Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[S:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C(OC([N:27]1[CH2:33][CH2:32][CH2:31][N:30]([C:34]([C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)=[O:35])[CH2:29][CH2:28]1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl-].[Na+].O.CCOC(C)=O.O1CCOCC1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:39]2[CH:38]=[CH:37][C:36]([C:34]([N:30]3[CH2:31][CH2:32][CH2:33][NH:27][CH2:28][CH2:29]3)=[O:35])=[CH:41][CH:40]=2)=[N:3][C:4]=1[C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][N:13]=1
Reactant: Nc1ncc(Br)nc1-c1nnc(-c2ccccc2)s1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc(B(O)O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1ncc(-c2ccc(C(=O)N3CCCNCC3)cc2)nc1-c1nnc(-c2ccccc2)s1
Temperature: 140 °C

Procedure:
5-bromo-3-(5-phenyl-1,3,4-thiadiazol-2-yl)pyrazin-2-amine (70 mg, 0.1257 mmol) and [4-(4-tert-butoxycarbonyl-1,4-diazepane-1-carbonyl)phenyl]boronic acid (43.77 mg, 0.1257 mmol) (60% pure) were taken into dioxane (700.1 μL), treated with Na2CO3 (125.7 μL of 2 M, 0.2514 mmol) and degassed/nitrogen flushed (5×). The reaction was then treated with palladium; triphenylphosphane (14.53 mg, 0.01257 mmol), degassed again and heated in the microwave at 140° C. for 30 minutes. The reaction was treated with EtOAc and brine, the organics separated, dried over MgSO4, filtered and concentrated under vacuum. The product was purified by column chromatography eluting 50% EtOAc/Petroleum ether followed by 10% MeOH/DCM to give the desired product which was dissolved in DCM (2.000 mL) and treating with TFA (2.960 g, 2.000 mL, 25.96 mmol). After stirring at RT for 30 minutes and concentration, the residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound (42 mg, 74% Yield). 1H NMR (400.0 MHz, DMSO) d 1.60 (1H, m), 1.77 (1H, m), 2.72-2.39 (4H, 3.40 (2H, m), 3.60-3.67 (2H, m), 7.52 (2H, d), 7.58-7.65 (3H, m), 7.99 (1H, m), 8.00 (2H, br s), 8.10-8.14 (3H, m), 8.95 (1H, s); MS (ES+) 458.07
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=O.[CH3:8][N:9]([CH3:14])[CH2:10][CH2:11][CH2:12][NH2:13].[BH4-].[Na+]>CO>[CH2:6]([NH:13][CH2:12][CH2:11][CH2:10][N:9]([CH3:14])[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCC=O
Reactant: CN(C)CCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCNCCCN(C)C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
A solution of n-capronaldehyde (3.79 g, 37.8 mmol) and N,N-dimethylpropane-1,3-diamine (5 mL, 39.7 mmol) in anhydrous methanol (140 mL) was stirred at room temperature for 3 hours. To this solution was added slowly sodium borohydride (2.15 g, 56.8 mmol) over 5 minutes. The solution was stirred for 30 minutes then quenched with 1M NaOH (75 mL), diluted with water (125 mL) and extracted with ethyl acetate (3×150 mL). The combined ethyl acetate extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography (gradient: 100% DCM to 10% MeOH in DCM with 1% NH4OH) to afford the title compound as a pale yellow oil (3.79 g, 54%).
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][CH2:13][C@@H:14]1[O:32][CH2:31][C@:17]2([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[F:40])[N:18]=[C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:20][CH2:21][C@@H:16]2[CH2:15]1)C1C=CC=CC=1.CO>ClCCl>[F:40][C:34]1[CH:35]=[C:36]([F:39])[CH:37]=[CH:38][C:33]=1[C@:17]12[CH2:31][O:32][C@@H:14]([CH2:13][OH:12])[CH2:15][C@H:16]1[CH2:21][S:20][C:19]([NH:22][C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[N:18]2
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1)c1ccccc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CO)C[C@H]2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Boron trichloride (1 M solution in heptane, 89.7 mL, 89.7 mmol) was added to a 0° C. solution of C8 (15.20 g, 29.89 mmol) in dichloromethane (150 mL). After 15 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 4 hours. Methanol (50 mL) was then added, first drop-wise {Caution: violent reaction} and then at a steady rate, while the interior of the flask was flushed with nitrogen gas. The mixture was heated at reflux for 30 minutes, cooled to room temperature and concentrated in vacuo. The residue was again dissolved in methanol, stirred, and concentrated in vacuo. The resulting material was taken up in dichloromethane and washed sequentially with 1 M aqueous sodium hydroxide solution, water, and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Chromatographic purification on silica gel (Gradient: 0% to 3% methanol in ethyl acetate) provided the product as a yellow foam. Yield: 11.97 g, 28.60 mmol, 96%. LCMS m/z 419.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.13 (d, J=7.4 Hz, 2H), 7.50-7.56 (m, 1H), 7.41-7.49 (m, 3H), 7.02-7.11 (m, 2H), 4.13 (dd, J=11.9, 1.8 Hz, 1H), 3.90 (d, J=12.1 Hz, 1H), 3.72-3.80 (m, 1H), 3.59 (d, J=5.1 Hz, 2H), 3.14-3.24 (br m, 1H), 2.96 (dd, half of ABX pattern, J=13.1, 4.1 Hz, 1H), 2.75 (dd, half of ABX pattern, J=13.1, 2.7 Hz, 1H), 1.80-1.92 (m, 1H), 1.70 (ddd, J=13.4, 4.2, 2.4 Hz, 1H).
Reaction SMILES: N#N.[F:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]([CH:24]=[CH2:25])=[N:11]2)[CH:7]=[N:8][CH:9]=1>CO.[Pd]>[CH2:24]([C:12]1[C:13]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[CH:14][N:10]([C:6]2[CH:7]=[N:8][CH:9]=[C:4]([F:3])[CH:5]=2)[N:11]=1)[CH3:25]
Reactant: C=Cc1nn(-c2cncc(F)c2)cc1N(C)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: CCc1nn(-c2cncc(F)c2)cc1N(C)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 60 h
Yield: 83.9 %

Procedure:
To a N2-purged solution of tert-butyl (1-(5-fluoropyridin-3-yl)-3-vinyl-1H-pyrazol-4-yl)(methyl)carbamate (0.730 g, 2.293 mmol) in methanol (15.29 ml) was added 10% palladium on carbon (0.036 g, 0.339 mmol). The reaction was purged with hydrogen and run under 80 psi of hydrogen at room temperature for 60 hours. The reaction gave less than 20% conversion. The reaction mixture was filtered through celite, concentrated, and redissolved in ethyl acetate (4 mL) and transferred to a bomb. The reaction was heated at 50° C. at 600 psi of hydrogen for 20 hours. The reaction was only 50% complete. Methanol (1 mL) and 10% palladium on carbon (36 mg) were added, and the reaction was heated at 80° C. at 650 psi of hydrogen for 20 hours. The reaction was filtered through celite and concentrated to give tert-butyl (3-ethyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)(methyl)carbamate (616 mg, 1.923 mmol, 84% yield) as yellow oil: IR (thin film) 1692 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.71 (t, J=1.4 Hz, 1H), 8.35 (d, J=2.6 Hz, 1H), 7.83 (dt, J=9.5, 2.3 Hz, 2H), 3.18 (s, 3H), 2.65 (q, J=7.5 Hz, 2H), 1.44 (s, 9H), 1.25 (t, J=7.1 Hz, 3H); EIMS m/z 320.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][N:24]([CH3:47])[C:25]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:30][CH2:29][CH:28]([CH:31]([OH:40])[CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:27][CH2:26]1.C(OCC)C>C(Cl)Cl>[CH3:23][N:24]([CH3:47])[C:25]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:30][CH2:29][CH:28]([C:31](=[O:40])[CH2:32][O:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:27][CH2:26]1
Reactant: CN(C)C1(c2ccccc2)CCC(C(O)COc2ccccc2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C)C1(c2ccccc2)CCC(C(=O)COc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 15% solution of Dess-Martin periodinane in methylene chloride (22.9 g, 8.10 mmol) was added to a solution of 1-(4-dimethylamino-4-phenylcyclohexyl)-2-phenoxyethanol (800 mg, 2.35 mmol) in anhydrous methylene chloride (25 ml). The mixture was stirred at room temperature for 4 h and then at 40° C. for 1.5 h and diethyl ether (100 ml) was then added. The suspension was washed with 25% potassium carbonate solution, 5% sodium bicarbonate solution, 1 M sodium thiosulfate solution and water (50 ml of each). The organic phase was dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: [H-].[Na+].COP([CH2:9][C:10]([O:12]C)=[O:11])(OC)=O.[CH3:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([CH:26]=O)[CH:22]=[CH:21]2.O.[OH-].[Li+]>O1CCCC1.O>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23](/[CH:26]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:22]=[CH:21]2
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: COc1cccc2ccc(C=O)nc12
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2ccc(/C=C/C(=O)O)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a suspension of sodium hydride (60%) (0.8 mg, 20.0 mmol) in tetrahydrofuran (80 mL) was added methyl 2-(dimethoxyphosphoryl)acetate (2.65 mg, 12 mmol) dropwise at 0° C. After the addition was completed, the mixture was stirred for 30 min at 0° C. A solution of 8-methoxyquinoline-2-carbaldehyde (1.87 g, 10.0 mmol) in tetrahydrofuran (20 mL) was then added dropwise over a period of 50 min. The mixture was stirred at 0° C. for 1 h. A solution of lithium hydroxide hydrate (1.26 g, 30.0 mmol) in water (20 mL) was added cautiously to the solution. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. To the residue was added water (20 mL), and the pH of the aqueous layer was then adjust to 4 with 1 N hydrogen chloride solution. The precipitate was collected by filtration and then dried in vacuum to give 1.9 g of the product as a white solid. MS (ESI): m/z 230.1 [M+H]+.
Reaction SMILES: C([Li])CCC.[CH:6](=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22]>>[F:15][C:16]1[C:17]([F:22])=[CH:18][CH:19]=[CH:20][C:21]=1[CH:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Fc1ccccc1F
Reactant: CCCCCCCC=O
Agent: [Li]CCCC
Product: CCCCCCCC(O)c1cccc(F)c1F

Procedure:
Quantities: n-butyllithium (30 cm3, 10.0M in hexanes, 0.3 mol), octanal (38.5 g, 0.3 mol) and 1,2-difluorobenzene (34.5 g, 0.3 mol). The experimental procedure was as described in Example 16.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:29])[O:11][C:12]2[C:17]([C:18]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[CH:16][CH:15]=[C:14]([O:27][CH3:28])[CH:13]=2.[Br:30][CH2:31][CH2:32]Br.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.O>CC(C)=O>[Br:30][CH2:31][CH2:32][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([O:27][CH3:28])=[CH:15][CH:16]=3)[O:11][C:10](=[O:29])[C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:21][CH:22]=1
Reactant: COc1ccc2c(Cc3ccc(O)cc3)c(-c3ccc(Cl)cc3Cl)c(=O)oc2c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc2c(Cc3ccc(OCCBr)cc3)c(-c3ccc(Cl)cc3Cl)c(=O)oc2c1
Reaction time: 48 h
Yield: 60.5 %

Procedure:
A mixture of 3-(2,4-dichlorophenyl)-4-(4-hydroxybenzyl)-7-methoxy-chromen-2-one (6.4 g, 15.0 mmol), 1,2-dibromoethane (12.9 mL, 149.8 mmol) and K2CO3 (4.14 g, 30 mmol) in acetone (65 mL) was stirred at reflux temperature for 20.5 h. An additional portion of K2CO3 (241.6 mg, 1.75 mmol) and 1,2-dibromoethane (3.2 mL, 37.5 mmol) was added at that time and once more 7.5 h later. Heating was continued for an additional 20 h, for a total reaction time of 48 h. The resultant mixture was cooled to room temperature and poured into CH2Cl2/H2O. The layers were separated, and the aqueous phase was extracted with CH2Cl2 (2×). The combined organic layers were washed with brine (2×) and dried (MgSO4), and the solvent was removed in vacuo. The resultant residue was purified using flash chromatography (300 g silica gel, 4.5:1:1→4:1:1→3:1:1 hexanes:CH2Cl2:AcOEt) to provide the title compound as a white solid (4.851 g, 61%) in addition to recovered starting material (2.054 g, 32%). 1H NMR (300 MHz, CDCl3) δ 7.50 (d, J=2.0 Hz, 1H), 7.44 (d, J=9.0 Hz, 1H), 7.26 (dd, J=2.0, 8.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.98–6.91 (m, 2H), 6.88 (d, J=2.0 Hz, 1H), 6.79–6.74 (m, 3H), 4.23 (t, J=6.5 Hz, 2H), 4.04 (d, J=15.5 Hz, 1H), 3.87 (s, 3H), 3.78 (d, J=15.5 Hz, 1H), 3.61 (t, J=6.5 Hz, 2H); MS (ESI) m/z 532.7 (M+H)+; HPLC tR 8.38 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:22])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:23][C:24]1[N:25]=[CH:26][NH:27][C:28]=1[C:29](O)=[O:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:23][C:24]1[N:25]=[CH:26][NH:27][C:28]=1[C:29]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH:19]([CH3:20])[CH3:21])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:22])=[O:30]
Reactant: CC(C)c1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(O)c1[nH]cnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)c1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 21.6 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(1-methylethyl)benzonitrile (0.068 g, 0.213 mmol), 4-chloro-1H-imidazole-5-carboxylic acid (0.040 g, 0.273 mmol), and DIPEA (0.075 mL, 0.427 mmol) were combined in THF (6 mL) and treated with HATU (0.089 g, 0.235 mmol) at 25° C. overnight. The reaction mixture was concentrated to dryness and partitioned between DCM and water. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by mass-directed HPLC on a SunFire prep C-18 column eluted with 30 to 85% CH3CN/H2O (0.1% formic acid buffer). Appropriate fractions were combined, concentrated to dryness, chased twice with ethanol and twice with toluene to remove residual water to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(1-methylethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (0.0205 g, 0.046 mmol, 21.49% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.15 (br. s., 1H), 8.23 (br. s., 1H), 7.77 (s, 1H), 7.43-7.55 (m, 2H), 7.36 (t, J=7.71 Hz, 1H), 7.24 (br. s., 1H), 7.13 (br. s., 1H), 4.54 (d, J=4.99 Hz, 2H), 2.95 (spt, 1H), 1.18 (d, J=6.96 Hz, 6H). LC-MS (ES−) m/z 445.09, 447.18 [M−1]. LC-MS (ES+) m/z 447.08, 449.06 [M+H].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH3:13])[N:5]=[C:4]([CH3:14])[CH:3]=1>[Pt]>[CH3:13][O:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:2][CH2:3][CH:4]([CH3:14])[NH:5]2
Reactant: COc1cccc2nc(C)cc(Cl)c12
Agent: [Pt]
Product: COc1cccc2c1CCC(C)N2

Procedure:
4-Chloro-5-methoxyquinaldine was reduced with platinum on carbon to give 5-methoxy-2-methyltetrahydroquinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[O:11].[Br:12][C:13]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[C:26]([Br:33])[C:14]=1[CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:12][C:13]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[C:26]([Br:33])[C:14]=1[CH2:15][N:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:10]([NH:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])=[O:11]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: COc1ccc(CNCc2c(Br)cc([N+](=O)[O-])cc2Br)cc1
Solvent: ClCCl
Product: COc1ccc(CN(Cc2c(Br)cc([N+](=O)[O-])cc2Br)C(=O)Nc2c(Cl)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,6-dichlorophenylisocyanate (1.54 g, 8.18 mmol) was added under nitrogen to a solution of N-(2,6-dibromo-4-nitrobenzyl)-N-(-4-methoxybenzyl)amine (3.35 g, 7.79 mmol) in CH2Cl2 (95 mL). The resulting mixture was stirred at rt for ca. 3 h. The reaction mixture was then concentrated under reduced pressure to yield N-(2,6-dibromo-4-nitrobenzyl)-N′-(2,6-dichlorophenyl)-N-(4-methoxybenzyl)urea as a yellow solid. Mass spectrum (ESI) 616 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+:14]([O-])([O-:16])=[O:15].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)S(=O)(=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 103.9 %

Procedure:
To a solution of 1-chloro-4-(isopropylsulfonyl)benzene (Step B, 679 mg, 3.1 mmol) in sulfuric acid (3 mL) was added potassium nitrate (555 mg, 5.5 mmol) at 80° C. The mixture was stirred at 90° C. for 2 h. Ice water (5 mL) was added, and the mixture was extracted with ethyl acetate (25 mL) and washed with water (10 mL×2) and brine (10 mL). The organic extracts were dried over sodium sulfate and concentrated to afford the title compound (849 mg, containing ethyl acetate) as a white solid.
Reaction SMILES: [CH:1]1([C:6]2[CH:10]=[C:9]([NH:11][C:12]3[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=3[C:14]([O:16]C)=[O:15])[N:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1COCC1.[OH-].[Na+]>CO>[CH:1]1([C:6]2[CH:10]=[C:9]([NH:11][C:12]3[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=3[C:14]([OH:16])=[O:15])[N:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccccc1Nc1cc(C2CCCC2)nn1-c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1-n1nc(C2CCCC2)cc1Nc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 21 h
Yield: 79.3 %

Procedure:
To a solution of methyl 2-{[3-cyclopentyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzoate (0.59 mmol, 220 mg) in MeOH (1.8 mL) was added THF (5.4 mL) and 1N aqueous NaOH (1.8 mL). The reaction was stirred at rt for 21 h. The organic solvents were removed under reduced pressure, the residue was diluted with water, and the aqueous solution extracted with diethylether (2×5 mL). The aqueous layer was acidified to pH=1 to 2 with 1N aqueous HCl. The mixture was extracted with ethyl acetate (3×5 mL). After removal of the solvent under reduced pressure, the product was obtained as a white solid (169 mg, 79%). 1H NMR (400 MHz, DMSO-d6) δ 1.58-1.62 (m, 2H), 1.65-1.78 (m, 4H), 1.90-2.01 (m, 2H), 2.06 (s, 3H), 2.99-3.10 (m, 1H), 6.23 (s, 1H), 6.80 (t, 1H), 7.20-7.30 (m, 3H), 7.30-7.40 (m, 2H), 7.42-7.51 (m, 1H), 7.81 (d, 1H), 9.84 (s, 1H), 13.14 (s, 1H). ES-MS m/z 362.3 (MH+), HPLC RT (min) 3.39.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=3)[C:6]=2[CH:19]=1.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:12][C@H:10]([C:8]2[N:7]([C:13]3[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=3)[C:6]3[CH:19]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[N:24]=[CH:23][N:22]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccnn1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1ccnn1C
Temperature: 80 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(2-methyl-2H-pyrazol-3-yl)-1H-benzoimidazol-2-yl]ethylamine, (0.093 g, 0.359 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.078 g, 0.502 mmol) and DIPEA (0.12 mL, 0.646 mmol) in IPA (2 mL) was stirred at 80° C. in a sealed microwave tube for 16 h. After cooling, mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH then concentrated in vacuo. Residue was purified by silica gel chromatography eluting with 100% DCM—8% (2M ammonia in methanol) in DCM to give 416 as a white solid (0.107 g, 79%). LCMS (Method K): RT 3.16, 3.28 min [M+H]+ 378.0. 1H NMR (DMSO-d6, 400 MHz): δ 7.92-7.87 (1H, s), 7.87-7.84 (1H, m), 7.75-7.75 (1H, m), 7.60-7.54 (1H, m), 7.30-7.19 (3H, m), 6.96 (1H, m), 6.61-6.44 (1H, m), 5.47-5.38 (1H, m), 3.59-3.53 (3H, m), 3.17 (0H, d, J=5.25 Hz), 1.58-1.51 (3H, m). Signals split due to presence of rotamers/tautomers
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:33](Cl)=[O:34]>CCCCCCC.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:27])[NH:10][CH2:11][CH2:12][N:13]([C:33](=[O:34])[C:32]1[CH:36]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:38]=[C:30]([C:29]([F:28])([F:43])[F:44])[CH:31]=1)[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(NCCNc1cnccc1-c1ccccc1Cl)OCc1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(NCCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl)OCc1ccccc1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from {2-[4-(2-chloro-phenyl)-pyridin-3-ylamino]ethyl}-carbamic acid benzyl ester and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light brown solid (36%). MS (ESI): m/z=622.13 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](OC)=[CH:11][C:10]=1[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)O)C1C=CC=CC=1.Cl.[CH3:28]O>[OH-].[Pd+2].[OH-]>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:17][C:10]2[CH:11]=[C:12]([CH3:28])[CH:13]=[CH:14][C:9]=2[OH:8])=[CH:24][CH:23]=1
Reactant: COc1ccc(C(O)c2cc(OC)ccc2OCc2ccccc2)cc1
Reactant: CO
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Product: COc1ccc(Cc2cc(C)ccc2O)cc1
Reaction time: 72 h
Yield: 80 %

Procedure:
To a solution of (2-benzyloxy-5-methoxyphenyl)-(4-methoxyphenyl)-methanol (1.46 g, 4.3 mmol) in methanol (20 ml), a 20% palladium hydroxide catalyst (73 mg) was added and furthermore 36% HCl (0.1 mL) was added thereto. The mixture was stirred under a hydrogen atmosphere for 72 hours, and then the catalyst was filtered off. The solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (0.8 g, 80%).
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].C[N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[NH:11][C:10]2[N:20]=[CH:21][CH:22]=[CH:23][C:9]1=2>O1CCOCC1>[Cl:1][CH:2]([CH3:6])[C:3]([N:11]1[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[C:14](=[O:15])[NH:8][C:9]2[CH:23]=[CH:22][CH:21]=[N:20][C:10]1=2)=[O:4]
Reactant: CC(Cl)C(=O)Cl
Reactant: CN1C(=O)c2ccccc2Nc2ncccc21
Solvent: C1COCCO1
Product: CC(Cl)C(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
A solution of 2-chloropropionyl chloride and 5-methyl-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one in dioxane was reacted to obtain 11-(2-chloropropionyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one which after crystallization from acetonitrile melted at 210°-212° C.