73 (t, J=6.4 Hz, 1H), 3.00-2.78 (m, 2H), 1.37 (s, 3H), 1.28 (s, 3H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:33]=[C:32]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:31]=[CH:30][C:16]=2[C:17]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[C:26]([O:28]C)=[O:27])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:33]=[C:32]([N:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[CH:31]=[CH:30][C:16]=2[C:17]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[C:26]([OH:28])=[O:27])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccncc1NC(=O)c1ccc(N2CCCC2)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC3)ccc2C(=O)Nc2cnccc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of methyl 3-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]pyridine-4-carboxylate (2.78 g, 5.3 mmol) in MeOH (100 mL) and THF (50 mL) was treated with 1 N NaOH (11 mL) and stirred at ambient temperature for 4 h. The reaction was quenched with glacial acetic acid (1 g) and concentrated to dryness. The residue was mixed with brine (50 mL) and extracted with 10% MeOH in CHCl3 (3×). The extracts were dried over MgSO4 and concentrated to 2.2 g (4.3 mmol, 81%) of a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[CH:8][C:7]=1[CH3:30].[OH-].[Na+].O.Cl>C(O)C>[Br:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[CH:14][CH2:13][S:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])=[C:7]([CH3:30])[CH:8]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)COc1ccc(SCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(SCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)ccc1OCC(=O)O
Yield: 93.5 %

Procedure:
A solution of {4-[3,3-bis-(4-bromo-phenyl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid methyl ester (530 mg, 0.94 mmol) in ethanol (20 ml) and 1M NaOH (2.0 ml, 2.0 mmol) was stirred at room temp. for 2 h. The reaction mixture added water (20 ml) and 1N HCl (3.0 ml). The water phase was extracted with dichloromethane (2×50 ml) and the combined organic phases were dried with MgSO4, filtered and evaporated to give 482 mg (93%) of {4-[3,3-bis-(4-bromo-phenyl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid.