Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)OCC)C.C([Li])CCC.[CH2:21]([O:23][C:24]([CH:26]1[CH:28]([CH:29]=O)[C:27]1([CH3:32])[CH3:31])=[O:25])[CH3:22].O>O1CCCC1.CCCCCC>[CH2:21]([O:23][C:24]([CH:26]1[CH:28]([CH:29]=[CH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:27]1([CH3:31])[CH3:32])=[O:25])[CH3:22]
Reactant: CCOC(=O)C1C(C=O)C1(C)C
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1C(C=Cc2ccccc2)C1(C)C
Temperature: -70 °C
Yield: 69.6 %

Procedure:
22.8 g (0.1 mol) of benzylphosphonic acid diethyl ester were dissolved in 400 ml of absolute tetrahydrofuran and the solution was cooled to -70° C. 0.11 mol of n-butyl-lithium (as a 15% strength solution in hexane) were added dropwise under a counter-current of nitrogen and while stirring well; the mixture was then stirred at -70° C. for a further 15 minutes, and thereafter 18.6 g (0.1 mol) of 2,2-dimethyl-3-formyl-cyclopropanecarboxylic acid ethyl ester were added dropwise at -65° C., again still under nitrogen. The reaction mixture was then allowed to come to room temperature and was stirred further for 3 hours at 25° C. Thereafter, the reaction batch was poured into 2 liters of water and extracted with 600 ml of ether. The ether phase was dried over sodium sulphate and the solvent was then stripped off in vacuo. The oily residue was distilled at 145°-150° C./3 mm Hg. 2,2 -Dimethyl-3-(2-phenyl-vinyl)-cyclopropanecarboxylic acid ethyl ester having a refractive index nD23 of 1.5022 was obtained in 69.6% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]([NH:17][C:18]([C:20]2[N:21]([CH3:37])[CH:22]=[C:23]([NH:25][C:26]([C:28]3[N:29]([CH3:36])[CH:30]=[C:31]([N+:33]([O-])=O)[CH:32]=3)=[O:27])[CH:24]=2)=[O:19])[S:12][C:13]=1[CH:14]([CH3:16])[CH3:15])=[O:8].[CH2:39]([OH:41])C>[Pd]>[CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]([NH:17][C:18]([C:20]2[N:21]([CH3:37])[CH:22]=[C:23]([NH:25][C:26]([C:28]3[N:29]([CH3:36])[CH:30]=[C:31]([NH:33][CH:39]=[O:41])[CH:32]=3)=[O:27])[CH:24]=2)=[O:19])[S:12][C:13]=1[CH:14]([CH3:16])[CH3:15])=[O:8]
Reactant: CCO
Reactant: CC(C)c1sc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])cn3C)cn2C)nc1C(=O)NCCCN(C)C
Agent: [Pd]
Product: CC(C)c1sc(NC(=O)c2cc(NC(=O)c3cc(NC=O)cn3C)cn2C)nc1C(=O)NCCCN(C)C
Reaction time: 5 h
Yield: 51 %

Procedure:
N-[3-(Dimethylamino)propyl]-5-isopropyl-2-{[(1-methyl-4-{[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-1H-pyrrol-2-yl)carbonyl]amino}-1,3-thiazole-4-carboxamide (90 mg, 0.165 mmol; see step (v) above) was suspended in ethanol (20 mL) then Pd/C (97 mg, 10%) was added at 0° C. under nitrogen. The reaction mixture was hydrogenated at room temperature and atmospheric pressure for 5 h. The catalyst was removed under reduced pressure then ethyl formate (20 mL) was added to the ethanolic solution of the amine. The reaction mixture was heated under reflux for 3 days, then the solvent was removed under reduced pressure. The crude product was dissolved in water (2 mL) containing 0.1% TFA, then purified by HPLC. The fractions collected were freeze-dried to give the desired product as pale yellow solid (55 mg, 51%) with no distinct m.p.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.Cl[S:13]Cl.C1[CH2:19][O:18]CC1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[O:8][C:19](=[O:18])[S:13][N:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(N)=O)cc1
Reactant: C1CCOC1
Reactant: ClSCl
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nsc(=O)o2)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 88 %

Procedure:
4-Methoxybenzamide (3.0 g, 19.9 mmol) was suspended in a mixture of toluene (30 mL) and THF (15 mL), and chlorosulfenyl chloride (3.35 mL, 39.7 mmol) was then added to the suspension. The obtained mixture was stirred at 80° C. for 2.5 hours. The reaction solution was cooled to room temperature, and it was then concentrated under reduced pressure. Thereafter, diethyl ether was added to the residue, and insoluble materials were then removed by filtration, so as to obtain the title compound (3.64 g, 88%) in the form of a colorless solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[C@@H:3]([NH:7][S:8]([C:11]1[CH:23]=[CH:22][C:14]2[N:15]=[C:16]([S:18][CH2:19][CH2:20][CH3:21])[O:17][C:13]=2[CH:12]=1)(=[O:10])=[O:9])[C:4](O)=[O:5].C(Cl)(=O)C([Cl:28])=O.CN(C=O)C>ClCCl>[CH3:1][CH:2]([CH3:24])[C@@H:3]([NH:7][S:8]([C:11]1[CH:23]=[CH:22][C:14]2[N:15]=[C:16]([S:18][CH2:19][CH2:20][CH3:21])[O:17][C:13]=2[CH:12]=1)(=[O:10])=[O:9])[C:4]([Cl:28])=[O:5]
Reactant: CCCSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc2o1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)Cl)C(C)C)cc2o1
Temperature: 0 °C

Procedure:
(2R)-3-methyl-2-[(2-propylthiobenzoxazol-6-sulfonyl)amino]butanoic acid (112 mg, 0.3 mmol) prepared in Example 19 was dissolved in dichloromethane (2 mL) and cooled down to 0° C., and, oxalylchloride (0.08 mL, 3 equi.) and DMF of catalytic amount were added. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent and dried under reduced pressure. Then, (2R)-3-methyl-2-[(2-propylthiobenzoxazol-6-sulfonyl)amino]butanoic chloride thus obtained was dissolved in THF (1 mL). Hydroxylamine hydrochloride (0.21 g, 10 equi.) and NaHCO3 (0.303 g, 12 equi.) was dissolved in THF/H2O (2 mL/2 mL) and cooled down to 0° C. to prepare a hydroxylamine solution. Then, acid chloride THF solution was slowly added to the hydroxylamine solution while maintaining the temperature of 0° C. After 1 hour, the solvent was removed from the reaction solution. Then, the product was extracted with ethylacetate (5 mL), washed with H2O and 0.1N HCl and dried over MgSO4. The dried material was distilled under reduced pressure and vacuum-dried to prepare the titled compound, (2R)-N-hydroxy-3-methyl-2-[(2-propylthiobenzoxazol-6-sulfonyl)amino]butyric amide (100 mg, 85%).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].C(N([CH2:12][CH3:13])CC)C.[C:14](Cl)(=[O:18])[CH:15](C)C>O1CCCC1>[C:14]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])(=[O:18])[CH2:15][CH2:12][CH3:13]
Reactant: CN(C)CCO
Reactant: CCN(CC)CC
Reactant: CC(C)C(=O)Cl
Solvent: C1CCOC1
Product: CCCC(=O)OCCN(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 18.1 %

Procedure:
To a solution of N,N-dimethyl ethanolamine (4.45 g, 0.05 mol) in 140 mL of anhydrous tetrahydrofuran at room temperature under nitrogen was added triethylamine (5.05 g, 0.05 mol) and stirred for 15 min. The reaction mixture was then cooled at 0° C. and isobutyryl chloride (5.5 g, 0.05 mol) in 10 mL of tetrahydrofuran was added dropwise over 20 min. The resulting suspension was allowed to warm to room temperature and stirred overnight. The resulting solution was filtered and the solvent evaporated. The resulting product was then diluted by adding 200 mL of ether and subsequently washed with 10% aqueous NaOH solution, water and brine. After removal of the solvent, the crude product was chromatographed on a silica gel column using chloroform as the eluent to give liquid product (1.44 g, 50%). 1H NMR (CDCI3): δ 4.10 (t, J=5.82 Hz, 2H), 2.50 (m, 3H), 2.21 (s, 6H), 1.11 (s, 3H), 1.08 (s, 3H); MS m/z 159 (M+), 115, 71, 58 (100%), 42.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[OH-].[Na+].Cl>O.C(O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[C:27]([OH:29])=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(=NOCc1cccnc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: O=C(O)C(=NOCc1cccnc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 1 h
Yield: 73.8 %

Procedure:
A mixture of 7 g of the product of Step A, 35 ml of dioxane, 35 ml of ethanol and 21 ml of aqueous N sodium hydroxide was stirred at 35°-40° C. for one hour and after cooling, the pH was adjusted to 2 by addition of aqueous N hydrochloric acid. 250 ml of water were added and the mixture was vacuum filtered. The product was washed and dried to obtain 4.9 g of 2-(2-tritylamino-thiazol-4-yl)-2-(3-pyridinylmethoxyimino)-acetic acid. mp=192° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]([C:6]1[O:10][N:9]=[C:8]([CH3:11])[C:7]=1[C:12]([O:14]CC)=[O:13])=[O:5])[CH3:2].[OH-].[K+]>O.C(O)C>[CH2:17]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[O:10][N:9]=[C:8]([CH3:11])[C:7]=1[C:12]([OH:14])=[O:13])=[O:5])[CH3:18]
Reactant: CCOC(=O)c1c(C)noc1C(=O)N(CC)CC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCN(CC)C(=O)c1onc(C)c1C(=O)O
Yield: 67.4 %

Procedure:
5.0 g of the ester from Example 9 and 1.4 g of potassium hydroxide in 10 ml of water and 20 ml of ethanol are stirred at room temperature. When the reaction is complete, the mixture is diluted with water and extracted with dichloromethane. Thereafter, the aqueous phase is acidified with hydrochloric acid and extracted with dichloromethane, and the organic phase is evaporated down. 3.0 g of 5-diethylaminocarbonyl-3-methylisoxazole-4-carboxylic acid are obtained as a pale oil (compound No. 4).
Reaction SMILES: [CH:1]([C:3]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]([NH-:16])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=O.[NH:17]1[C:21]2[N:22]=[CH:23][CH:24]=[C:25]([C:26]([OH:28])=[O:27])[C:20]=2[CH:19]=[CH:18]1.[CH3:29][N:30]([CH3:44])[CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:36]=[C:37]([NH2:43])[C:38]([NH2:42])=[CH:39][C:40]=1[F:41]>CN(C)C=O>[NH:17]1[C:21]2[N:22]=[CH:23][CH:24]=[C:25]([C:26]([OH:28])=[O:27])[C:20]=2[CH:19]=[CH:18]1.[CH3:44][N:30]([CH3:29])[CH2:31][CH2:32][CH2:33][O:34][C:35]1[C:40]([F:41])=[CH:39][C:38]2[N:42]=[C:1]([C:3]3[C:15]4[C:14]5[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=5)[CH:8]([NH-:16])[C:7]=4[CH:6]=[CH:5][CH:4]=3)[NH:43][C:37]=2[CH:36]=1
Reactant: CN(C)CCCOc1cc(N)c(N)cc1F
Reactant: [NH-]C1c2ccccc2-c2c(C=O)cccc21
Agent: O=C(O)c1ccnc2[nH]ccc12
Solvent: CN(C)C=O
Product: CN(C)CCCOc1cc2[nH]c(-c3cccc4c3-c3ccccc3C4[NH-])nc2cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Stir, at room temperature under argon, a mixture of 100 mg of (4-formyl-9H-fluoren-9(R,S)-yl)amide of 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid, prepared as in Example 234, 65 mg of 4-(3-dimethylaminopropoxy)-5-fluorobenzene-1,2-diamine, prepared in the previous stage, and 46 mg of ferric trichloride in 5 ml of anhydrous dimethylformamide. After 48 hours, evaporate the reaction medium to dryness and then purify the residue by flash chromatography on silica gel (20-40 μm), eluting with a mixture of dichloromethane and ammonia as a 7N solution in methanol (95/5 then 9/1 by volume). In this way, we obtain 42 mg of {4-[6-(3-dimethylaminopropoxy)-5-fluoro-1H-benzimidazol-2-yl]-9H-fluoren-9(R,S)-yl}amide 1H-pyrrolo[2,3-b]-pyridine-4-carboxylic acid, in the form of a yellow solid with the following characteristics:
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([C:13](=O)[CH3:14])[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+].O1CCCC1>CO.C(#N)C>[CH2:1]([C:3]1[CH:12]=[C:11]([CH:13]([NH2:29])[CH3:14])[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2)[CH3:2]
Reactant: CCc1cc(C(C)=O)c(-c2cccc(F)c2)c2ncccc12
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC#N
Product: CCc1cc(C(C)N)c(-c2cccc(F)c2)c2ncccc12
Temperature: 65 °C

Procedure:
A mixture of 1-[5-ethyl-8-(3-fluorophenyl)quinolin-7-yl]ethanone (6.1 mg, 0.021 mmol) and ammonium acetate (0.017 g, 0.22 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.052 mL, 0.052 mmol) was added to the mixture. The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C19H20FN2 (M+H)+: m/z=295.2; Found: 295.1.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][Cl:28]>CO>[Cl:28][CH2:27][CH2:26][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=c1[nH]c(-c2ccccc2)c(O)c2ccccc12
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=c1[nH]c(-c2ccccc2)c(OCCCl)c2ccccc12
Reaction time: 0.17 h
Yield: 44 %

Procedure:
To a suspension of 180 mg (0.76 mmol) of 4-hydroxy-3-phenyl-2H-isoquinolin-1-one in methanol (6 mL), 315 mg (2.28 mmol) of potassium carbonate and 1901 (2.28 mmol) of 1-bromo-2-chloroethane were added and the mixture was submitted to microwaves at 120° C. for 10 min. The solvent was concentrated under reduced pressure and the resulting crude was purified by flash chromatography (eluant: ethyl acetate/hexane 1/2) affording 100 mg of the title compound (44%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[CH:34]=[C:33]([CH2:35][CH2:36][CH3:37])[CH:32]=[CH:31][N:30]=1)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[CH:34]=[C:33]([CH2:35][CH2:36][CH3:37])[CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: CCCc1ccnc(C(=O)CBr)c1
Agent: Br
Product: CCCc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)OC)c1

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(penylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-4-propylpyridine hydrobromide (Preparation is described in Example 65).
Reaction SMILES: ON1[C:6](=O)[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[O-]O.C1(C(C)C)C=CC=CC=1.C1CCCCCCC1.O=O>>[CH:3]1([OH:12])[CH2:4][CH2:11][CH2:10][CH2:9][CH2:8][CH2:5][CH2:6]1.[C:3]1(=[O:12])[CH2:4][CH2:11][CH2:10][CH2:9][CH2:8][CH2:5][CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Agent: [O-]O
Solvent: CC(C)c1ccccc1
Solvent: C1CCCCCCC1
Product: O=C1CCCCCCC1
Product: OC1CCCCCCC1

Procedure:
2 mmol of N-hydroxyphthalimide and 4 mmol of cumene hydroperoxide are added at a temperature of 130° C. to 200 mmol of cyclooctane in a round-bottomed flask having an attached reflux condenser. Oxygen at approximately 15 l/h is passed through the reaction mixture for 8 hours at said temperature. Cyclooctanol is obtained at a selectivity of 17% and cyclooctanone at a selectivity of 46%, at a cyclooctcane conversion rate of 53%.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][OH:8].[C:9]1([CH3:20])[CH:14]=[CH:13][C:12]([S:15]([O:18]C)(=[O:17])=[O:16])=[CH:11][CH:10]=1>CC(C)=O>[C:9]1([CH3:20])[CH:10]=[CH:11][C:12]([S:15]([O-:18])(=[O:16])=[O:17])=[CH:13][CH:14]=1.[CH3:1][N+:2]1([CH3:9])[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][OH:8]
Reactant: CN1CCCC1CO
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CC(C)=O
Product: C[N+]1(C)CCCC1CO
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Yield: 138.6 %

Procedure:
In 10 ml of acetone was dissolved 1.47 g of 1-methyl-2-pyrrolidinemethanol, and 2.38 g of methyl p-toluenesulfonate was added dropwise to the resulting solution. The mixture was stirred at room temperature, heated under reflux, and cooled to precipitate crystals. The crystals were collected by filtration and dried to give 2.67 g of the desired compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[CH:15]([N:18]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O)[CH3:19])([CH3:17])[CH3:16].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[CH:15]([N:18]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)N(C)c1ccccc1C=O
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N(C)c1ccccc1CN1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl piperidin-4-ylcarbamate (262 mg, 1.31 mmol) (Aldrich) and 2-(N-isopropyl-N-methylamino)benzaldehyde (150 mg, 0.85 mmol) in CH2Cl2 (6 mL) was added Na(OAc)3BH (288 mg, 1.36 mmol) followed by AcOH (0.1 mL). This mixture was stirred for 3 h at RT. The reaction was quenched by adding 2M NaOH—H2O (5 mL) and stirred for 5 min. The mixture was then extracted with CH2Cl2 (2×25 mL), and the organic layer was washed with brine, and dried, and the solvent was removed. The crude material was purified by silica gel column chromatography eluting with 5% NH3-MeOH in CH2Cl2 gave Compound 221.
Reaction SMILES: [CH3:1][C:2]([CH3:35])([O:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]2=[C:18]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[C:19]3[CH:20]=[CH:21][C:22]([C:25]([O:27]C)=[O:26])=[CH:23][C:24]=3[N:10]2[CH2:9][CH2:8]1)=[O:6])[CH3:3]>CO.C1COCC1.[OH-].[Na+]>[CH3:3][C:2]([CH3:35])([O:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]2=[C:18]([CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][C:24]=3[N:10]2[CH2:9][CH2:8]1)=[O:6])[CH3:1]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C(=O)OC(C)(C)C)c1ccccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccccc21
Temperature: 50 °C
Yield: 96.5 %

Procedure:
A solution of methyl 5-[(1,1-dimethylethoxy)carbonyl]-13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-carboxylate (1.08 g, 2.28 mmol) in MeOH (40 mL), THF (30 mL) and 5N aqueous NaOH (2 mL) was heated at 50° C. overnight. Additional 10N aqueous NaOH (6 mL) was added and the reaction mixture was again heated at 50° C. for 5 h. The reaction was cooled, concentrated under vacuum and partitioned between EtOAc (60 mL) and ½ saturated aqueous NH4Cl (30 mL). The organic layer was washed with brine (10 mL) and the combined aqueous layers were extracted with EtOAc (40 mL). The combined organic layers were dried (MgSO4), filtered, concentrated to yield 5-[(1,1-dimethylethoxy)carbonyl]-13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-carboxylic acid (1.01 g, 2.20 mmol, 96%) as a yellow solid. 1HNMR (500 MHz, Acetone-d6) δ 8.23 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.60-7.51 (m, 3H), 7.48-7.41 (m, 1H), 4.81 (br s, 1H), 4.66 (br s, 1H), 3.86 (br s, 1H), 3.59 (br s, 1H), 3.12-2.97 (m, 1H), 2.15-1.67 (m, 6H), 1.52-1.20 (m, 4H), 1.18 (s, 9H). LCMS: m/e 461 (M+H)+, ret time 2.26 min, column C, 2 minute gradient, start at 0% B.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[N:11]2[CH:12]=[CH:13][C:14]([C:16]([CH3:26])([O:18][Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:17])=[N:15][C:10]2=[N:9][CH:8]=1.C([Sn](Cl)(CCCC)CCCC)CCC.Cl[C:42]1[CH:47]=[CH:46][N:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[N:43]=1>C1COCC1.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>[CH3:17][C:16]([C:14]1[CH:13]=[CH:12][N:11]2[C:7]([C:42]3[CH:47]=[CH:46][N:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[N:43]=3)=[CH:8][N:9]=[C:10]2[N:15]=1)([O:18][Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:26]
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(Br)cnc2n1
Reactant: FC(F)(F)c1nccc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(C(F)(F)F)n3)cnc2n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 31.1 %

Procedure:
A solution of isopropylmagnesium chloride (2.0M in THF, 525 μl, 1.05 mmol) was added dropwise to a stirred suspension of 3-bromo-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (370 mg, 1.0 mmol) in THF (5 ml) at −78° C. under N2. The resulting solution was stirred at −78° C. for 15 min and then tributyltin chloride (298 μl, 1.1 mmol) was added. The reaction was warmed to 0° C. and stirred for 1 h. 4-Chloro-2-trifluoromethylpyrimidine (200 mg, 1.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (110 mg, 10 mol %) were added and the reaction heated at reflux for 18 h. The mixture was concentrated under reduced pressure while dry loading onto silica and then purified by column chromatography on silica using 50-80% EtOAc/isohexanes as the eluent to afford 7-(1-methyl-1-triethylsilanyloxyethyl)-3-(2-trifluoromethylpyrimidin-4-yl)imidazo[1,2-α]pyrimidine (136 mg): 1H NMR (400 MHz, CDCl3) δ 10.10 (1H, d, J 7.4), 8.82 (1H, d, J 5.5), 8.57 (1H, s), 7.78 (1H, d, J 5.5), 7.67 (1H, d, J 7.4), 1.70 (6H, s), 1.00 (9H, t, J 8.0), 0.68 (6H, q, J 8.0); m/z (ES+) 438 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:3]=1.[F-:24].[Cs+].CS(C)=O.CCCCCC>CCOC(C)=O>[F:24][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:3]=1
Reactant: [F-]
Reactant: CC(C)Oc1ccc(-c2cc(Cl)cc(-c3ccccn3)n2)cc1
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2cc(F)cc(-c3ccccn3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 2 dram vial equipped with a stir bar and charged with 4-chloro-6-(4-isopropoxyphenyl)-2,2′-bipyridine (all material from step 1) was added cesium fluoride (200 mg, 1.32 mmol) and DMSO (0.7 mL). The vial was sealed with a septum cap and then placed in a 140° C. heating block with stirring for 18 h. The reaction mixture was allowed to cool to room temperature. The mixture was transfered to a 125 mL separatory funnel and was diluted with EtOAc (50 mL) and then twice washed with water:brine (25 mL:25 mL). The organic solution was dried over MgSO4; filtered; then concentrated in vacuo to afford an amber solid residue which was subjected to silica gel chromatography (hexane:EtOAc) to afford 4-fluoro-6-(4-isopropoxyphenyl)-2,2′-bipyridine as a colorless solid (16 mg, 29% over two steps). 1H-NMR (400 MHz, CDCl3) δ 8.72-8.67 (m, 1H), 8.62 (dt, J=7.8, 1.0 Hz, 1H), 8.10-8.05 (m, 3H), 7.86 (td, J=7.8, 1.8 Hz, 1H), 7.41 (dd, J=10.0, 2.3 Hz, 1H), 7.35 (ddd, J=7.5, 4.8, 1.3 Hz, 1H), 7.04-6.99 (m, 2H), 4.66 (spt, J=6.1 Hz, 1H), 1.40 (d, J=6.0 Hz, 6H); MS: MS m/z 309.2 (M++1).