Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(Cl)CCl.C(N(C(C)C)C(C)C)C.[CH2:28]([N:30]1[N:34]=[N:33][C:32]([C:35]2[S:39][C:38]([NH2:40])=[N:37][C:36]=2[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N:31]1)[CH3:29]>CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([NH:40][C:38]2[S:39][C:35]([C:32]3[N:33]=[N:34][N:30]([CH2:28][CH3:29])[N:31]=3)=[C:36]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:37]=2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCn1nnc(-c2sc(N)nc2-c2ccccc2)n1
Reactant: COc1ccc(CC(=O)O)cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCn1nnc(-c2sc(NC(=O)Cc3ccc(OC)c(OC)c3)nc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
200 μL of a 0.6M stock solution of (3,4-dimethoxy-phenyl)-acetic acid was mixed with 200 μL of a 0.3M stock solution of EDC containing 1 eq. of ethyl-diisopropyl-amine. Then 100 μL of a 0.3M stock solution of 5-(2-ethyl-2H-tetrazol-5-yl)-4-phenyl-thiazol-2-ylamine containing 1 eq. of DMAP was added. The reaction mixture was shaken overnight at ambient temperature. Purification was performed by preparative LC-MS. Yield: 13%.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9](=[O:19])[CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:20]([O:22]C)=O)[CH:4]=1)[CH3:2].CN(C)C=O.[H-].[Na+].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:35][CH:34]=1>C(OCC)(=O)C>[CH2:1]([C:3]1[S:7][C:6]2[N:8]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([C:39]4[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=4)=[CH:37][CH:38]=3)[C:9](=[O:19])[C:10]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:20]([OH:22])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCc1cc(C(=O)OC)c(NC(=O)CCCc2ccccc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(O)c(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22 %

Procedure:
To a mixture of methyl 5-ethyl-2-[(4-phenylbutanoyl)amino]thiophene-3-carboxylate (15 g) and N,N-dimethylformamide (150 mL) was added 60% sodium hydride (2.17 g), and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added 4′-(bromomethyl)biphenyl-2-carbonitrile (14.8 g), and the mixture was further stirred for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. After purification by silica gel column chromatography, the obtained residue was dissolved in tetrahydrofuran (200 mL), potassium tert-butoxide (5.3 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was extracted with saturated aqueous ammonium chloride solution and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless oil (4.89 g, 22%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]/[CH2:12][OH:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][CH2:12][OH:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(/C=C/CO)cc1N
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1ccc(CCCO)cc1N
Reaction time: 8 h
Yield: 39.6 %

Procedure:
A mixture of (E)-3-(3-amino-4-methoxy-phenyl)-prop-2-en-1-ol (250 mg) and palladium hydroxide on carbon (20%, 50 mg) in ethyl acetate (10 mL) was stirred under hydrogen atmosphere (balloon pressure) overnight. The resulting mixture was filtered over a CELITE™ pad, the filter cake was washed with dichloromethane and the filtrate was evaporated under reduced pressure to give 100 mg of 3-(3-amino-4-methoxy-phenyl)-propan-1-ol without further purifications.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N=CO[CH2:25][NH:26][C:27](=[O:30])[O:28][CH3:29].C(O)(=O)C>ClC(Cl)Cl>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[NH:21][C:25]3=[N:26][C:27](=[O:30])[O:28][CH3:29])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)NCOC=N
Reactant: Nc1ccccc1NC1CCN(Cc2ccccc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)N=c1[nH]c2ccccc2n1C1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 5 parts of N-[1-(phenylmethyl)-4-piperidinyl]-1,2-benzenediamine, 2.35 parts of methyl (iminomethoxymethyl)carbamate, 5 parts of acetic acid and 75 parts of trichloromethane is stirred and refluxed for 48 hours. The reaction mixture is evaporated and the residue is taken up in water. The solution is neutralized with ammonium hydroxide solution. The precipitated product is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1.75 parts of methyl {1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-benzimidazol-2-ylidene}carbamate; mp. 169.7° C.
Reaction SMILES: CO[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=[CH:17][C:4]1=2.[C:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])#[N:23].C(N(C(C)C)CC)(C)C.C1C=CC=CC=1>C(OCC)(=O)C.[Ti](Cl)(Cl)(Cl)Cl.CO>[CH3:21][O:20][C:18]([C:15]1[CH:16]=[CH:17][C:4]2[CH:3]([CH:24]([C:22]#[N:23])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[CH2:7][O:6][C:5]=2[CH:14]=1)=[O:19]
Reactant: COC(=O)c1ccc2c(c1)OCc1ccccc1C2OC
Reactant: CCOC(=O)CC#N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)C1c2ccccc2COc2cc(C(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 11 %

Procedure:
Titanium tetrachloride (2.3 m) was added to a mixture of 4.95 g of methyl 11-methoxy-6,11-dihydrodibenz[b,e]oxepin-3-carboxylate, 2.8 ml of ethyl cyanoacetate, 4.6 ml of diisopropylethylamine and 400 ml of benzene under ice cooling, and the mixture was stirred at room temperature for 2 days. Methanol (5 ml) was added thereto, and the mixture was diluted with ethyl acetate. The solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (3/1)] to give 0.72 g (11%) of the product.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]([CH2:18][CH3:19])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:20][N:21]([CH3:34])[S:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])=[O:23].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:28]2[CH:27]=[CH:26][C:25]([S:22]([N:21]([CH3:34])[CH3:20])(=[O:23])=[O:24])=[CH:30][CH:29]=2)=[N:3][C:4]=1[C:9]1[N:10]([CH2:18][CH3:19])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]=1
Reactant: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Reactant: CN(C)S(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(-c2nc(-c3ccc(S(=O)(=O)N(C)C)cc3)cnc2N)nc2cnccc21
Temperature: 200 °C
Reaction time: 0.13 h
Yield: 18.7 %

Procedure:
5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.032 g, 0.10 mmol) (made in example 2), 4-dimethylaminosulphonylphenylboronic acid (0.046 g, 0.20 mmol), Pd(PPh3)2Cl2 (0.0035 g, 0.005 mmol) and K2CO3 (0.050 g, 0.36 mmol) were combined in 0.5 mL of N,N-dimethylformamide and heated to 200° C. in the SmithSynthesizer microwave for 8 minutes and then for a further 8 minutes at 250° C. The reaction mixture was concentrated in vacuo and the residue purified by HPLC to give 0.0079 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[CH:29][CH:28]=[CH:27]2>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:31]=2[N:30]=[CH:29][CH:28]=[CH:27]3)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Nc1cccc2cccnc12
Product: O=C(Nc1cccc2cccnc12)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 8-amino quinoline (74 mg, 0.51 mmol). The title compound was obtained as a yellow solid (20 mg, 10% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.83 (1H, m), 9.01 (3H, m), 8.83 (1H, m), 8.47 (1H, m), 8.28 (1H, m), 7.82 (1H, m), 7.66 (2H, m), 1.25 (1H, m). MS m/z: 477.23, 479.23 [M+H]+.
Reaction SMILES: C12BC(CCC1)CCC2.[CH:10](/[C:18]1[O:19][CH:20]=[C:21]([CH:23]=[CH2:24])[N:22]=1)=[CH:11]\[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-:25].[Na+].OO>O1CCCC1.C(OCC)(=O)C.O>[OH:25][CH2:24][CH2:23][C:21]1[N:22]=[C:18](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:19][CH:20]=1
Reactant: [OH-]
Reactant: C=Cc1coc(/C=C/c2ccccc2)n1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCc1coc(/C=C/c2ccccc2)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
9-Borabicyclo[3.3.1]nonane (0.5N tetrahydrofuran solution, 158 ml) was added to a solution of 2-(trans-styryl)-4-vinyloxazole (13.0 g) in tetrahydrofuran (500 ml) at 0° C., and the mixture was stirred at room temperature for 15 hours. Water (10 ml), a 3N aqueous solution (80 ml) of sodium hydroxide and aqueous hydrogen peroxide (80 ml) were successively added dropwise to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 6 hours. After water (600 ml) and ethyl acetate (200 ml) were added to the resultant reaction mixture to separate an organic layer, the water layer was extracted with ethyl acetate (200 ml). After the organic layers were collected, washed with saturated saline (200 ml) and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1→ethyl acetate alone) to obtain the title compound (14.1 g) as a colorless solid.
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:46](O)(=[S:48])[CH3:47]>C1COCC1>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@H:7]1[CH2:11][CH2:10][C@H:9]([O:12][C:46](=[S:48])[CH3:47])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](O)C1
Reactant: CC(O)=S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=S)O[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)C1
Reaction time: 8 h

Procedure:
To a solution of (±)-cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentanol (from Example 51 above) (2.6 g, 12.02 mmol) and triphenyl phosphine (Aldrich, 7.9 g, 30.12 mmol) in dry THF (100 mL) at 0° C. was added dropwise diethyl azodicarboxylate (Aldrich, 4.8 mL, 30.48 mmol). After stirring for 15 minutes thioacetic acid (Aldrich, 2.2 mL, 30.78 mmol) was added dropwise. The reaction mixture was allowed to reach room temperature slowly and stirred overnight. Then, the reaction mixture was concentrated and the residue was purified by flash chromatography (silica gel, 0-5% ether in hexanes gradient) to give (±)-trans-thioacetic acid-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl] ester as a light yellow liquid. (Yield 2.36 g, 72%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:28]([NH:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[CH:41]=[C:40]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:11]=[C:10]([C:18]4[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:9]=3)[CH:3]=2)[CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cn1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)c2)c1

Procedure:
3′-[4-Trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.2) (0.448 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure III. Obtained as light yellow solid (0.56 g), which was subsequently deprotected.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:12]3[CH2:18][C:17]4[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:16]=4[O:15][CH2:14][CH2:13]3)[C:4]=2[CH2:3]1.[NH2:27][C:28]1[C:33]([S:34]([N:37]2[CH2:41][CH2:40][C@@H:39]([NH:42]C(=O)OC(C)(C)C)[CH2:38]2)(=[O:36])=[O:35])=[CH:32][C:31](Br)=[CH:30][N:29]=1>>[NH2:42][C@@H:39]1[CH2:40][CH2:41][N:37]([S:34]([C:33]2[C:28]([NH2:27])=[N:29][CH:30]=[C:31]([C:20]3[CH:21]=[CH:22][C:16]4[O:15][CH2:14][CH2:13][N:12]([C:5]5[C:4]6[CH2:3][C:2]([CH3:1])([CH3:26])[CH:11]=[CH:10][C:9]=6[N:8]=[CH:7][N:6]=5)[CH2:18][C:17]=4[CH:19]=3)[CH:32]=2)(=[O:35])=[O:36])[CH2:38]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(S(=O)(=O)c2cc(Br)cnc2N)C1
Reactant: CC1(C)C=Cc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Product: CC1(C)C=Cc2ncnc(N3CCOc4ccc(-c5cnc(N)c(S(=O)(=O)N6CC[C@@H](N)C6)c5)cc4C3)c2C1

Procedure:
Prepared according to the method of example 5 by using [4-(6,6-dimethyl-5,6-dihydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) and 1,1-dimethylethyl {(3R)-1-[(2-amino-5-bromopyridin-3-yl)sulfonyl]pyrrolidin-3-yl}carbamate (reagent preparation 25) in step 1. 1H NMR (400 MHz, d6-DMSO): 8.57 (d, 1H), 8.41 (s, 1H), 8.02 (d, 1H), 7.58 (d, 1H), 7.47 (dd, 1H), 7.02 (d, 1H), 6.75 (brs, 2H), 6.26 (dd, 2H), 4.63 (s, 2H), 4.33 (m, 2H), 3.84 (m, 2H), 3.37 (m, 2H), 3.27 (m, 2H), 2.89 (m, 1H), 2.71 (s, 2H), 1.86 (m, 3H), 1.53 (m, 1H), 0.95 (s, 6H); MS (EI) for C28H33N7O3S: 548 (MH+).
Reaction SMILES: [Br:1]Br.[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[N:4]1>C(Cl)(Cl)Cl>[Br:1][C:5]1[C:6]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:3][N:4]=1
Reactant: c1cnc2[nH]ncc2c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Brc1n[nH]c2ncccc12
Reaction time: 8 h
Yield: 85.7 %

Procedure:
Bromine (1.91 mL, 37.1 mmol) was added dropwise to a solution of 1H-pyrazolo[3,4-b]pyridine (2.6 g, 21.8 mmol) in CHCl3 (100 mL), and the reaction mixture was left at room temperature overnight. The reaction mixture was concentrated, and the resulting residue was taken up in ethyl acetate (200 mL) and saturated NaHCO3 (50 mL) The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were dried, filtered and concentrated to give 3-bromo-1H-pyrazolo[3,4-b]pyridine (3.7 g, 86%) as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2F)[CH:14]=1)=[O:7].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][NH2:39])[CH2:32][CH2:31]1>>[CH3:1][N:2]([CH3:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:39][CH2:38][CH2:37][CH2:36][N:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)[CH:14]=1)=[O:7]
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccccc1F
Reactant: NCCCN1CCOCC1
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccccc1NCCCN1CCOCC1
Yield: 33 %

Procedure:
Using an analogous procedure to that described in Example 20, N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-2-fluorobenzamide was reacted with 3-morpholinopropylamine to give the title compound in 33% yield; m.p. 239-240° C.; NMR Spectrum: (DMSOd6) 1.7 (m, 2H), 2.17 (s, 3H), 2.31 (m, 6H), 2.95 (s, 6H), 3.15 (q, 2H), 3.53 (t, 4H), 6.6 (t, 1H), 6.72 (d, 1H), 6.89 (m, 1H), 7.2 (m, 3H), 7.3 (m, 2H), (m, 1H), 7.65 (m, 1H), 7.75 (m, 2H), 9.69 (s, 1H), 10.06 (s, 1H); Mass Spectrum: M+H+ 516.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([CH2:16][CH3:17])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[CH2:16]([C:15]1[C:7]2[CH:6]([CH2:5][C:4]([OH:19])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([OH:18])[CH:14]=1)[CH3:17]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(CC)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(O)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a solution of (4-ethyl-1,6-dihydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.19 g, 0.70 mmol) in THF (8 mL) and H2O (2 mL) was added LiOH (0.178 g) at 0° C. The resulting mixture was stirred at room temperature for 2 hours then cooled to 0° C. and acidified to pH 3 with 6N HCl. The mixture was concentrated in vacuo and the residue purified by preparative HPLC to give (4-ethyl-1,6-dihydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid (0.080 g, 50%). 1H NMR (400 MHz, DMSO-d6δ 9.26 (s, 1H), 6.87 (s, 1H), 6.69 (s, 1H), 5.40 (m, 1H), 2.92 (m, 1H), 2.55 (m, 2H), 2.00 (m, 1H), 1.16 (m, 3H). MS (ESI) m/z: 235 [M−1]−. HPLC purity: 92.64% (220 nm), 95.63% (Maxplot).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10](O)=[O:11])=[CH:6][CH:5]=1.S(Cl)([Cl:19])=O>CN(C=O)C>[F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([Cl:19])=[O:11])=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COc1ccc(OC(F)(F)F)cc1
Solvent: CN(C)C=O
Product: O=C(Cl)COc1ccc(OC(F)(F)F)cc1
Reaction time: 14 h

Procedure:
(4-Trifluoromethoxyphenoxy)-acetic acid (20.7 g, 88 mmol) was dissolved in thionyl chloride (100 mL). DMF (3 drops) was added to the solution. The solution was stirred for 14 hours. The thionyl chloride was removed in vacuo. The resulting oil was dissolved in dichloromethane, filtered through sodium sulfate and concentrate in vacuo to afford the title compound as a paste-like solid (21.8 g, 97% from the phenol): MS (EI-GCMS) for C9H6ClF3O3: 254 (M+).
Reaction SMILES: [OH:1][CH2:2][C:3](=[CH2:6])[C:4]#[N:5].[CH3:7][NH:8][CH3:9]>C1COCC1>[OH:1][CH2:2][CH:3]([CH2:6][N:8]([CH3:9])[CH3:7])[C:4]#[N:5]
Reactant: CNC
Reactant: C=C(C#N)CO
Solvent: C1CCOC1
Product: CN(C)CC(C#N)CO
Temperature: 45 °C

Procedure:
2-hydroxymethyl-acrylonitrile (37 mmol, 3.1 g, prepared as per procedure described by Csuk et al. in Tetrahedron, 1996, 52, 9759-9776) was treated with dimethylamine (25 mL of a 2M solution in THF) and the reaction was heated in a sealed vessel at 45° C. for 14 h. The reaction was cooled to room temperature and all the volatiles were removed by concentration under vacuum. The crude 2-hydroxymethyl-3-dimethylaminopropionitrile thus obtained was dissolved in dry THF (50-60 mL) and this solution was added dropwise to a cold (−78° C.) suspension of LAH (6 g) in THF (300 ML). The reaction was gradually warmed to room temperature and stirred for an additional 12 h at room temperature. The reaction was then cooled in an ice bath and very carefully quenched by the sequential addition of H2O (6 mL), 4M NaOH (6 mL) and H2O (18 mL). The white slurry thus obtained was filtered through celite and the filter bed was washed with additional CH2Cl2. The entire filtrate was then concentrated under vacuum to provide crude amine 23.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:13]2[CH:14]=[N:15][C:16](F)=[CH:17][CH:18]=2)=[CH:10]OC)[C:5]([NH2:8])=[N:6][CH:7]=1.Cl(O)(=O)(=O)=[O:21]>O1CCOCC1.O.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([OH:21])=[N:15][CH:14]=3)=[CH:10][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: COC=C(c1ccc(F)nc1)c1cc(Br)cnc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccc(-c2c[nH]c3ncc(Br)cc23)cn1
Yield: 77 %

Procedure:
To a solution of 5-bromo-3-[1-(6-fluoro-pyridin-3-yl)-2-methoxy-vinyl]-pyridin-2-ylamine (220 mg, 0.678 mmol) in 1,4-dioxane (3 ml) in a Smith process vial was added 0.3 ml of 70% aqueous perchloric acid. The reaction was irradiated in a Personal Chemistry® microwave to 150° C. for 300 s. The reaction mixture was diluted with water and neutralized to pH 7 by addition of an aqueous solution of sodium hydroxide. The resulting precipitate was filtered, washed with water, and dried in vacuo to yield the title compound as a beige solid (152 mg, 77% yield). 1H NMR (DMSO-d6): δ 12.1 (broad s, 1H), 11.7 (broad s, 1H), 8.32 (d, J=2.5 Hz, 1H), 8.30 (d, J=2.5 Hz, 1H), 7.83 (dd, J=2.5, 11.5 Hz, 1H), 7.82 (s, 2H), 7.67 (s, 1H), 6.43 (d, J=11.5 Hz, 1H); MS: m/z 290 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH:7]([CH2:11][C:12](=[O:30])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH2:15][CH2:14]2)[C:8]([OH:10])=O)=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].C([O:39][C:40](=[O:54])[CH2:41][N:42]1[CH2:47][CH2:46][N:45]([CH:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH2:44][CH2:43]1)C>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH:7]([CH2:11][C:12](=[O:30])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH2:15][CH2:14]2)[C:8]([N:51]2[CH2:52][CH2:53][CH:48]([N:45]3[CH2:46][CH2:47][N:42]([CH2:41][C:40]([OH:54])=[O:39])[CH2:43][CH2:44]3)[CH2:49][CH2:50]2)=[O:10])=[CH:4][C:3]=1[C:33]([F:36])([F:34])[F:35]
Reactant: CCOC(=O)CN1CCN(C2CCNCC2)CC1
Reactant: O=C(O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)Cc1ccc(Cl)c(C(F)(F)F)c1
Product: O=C(O)CN1CCN(C2CCN(C(=O)C(CC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)Cc3ccc(Cl)c(C(F)(F)F)c3)CC2)CC1

Procedure:
Prepared analogously to Example 16.4 from 105 mg (0.2 mmol) 2-(4-chloro-3-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 51 mg (0.2 mmol) ethyl(4-piperidin-4-yl-piperazin-1-yl)-acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:27]([O:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:26][CH:25]=[CH:24][C:23]=2[F:35])[C:18]([Cl:36])=[CH:17][N:16]=1>>[Cl:36][C:18]1[C:19]([NH:21][C:22]2[C:27]([O:28][CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[CH:26][CH:25]=[CH:24][C:23]=2[F:35])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: Fc1cccc(OC2CCOCC2)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Product: O=C1CCCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4OC4CCOCC4)n3)cc2N1

Procedure:
8-{5-Chloro-4-[2-fluoro-6-(tetrahydro-pyran-4-yloxy)-phenylamino]-pyrimidin-2-ylamino}-1,3,4,5-tetrahydro-1-benzazepin-2-one was prepared from 8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(tetrahydro-pyran-4-yloxy)-phenyl]-amine in an analogous manner to Example 1221d. Title compound was isolated as a white solid (80 mg, 60%). HPLC purity 99%, LCMS 498.21 (M+H), 1H-NMR (DMSO-D6, 400 MHZ) Δ 9.47 (s, 1H), 9.13 (s, 1H), 8.77 (s, 1H), 8.15 (s, 1H), 7.33-7.30 (m, 1H), 7.11 (d, J=8.2 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.93-6.89 (m, 2H), 6.82 (d, J=8.3 Hz, 1H), 4.61-4.59 (m, 1H), 3.60-3.56 (m, 2H), 3.37-3.33 (m, 2H), 2.55-2.52 (m, 2H), 2.07-2.03 (m, 4H), 1.78-1.74 (m, 2H), 1.48-1.45 (m, 2H).