Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:14]=[CH:13][C:12]=2[NH:22]C(=O)OC(C)(C)C)=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:31][P:32]1(=[O:43])[O:37][CH2:36][C:35]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:34][O:33]1.CCN(C(C)C)C(C)C>CS(C)=O>[NH2:22][C:12]1[CH:13]=[CH:14][C:15]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:16][C:11]=1[NH:10][C:8](=[O:9])[C:5]1[CH:4]=[CH:3][C:2]([N:40]2[CH2:41][CH2:42][C:35]3([CH2:34][O:33][P:32]([CH3:31])(=[O:43])[O:37][CH2:36]3)[CH2:38][CH2:39]2)=[N:7][CH:6]=1
Reactant: CP1(=O)OCC2(CCNCC2)CO1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(Cl)nc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CP1(=O)OCC2(CCN(c3ccc(C(=O)Nc4cc(-c5cccs5)ccc4N)cn3)CC2)CO1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
tert-Butyl [2-{[(6-chloropyridin-3-yl)carbonyl]amino}-4-(2-thienyl)phenyl]-carbamate (150 mg, 0.35 mmol), 3-methyl-2,4-dioxa-9-aza-3-phosphaspiro[5.5]undecane 3-oxide hydrochloride (169 mg, 0.70 mmol), and DIEA (183 μL, 1.05 mmol) were combined in DMSO (4 mL) and stirred at 90° C. for 24 h. The mixture was directly purified by reverse phase HPLC (35-90% MeCN/water w/0.025% TFA) to afford the desired product as a yellow solid. The solid was dissolved in a mixture of CH2Cl2 (4 mL) and TFA (1 mL) and stirred at room temperature for 2 h. The solution was diluted with 1,2-DCE and evaporated. The resulting residue was purified by reverse phase HPLC (10-70% MeCN/water w/0.025% TFA). Fractions containing the product were diluted with saturated NaHCO3 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated to give the desired product as a colorless solid. 1H NMR (DMSO-d6, 600 MHz) δ 9.48 (d, J=3.3, 1H), 8.72 (t, J=2.7 Hz, 1H), 8.08-8.05 (m, 1H), 7.43 (d, J=2.3 Hz, 1H), 7.33 (dd, J=4.9, 0.9 Hz, 1H), 7.26 (dt, J=8.4, 1.7 Hz, 1H), 7.22 (dd, J=3.6, 1.2 Hz, 1H), 7.02 (dd, J=5.0, 3.6 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.51 (dd, J=8.9, 6.0 Hz, 1H), 5.10 (s, 2H), 4.15-3.97 (m, 3H), 3.93-3.82 (m, 1H), 3.62-3.50 (m, 3H), 3.36-3.28 (m, 1H), 2.06-1.98 (m, 1H), 1.93-1.80 (m, 3H), 1.50 (d, J=17.4 Hz, 1.5H), 1.49 (d, J=17.4 Hz, 1.5H). MS: cal'd 499 (MH+), exp 499 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>CCO.O>[Br:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Br)c(C)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C)c(Br)cc1C(=O)O
Yield: 81.6 %

Procedure:
Methyl 5-bromo-2-methoxy-4-methylbenzoate (11.64 g, 0.045 mol) was dissolved in a mixture of EtOH:H2O (1:1 ratio, 150 mL), NaOH (5.8 g, 0.145 mol) was added and reaction mixture was refluxed for 30 min. The EtOH solvent was removed from the mixture by distillation which leads to precipitation of the desired product as its sodium salt. The residue was diluted with H2O (75 mL) and the pH was adjusted to ˜2 with concentrated HCl. The precipitate was collected by filtration, washed with H2O (3×50 mL) and air dried to give pure 5-bromo-2-methoxy-4-methylbenzoic acid 12a (9 g, 82% yield) as a beige solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13](O)=O)=[CH:2]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[CH3:37][O:38][C:39]1[CH:40]=[CH:41][C:42]2[O:47][CH2:46][C@H:45]([CH2:48][NH2:49])[O:44][C:43]=2[CH:50]=1>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][CH2:13][NH:49][CH2:48][CH:45]2[O:44][C:43]3[CH:50]=[C:39]([O:38][CH3:37])[CH:40]=[CH:41][C:42]=3[O:47][CH2:46]2)=[CH:2]1
Reactant: COc1ccc2c(c1)O[C@@H](CN)CO2
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)OC(CNCCCCc1c[nH]c3ccccc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
3-Indolebutyric acid (1.3 g, 6.5 mmole), 1-hydroxybenzotriazole hydrate (1.1 g, 7.8 mmole) and 1,3-diisopropylcarbodiimide (2.4 ml, 15.6 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise (S)-7-methoxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.5 g, 6.5 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and replaced with dichloromethane. The mixture was then washed with H2O. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Evaporation of product fractions gave 1.5 g (61%) of the desired product, (S)-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(1H-indol-3-yl)-butanamide, as a foam.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH:13]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][CH2:22]2)[CH2:12][CH2:11]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33](O)[CH3:34].C(OCC)(=O)C>[Pd]>[C:6]1([CH2:7][CH2:2][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH:13]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:23][CH2:22]2)[CH2:12][CH2:11]3)[CH:34]=[CH:33][CH:3]=[CH:4][CH:5]=1
Reactant: O=C1c2ccc(-c3ccccc3)cc2CCC1CCN1CCC(c2ccccc2)CC1
Reactant: CCO
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1c2ccc(CCc3ccccc3)cc2CCC1CCN1CCC(c2ccccc2)CC1
Yield: 99.9 %

Procedure:
Compound 3 (100 mg, 0.23 mmol) was dissolved in a mixture of 4:1 ethanol/ethyl acetate solution (25 mL) and stirred with 10% Pd on carbon (20 mg) at room temperature and under a hydrogen gas (balloon) for 18 hours. The reaction mixture was filtered through a Celite pad and evaporated to dryness. The residue was triturated with hexanes to afford the title compound as a yellow solid (103 mg, 99.9%).
Reaction SMILES: [CH2:1]([N:8]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:22]([N:24]([CH:38]([CH3:40])[CH3:39])[C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]3)=[O:23])[C:19]([CH3:21])=[CH:20][C:15]=2[O:14][C:13]([CH2:42][OH:43])([CH3:41])[C:12]1=[O:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:54]I.[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]([CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:22]([N:24]([CH:38]([CH3:39])[CH3:40])[C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:26]3)=[O:23])[C:19]([CH3:21])=[CH:20][C:15]=2[O:14][C:13]([CH2:42][O:43][CH3:54])([CH3:41])[C:12]1=[O:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCN(Cc1ccccc1)Cc1ccccc1)C(=O)C(C)(CO)O2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCC1(C)Oc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc2N(CCN(Cc2ccccc2)Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
To a solution of the obtained 2-methyl-2-propanyl (3R)-3-[({4-[2-(dibenzylamino)ethyl]-2-(hydroxymethyl)-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(2-propanyl)amino]-1-piperidine carboxylate (22.5 g) in N,N-dimethylformamide (80 ml) were added sodium hydride (1.6 g) and methyl iodide (5.5 g) under ice-cooling. The mixture was stirred for 30 minutes, and then, cooled to room temperature, and further stirred for 2 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution, and the mixture was ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure, followed by purification with silica gel chromatography to give the title compound (19.2 g).
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17]2[N:22]=[C:21]([NH2:23])[C:20]([NH2:24])=[C:19]([NH2:25])[N:18]=2)=[N:9]1.N1C=CC=CC=1.Cl[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38]>ClCCl.CO>[NH2:25][C:19]1[C:20]([NH:24][C:37](=[O:38])[O:39][CH:40]([CH3:42])[CH3:41])=[C:21]([NH2:23])[N:22]=[C:17]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:8]([CH2:7][C:6]3[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=3[F:4])[N:9]=2)[N:18]=1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1N
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)OC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N

Procedure:
Prepared in analogy to Example 2 with 150 mg (0.43 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine trihydrochloride from Example 8A, 7.5 ml of pyridine and 52.47 mg (0.43 mmol) of isopropyl chloroformate. The residue is taken up in a dichloromethane/methanol mixture, filtered and dried.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:18]([C:10]1[CH:9]=[C:8]2[C:17]3=[C:16]4[C:5](=[CH:4][CH:3]=[C:2]([C:26]5[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=5)[C:15]4=[CH:14][CH:13]=[C:12]3[CH:11]=1)[CH:6]=[CH:7]2)([CH3:19])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cc2ccc3ccc(Br)c4ccc(c1)c2c34
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccc3ccc4cc(C(C)(C)C)cc5ccc2c3c45)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
A mixed solution of 2.3 g of 1-bromo-7-t-butylpyrene, 1.2 g of 4-methylphenylboronic acid, 3.8 g of tripotassium phosphate, 0.58 g of tetrabutylammonium bromide, 12 mg of palladium acetate and 30 ml of dimethylformamide was heated and stirred under a nitrogen gas stream at 130° C. for 2 hours. The solution was cooled to room temperature and 30 ml of water was poured into the solution, followed by extraction with 50 ml of dichloromethane. The organic layer was washed twice with 20 ml of water, dried over magnesium sulfate and then evaporated. The concentrate was purified by silica gel column chromatography and then vacuum-dried to obtain 1.5 g of 7-t-butyl-1-(4-methylphenyl)pyrene.
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[CH2:8]([CH:10]1[O:12][CH2:11]1)Cl>>[O:12]1[CH2:11][CH:10]1[CH2:8][N:3]1[CH:7]=[CH:6][CH:5]=[N:4]1
Reactant: c1cn[nH]c1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Product: c1cnn(CC2CO2)c1

Procedure:
Compounds of formula 2. Reaction of sodium hydroxide with appropriate 1H-pyrazole starting material in neat epichlorohydrin at room temperature furnishes the corresponding 1-oxiranylmethyl-1H-pyrazole compound. To this product is added distilled water and an excess of secondary amine. The reaction mixture is then heated at moderate to high temperature (˜80° C.) for several hours. After suitable work-up (typically column chromatography), the corresponding 1-amino-3-(pyrazol-1-yl)-propan-2-ol compound is isolated.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:20]C(Br)C.O>C1COCC1>[Br:20][C:5]1[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Reactant: CC(Br)Br
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1nc(Cl)ccc1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 52.7 %

Procedure:
A solution of N-(6-chloro-2-pyridinyl)-2,2-dimethylpropanamide (4.83 g, 22.7 mmol) in THF (40 ml) at −78° C. under argon was treated with n-butyl lithium (20 ml, 2.5M in Hexanes, 50 mmol) over 10 min and then allowed warm to 0° C., stirred at 0° C. for 3 h and then recooled to −78° C. The reaction was then treated dropwise with dibromoethane (2.057 ml, 23.9 mmol) and the reaction was allowed warm to rt and stirred at rt for 0.5 h. The reaction was then treated with water (5 ml), stirred at rt for 5 min, treated with more water (500 ml) and extracted with diethyl ether (3×500 ml). The organic extracts were dried (MgSO4), filtered, evaporated and the residue chromatographed (0-25% ethyl acetate:Hexane) to give the product as a yellow solid (3.489 g, 53%).
Reaction SMILES: Br[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[N:30]=[CH:29][CH:28]=[N:27]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:32]B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH3:32][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[N:30]=[CH:29][CH:28]=[N:27]2)=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Br)c1ccccc1-n1nccn1
Reactant: CB(O)O
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: [K+]
Solvent: C1COCCO1
Product: Cc1cc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1

Procedure:
A mixture of N-[(1S,2S)-2-{[3-bromo-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 107; 67 mg, 0.14 mmol), methylboronic acid (CAS number 13061-96-6; 24 mg, 0.41 mmol), tetrakis(triphenylphosphine)palladium (16 mg, 0.014 mmol) and potassium carbonate (aq. 2 M, 271 μl, 0.54 mmol) in 1,4-dioxane (450 μl) was sealed, evacuated and purged with nitrogen and then subjected to microwave irradiation at 140° C. for 30 minutes. The reaction was partitioned between ethyl acetate and water, washing with water, brine, dried over magnesium sulfate and concentrated in vacuo. This was then purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)=[O:12].[C:37]([O-:40])(=[O:39])[CH3:38].[Na+].[I-].[Na+]>C(O)(=O)C>[C:37]([O:40][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)=[O:12])(=[O:39])[CH3:38]
Reactant: O=C(Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1)c1ccccc1OCCCCCCBr
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCCCCCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Yield: 55.6 %

Procedure:
A mixture of 1-{4-[2-(6-bromohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (2.00 g), sodium acetate (0.36 g), sodium iodide (0.55 g) and acetic acid (20 ml) is refluxed for 1 day. The solvent is distilled off and the resulting residue is extracted with ethyl acetate. The organic layer is washed successively with 2N aqueous sodium hydroxide solution and saturated saline solution, and dried over magnesium sulfate. The solvent is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; chloroform:methanol=500:1), and recrystallized from ethanol to give 1-{4-[2-(6-acetyloxyhexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (1.07 g) as white powder, m.p. 145-146° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([CH2:21][O:22][C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH:33]=[N:32][N:31]=[N:30]5)=[CH:25][CH:24]=4)[N:20]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O.[Cl-].[NH4+]>CCO.C1COCC1.O.[Fe]>[N:29]1([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH2:21][C:19]3[N:20]=[C:16]([CH:13]4[CH2:12][CH2:11][N:10]([C:7]5[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][N:6]=5)[CH2:15][CH2:14]4)[S:17][CH:18]=3)=[CH:24][CH:25]=2)[CH:33]=[N:32][N:31]=[N:30]1
Reactant: O=[N+]([O-])c1cnc(N2CCC(c3nc(COc4ccc(-n5cnnn5)cc4)cs3)CC2)nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1cnc(N2CCC(c3nc(COc4ccc(-n5cnnn5)cc4)cs3)CC2)nc1
Temperature: 100 °C

Procedure:
5-Nitro-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine (Example 192) (1.07 mmol), ammonium chloride (3 eq.) and iron powder (3 eq.) were suspended in EtOH:THF:H2O (40:20:10) and heated at 100° C. for 5 hours. The hot reaction mixture was filtered through a pad of celite and the filtrate was concentrated. The resulting oil was dissolved in DMF and water and extracted with ethylacetate. The organic layer was washed with water, brine and dried over sodium sulfate. The resulting filtrate was concentrated under reduced pressure. Purification using silica gel chromatography (DCM/MeOH 98:2) provided the expected product. 1H NMR (DMSO-d6): δ 9.96 (1H, s), 7.97 (2H, m), 7.90 (2H, m), 7.63 (1H, s), 5.19 (2H, s), 4.44 (2H, m), 3.73 (1H, m), 2.97 (2H, m), 2.20 (2H, m), 1.95 (2H, m).
Reaction SMILES: [Na].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[C:12](OCC)(=[O:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.O>C(O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:10]#[N:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccncc1
Reactant: N#CCc1ccc(F)cc1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: N#CC(C(=O)c1ccncc1)c1ccc(F)cc1

Procedure:
Sodium (2.48 g) was dissolved in dry ethanol (37 ml) under nitrogen atmosphere. To the solution was added 4-fluorophenylacetonitrile (11.65 g) and ethyl isonicotinate (16.41 ml) and the solution was refluxed for hours. The reaction mixture was cooled and poured into water. The ethanol of the mixture was removed under reduced pressure. The resulting aqueous solution was washed with ether and neutralized with diluted hydrochloric acid. The separated solid was collected, washed with water and dried to give 2-(4-fluorophenyl)-3-oxo-3-(pyridin-4-yl)propanenitrile (16.43 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([C:8]([CH3:27])([CH3:26])[CH2:9][C:10]([CH2:16][C:17]2[NH:25][C:20]3=[CH:21][N:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:7]=1.B1([C:36]2[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=2)OCCCO1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CO.CN(C=O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:12][C:11]([F:14])([F:13])[C:10]([CH2:16][C:17]1[NH:25][C:20]2=[CH:21][N:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1)([OH:15])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:3]=[CH:4][C:5]=1[O:28][CH3:29])([CH3:27])[CH3:26]
Reactant: c1cncc(B2OCCCO2)c1
Reactant: COc1ccc(Br)cc1C(C)(C)CC(O)(Cc1cc2ccncc2[nH]1)C(F)(F)F
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: [K+]
Solvent: CO
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cccnc2)cc1C(C)(C)CC(O)(Cc1cc2ccncc2[nH]1)C(F)(F)F
Temperature: 25 °C
Yield: 47.9 %

Procedure:
A mixture of 4-(5-bromo-2-methoxyphenyl)-1,1,1-trifluoro-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol (188 mg, 0.4 mmol), pyridine 3-boronic acid 1,3-propanediol cyclic ester (89 mg, 0.6 mmol), potassium carbonate (K2CO3; 166 mg, 1.2 mmol), and Pd(PPh3)4 (46.2 mg, 0.04 mmol) in 3.0 mL of DME-MeOH-DMF (1:1.5:0.5) was microwaved for 20 minutes at 120° C., cooled to room temperature, diluted with 20 mL of ethyl acetate and filtered through diatomaceous earth. The filtrate was washed with 5 mL of 1.0 M aqueous sodium hydroxide solution, water, and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography to yield 90 mg (48% yield) of the title compound as a white foam.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH:11][CH3:12])=[O:10])[CH:4]=1)=[O:2].O1CCC[CH2:14]1.C[Mg]Br.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[OH:2][CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH:11][CH3:12])=[O:10])[CH:4]=1)[CH3:14]
Reactant: CNC(=O)c1cc(C=O)ccn1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(C(C)O)ccn1
Reaction time: 1 h

Procedure:
At 0° C. and under argon, 393 mg (2.394 mmol) of 4-formyl-N-methylpyridine-2-carboxamide Example 42A were initially charged in 66 ml abs. tetrahydrofuran. At 0° C., 343 mg (2.873 mmol) of methylmagnesium bromide [1.4 mol in toluene/tetrahydrofuran 3/1] were added dropwise, and the reaction solution was stirred at this temperature for 1 h. 200 μl of semisaturated aqueous sodium bicarbonate solution and 200 ml of ethyl acetate were added to the reaction solution. The precipitate was filtered off and washed with ethyl acetate. The filtrate was evaporated.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13](Cl)[N:12]=[C:11]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=3[CH3:23])[N:10]=2)=[CH:4][CH:3]=1.[CH3:24][S-:25].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]=[C:11]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=3[CH3:23])[N:12]=[C:13]([S:25][CH3:24])[N:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc(Br)cc2)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(Nc2ccc(Br)cc2)nc(-c2cc(Cl)ccc2C)n1
Reaction time: 24 h
Yield: 57 %

Procedure:
A mixture of the title compound of Example 20 (234 mg, 0.57 mmol), sodium thiomethoxide (50 mg, 0.71 mmol), and tetrahydrofuran (5 ml) was stirred for 24 hours. After concentrating under reduced pressure, the residue was dissolved in dichloromethane (25 ml). The solution was washed with water (25 ml) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane-hexane (1:1) to provide the title compound (137 mg, 57% yield). 1H NMR (DMSO-d6) 10.42 (s, 1H), 7.88 (s, 1H), 7.70 (s, 2H), 7.45-7.55 (m, 3H), 7.38 (m, 1H), 2.55 (s, 3H), 2.50 (s, 3H).
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[O:10]=[C:11]1[O:17][C@H:16]([C@H:18]([CH2:20][OH:21])[OH:19])[C:14]([OH:15])=[C:12]1[OH:13].[CH3:22][C:23]([CH3:25])=O>>[CH3:22][C:23]1([CH3:25])[O:19][C@H:18]([C@H:16]2[O:17][C:11](=[O:10])[C:12]([OH:13])=[C:14]2[OH:15])[CH2:20][O:21]1
Reactant: CC(C)=O
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: CC1(C)OC[C@@H]([C@H]2OC(=O)C(O)=C2O)O1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
55 g of 24% strength oleum were added dropwise to 480 ml of acetone (water content about 1.4%) at -10° C. 120 g of L-ascorbic acid were introduced into the resulting mixture at about 0° C., and the reaction mixture was stirred for 6 h at 0° C. It was then cooled to -15° C. and the crystals formed were filtered off under suction. The resulting filter cake was pressed dry, washed with twice 100 ml of ice cold acetone and dried at room temperature under reduced pressure from a water pump.