Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].CC1(C)[O:14][C:13](=O)[CH:12]=[C:11]([CH3:16])[O:10]1>CC(C)=O>[C:13]([O:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])(=[O:14])[CH2:12][C:11]([CH3:16])=[O:10]
Reactant: C[Si](C)(C)CCO
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: CC(C)=O
Product: CC(=O)CC(=O)OCC[Si](C)(C)C

Procedure:
A mixture of 6.70 g of 2-trimethylsilylethanol (56.7 mmol) and 8.05 g of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (56.7 mmol) was placed in a round bottom flask equipped with a short distillation apparatus and heated to to drive off acetone. The calculated amount of acetone was collected, and the residue was distilled under reduced pressure. The fraction boiling at 106°-110° C. (5-10 mmHg) was collected (8.52 g, 74%). The product was used in the next step after spectral characterization.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[Cl:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9](Cl)=[O:10]>O>[Cl:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9]([NH:2][OH:3])=[O:10]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(CCl)C(=O)NO
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.9 %

Procedure:
A stirred solution of 28.0 grams (0.40 mole) of hydroxylamine hydrochloride in 60 ml of water was cooled to 0° and a solution of 16.0 grams (0.40 mole) of sodium hydroxide in 40 ml of water was added dropwise while maintaining the temperature of the reaction mixture at 0°-5°. Upon completion of addition 31.0 grams (0.20 mole) of 3-chloro-2,2-dimethylpropionyl chloride was added dropwise during a 45-minute period while maintaining the temperature of the reaction mixture at -3° to -5°. Upon completion of addition the reaction mixture was maintained at 5° for one hour, then was allowed to warm to ambient temperature where it was stirred for 16 hours. A white solid precipitate was collected by filtration and air-dried. The dried solid was recrystallized from ethanol-water to give 12.4 grams of 3-chloro-N-hydroxy-2,2-dimethylpropanamide; mp 148°-151°, decomposes.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].OO.[O-:13]Cl=O.[Na+].S([O-])([O-])=O.[Na+].[Na+].Cl>C(#N)C.O>[N+:1]([C:4]1[S:8][C:7]([C:9]([OH:13])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: O=S([O-])[O-]
Agent: OO
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a cold (0° C.) mixture of 5-nitro-thiophene-2-carboxaldehyde (10-1) (7.86 g, 50 mmol), NaH2PO4 (1.86 g, dissolved in 20 mL water), 30% H2O2 (6 mL) in acetonitrile (50 mL), a solution of NaClO2 (8 g) in water (70 mL) was added over a period of 1 h. After stirring at RT for 5 h, the reaction mixture was treated with sodium sulfite (500 mg) and 1M aq. HCl. The resultant mixture was extracted with ethyl acetate (3×). The organic extracts were combined, washed with brine, dried over anhdrous magnesium sulfate, filtered, and concentrated under vacuum to provide acid 10-2.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[CH:22]=[C:23]([CH2:29]O)[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1.[Br:31]N1C(=O)CCC1=O>ClCCl>[Br:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([CH2:29][Br:31])[CH:22]=1
Reactant: COc1cc(Br)cc(CO)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(Br)cc(CBr)c1
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
Triphenylphosphine (28 g; KANTO) was added to a dichloromethane (150 mL) solution of Intermediate 1 (22.05 g) with ice cooling, the resulting mixture was stirred for approx. 10 minutes followed by the addition of N-bromosuccinimide (20 g; TCI), and the resulting mixture was stirred at room temperature for 13 hours and 30 minutes. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (n-hexane/ethyl acetate) to give the title compound (23.94 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:13][CH:14]([OH:23])[CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[O:11][CH2:13][CH:14]([OH:23])[CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: OC(CCl)CCc1cccnc1
Reactant: COc1ccc(O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(OCC(O)CCc2cccnc2)cc1OC
Yield: 6.6 %

Procedure:
Prepared according to the method described in Example 24b) from 3,4-dimethoxyphenol (0.77 g), (±)-α-(chloromethyl)-3-pyridinepropanol (1.0 g) and sodium hydroxide (0.2 g) in ethanol (45 ml) and water (5 ml) with heating at reflux for 1 hour. After work up the residue was purified by column chromatography over silica eluting with hexane:acetone (2:1) to give the title compound as a colourless oil (0.10 g).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]2[CH2:15][O:16][C@H:12]([O:13]2)[C@@H:11]([OH:17])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O.C(Cl)(Cl)Cl>N1C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@H:14]2[CH2:15][O:16][C@H:12]([O:13]2)[C@@H:11]([O:17][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O[C@H]1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](OCc3ccccc3)[C@H]3CO[C@@H]2O3)cc1
Reaction time: 24 h
Yield: 85.6 %

Procedure:
A solution of 1,6-anhydro-4-O-benzyl-3-deoxy-β-D-arabinohexopyranose (see Example 2) (2.0 g) in dry pyridine (30 ml) containing p-toluenesulphonyl chloride (2.0 g) was allowed to stand at room temperature for 24 h. Water (0.5 ml) was added and five minutes later chloroform (100 ml). The mixture was washed with water (×2), 2M aqueous hydrochloric acid, 1M aqueous sodium hydroxide, and water. The organic layer was dried (MgSO4) and concentrated to a light yellow syrup. Trituration with ethanol gave crystalline title compound (2.83 g, 83%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:22])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:13](=[O:22])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=c1[nH]c2cnc3ccc(Br)cc3c2n1-c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1n(-c2ccccc2)c2cnc3ccc(Br)cc3c2n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
50 mg (0.13 mmol) of 8-bromo-1-(2-chloro-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one [see under B)], 48.8 mg (0.40 mmol) of phenylboronic acid (Fluka, Buchs, Switzerland), 53 mg (0.27 mmol) of cupric acetate anhydrous (Fluka, Buchs, Switzerland) and 56 μl (0.4 mmol) of triethylamine are dissolved in 1 ml of anhydrous dichloromethane and the suspension is stirred for 16 h at room temperature. After this time, additional phenylboronic acid (24 mg), cupric acetate anhydrous (27 mg) and triethylamine (28 μl) are added and the suspension is stirred at room temperature for 24 h. The suspension is evaporated to dryness and the crude compound is purified by clash chromatography (dichloromethan with 0.5% of methanol) to obtain the title compound: Analytical HPLC: tret=8.22 min (Grad. 2); ES-MS: m/e0=449.9. 451.9.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[NH:5].C([O-])(O)=O.[Na+].[CH2:23]([O:25][C:26](=[O:31])[C:27](=[O:30])[CH2:28]Br)[CH3:24]>CC(O)C>[CH2:23]([O:25][C:26]([C:27]1([OH:30])[CH2:28][N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[C:4]([C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=2[Cl:1])=[N:5]1)=[O:31])[CH3:24]
Reactant: N=C(Nc1ccc(Cl)cc1)c1ccccc1Cl
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)C1(O)CN(c2ccc(Cl)cc2)C(c2ccccc2Cl)=N1
Temperature: 80 °C

Procedure:
A mixture of 2-chloro-N-(4-chloro-phenyl)-benzamidine (I-5a), 25.1 g, 95 mmol) and NaHCO3 (84 g, 189 mmol) in 2-propanol (473 ml) was treated with 3-bromo-2-oxo-propionic acid ethyl ester (14.3 ml, 22 g, 113 mmol). The reaction mixture was heated at 80° C. for 17 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was diluted with CH2Cl2 and the organic solution was washed with H2O, dried over MgSO4, and concentrated in vacuo to provide the product, 1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylic acid ethyl ester I-5b, as a dark red residue (36 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[C:17]([C:23](O)=[O:24])[NH:18]4)=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.Cl.Cl.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][C@@H:37]([N:39]2[CH2:44][CH2:43][C@H:42]([OH:45])[C@@H:41]([CH3:46])[CH2:40]2)[CH3:38])[CH2:32][CH2:31]1>>[OH:45][C@H:42]1[CH2:43][CH2:44][N:39]([C@@H:37]([CH3:38])[CH2:36][N:33]2[CH2:32][CH2:31][CH:30]([NH:29][C:23]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[C:14]([O:13][CH2:12][C:9]3[C:8]5[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=5[O:11][CH:10]=3)[CH:22]=[CH:21][CH:20]=4)=[O:24])[CH2:35][CH2:34]2)[CH2:40][C@@H:41]1[CH3:46]
Reactant: COc1cccc2occ(COc3cccc4[nH]c(C(=O)O)cc34)c12
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: COc1cccc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@H](C)N6CC[C@H](O)[C@@H](C)C6)CC5)cc34)c12

Procedure:
This compound is synthesized analogously to example 1 from 4-(4-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 122 (see example 94) and amine 56.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][C:30]([CH:32]=[CH2:33])=[CH:31][C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C(O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][C:30]([CH2:32][CH3:33])=[CH:31][C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C=Cc1ccc2c(c1)CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc2c(c1)CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
A mixture of the product of example 164 (100 mg) and Pd—C (20 mg) in ethanol (2 ml) stirred under a hydrogen balloon at room temperature for 1 hour. The mixture was filtered through the celite and distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography eluting with chloroform-methanol (15:1) to give the titled compound (50 mg).
Reaction SMILES: C(OC([N:8]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][N:17]2[CH2:22][C:23]([O:25][C@H:26]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH:44]([F:46])[F:45])=[C:39]([O:47][CH2:48][CH:49]2[CH2:51][CH2:50]2)[CH:38]=1)[CH2:27][C:28]1[C:33]([Cl:34])=[CH:32][N+:31]([O-:35])=[CH:30][C:29]=1[Cl:36])=[O:24])[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.O1CCOCC1>C(Cl)Cl.Cl>[Cl:36][C:29]1[CH:30]=[N+:31]([O-:35])[CH:32]=[C:33]([Cl:34])[C:28]=1[CH2:27][C@@H:26]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH:44]([F:45])[F:46])=[C:39]([O:47][CH2:48][CH:49]2[CH2:51][CH2:50]2)[CH:38]=1)[O:25][C:23](=[O:24])[CH2:22][N:17]1[C:18]2[C:14](=[C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:16]1
Reactant: CC(C)(C)OC(=O)N(c1cccc2c1ccn2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc2c1ccn2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To a solution of (S)-4-(2-(2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-1H-indol-1-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (420 mg, 0.545 mmol) in DCM (10 ml), 4M HCl in dioxane (1.363 ml, 5.45 mmol) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated and the resulting crude was purified by HPLC preparative (Method 3) recovering (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-(methylsulfonamido)-1H-indol-1-yl)acetoxy)ethyl)pyridine 1-oxide (180 mg, 0.268 mmol, 49% yield). MS/ESI+ 670.09 [MH]+; [αD]=−14.56, c=0.5 in DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 9.51 (s, 1H) 8.52 (s, 2H) 7.24 (d, 1H) 7.16 (d, 1H) 6.96-7.12 (m, 4H) 6.92 (dd, 1H) 7.06 (t, 1H) 6.76 (d, 1H) 6.02 (dd, 1H) 5.22 (d, 1H) 5.05 (d, 1H) 3.89 (d, 2H) 3.41 (dd, 1H) 3.21 (dd, 1H) 2.95 (s, 3H) 1.10-1.33 (m, 1H) 0.51-0.69 (m, 2H) 0.27-0.44 (m, 2H).
Reaction SMILES: C1C=CC(O[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][C:10]#[N:11])=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]([C:26]2[C:35]3[C:30](=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:32]=[CH:33][CH:34]=3)[N:29]=[CH:28][C:27]=2[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:41])[CH:23]=[CH:24][CH:25]=1>C(#N)C>[C:40]([C:27]1[CH:28]=[N:29][C:30]2[C:35]([C:26]=1[C:22]1[CH:21]=[C:20]([NH:19][C:8](=[N:9][C:10]#[N:11])[O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:25]=[CH:24][CH:23]=1)=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([F:39])([F:37])[F:38])(=[O:41])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Solvent: CC#N
Product: N#CN=C(Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Oc1ccccc1
Yield: 46.6 %

Procedure:
A mixture of diphenyl cyanocarbonimidate (0.6 g, 2.52 mmol) and [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone (0.1 g, 0.26 mmol) in 30 mL of acetonitrile was refluxed for 3 days. Removal of solvent under reduced pressure gave a crude product that was purified by silica gel chromatography eluting with ethyl acetate/hexanes (5% to 30%) to give 65 mg (47%) of the title compound as an off-white solid. MS (ES) m/z 534.9.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1Cl
Reactant: NCCc1ccccc1
Product: Cc1sc2nc(-c3cccnc3)nc(NCCc3ccccc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-3-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-phenethylamino-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][N:29]2[CH2:34][CH2:35][NH2:36])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][N:29]2[CH2:34][CH2:35][NH:36][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: NCCN1CCCCC1CN1CCCCCC1
Solvent: CC#N
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCCCC2CN2CCCCCC2)c2ccccc21
Yield: 39 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[(hexahydro-1H-azepin-l-yl)methyl]-piperidin-l-yl]ethanamine in a yield of 39% of theory. Colourless crystals, m.p. 156°-158° C. (acetonitrile).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([C:18](O)=[O:19])=[CH:16][N:15]=[C:14]2[N:21]([CH3:25])[N:22]=[C:23]([CH3:24])[C:13]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2=NC=CC=C2N=N1.C(N(CC)CC)C.[CH3:55][O:56][C:57]1[CH:62]=[CH:61][C:60]([CH2:63][NH2:64])=[CH:59][CH:58]=1>CN(C)C=O>[CH3:55][O:56][C:57]1[CH:62]=[CH:61][C:60]([CH2:63][NH:64][C:18]([C:17]2[C:12]([NH:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[C:13]3[C:23]([CH3:24])=[N:22][N:21]([CH3:25])[C:14]3=[N:15][CH:16]=2)=[O:19])=[CH:59][CH:58]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1nn(C)c2ncc(C(=O)O)c(NCCNC(=O)OC(C)(C)C)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CNC(=O)c2cnc3c(c(C)nn3C)c2NCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 279.4 %

Procedure:
To a solution of 4-[2-(tert-butoxycarbonylamino)ethylamino]-1,3-dimethyl-pyrazolo[3,4-b]pyridine-5-carboxylic acid (96.1 mg, 0.275 mmol) in N,N-dimethylformamide (2.5 ml) was subsequently added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (91.8 mg, 0.479 mmol), 3-hydroxytriazolo[4,5-b]pyridine (39.7 mg, 0.292 mmol) and triethylamine (0.115 ml, 0.825 mmol). The reaction mixture was stirred for five minutes after which (4-methoxyphenyl)methanamine (0.072 ml, 0.550 mmol) was added. The reaction mixture was stirred at room temperature over night. The reaction mixture was partitioned between water (40 ml) and EtOAc (50 ml). The organic layer was separated and the aqueous phase was further extracted with EtOAc (3×40 ml) and dichloromethane (1×50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield 360 mg of a yellow liquid which was purified by column chromatography (silicagel using a gradient of MeOH (1-7%) in dichloromethane) to give 43 mg of a colorless sticky oil (0.092 mmol, 33%) MS (ESI) m/z=469.3 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:31])[CH2:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8]C1C2SC=CC=2N=CN=1.Cl[C:33]1[C:34]2[CH:41]=[CH:40][S:39][C:35]=2[N:36]=[CH:37][N:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>[Cu]Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:31])[CH2:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:33]1[C:34]2[CH:41]=[CH:40][S:39][C:35]=2[N:36]=[CH:37][N:38]=1
Reactant: O=C(CC(=O)Nc1ccc(Oc2ncnc3ccsc23)c(F)c1)Nc1ccc(F)cc1
Reactant: Clc1ncnc2sccc12
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Product: O=C(CC(=O)Nc1ccc(Oc2ncnc3sccc23)c(F)c1)Nc1ccc(F)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
N1-(3-Fluoro-4-hydroxyphenyl)-N3-(4-fluorophenyl)malonamide (46 mg, 0.15 mmol, Compound B of Example 25), 4-chlorothieno[2,3-d]pyrimidine (17 mg, 0.10 mmol), cesium carbonate (49 mg, 0.15 mmol), and copper(I) chloride (10 mg, 0.10 mmol) were placed in a test tube. The tube was sealed, flushed with nitrogen, charged with 1-methyl-2-pyrrolidinone (0.3 mL) followed by 2,2,6,6-tetramethyl-3,5-heptanedione (4.0 μL, 0.02 mmol). The reaction was stirred at 120° C. for 1 h. The reaction mixture was purified by preparative HPLC. The appropriate fraction was concentrated to remove methanol and the resulting aqueous solution was made basic with saturated NaHCO3 solution (5 mL). The aqueous solution was extracted with EtOAc (3×10 mL) and the combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to give the desired product as a colorless oil. Lyophilization with methanol/water gave the title compound (27 mg, 61%) as a white solid. 1H NMR (DMSO-d6) δ 10.7 (s, 1H), 10.4 (s, 1H), 8.77 (s, 1H), 8.15 (d, 1H, J=5.9 Hz), 7.95 (dd, 1H, J=12.8, 2.0 Hz), 7.85 (d, 1H, J=5.9 Hz), 7.77 (m, 2H), 7.54 (m, 2H), 7.30 (t, 2H, J=8.8 Hz), 3.48 (s, 2H); MS(ESI+) m/z 441.1 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[N:8][C:9]([C:15]2[NH:16][C:17](=[O:24])[C:18]([CH:21]([CH3:23])[CH3:22])([CH3:20])[N:19]=2)=[C:10]([CH:14]=1)[C:11](O)=[O:12].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:14]=[C:10]2[C:11](=[O:12])[N:19]3[C:18]([CH:21]([CH3:23])[CH3:22])([CH3:20])[C:17](=[O:24])[N:16]=[C:15]3[C:9]2=[N:8][CH:7]=1
Reactant: CC(C)C1(C)N=C(c2ncc(C3OCCO3)cc2C(=O)O)NC1=O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(C)C1(C)C(=O)N=C2c3ncc(C4OCCO4)cc3C(=O)N21
Yield: 117.3 %

Procedure:
5-(1,3-Dioxolan-2-yl)-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid (10.02 g, 0.03 mol) and acetic anhydride in toluene is heated at reflux temperature for 5 hours. Concentration in vacuo gives the title compound as an orange solid (11.10 g, 100%), mp 146°-148° C., identified by IR and NMR spectral analyses.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].[OH:10][C:11]1[CH:20]=[CH:19][C:14]2[S:15][C:16](=[O:18])[O:17][C:13]=2[CH:12]=1.O>CN(C)C=O>[CH2:7]([O:10][C:11]1[CH:20]=[CH:19][C:14]2[S:15][C:16](=[O:18])[O:17][C:13]=2[CH:12]=1)[CH3:8]
Reactant: CCI
Reactant: O=c1oc2cc(O)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2sc(=O)oc2c1
Reaction time: 4 h

Procedure:
Potassium carbonate (533 mg) and ethyl iodide (160 μL) were added to a solution of 6-hydroxy-1,3-benzoxathiol-2-one (336 mg) in N,N-dimethylformamide (10 mL) to form a reaction solution. This reaction solution was stirred for 4 hours at normal temperature. Water was added to the reaction solution. The precipitated crystals were filtered off, thoroughly washed with water and diisopropyl ether, and then dried under reduced pressure to obtain the target product (245 mg) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18](OC)=[O:19])[CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>ClCCl>[CH:18]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:19]
Reactant: COC(=O)[C@H](CSc1ccccc1)NC(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C=O)CSc1ccccc1
Reaction time: 3 h

Procedure:
A solution of Example 133A (8.1 g, 26.0 mmol) in dichloromethane at −78° C. was treated with 1M DIBAL-H in dichloromethane (52 mL, 52 mmol), stirred for 3 hours, quenched with methanol (20 mL), and poured into saturated NaH2PO4. The mixture was extracted with ethyl acetate (3×300 mL), and the combined extracts were dried (Na2SO4), filtered, concentrated, and purified by flash column chromatography on silica gel with 30% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 280 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]=1[C:19]([N:21]1C[CH2:24][C@@H:23]([OH:26])[CH2:22]1)=[O:20].Cl.N1CC(O)C1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]=1[C:19]([N:21]1[CH2:24][CH:23]([OH:26])[CH2:22]1)=[O:20]
Reactant: O=C(c1[nH]c2ccncc2c1Nc1ccc(I)cc1F)N1CC[C@@H](O)C1
Agent: Cl
Agent: OC1CNC1
Product: O=C(c1[nH]c2ccncc2c1Nc1ccc(I)cc1F)N1CC(O)C1

Procedure:
The title compound was prepared in an analogous fashion to [3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridin-2-yl]-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone, replacing (R)-pyrrolidin-3-ol hydrochloride with azetidin-3-ol hydrochloride. 1H-NMR (400 MHz, MeOD) 6 ppm 8.84 (s, 1H), 8.34 (d, J=6.55 Hz, 1H), 7.77 (d, J=6.58 Hz, 1H), 7.50 (dd, J=10.88 Hz, 1H), 7.29 (d, J=8.54 Hz, 1H), 6.62 (t, J=8.83 Hz, 1H), 4.60-4.52 (m, 1H), 4.50-4.31 (m, 2H), 4.19-3.82 (m, 2H); LC-MS (method E): [M+H]+=453.1, RT=3.55 min.