Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH:52]1[CH2:57][CH2:56][CH:55]([O:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65](=[O:67])[CH3:66])[CH2:54][CH2:53]1>CN(C=O)C.O>[C:65]([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=1[O:58][CH:55]1[CH2:56][CH2:57][N:52]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]2[CH:17]=[C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:20][N:19]=2)=[O:22])[CH2:53][CH2:54]1)(=[O:67])[CH3:66]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: CC(=O)c1ccccc1OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 8 h
Yield: 50.9 %

Procedure:
DIPEA (232 mg, 1.8 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (144 mg, 0.6 mmol) in DMF (2 mL) followed by HOBt (97 mg, 0.7 mmol) and EDCI.HCl (137 mg, 0.7 mmol). After 2 minutes 1-[2-(piperidin-4-yloxy)-phenyl]-ethanone dihydrochloride (prepared according to Step 1 and 5 of the General Scheme) (150 mg, 0.6 mmol) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 5% MeoH in CHCl3 as eluent) to afford 112 mg (50.9% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-acetyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 447.2, 95.68%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.2 (bs, 1H), 7.8 (d, 2H), 7.5 (m, 4H), 7.4 (m, 1H), 7.3 (m, 1H), 7.2 (s, 1H), 7.0 (t, 1H), 4.8 (m, 1H), 4.4 (m, 2H), 3.8 (m, 1H), 3.4 (m, 1H), 3.5 (m, 2H), 2.5 (s, 3H), 2.0 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:43])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:42])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:34])=[CH:29][CH:28]=2)[CH3:19])[CH2:12][CH2:11]1.[H-].[Na+].Cl[C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54].O>O1CCCC1.C(OCC)(=O)C>[C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[C:20](=[O:42])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([C:27]2[CH:28]=[CH:29][C:30]([N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[CH3:34])=[CH:31][CH:32]=2)[C:53](=[O:54])[O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:12][CH2:11]1)=[O:43]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(N(C)C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN(C(=O)OCc1ccccc1)c1ccc(N(C)C(=O)OC(C)(C)C)cc1
Reaction time: 0.25 h
Yield: 92.7 %

Procedure:
The compound (593 mg, 0.883 mmol) obtained in Example 97a was dissolved in tetrahydrofuran (9 mL), 55% sodium hydride (42 mg, 0.971 mmol) was added under ice cooling, and the mixture was stirred under ice cooling under a nitrogen atmosphere for 15 minutes. Subsequently, benzyl chloroformate (0.19 mL, 1.32 mmol) was added, and the mixture was stirred at room temperature for 18 hours. After the reaction was completed, water was added, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate, 1:5→1:15, v/v) to give the title compound (660 mg; yield, 93%) as a colorless oily substance.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:23][CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:39]>O1CCOCC1>[ClH:39].[ClH:39].[CH2:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[CH:20]=[C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:16]=[N:17][C:18]=2[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:22][CH:23]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4-[5-(4-Benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.50 mmol, 260 mg) was dissolved in 4.0 M HCl in dioxane and stirred for 45 min at room temperature. The solvent was evaporated, and the resultant solid was washed with ether and dried to provide 4-(4-benzyloxy-phenyl)-3-butyl-6-(piperidin-4-yloxy)-pyridazine dihydrochloride.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][NH:7][C:8](=[O:18])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([NH2:16])[C:10]=1[Cl:17].O[CH2:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>O>[CH3:6][NH:7][C:8](=[O:18])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([NH:16][CH2:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:10]=1[Cl:17]
Reactant: CNC(=O)c1cc(Cl)cc(N)c1Cl
Reactant: O=S(=O)(CO)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CNC(=O)c1cc(Cl)cc(NCS(=O)(=O)c2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Yield: 83.8 %

Procedure:
0.8 g of concentrated sulfuric acid was added to 1.8 g (8.2 mmoles) of 2,5-dichloro-3-aminobenzoic acid N-methylamide, 1.87 g (9 mmoles) of hydroxymethyl-(4-chlorophenyl)-sulfone and 50 ml of water whilst stirring at room temperature. The mixture was stirred for a further 2 hours at room temperature and the solid was then filtered off, washed with water and recrystallized from acetonitrile. 2.8 g (83% of theory) of 2,5-dichloro-3-[(4-chlorophenyl)-sulfonylmethylamino]-benzoic acid N-methylamide were obtained in the form of a colorless solid of melting point 175°-182° C (with decomposition).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:32]([O:39][C:40]1[CH:57]=[CH:56][C:43]([C:44]([NH:46][CH2:47][C:48](=[O:55])[N:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[O:45])=[CH:42][CH:41]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[C:58]1([CH2:64][C:65](O)=[O:66])[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>O.CN(C=O)C>[CH2:32]([O:39][C:40]1[CH:57]=[CH:56][C:43]([C:44]([NH:46][CH2:47][C:48](=[O:55])[N:49]2[CH2:50][CH2:51][N:52]([C:65](=[O:66])[CH2:64][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH2:53][CH2:54]2)=[O:45])=[CH:42][CH:41]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)Cc2ccccc2)CC1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
EDCI.HCl (122 mg, 0.634 mmol), HOBT (68 mg, 0.51 mmol) and DIPEA (220 μL, 1.27 mmol) were added to a mixture of 4-benzyloxy-N-(2-oxo-2-piperazin-1-yl-ethyl)-benzamide (150 mg, 0.42 mmol), DMF (5 mL) and phenyl acetic acid (69 mg, 0.51 mmol). The resulting mixture was allowed to stir at room temperature overnight. Water was then added, and the product was extracted using EtOAc. The organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford a crude product, which was purified twice by column chromatography (using silica gel with a mesh size of 60-120, and 80:20 EtOAc:hexane as the eluent) to afford 4-benzyloxy-N-[2-oxo-2-(4-phenylacetyl-piperazin-1-yl)-ethyl]-benzamide in 55% yield. LC-MS purity: 92% 1H NMR (DMSO-D6): δ 8.4 (t, 1H), 7.8 (d, 2H), 7.4 (m, 7H), 7.2 (d, 3H), 7.1 (d, 2H), 5.2 (s, 2H), 4.1 (d, 2H), 3.8 (d, 2H), 3.5 (m, 8H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]([C:15]2[N:16]=[C:17]([CH2:20][N:21]3[CH2:26][C@H:25]([CH3:27])[O:24][C@H:23]([CH3:28])[CH2:22]3)[S:18][CH:19]=2)=[O:14])[CH:3]=1.[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[S:37]([NH:40][C:41]1[C:42]([O:56][CH3:57])=[N:43][CH:44]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:46]=1)(=[O:39])=[O:38].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1.C(=O)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[S:37]([NH:40][C:41]1[CH:46]=[C:45]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][N:8]3[CH3:11])=[C:4]([NH:12][C:13]([C:15]3[N:16]=[C:17]([CH2:20][N:21]4[CH2:26][C@H:25]([CH3:27])[O:24][C@H:23]([CH3:28])[CH2:22]4)[S:18][CH:19]=3)=[O:14])[CH:3]=2)[CH:44]=[N:43][C:42]=1[O:56][CH3:57])(=[O:39])=[O:38]
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(F)cc1F
Reactant: C[C@@H]1CN(Cc2nc(C(=O)Nc3cc(Br)cc4c3cnn4C)cs2)C[C@H](C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cnn(C)c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 100 °C
Yield: 25.7 %

Procedure:
N-(6-Bromo-1-methyl-1H-indazol-4-yl)-2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-thiazole-4-carboxamide (50 mg, 0.108 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (46 mg, 0.108 mmol), Pd(dppf)Cl2 (16 mg, 0.022 mmol) and tripotassium phosphate (69 mg, 0.323 mmol) were added to 1,4-dioxane (1 ml) and water (0.25 ml) then put in the microwave. The reaction mixture was heated at 100° C. for 20 min. The solvent was blown down to give a brown oil which was dissolved in water (1 ml) and dioxane (1 ml), put in cardice for 15 min then put on freeze dryer to give a brown solid which was purified by MDAP (Method E) to give the title compound as a white solid (19 mg).
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[Br:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([NH2:21])=[C:16]([Cl:22])[CH:15]=1.C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:21]/[C:17]1[C:18]([Cl:20])=[CH:19][C:14]([Br:13])=[CH:15][C:16]=1[Cl:22])=[N+:2]=[N-:3]
Reactant: Nc1c(Cl)cc(Br)cc1Cl
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=Nc1c(F)cncc1/C=N/c1c(Cl)cc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 4-azido-5-fluoropyridine-3-carbaldehyde (10.0 g, 60.0 mmol) and 4-bromo-2,6-dichlorophenylamine (14.4 g, 60.0 mmol) in DCM (200 mL) was cooled to 0° C., under an atmosphere of nitrogen. Triethylamine (25 mL, 180 mmol) was added, followed by dropwise addition of titanium (IV) chloride solution (1 N in DCM, 36 mL, 36 mmol). The reaction mixture was stirred at 0° C. then allowed to reach room temperature overnight. The resultant mixture was concentrated under reduced pressure and the residue was suspended in toluene and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford the title compound (quantitative yield). This was used in the next step without further purification.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][N:8]2[C:20]3[C:19]4[NH:21][C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=5[C:18]=4[C:17]4[C:28](=[O:32])[NH:29][C:30](=[O:31])[C:16]=4[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:4][O:3]1.C(=O)([O-])O.[K+]>Cl.C(O)C>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][N:8]1[C:20]2[C:19]3[NH:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[C:18]=3[C:17]3[C:28](=[O:32])[NH:29][C:30](=[O:31])[C:16]=3[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: CC1(C)OCC(Cn2c3ccccc3c3c4c(c5c6ccccc6[nH]c5c32)C(=O)NC4=O)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCO
Product: O=C1NC(=O)c2c1c1c3ccccc3[nH]c1c1c2c2ccccc2n1CC(O)CO

Procedure:
150 mg (0.34 mmol) 12-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-6,7,12,13-tetrahydro-5,7-dioxo-5H-indolo-[2,3-a]pyrrolo[3,4-c]carbazole in 50 ml 1N hydrochloric acid/ethanol (1:1 v/v) are stirred for 16 hours at 60° C. After cooling, the reaction mixture is neutralised with 10% potassium hydrogen carbonate solution and extracted twice with, in each case, 100 ml ethyl acetate. The ethyl acetate extracts are washed with 100 ml of water, dried over anhydrous sodium sulphate, filtered and evaporated. The residue is chromatographed on silica gel with toluene/acetone (4:1 v/v) and the fraction with the Rf 0.2 in toluene/acetone (3:1 v/v) is isolated. 12-(2,3-Dihydroxy-1-propyl)-6,7,12,13-tetrahydro-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole is obtained in the form of an orange amorphous powder which decomposes from about 310° C.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:31])[C@@H:15]([C:24]1([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)C1C=CC=CC=1.[O:32]1CCCC1.O.OO.O.[OH-].[Li+]>O.O1CCCC1>[OH:30][C:24]1([C@@H:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:14]([OH:31])=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COc1ccc([C@@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)C2(O)CCCCC2)cc1
Reactant: C1CCOC1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COc1ccc([C@@H](C(=O)O)C2(O)CCCCC2)cc1
Yield: 89 %

Procedure:
A solution of (4S)-4-benzyl-3-[(2R)-2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)-acetyl]-1,3-oxazolidin-2-one (1.02 g, 2.4 mmol) in 4:1 tetrahydrofuran/water (25 mL) at 0° C. was treated dropwise with a premixed solution of hydrogen peroxide (50% in water, 0.59 mL, 9.6 mmol) and lithium hydroxide monohydrate (115 mg, 4.8 mmol) in water (1 mL). The reaction was stirred at 25° C. for 2 h after which time the tetrahydrofuran was evaporated in vacuo and the aqueous layer was treated with a 2 N aqueous solution of sodium hydroxide (5 mL). The aqueous layer was extracted with ethyl acetate (2×15 mL) followed by methylene chloride (2×15 mL) and the aqueous layer was acidified to pH=2 with a 2 N aqueous solution of hydrochloric acid. The product was extracted with ethyl acetate (3×50 mL) and the combined organic extracts were dried over magnesium sulfate and concentrated to yield a white solid which was recrystallized from ethyl acetate/hexane to yield 565 mg (89%) (2R)-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetic acid. MS (ESI) m/z 247; MS (ESI) m/z 263; [α]D25=+71° (c=0.010 g/mL, EtOH); HRMS: calcd for C15H2OO4+NH4+, 282.16998; found (ESI-FT/MS, [M+NH4]1+), 282.1706; enantiomeric excess >99%. The enantiomeric purity was determined, compared to the racemate, under the following Supercritical Fluid Chromatography conditions using Analytical Supercritical Fluid Chromatography (Berger Instruments, Inc. Newark, Del. USA):
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12].CCOC(C)=O>CN(C1CCCCC1)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][S:11](=[O:13])(=[O:12])[N:14]([CH3:16])[CH3:15])=[CH:3][CH:4]=1)=[O:7]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=Cc1ccc(O)cc1
Solvent: CN(C)C1CCCCC1
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)Oc1ccc(C=O)cc1
Temperature: 92.5 °C

Procedure:
A stirred solution of 4-hydroxybenzaldehyde (1.0 g, 8.02 mmol) in N,N-dimethylcyclohexylamine (7 mL) was heated to 90-95° C. and at this temperature ClSO2NMe2 (0.87 mL, 8.02 mL) was added dropwise. The reaction mixture was then heated at 90-95° C. for 3 h. After cooling to room temperature, EtOAc (100 mL) was added and the organic layer was washed with 1M hydrochloric acid (2×100 mL) and then brine (3×50 mL), dried (Na2SO4), filtered and evaporated to give a yellow oil which solidified to a yellow wax upon storage in the refrigerator (1.82 g, 99%); 1H (270 MHz, CDCl3) 3.08 (6H, s), 7.46 (2H AA′BB′), 7.94 (2H AA′BB′) and 10.0 (1H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:24][C:23]4[CH:25]=[C:26]([Br:29])[CH:27]=[CH:28][C:22]=4[N:21]=3)=[CH:16][C:15]=2[NH2:30])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([C:35]1[C:36]([N:42]=[CH:43][N:44]([CH3:46])C)=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=1)#N>>[CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:24][C:23]4[CH:25]=[C:26]([Br:29])[CH:27]=[CH:28][C:22]=4[N:21]=3)=[CH:16][C:15]=2[NH:30][C:46]2[C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[N:37][C:36]=3[N:42]=[CH:43][N:44]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(-c2nc3ccc(Br)cc3[nH]2)ccc1Oc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Product: Cc1ccc2c(Nc3cc(-c4nc5ccc(Br)cc5[nH]4)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1

Procedure:
The product from Example 147C was reacted with the product from Example 10B using the procedure described in Example 147D substituting the product from Example 10B for the product from Example 36E to provide [2-(4-Benzyloxy-phenoxy)-5-(6-bromo-1H-benzoimidazol-2-yl)-phenyl]-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine which was debenzylated according to the procedure described in Example 147E to provide the crude product which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.74 (s, 3H), 6.77 (d, J=9.19 Hz, 2H), 6.95 (d, J=8.82 Hz, 2H), 7.01 (d, J=8.82 Hz, 1H), 7.35 (dd, J=8.46, 1.84 Hz, 1H), 7.54 (d, J=8.82 Hz, 1H), 7.74-7.85 (m, 2H), 8.10 (dd, J=8.82, 2.21 Hz, 1H), 8.36 (d, J=2.21 Hz, 1H), 8.90 (s, 1H), 8.95 (d, J=8.46 Hz, 1H), 9.45 (bs, 1H), 11.35 (bs, 1H); MS (ESI+) m/z 539/541 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH2:20][OH:21])[C:4]([CH:5]=[CH:6][C:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C:8]=3[CH2:9][CH2:10][C@@H:11]2[OH:22])=[CH:3]1>CCOCC>[OH:22][C@H:11]1[CH2:10][CH2:9][C:8]2=[C:7]3[C@H:16]([CH2:15][CH2:14][C@:12]12[CH3:13])[C@:17]1([CH2:20][OH:21])[C:4](=[CH:3][C:2](=[O:1])[CH2:19][CH2:18]1)[CH:5]=[CH:6]3
Reactant: C[C@]12CC[C@H]3C(=C1CC[C@@H]2O)C=CC1=C[C@@H](O)CC[C@@]13CO
Solvent: CCOCC
Product: C[C@]12CC[C@H]3C(=C1CC[C@@H]2O)C=CC1=CC(=O)CC[C@@]13CO

Procedure:
A mixture of 20 mg. of 3β,17β,19-trihydroxyandrosta-4,6,8(14)-triene, 20 mg. of dichlorodicyanoquinone and 2.0 ml. of ether was shaken under nitrogen for 20 minutes. Subsequent filtration afforded the compound 17β,19-dihydroxyandrosta-4,6,8-(14)-trien-3-one, λ max 344 mμ.
Reaction SMILES: COC([C@@H]1C[C@@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1C(=S)CC(=O)C)=O.COC([C@H]1C[C@@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1C(=S)CC(=O)C)=O.S(O)(O)(=O)=O.C(NN)CC1C=CC=CC=1.[CH3:72][O:73][C:74]([C@H:76]1[CH2:80][C@@H:79]([S:81]([C:84]2[CH:89]=[CH:88][CH:87]=[CH:86][C:85]=2[C:90]([F:93])([F:92])[F:91])(=[O:83])=[O:82])[CH2:78][N:77]1[C:94]1[N:95]([CH2:100][CH2:101][C:102]2[CH:107]=[CH:106][CH:105]=[CH:104][CH:103]=2)[N:96]=[C:97]([CH3:99])[CH:98]=1)=[O:75]>>[CH3:72][O:73][C:74]([C@@H:76]1[CH2:80][C@@H:79]([S:81]([C:84]2[CH:89]=[CH:88][CH:87]=[CH:86][C:85]=2[C:90]([F:91])([F:92])[F:93])(=[O:82])=[O:83])[CH2:78][N:77]1[C:94]1[N:95]([CH2:100][CH2:101][C:102]2[CH:103]=[CH:104][CH:105]=[CH:106][CH:107]=2)[N:96]=[C:97]([CH3:99])[CH:98]=1)=[O:75]
Reactant: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1CCc1ccccc1
Agent: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Agent: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Agent: NNCCc1ccccc1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1CCc1ccccc1

Procedure:
In analogy to the procedure described in example 192 h, a mixture of (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) and of (2R,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with 2-phenethyl-hydrazine sulfate (CAS Reg. No. 56-51-4) to give a mixture of the title compound and (2R,4R)-1-(5-methyl-2-phenethyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as orange oil. MS (ESI): m/z=522.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:13])[CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)=[O:4].N1C=CC=C1.[F:19][C:20]([F:44])([F:43])[C:21]1[CH:26]=[CH:25][C:24]([S:27][CH2:28][CH2:29][O:30][C:31](=O)[O:32]C2C=CC([N+]([O-])=O)=CC=2)=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>CC(=O)OCC.C(Cl)Cl.CN(C1C=CN=CC=1)C.[Pd].O>[CH3:13][N:6]1[CH:7]=[C:8]([NH:10][C:31]([O:30][CH2:29][CH2:28][S:27][C:24]2[CH:25]=[CH:26][C:21]([C:20]([F:19])([F:44])[F:43])=[CH:22][CH:23]=2)=[O:32])[CH:9]=[C:5]1[C:3]([O:2][CH3:1])=[O:4]
Reactant: O=C(OCCSc1ccc(C(F)(F)F)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])cn1C
Agent: [Pd]
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1cc[nH]c1
Product: COC(=O)c1cc(NC(=O)OCCSc2ccc(C(F)(F)F)cc2)cn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
After 1-methyl-4-nitropyrrole-2-carboxylic acid methyl ester (1.17 g, 6.35 mmol) was dissolved in EA (20 ml), 10% Pd/C (50 mg, catalytic weight) was added thereto. The mixture was stirred for 1 hour at room temperature under hydrogen atmosphere to reduce a nitro group (NO2) into an amino group (NH2), whereby a pyrrole-type amino acid was obtained. 10% Pd/C was filtered out by celite 545 filter, and the filtrate was washed with EA and MeOH and concentrated under vacuum. To the residue were added carbonic acid 4-nitro-phenyl ester 2-(4-trifluoromethyl-phenylsulfanyl)-ethyl ester (2.23 g, 5.76 mmol) dissolved in anhydrous DCM (30 ml), DIEA (2.01 μm, 11.56 mmol), DMAP (1.41 g, 11.56 mmol), and HOBt (1.77 g, 11.56 mmol), and the mixture was stirred for 12 hours at room temperature. The reaction was stopped by adding water and the reaction mixture was extracted with DCM. The organic layer was dried over anhydrous MgSO4 and concentrated. The residue was purified by silica gel column chromatography (EA/n-hexane=1/3, v/v) to give methyl 1-methyl-4-[2-(4-trifluoromethyl-phenylsulfanyl)-ethoxycarbonylamino]-1H-pyrrole-2-carboxylate (1.98 g, 85.42%) of a pale yellow solid.