Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24])=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24])=[O:19]
Reactant: C[C@@H](CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@@H](CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A mixture of tert-butyl{(2S)-1-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate 60 (0.237 g, 0.528 mmol) and Pd/C (0.200 g) in methanol (20 mL) was hydrogenated at 35 psi at room temperature for 2 h. The mixture was filtered through a Celite pad and concentrated to provide 61 (crude, 0.189 g. quant.) as a colorless foam which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[N:3]=1.Cl[S:18]([OH:21])(=[O:20])=[O:19].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[OH-:8].[NH2:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:5]=[C:6]([NH2:9])[N+:7]=1[O:8][S:18]([OH:21])(=[O:20])=[O:19]
Reactant: CN1CCN(c2cc(N)[n+]([O-])c(N)n2)CC1
Reactant: O=S(=O)(O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2cc(N)[n+](OS(=O)(=O)O)c(N)n2)CC1
Product: [OH-]
Reaction time: 8 h

Procedure:
A mixture of 1.00 grams of 2,4-diamino-6-(4-methyl-1-piperazinyl)pyrimidine-3-oxide, 1.50 grams of chlorosulfonic acid, and 2.5 grams of di-isopropylethylamine in 25 ml of chloroform is stirred overnight. The mixture is concentrated in vacuo. The residue is stirred with aqueous sodium bicarbonate, filtered and washed with ether to give the crude product. This is recrystallized from DMF and ethyl acetate to yield the purified 2,6-diamino-4-(4-methyl-1-piperazinyl)-1-(sulfooxy)pyrimidinium hydroxide, inner salt.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:11]1[N:12]=[C:13]([NH:16][C:17](=[O:20])[CH2:18][Cl:19])[S:14][CH:15]=1)[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[K+]>C(O)C.O>[CH2:1]([O:3][N:4]=[C:5]([C:11]1[N:12]=[C:13]([NH:16][C:17](=[O:20])[CH2:18][Cl:19])[S:14][CH:15]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCON=C(C(=O)OCC)c1csc(NC(=O)CCl)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Yield: 91 %

Procedure:
1.06 g of ethyl α-ethoxyimino-2-(chloroacetylamino)-thiazol-4-ylacetate is suspended in a solution of 0.94 g of potassium hydroxide in a mixture of 40 ml of ethanol and 2 ml of water and the suspension is stirred at room temperature to make it to be a solution, followed by further stirring for 45 minutes at room temperature. The reaction solution is subjected to the distillation of ethanol under reduced pressure and the residue is adjusted to pH 2.0 with 1 N hydrochloric acid under ice-cooling, to precipitate crystals. The crystals are filtered, washed with water and dried. The procedure yields 0.88 g of α-ethoxyimino-2-(chloroacetylamino)thiazol-4-ylacetic acid. Yield 91%.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH:6]([CH:8]=O)[CH2:5][C@H:4]([CH3:10])[O:3]1.[Br:11][C:12]1[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.C(OCC)(=O)C>[Br:11][C:12]1[N:17]=[C:16]([NH:18][CH2:8][CH:6]2[CH2:7][C@H:2]([CH3:1])[O:3][C@H:4]([CH3:10])[CH2:5]2)[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc(Br)n1
Reactant: C[C@@H]1CC(C=O)C[C@H](C)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@@H]1CC(CNc2cccc(Br)n2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 43.8 %

Procedure:
The mixture of (2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-carbaldehyde (120 mg, 0.84 mmol) and 6-bromo-2-aminopyridine (219 mg, 1.26 mmol) in 5 ml DCM was stirred at ambient temperature for about 40 min. To this solution was added sodium triacetoxy borohydride (268 mg, 1.26 mmol), followed by the addition of 0.01 ml acetic acid. The resulting solution was stirred at ambient temperature for about 40 hours. The reaction mixture was concentrated in vacuo to yield a residue was diluted with ethyl acetate, washed with sodium bicarbonate, brine, dried, concentrated. The resulting residue was purified by ISCO eluting with 10% to 20% ethyl acetate in heptane to yield 110 mg of the desired product as colorless oil. LCMS (m/z): 299/301 (MH+), retention time=1.01 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:3]1.CC1C=C(C=C(C)C=1N(C)C)[CH:16]=[O:17]>O1CCOCC1>[CH3:11][C:2]1([CH3:1])[N:3]=[C:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:16][O:17]1
Reactant: Cc1cc(C=O)cc(C)c1N(C)C
Reactant: CC1(C)N=C1c1ccccc1
Solvent: C1COCCO1
Product: CC1(C)N=C(c2ccccc2)CO1

Procedure:
2.6 g of 2,2-dimethyl-3-phenyl-2H-azirine and 2,5 g of 3,5-dimethyl-4-(dimethylamino)benzaldehyde were exposed to light for 2 hours in 300 ml of 1,4-dioxane (with the light source described in Example 2). After purification as described in Example 12 and crystallization from n-pentane, there was obtained 5-[4-dimethylamino)-3,5-xylyl]-2,2-dimethyl-4-phenyl-3-oxazoline which melted at 91°-92° C. after drying for 2 hours at 50° C. and 13 Torr.
Reaction SMILES: [O:1]=[S:2]1(=[O:49])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]3[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.[CH:50]1([S:53]([NH2:56])(=[O:55])=[O:54])[CH2:52][CH2:51]1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH:50]1([S:53]([NH:56][C:37](=[O:38])[C:36]2[CH:35]=[CH:34][C:33]([C:20]3[C:21]([CH3:32])([CH3:31])[C@H:22]4[C@:17]([CH3:42])([CH2:18][CH:19]=3)[C@@H:16]3[C@:25]([CH3:30])([C@@:26]5([CH3:29])[C@H:13]([CH2:14][CH2:15]3)[C@H:12]3[C@H:43]([C:46]([CH3:48])=[CH2:47])[CH2:44][CH2:45][C@:11]3([NH:10][CH2:9][CH2:8][N:5]3[CH2:6][CH2:7][S:2](=[O:1])(=[O:49])[CH2:3][CH2:4]3)[CH2:28][CH2:27]5)[CH2:24][CH2:23]4)=[CH:41][CH:40]=2)(=[O:55])=[O:54])[CH2:52][CH2:51]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)Cl)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)NS(=O)(=O)C7CC7)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 12 %

Procedure:
A mixture of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-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)benzoyl chloride (30 mg, 0.042 mmol), cyclopropanesulfonamide (6.15 mg, 0.051 mmol), Hunig's Base (0.022 mL, 0.127 mmol) and DMAP (2.58 mg, 0.021 mmol) in dichloromethane (1 mL) was stirred for 16 h at room temperature. The crude reaction mixture was purified by prep HPLC to provide the title compound as a white solid (4 mg, 11%). LCMS: m/e 794.53 (M+H)+, 2.44 min (method 10). 1H NMR (500 MHz, Acetic acid d4) δ ppm 7.94 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.2 Hz, 2H), 5.38 (d, J=4.6 Hz, 1H), 4.84 (s, 1H), 4.74 (s, 1H), 3.56-3.39 (m, 1H), 3.38-3.21 (m, 7H), 3.21-3.11 (m, 3H), 3.11-3.03 (m, 2H), 3.01-2.89 (m, 1H), 2.41-1.16 (m, 26H), 1.76 (s, 3H), 1.29 (s, 3H), 1.15 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: C([O:5][C:6]1[C:11]([CH2:12][NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[CH:16][C:15]=2[C:24]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=O)=[CH:10][CH:9]=[CH:8][N:7]=1)(C)(C)C.[O-]C#[N:37].[Na+].C(OCC)(=O)C.[C:45](=[O:48])(O)[O-]>C(O)(=O)C>[OH:5][C:6]1[C:11]([CH2:12][N:13]2[C:14]3[C:15](=[CH:16][C:17]([O:20][CH2:21][C:22]#[CH:23])=[CH:18][CH:19]=3)[C:24]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=3)=[N:37][C:45]2=[O:48])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: N#C[O-]
Reactant: O=C([O-])O
Reactant: C#CCOc1ccc(NCc2cccnc2OC(C)(C)C)c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccnc1O
Reaction time: 8 h

Procedure:
A solution of 290 mg (0.635 mmol) of {2-[(2-tert-butoxy-pyridin-3-ylmethyl)-amino]-5-propargyloxy-phenyl}-(4-isopropyl-phenyl)-methanone and in 7 ml acetic acid is reacted with 50 mg (0.762 mmol) sodium cyanate. After stirring overnight the mixture is distributed between ethyl acetate and aqueous bicarbonate solution. The organic layer is concentrated to yield the title compound in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[NH:30]([CH2:34][CH2:35]O)[CH2:31][CH2:32][OH:33]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:35][CH2:34][NH:30][CH2:31][CH2:32][OH:33])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: OCCNCCO
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCNCCO

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{2-[(2-hydroxyethyl)amino]ethyl}-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and diethanolamine following General Procedure K.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:10]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[CH2:16])#[N:11]>C(Cl)Cl>[NH2:9][C:3]1[C:2](/[CH:16]=[CH:15]/[C:14]2[CH:13]=[C:12]([CH:19]=[CH:18][CH:17]=2)[C:10]#[N:11])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1
Reactant: Nc1ncc(Cl)cc1Br
Reactant: C=Cc1cccc(C#N)c1
Solvent: ClCCl
Product: N#Cc1cccc(/C=C/c2cc(Cl)cnc2N)c1

Procedure:
The title compound was prepared from 3-bromo-5-chloro-2-pyridinamine and 3-cyanostyrene. Methylene chloride extracts of the crude reaction mixture were concentrated and the desired product purified by column chromatography on silica gel eluting with methylene chloride—methanol (98:2) to give a yellow solid:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21])[C:9]([CH2:24]Cl)=[CH:8]2.CN(C=O)C.[N-:31]=[N+:32]=[N-:33].[Na+]>>[N:31]([CH2:24][C:9]1[C:10]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])=[N:11][C:12]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[Cl:2])=[N+:32]=[N-:33]
Reactant: Fc1ccc(C(F)(F)F)c(-c2nc3c(Cl)cccc3cc2CCl)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc2cccc(Cl)c2nc1-c1cc(F)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirring solution of 8-chloro-3-(chloromethyl)-2-(5-fluoro-2-(trifluoro-methyl)phenyl)quinoline hydrochloride (0.3482 g, 0.8480 mmol) in DMF (4.240 mL, 0.8480 mmol) was added sodium azide (0.1103 g, 1.696 mmol) at room temperature and the mixture was stirred at room temperature. After 1.5 h, the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The organic layer was washed with brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min, then 50% isocratic of EtOAc for 5 min as eluent to give 3-(azidomethyl)-8-chloro-2-(5-fluoro-2-(trifluoromethyl)phenyl)quinoline as a colorless syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65 (1 H, s), 8.12 (1 H, dd, J=8.3, 1.3 Hz), 7.99-8.06 (2 H, m), 7.69 (1 H, dd, J=8.1, 7.5 Hz), 7.58-7.66 (2 H, m), 4.44-4.59 (2 H, m); LC-MS (ESI) m/z 381.1 [M+H]+. To a solution of 3-(azidomethyl)-8-chloro-2-(5-fluoro-2-(trifluoromethyl)phenyl)-quinoline (0.2573 g, 0.676 mmol) in methanol (6.76 mL, 0.676 mmol) was added palladium, 10 wt. % on activated carbon (0.0360 g, 0.0338 mmol). After repeating three times of evacuation of air in the flask by house vacuum and filling the flask with H2, the mixture was stirred under H2. After 30 min, the mixture was filtered through a pad of Celite™ and rinsed the pad with MeOH. The filtrate was concentrated under reduced pressure to give green syrup. The green syrup was purified by column chromatography on a 40 g of Redi-Sep™ column using 0% to 20% gradient of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 over 14 min, and then 20% isocratic of CH2Cl2:MeOH:NH4OH (89:9:1) for 20 min as eluent to give (8-chloro-2-(5-fluoro-2-(trifluoromethyl)phenyl)quinolin-3-yl)methanamine as a yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (1 H, s), 8.04 (1 H, dd, J=8.4, 1.2 Hz), 8.01 (1 H, dd, J=8.5, 5.4 Hz), 7.93 (1 H, dd, J=7.4, 1.4 Hz), 7.54-7.67 (3 H, m), 3.48-3.74 (2 H, m), 1.96 (2 H, br. s.); LC-MS (ESI) m/z 355.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10].F[B-](F)(F)F.[CH2:23]([O+](CC)CC)[CH3:24].O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:12][C:13]([O:17][CH2:23][CH3:24])=[N:14][CH2:15][CH2:16]1)=[O:10]
Reactant: O=C1CN(C(=O)c2ccc(F)cc2Cl)CCN1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC1=NCCN(C(=O)c2ccc(F)cc2Cl)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.1 %

Procedure:
4-[(2-Chloro-4-fluorophenyl)carbonyl]-2-piperazinone (0.770 g, 3 mmol, e.g. as prepared in Intermediate 2) was dissolved in Dichloromethane (8 mL) and to this was added triethyloxonium tetrafluoroborate (1.425 g, 7.50 mmol). The reaction mixture was stirred for 18 hours at room temperature. Dichloromethane (30 ml) and iced water (15 ml) were added and the pH was adjusted to pH 7 with solid sodium hydrogen carbonate. The organic phase was separated, washed with brine, dried and evaporated to give crude 1-[(2-chloro-4-fluorophenyl)carbonyl]-5-(ethyloxy)-1,2,3,6-tetrahydropyrazine (0.556 g) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][C:15](B(O)O)=[CH:16][CH:17]=2)[CH:12]=[N:11]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(Cl)Cl.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>[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:2]3[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=3)=[CH:16][CH:17]=2)[CH:12]=[N:11]1
Reactant: Oc1ccc(Br)cn1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ncc2cc(-c3ccc(=O)[nH]c3)ccc21
Temperature: 80 °C

Procedure:
The suspension of 5-bromo-2-hydroxypyridine (80 mg, 0.46 mmol), 1-methyl-1H-indazol-5-ylboronic acid (121 mg, 0.69 mmol) and 2N sodium carbonate solution (1.0 mL, 2 mmol) in DMF (2.1 mL) was degassed with N2 for 5 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (53 mg, 0.04 mmol), and the resulting mixture was heated at 80° C. overnight. The mixture was then diluted with CH2Cl2, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to give the product. LCMS-ESI+ (m/z): [M+H]+ calcd for C13H12N3O: 226.25; Found: 226.3.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH:20]([OH:22])[CH3:21])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH:20]([OH:22])[CH3:21])=[CH:13][CH:12]=2)[C:3]([OH:23])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C#CCC(C)O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)CC#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 108.7 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(4-hydroxy-pent-1-ynyl)-phenyl]-propionic acid methyl ester (545 mg, 1.73 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was treated with lithium hydroxide (830 mg, 19.8 mmol). The reaction mixture was stirred at 25° C. for 3 d. At this time, the reaction was concentrated in vacuo. The residue was diluted with water (40 mL). This solution was acidified to pH=2 with concentrated hydrochloric acid and then extracted with ethyl acetate (2×40 mL). The combined organic extracts were then washed with a half-saturated sodium chloride solution (1×40 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 3-cyclopentyl-2-[4-(4-hydroxy-pent-1-ynyl)-phenyl]-propionic acid (565 mg, quant.) as a light brown solid: mp 73-76° C.; EI-HRMS m/e calcd for C19H24O3 (M) 300.1725, found 300.1724.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:5]=[CH:6][NH:7][C:8](=[O:31])[C:9]=2[CH:10]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[O:27][C:26]([CH3:29])=[CH:25][C:24]3=[O:30])[C:11]=1[C:12](OCCC#N)=[O:13].[CH2:32]1[CH2:36]OCC1.C(N1C=CN=C1)([N:39]1C=CN=C1)=O.N>ClCCl.CO.C(OCC)(=O)C>[CH2:36]([O:31][C:8]1[N:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=1[O:27][C:26]([CH3:29])=[CH:25][C:24]3=[O:30])[C:11]([C:12]([NH2:39])=[O:13])=[C:2]([CH3:1])[NH:3]2)[CH3:32]
Reactant: C1CCOC1
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc3c(=O)cc(C)oc23)c2c(cc[nH]c2=O)N1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOc1nccc2c1C(c1cccc3c(=O)cc(C)oc13)C(C(N)=O)=C(C)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
155 mg (0.395 mmol) of the compound from Example 31A are introduced into 10 ml of THF and, after addition of 80.1 mg (0.494 mmol) of 1,1′-carbonyldiimidazole, stirred at room temperature overnight. A TLC check (silica gel; mobile phase: ethyl acetate or dichloromethane/methanol 9:1) shows complete conversion. The volatile components are removed in a rotary evaporator, and the residue is taken up in 3 ml of DMF. Then 553 mg of ammonia (28% by weight solution in water, 3.95 mmol) are added, and the reaction mixture is heated at 100° C. for 10 min. The solvent is removed under reduced pressure, and the residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 30 mg (19% of theory) of the title compound are obtained.
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[CH:23]1([CH2:26]C=O)[CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH:23]1([CH2:26][N:8]2[CH2:9][CH2:10][C:4]3=[CH:3][N:2]([C:11]4[CH:12]=[CH:13][C:14]([N:17]5[CH2:21][CH2:20][CH2:19][C:18]5=[O:22])=[CH:15][CH:16]=4)[N:1]=[C:5]3[CH2:6][CH2:7]2)[CH2:25][CH2:24]1
Reactant: O=C1CCCN1c1ccc(-n2cc3c(n2)CCNCC3)cc1
Reactant: O=CCC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1CCCN1c1ccc(-n2cc3c(n2)CCN(CC2CC2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-[4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]-2-pyrrolidinone (may be prepared as described in Description 22) (55 mg, 0.10 mmol) in dichloromethane (5 ml) was added cyclopropylacetaldehyde (26 mg, 0.30 mmol) and acetic acid (3 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (64 mg, 0.30 mmol) was added and stirring continued for 18 hours. The resulting crude mixture was diluted with methanol and then purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were collected and solvent evaporated in vacuo. Crude product was triturated with ethyl acetate to afford the title compound (E19). MS (ES+) m/e 351 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:38](=[CH:39][CH:40]=2)[C:16]2[N:17](COCC[Si](C)(C)C)[C:18]([C:20]4[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][C:21]=4[C:22]#[N:23])=[N:19][C:15]=2[C:14]2[CH:13]=[CH:12][C:11]([CH2:41][C:42]([OH:45])([CH3:44])[CH3:43])=[CH:10][C:9]3=2)[CH2:3][CH2:2]1.O>CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:38](=[CH:39][CH:40]=2)[C:16]2[NH:17][C:18]([C:20]4[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][C:21]=4[C:22]#[N:23])=[N:19][C:15]=2[C:14]2[CH:13]=[CH:12][C:11]([CH2:41][C:42]([OH:45])([CH3:43])[CH3:44])=[CH:10][C:9]3=2)[CH2:3][CH2:2]1
Reactant: CC(C)(O)Cc1ccc2c(c1)c1cc(OCC3CC3)ccc1c1c2nc(-c2c(C#N)cccc2C#N)n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CC(C)(O)Cc1ccc2c(c1)c1cc(OCC3CC3)ccc1c1[nH]c(-c3c(C#N)cccc3C#N)nc21
Yield: 36 %

Procedure:
Crude 2-(9-(cyclopropylmethoxy)-6-(2-hydroxy-2-methylpropyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile (1.37 mmol) from Step 6 above was dissolved in TBAF (1 M in THF, 10 mL) and the mixture heated at reflux for 1.5 h. Water was added, and the aqueous layer extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated. The material was purified by flash chromatography on silica (70% ethyl acetate in hexanes) to afford 2-[9-(cyclopropylmethoxy)-6-(2-hydroxy-2-methylpropyl)-1H-phenanthro[9,10-d]imidazol-2-yl] isophthalonitrile (240 mg).