Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([CH2:4][O:5][C:6]2[C:11]([C:12]3[N:16]([CH2:17][C:18]4[CH:23]=[CH:22][C:21](CCC(O)=O)=[CH:20][CH:19]=4)[C:15]4[CH:29]=[C:30](F)[C:31](F)=[CH:32][C:14]=4[N:13]=3)=[CH:10][CH:9]=CN=2)CC1.[Cl:35][C:36]1C=CC(C2NC3C=CC=CC=3N=2)=C(OC)[CH:37]=1.BrCC1CCCCC1>>[Cl:35][C:36]1[CH:9]=[CH:10][C:11]([C:12]2[N:16]([CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:15]3[CH:29]=[CH:30][CH:31]=[CH:32][C:14]=3[N:13]=2)=[C:6]([O:5][CH3:4])[CH:37]=1
Reactant: COc1cc(Cl)ccc1-c1nc2ccccc2[nH]1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Agent: BrCC1CCCCC1
Product: COc1cc(Cl)ccc1-c1nc2ccccc2n1CC1CCCCC1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-Chloro-2-methoxy-phenyl)-1H-benzoimidazole and bromomethyl-cyclohexane (CAS Reg. No 2550-36-9). Brown solid (48%). MS (Turbo Spray): m/z=355.3 (M+H).
Reaction SMILES: COC([C:5]1[CH2:10][C:9]([C:18]#[N:19])([C:11]2[CH:12]=[N:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:8][CH2:7][C:6]=1[OH:20])=O.[Na+].[Cl-].O>CS(C)=O>[F:17][C:14]1[N:13]=[CH:12][C:11]([C:9]2([C:18]#[N:19])[CH2:8][CH2:7][C:6](=[O:20])[CH2:5][CH2:10]2)=[CH:16][CH:15]=1
Reactant: COC(=O)C1=C(O)CCC(C#N)(c2ccc(F)nc2)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2ccc(F)nc2)CCC(=O)CC1
Temperature: 160 °C
Yield: 49989.7 %

Procedure:
To a solution of 5-Cyano-5-(6-fluoro-pyridin-3-yl)-2-hydroxy-cyclohex-1-enecarboxylic acid methyl ester (32 g crude, 0.11 mmol) in DMSO (110 mL) was added NaCl (7.78 g, 0.133 mol) and water (6.5 mL). The reaction mixture was heated at 160° C. for 3 h. It was cooled to room temperature and poured into water (300 mL). The aqueous layer was extracted with EtOAc (3×200 mL). The combined organic layer was washed with brine (300 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with a gradient elution of between 10-25% EtOAc in petroleum ether) to give the title compound (12 g, 50% over two steps). 1H NMR (CDCl3 400 MHz): ppm 8.34 (d, J=2.4 Hz, 1H), 7.95-7.82 (m, 1H), 7.00-6.92 (m, 1H), 2.95-2.87 (m, 2H), 2.60-2.2. (m, 2H), 2.50-2.40 (m, 2H), 2.28-2.20 (m, 2H).
Reaction SMILES: [Br-].[CH2:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7][CH2:6]1)[CH2:3][CH3:4].CC([O-])(C)C.[K+].[C:37]([C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=1)#[N:38].O>O1CCCC1>[CH2:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH:11]=[CH:43][C:42]2[CH:45]=[CH:46][C:39]([C:37]#[N:38])=[CH:40][CH:41]=2)[CH2:7][CH2:6]1)[CH2:3][CH3:4]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCC[C@H]1CC[C@H](C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](C=Cc2ccc(C#N)cc2)CC1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a mixture of 25.0 g (0.11 mol) of trans-4-propylcyclohexylmethyltriphenylphosphonium bromide and 100 ml of tetrahydrofuran (THF) was added 12.2 g (0.10 mol) of t-BuOK while maintaining a temperature of lower than −20° C., and stirred for 1 hour. Subsequently, 70 ml of solution of 12.9 g (0.10 mol) of 4-cyanobenzaldehyde in THF was added dropwise to the solution while maintaining a temperature of lower than −20° C., and stirred at the same temperature for 2 hours to react. After finishing of the reaction, 50 ml of water was added to the reaction product and then extracted with 100 ml of toluene. The organic layer thus obtained was washed with water thrice and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: toluene) to obtain 12.1 g of a crude 4-(2-(trans-4-propylcyclohexyl)vinyl)benzonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=[O:20])[CH:7]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][OH:20])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)Cc1cccc(Oc2ccccc2CO)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
To [3-(2-formyl-phenoxy)-phenyl]-acetic acid ethyl ester (1.0 g, 3.5 mmol) in MeOH (20 mL) was added sodium borohydride (0.16 g, 4.2 mmol), and the reaction was stirred for 10 minutes at room temperature. Once no starting material was seen by analytical tlc, the mixture was worked-up to give the desired product (1 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:30](Cl)(=[O:32])[CH3:31]>>[C:30]([N:20]1[CH2:21][CH2:22][C:16]2[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])=[N:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=3)=[N:18][C:17]=2[CH2:19]1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(C)=O)C3)cc1

Procedure:
Compound dp was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with acetyl chloride. LC-MS: m/z=+439 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH:20]1([CH2:25][CH2:26][NH2:27])[CH2:24][CH2:23][CH2:22][CH2:21]1.[BH4-].[Na+]>CO>[CH:20]1([CH2:25][CH2:26][NH:27][CH2:18][C:16]2[CH:15]=[CH:14][C:3]([O:4][C:5]3[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=3)=[C:2]([F:1])[CH:17]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCCC1CCCC1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCC3CCCC3)cc2F)cn1
Reaction time: 8 h
Yield: 9.5 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.650 g, 2.50 mmol), 2-cyclopentylethylamine (0.792 g, 2.75 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (12 mL), cap and stir overnight. Add NaBH4 (slight excess) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 10% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound (0.0850 g, 10%): TOF MS ES+ 358.2 (M+H)+, HRMS calcd for C20H25N3O2F 358.1931 (M+H)+, found 358.1925, time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.8 min, 94.2% purity.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:11][CH2:12][CH2:13][CH2:14][OH:15]>C(O)C>[OH:15][CH2:14][CH2:13][CH2:12][NH:11][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: Clc1ccc2ncnn2n1
Reactant: NCCCO
Solvent: CCO
Product: OCCCNc1ccc2ncnn2n1
Yield: 72 %

Procedure:
6-Chloro[1,2,4]triazolo[1,5-b]pyridazine (928 mg) was dissolved in ethanol (10 ml). 3-Amino-1-propanol (1.23 g) was added to the solution. The mixture was refluxed under heating for 20 hours. After being cooled, the mixture was concentrated under reduced pressure to an half of its volume. The resulting precipitates were washed with ethanol and dried to yield the title compound (835 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[B:11]([OH:13])[OH:12])=[O:4].[CH2:14]([N:18]([CH2:22][CH2:23]O)[CH2:19][CH2:20]O)[CH2:15][CH2:16][CH3:17]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[B:11]1[O:13][CH2:23][CH2:22][N:18]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:19][CH2:20][O:12]1)=[O:4]
Reactant: CCCCN(CCO)CCO
Reactant: COC(=O)c1ccccc1B(O)O
Solvent: Cc1ccccc1
Product: CCCCN1CCOB(c2ccccc2C(=O)OC)OCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a suspension of (2-methoxycarbonylphenyl)boronic acid (5.0 g, 27.8 mmol) in toluene (40 mL) was added N-butyldiethanolamine (4.8 mL, 29.2 mmol, 1.05 equiv.) via a syringe. The mixture was heated at 50° C. for two hours. After cooling to room temperature, the toluene was evaporated under reduced pressure and the remaining clear colorless crude oil was treated with heptanes (˜500 mL). The heptanes mixture was then sonicated ˜5 min and the resulting suspension was allowed to stand at room temperature overnight. The solid that precipitated was collected by filtration, washed with heptanes, and dried in a vacuum oven overnight to yield a white solid as the 2-(2′-methoxycarbonylphenyl)-6-butyl[1,3,6,2]dioxazaborocan. 1H NMR (DMSO-d6) δ: 7.55-7.59 (m, 1H), 7.17-7.29 (m, 2H), 7.12-7.14 (m, 1H), 3.85-3.92 (m, 2H), 3.78-3.82 (m, 1H), 3.78 (br. s., 1H), 3.67 (s, 3H), 3.26-3.30 (m, 1H), 3.12 (dt, J=5.2, 2.6 Hz, 2H), 3.03-3.11 (m, 2H), 2.41-2.49 (m, 4H), 1.45-1.55 (m, 2H), 0.98-1.05 (m, 2H), 0.83 (s, 1H), 0.71-0.77 (m, 3H). Amount obtained, 8.3 g, (98.1% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[OH:23])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O:34]CC)=[O:33].[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH:22]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[OH:23])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCC(O)c4ccc(Cl)cc4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(NCC(O)c1ccc(Cl)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 16 h
Yield: 83.2 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(2-(4-chlorophenyl)-2-hydroxyethylcarbamoyl)phenoxy)chroman-4-carboxylate (0.056 g, 0.11 mmol) in a solution of 3:1 THF/ethanol (2 ml) was added 1M sodium hydroxide (0.22 ml, 0.22 mmol), and the reaction was stirred for 16 hours. The reaction was concentrated, taken up in water, acidified with 1M hydrochloric acid, and extracted twice with EtOAc. The combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 46 mg of the title compound (87% yield).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][C:17](=[O:21])[CH:18]=[N+]=[N-])[CH3:15]>COC(C)(C)C.C(C1OC[C@@H](C(C)(C)C)N=1)(C1OC[C@@H](C(C)(C)C)N=1)(C)C>[CH2:14]([O:16][C:17]([C@H:18]1[CH2:11][C@@H:10]1[C:9]1[CH:12]=[CH:13][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:7][CH:8]=1)=[O:21])[CH3:15]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Agent: CC(C)(C1=N[C@H](C(C)(C)C)CO1)C1=N[C@H](C(C)(C)C)CO1
Solvent: COC(C)(C)C
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(OC(C)(C)C)cc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
In a one liter three necked flask equipped with a magnetic stirrer bar, an alcohol thermometer, nitrogen inlet and addition inlet sealed with a suba seal, (R,R)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline) (417 mg, 1.42 mmol) and copper(I) trifluoromethanesulfonate benzene complex (714 mg, 1.42 mmol) are dissolved in degassed tert-butyl methyl ether (120 mL) and stirred for 15 minutes under N2. 4-tert-Butoxystyrene (25 g, 142 mmol) is added and the mixture cooled to −10° C. (internal temperature) under N2. Ethyldiazoacetate (24.75 g, 184.4 mmol) is dissolved in 50 mL of tert-butyl methyl ether and 5 mL of the resulting solution is added dropwise with cooling over 30 minutes using a syringe pump. The addition is then stopped and the mixture stirred at −10° C. until the reaction starts (effervescence and color change). Once the reaction has started the mixture is cooled to −20° C. and the remaining solution added dropwise using a syringe pump over 3 hours maintaining the temperature at −20° C. Once the addition is completed the mixture is allowed to slowly warm to room temperature and stirred overnight. NMR of a reaction sample shows approx. 30% of unreacted starting material, therefore the mixture is cooled to −20° C. and a further 14.1 g of ethyl diazoacetate in 30 mL of tert-butyl methyl ether is added dropwise over 90 minutes, stirred for 1 hour at −20° C. and then allowed to warm to room temperature. The solvent is removed under vacuum and the residue is purified by flash chromatography (0-5% ethyl acetate in cyclohexane) to give the title compound (yield 29.7 g). GC (METHOD 1): tR=11.47 min; Mass spectrum (EI+): m/z=262 [M]+, e.e. 96% by chiral HPLC (Column: Daicel Chiralcel OJ-H, 4.6×250 mm, 5 μm Mobile phase: hexane:ethanol 95:5, 1 mL/min, 25° C.) tR=9.87 (9.13) min.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:14][CH:15]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:16]([O:18]CC1C=CC=CC=1)=[O:17])([CH2:6][N:7]1[C:11](=[O:12])[CH2:10][NH:9][C:8]1=[O:13])=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][P:4]([CH2:14][CH:15]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:16]([OH:18])=[O:17])([CH2:6][N:7]1[C:11](=[O:12])[CH2:10][NH:9][C:8]1=[O:13])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CC(CC(C)C)C(=O)OCc1ccccc1)CN1C(=O)CNC1=O
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(CC(CC(C)C)C(=O)O)CN1C(=O)CNC1=O
Reaction time: 1 h
Yield: 102.8 %

Procedure:
0.27 g (0.64 mmol) of benzyl 2(RS)-[[(RS)-(ethoxy)[(2,5-dioxo-1-imidazolidinyl)methyl]phosphinyl]methyl]-4-methylvalerate was dissolved in 10 ml of ethanol and the solution was hydrogenated in the presence of 0.2 g of 10% palladium/carbon at room temperature and under atmospheric pressure. After 1 hour, the catalyst was removed by filtration and the solvent was evaporated to give 0.22 g of 2(RS)-[[(RS)-(ethoxy)[(2,5-dioxo-1-imidazolidinyl)methyl]phosphinyl]methyl]-4-methylvaleric acid in the form of a foam;
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:10](I)=[CH:9][N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:5]2=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[Cl-].[Li+].[CH3:29][C:30]([CH:33]=[O:34])([CH3:32])[CH3:31]>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]2[C:10]([CH:33]([OH:34])[C:30]([CH3:32])([CH3:31])[CH3:29])=[CH:9][N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2nc(Cl)cnc21
Reactant: CC(C)(C)C=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)C(C)(C)C)c2nc(Cl)cnc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2-Chloro-7-iodo-5-triisopropylsilanyl-5H-pyrrolo[2,3-b]pyrazine (0.56 g, 1.28 mmol) was dissolved in 10 mL of dry tetrahydrofuran and stirred under argon with cooling to −78° C. A solution of isopropylmagnesium chloride with lithium chloride (3 mL, 1M, 3 mmol) was added via syringe. After 10 m, neat pivaldehyde (0.325 mL, 3 mmol, distilled) was added all at once. After 1 h at −78° C., the reaction was quenched by the addition of saturated aqueous ammonium chloride, then diluted with ethyl acetate and allowed to warm to ambient temperature. The organic layer was then washed successively with saturated aqueous sodium bicarbonate and brine. After drying over magnesium sulfate, the solution was filtered and solvent removed, and carried directly into the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1.C1(C([C:46]2[CH:57]=[CH:56][CH:55]=[CH:54][C:47]=2[C:48]([N:50]=[C:51]([O-:53])[O-])=[O:49])C2C=CC=CC=2)C=CC=CC=1>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:51](=[N:50][C:48](=[O:49])[C:47]5[CH:46]=[CH:57][CH:56]=[CH:55][CH:54]=5)[O:53][C:9]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:10]=5)[CH2:28][CH2:27]4)[CH2:22][CH2:23]3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C(N=C([O-])[O-])c1ccccc1C(c1ccccc1)c1ccccc1
Reactant: O=C(CC1CCNCC1)N1CCN(C2c3ccc(Cl)cc3CCc3cc(Br)cnc32)CC1
Solvent: CC(C)O
Product: O=C(N=C(Oc1ccccc1)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1)c1ccccc1

Procedure:
1-(3-Bromo-8-chloro-6,11-dihydro-5 H-benzo[5,6]cyclo-hepta[1,2-b] pyridin-11-yl)-4-[(4-piperidinyl)acetyl]piperazine (1 equivalent) (Formula 47.0, prepare as described in Preparative Example 11) and diphenylmethylbenzoylcarbonimidate (1.2 equivalents) [prepare as described in: A. Buschauer, Arch. Pharm., 377-378 (1987)] are dissolved in 2-propanol and the mixture is heated as described in Example 1 above to give the title compound (Formula 24.0).
Reaction SMILES: [Cl:1][C:2]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([Cl:18])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.[Br:19]N1C(=O)CCC1=O>C(#N)C>[Br:19][C:10]1[CH:11]=[C:6]([O:5][CH2:4][C:3]2[C:13]([Cl:18])=[CH:14][CH:15]=[C:16]([F:17])[C:2]=2[Cl:1])[C:7]([NH2:12])=[N:8][CH:9]=1
Reactant: Nc1ncccc1OCc1c(Cl)ccc(F)c1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ncc(Br)cc1OCc1c(Cl)ccc(F)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
A stirring solution of 3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine (9.07 g, 0.03 mol) in acetonitrile was cooled to 0° C. using an ice bath. To this solution was added N-bromosuccinimide (NBS) (5.33 g, 0.03 mol) portionwise. The reaction was stirred at 0° C. for 15 min. The reaction was concentrated to dryness under vacuum. The resulting dark oil was dissolved in EtOAc (500 mL), and purified via silica gel chromatography. The solvents were then removed in vacuo to yield 5-bromo-3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine (5.8 g, 0.015 mol, 51%) as a white crystalline solid. 1H NMR (CDCl3, 300 MHz) 1.85-1.95 (d, 3H), 4.7-5.0 (brs, 2H), 5.9-6.01 (q, 1H), 6.8-6.95 (d, 1H), 7.01-7.2 (t, 1H), 7.4-7.45 (m, 1H), 7.8-7.85 (d, 1H).
Reaction SMILES: OP([O-])(O)=O.[K+].[C-:7]#[N:8].[Na+].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][CH:19]=[C:20]([CH:22]=[O:23])[N:21]=2)=[CH:13][CH:12]=1>CN(C=O)C.O.O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[O:18][CH:19]=[C:20]([CH:22]([OH:23])[C:7]#[N:8])[N:21]=2)=[CH:15][CH:16]=1
Reactant: O=Cc1coc(-c2ccc(F)cc2)n1
Reactant: [C-]#N
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(O)c1coc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
KH2PO4 (712 mg, 5.23 mmol) and NaCN (251 mg, 5.12 mmol) were added to a solution of 2-(4-fluorophenyl)oxazole-4-carbaldehyde (500 mg, 2.62 mmol) in DMF-H2O (10 mL, 4:6, v/v). The resulting reaction mixture was stirred at room temperature for 1 h, then diluted with water and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxyacetonitrile (500 mg, yield 87%). 1H NMR (400 MHz, CDCl3) δ 8.07-8.02 (m, 2H), 7.88 (s, 1H), 7.20-7.16 (t, J=8.8 Hz, 2H), 5.62 (s, 1H), 4.38 (br s, 1H). MS (ESI) m/z: Calculated for C11H7FN2O2: 218.05. found: 218.8 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:19]([CH3:20])[N:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[C:11]([N+:25]([O-])=O)[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[Sn](Cl)Cl>CO>[NH2:25][C:11]1[CH:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:29][CH:28]=2)[CH:14]=[CH:13][C:12]=1[C:15]1[N:19]([CH3:20])[N:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=1
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(NC(=O)c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CO
Product: Cn1nc(C(F)(F)F)cc1-c1ccc(NC(=O)c2ccc(Cl)cc2)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 16 (42 mg, 0.1 mmol) was dissolved in 10 ml MeOH. Tin(II)chloride dehydrate (223 mg, 1 mmol) was added and the reaction mixture was stirred at r.t. for overnight. The reaction mixture was evaporated to dryness. The solid residue was dissolved in 6 N NaOH and extracted with DCM. The org. phase was washed with brine. After concentrated to dryness, the solid residue was dissolved in DMF and purified on prep HPLC to give compound 17.
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[N:13]1([CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][N:22]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.CO>C(Cl)(Cl)Cl>[N:13]1([CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:5]3[S:1][C:2]4[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=4[CH:4]=3)=[CH:23][N:22]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Brc1ccc(OCCN2CCCC2)nc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: c1ccc2sc(-c3ccc(OCCN4CCCC4)nc3)cc2c1
Yield: 68 %

Procedure:
By essentially following the procedure detailed in Example 1, Part B, the title compound was prepared from benzo[b]thiophene-2-boronic acid and 5-bromopyrid-2-yl 2-(1-pyrrolidinyl)ethyl ether (Part A) in 68% yield as an oil following flash chromatography (SiO2; gradient of 0-4% MeOH in CHCl3).
Reaction SMILES: [NH2:1][CH2:2][C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1.[CH2:45](C1C=C(C)C=CC=1S([O-])(=O)=O)[CH2:46]C1C=C(C)C=CC=1S([O-])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1COCC1.C(Cl)Cl>[N:1]1([CH2:2][C@:3]23[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]2[C@@H:5]2[C@@:18]([CH3:21])([CH2:19][CH2:20]3)[C@@:17]3([CH3:22])[C@@H:8]([C@:9]4([CH3:38])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=3)=[CH:11][CH2:10]4)[CH2:7][CH2:6]2)[CH2:46][CH2:45]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CCc2cc(C)ccc2S(=O)(=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=C(C)[C@@H]1CC[C@]2(CN3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C

Procedure:
tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aminomethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (200 mg, 0.667 mmol) was dissolved in DMF (10.00 mL) and THF (10.00 mL), ethane-1,2-diylbis(4-methylbenzenesulfonate) (247 mg, 0.667 mmol) was added, followed by K2CO3 (184 mg, 1.333 mmol) and the mixture was stirred at 100° C. until no starting material was detected by LCMS. An M+1=626.7 was observed by LC-MS. The reaction mixture was redissolved in CH2Cl2 (100 mL), washed by water (2×50 mL) and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo and the resultant residue was purified by silica gel chromatography using a mixture of ethyl acetate/hexanes. A white foam was obtained (130 mg, 65%) LCMS: m/e 426.7 (MH+), 4.393 min (method 8). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.90 (d, J=8.3 Hz, 2H), 7.24-7.11 (m, 2H), 5.30 (d, J=1.8 Hz, 1H), 4.70 (d, J=2.0 Hz, 1H), 4.60 (dd, J=2.3, 1.3 Hz, 1H), 2.56 (d, J=21.1 Hz, 1H), 2.44-2.33 (m, 1H), 2.26-2.05 (m, 3H), 2.04-1.89 (m, 1H), 1.86 (d, J=12.0 Hz, 1H), 1.82-1.58 (m, 18H), 1.56-1.37 (m, 7H), 1.35-1.21 (m, 6H), 1.19-1.06 (m, 6H), 1.03 (s, 3H), 0.99 (s, 3H), 0.93 (m, 6H)