Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([NH2:26])[CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12]([C:16](=[O:25])[C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[CH2:13]2)=[CH:8][CH:7]=1.[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:30]=1[C:31](Cl)=[O:32]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:26][C:31](=[O:32])[C:30]1[C:29]([Cl:28])=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:38])[CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12]([C:16](=[O:25])[C:17]3[C:18]([Cl:24])=[CH:19][CH:20]=[CH:21][C:22]=3[Cl:23])[CH2:13]2)=[CH:8][CH:7]=1
Reactant: COC(=O)C(N)Cc1ccc2c(c1)CN(C(=O)c1c(Cl)cccc1Cl)CC2
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: c1ccncc1
Product: COC(=O)C(Cc1ccc2c(c1)CN(C(=O)c1c(Cl)cccc1Cl)CC2)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A stirred solution of 2-amino-3-[2-(2,6-dichloro-benzoyl]-1,2,3,4-tetrahydro-isoquinolin-7-yl]-propionic acid methyl ester (1.18 g, Reference Example 10) in dry pyridine (50 mL), under nitrogen and at room temperature, was treated dropwise with 2,6-dichloro-benzoyl chloride (0.67 g). The mixture was stirred at room temperature for 25 minutes and then at 65° C. for 40 minutes. The resulting dark red solution was cooled to room temperature and then evaporated. The residual red oil was dissolved in dichloromethane and this solution was washed with aqueous sodium bicarbonate solution (5%), then with water, then dried over magnesium sulfate and then evaporated. The residue was coated onto silica (8.5 g) using dichloromethane and then subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane (1:1, v/v) to give the title compound.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25]([OH:27])=O)(=[O:3])[NH2:2].[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([C:25]([NH:28][CH:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:27])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: CN1CCC(N)CC1
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Product: CN1CCC(NC(=O)c2c(C(N)=O)nc3n2CCOc2cc(F)c(C#CC(C)(C)O)cc2-3)CC1

Procedure:
2-Carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.05 g) was reacted with 4-amino-1-methylpiperidine similar to as described in Example 2 to afford 17.8 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-(1-methyl-4-piperidyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 470 (M)+. 1H NMR (400 MHz, DMSO) δ 11.37 (d, J=7.0 Hz, 1H), 8.60 (d, J=8.5 Hz, 1H), 8.39 (s, 1H), 7.88 (s, 1H), 7.02 (d, J=10.6 Hz, 1H), 6.45 (s, 1H), 5.47 (s, 1H), 5.07-4.93 (m, 2H), 4.63-4.46 (m, 2H), 2.98-2.81 (m, 2H), 2.48-2.39 (m, 1H), 2.36 (s, 3H), 1.98-1.87 (m, 2H), 1.65-1.52 (m, 2H), 1.49 (s, 6H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13]C=1C(O)=O.CN(C=O)C>C(Cl)Cl>[F:7][C:8]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.1 %

Procedure:
Oxalyl chloride (0.488 mL, 5.76 mmol) was added to a suspension of 2-fluoro-3-(trifluoromethyl)benzoic acid (1.00 g, 4.81 mmol) in DCM (10 mL) containing catalytic DMF. The reaction was stirred at room temperature for 90 minutes and solvents were removed in vacuo to afford the desired compound (1.08 g, 99%). The product was used without additional purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4)nc23)CC1
Yield: 84.3 %

Procedure:
Beginning with 0.200 gm (0.88 mMol) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.114 mL (0.96 mMol) 4-fluorobenzoyl chloride, 0.260 gm (84%) of the title compound were prepared as an ivory solid essentially by the procedure described in Example 4. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH3:27])[C:13]2[CH:14]=[CH:15][C:16]([F:26])=[C:17]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:18]=2)=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([N:12]([CH3:27])[C:13]1[CH:14]=[CH:15][C:16]([F:26])=[C:17]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:22])[F:23])[CH:18]=1)[N:10]=2
Reactant: N#C[S-]
Reactant: CN(c1ccc(F)c(NC(=O)C(F)(F)F)c1)c1ccc(N)cn1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CN(c1ccc(F)c(NC(=O)C(F)(F)F)c1)c1ccc2nc(N)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.3 %

Procedure:
Potassium thiocyanate (2.96 g, 30.5 mmol) was suspended in acetic acid (20 mL), and the suspension was stirred at room temperature for 10 min. To the obtained solution was added N-{5-[(5-aminopyridin-2-yl)(methyl)amino]-2-fluorophenyl}-2,2,2-trifluoroacetamide (2.0 g, 6.96 mmol), and the mixture was further stirred at room temperature for 10 min. To the obtained solution was slowly added dropwise a solution of bromine (1.17 g, 7.30 mmol) in acetic acid (10 mL). After the completion of the dropwise addition, the mixture was stirred at room temperature for 20 hr. The yielded black insoluble material was filtered off, and washed with acetic acid. The filtrate and the washing solution were combined, and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (100 mL), and the suspension was washed with saturated aqueous sodium hydrogen carbonate solution (70 mL) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=40/60→0/100), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give the title compound (1.00 g, 43%) as a colorless powder.
Reaction SMILES: O[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[N:3]=1.C(N(CC)C1C=CC=CC=1)C.O=P(Cl)(Cl)[Cl:28]>>[Cl:28][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[N:3]=1
Reactant: COC(=O)c1cc2nccn2c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: COC(=O)c1cc2nccn2c(Cl)n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Methyl 5-hydroxyimidazo[1,2-c]pyrimidine-7-carboxylate (4.0 g, 21 mmol) and N,N-diethylaniline (6.6 mL, 41 mmol) were suspended in POCl3 (80 mL, 870 mmol) and heated at 50° C. for 30 minutes. The reaction mixture remained heterogeneous, so the temperature was raised to 100° C. After 30 minutes, LCMS analysis showed mostly the title compound, along with 5,7-dichloroimidazo[1,2-c]pyrimidine (which was presumably formed from 7-chloroimidazo[1,2-c]pyrimidin-5-ol carried through from the previous step). The reaction mixture was cooled to ambient temperature and concentrated down to remove the POCl3. The residue was cooled in an ice bath and quenched carefully with water. Solid K2CO3 was added to neutralize the solution to pH 7, which was then extracted with DCM. The combined organic layers were filtered through a Biotage phase separator cartridge and washed with DCM. The filtrate was concentrated down to a thick dark greenish brown residue. While sitting overnight, a precipitate formed. The resultant solid was triturated in DCM and Et2O to give afford methyl 5-chloroimidazo[1,2-c]pyrimidine-7-carboxylate (6.4 g, 21 mmol, 100% yield) as a brick-red solid. The solid was 70% pure, but could not be purified at this stage due to its insolubility. The crude material was used directly in the next step. MS (apci) m/z=212.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.O.Cl.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:17]3[CH2:18][CH2:19][NH:14][CH2:15][CH:16]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc[nH]c2c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: COc1ccc2c(C3=CCNCC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Preparation 30 from 6-methoxyindole (2.0 g, 14 mmol) and 4-piperidone hydrochloride hydrate (4.2 g, 27 mmol). The product was isolated as a yellow solid. Yield 2.8 g (90%). mp 190°-193° C. FDMS m/e=228 (M+ of free base).
Reaction SMILES: [OH-].[Na+].Cl.[CH3:4][S:5]([N:8]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1)(=[O:7])=[O:6].[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[NH:31][C:32](=O)[O:33]C1C=CC=CC=1>CS(C)=O.O>[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[NH:31][C:32]([N:13]1[CH2:12][CH2:11][C:10]2([C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:8]([S:5]([CH3:4])(=[O:6])=[O:7])[CH2:9]2)[CH2:15][CH2:14]1)=[O:33]
Reactant: O=C(Nc1nc2ccccc2s1)Oc1ccccc1
Reactant: CS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)N1CC2(CCN(C(=O)Nc3nc4ccccc4s3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.2 %

Procedure:
10 M aqueous NaOH solution (75 uL,) was added to a solution of 1-methylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride 2-1(225 mg, 0.74 mmol) in DMSO (2.5 mL). Phenyl N-(2-benzothiazolyl)carbamate 2-2 (200 mg, 0.74 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for 20 h. The mixture was diluted with water and extracted with EtOAc. The organic extract was washed with dil. NaOH and brine, and dried over Na2SO4. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 200 (279 mg, 85%) as a colorless amorphous solid.
Reaction SMILES: [CH:1]1[C:6]2[C:7](=O)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.B.C(O)C>C1COCC1>[CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Agent: B
Solvent: CCO
Solvent: C1CCOC1
Product: c1ccc2c(c1)CNc1ccccc1O2
Temperature: 25 °C
Yield: 101.9 %

Procedure:
Dibenzo[b,f][1,4]oxazepin-11(10H)-one (1.001 g, 4.7 mmol) was dissolved in THF (20 mL) and the borane (2M in THF, 20 mL, 40.0 mmol) was added. The reaction mixture was refluxed for 3 hours. The mixture was cooled down to room temperature and an excess of ethanol was added to quench the reaction. The resulting mixture was refluxed for 2 hours. The mixture was cooled down and concentrated in vacuo. The residue was dissolved in ethyl acetate and the organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated to afford title compound 398 (0.945 g, quantitative). MS (m/z): 198.1 (M+H). 1H NMR (CD3OD) δ (ppm): 7.29-7.19 (m, 2H), 7.16-7.04 (m, 2H), 7.01-6.99 (m, 1H), 6.82-6.78 (m, 1H), 6.63-6.59 (m, 2H), 4.88 (s, 1H), 4.39 (s, 2H). MS (m/z): 198.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([NH:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=2)[C:9]#N)=[CH:5][CH:4]=1.[CH:23]([CH:25]=C)=O>>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([N:7]2[CH:25]=[CH:23][CH:9]=[C:8]2[C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(NC(C#N)c2ccc(S(N)(=O)=O)cc2)cc1
Reactant: C=CC=O
Product: COc1ccc(-n2cccc2-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-methoxyanilino)-α-(4-sulfamoylphenyl)acetonitrile [prepared as described in step (ii) above] and acrolein as starting materials, the title compound was obtained as a yellow powder (yield 9%), melting at 112-114° C.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=1>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:21][CH2:20][C:17]3[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNc2cccn3nc(Cl)nc23)cc1

Procedure:
(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(4-methoxy-benzyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (2.00 g, 8.60 mmol), and 4-methoxy-benzenemethanamine, (1.26 mL, 9.72 mmol) in a manner analogous to Example 2d. Product isolated as an off-white solid, (1.51 g. 61%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.06 (d, J=6.90 Hz, 1H), 7.31 (d, J=8.2 Hz, 2H), 7.19 (m, 1H), 6.94 (t, J=14.4, 7.6 Hz, 1H), 6.87 (d, J=7.4 Hz, 2H), 6.42 (d, J=8.0 Hz, 1H), 4.40 (d, J=6.1 Hz, 2H), 3.71 (s, 3H). MS=289 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[H-].[Na+].Br[CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24]>CN(C=O)C>[CH3:1][C:2]1[N:3]([CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[CH:4]=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1c[nH]c(C)n1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(CCCN2C(=O)c3ccccc3C2=O)c(C)n1

Procedure:
In a similar manner to Example A, a mixture of 2,4-dimethylimidazole (24.0 g) was added to a suspension of sodium hydride (10.0 g, 60% dispersion) in DMF (300 ml). After stirring for. 1.5 hours, DMF (80 ml) was added followed by a slurry of N-(3-bromopropyl)phthalimide (63.8 g) in DMF (100 ml). The mixture was reacted and worked up as in Example A and the residue triturated with petroleum ether b.p. 60°-80° C. and then with ether. The residue was recrystallised from ethyl acetate to give N-[3-(2,4-dimethylimidazol-1-yl)propyl]phthalimide, m.p. 191°-122° C. 1H nmr indicated the presence of approximately 10% of N-[3-(2,5-dimethylimidazol-1-yl)propyl]phthalimide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:10]([N:11]2C(C(F)(F)F)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH2:14][CH:12]([NH:11]2)[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC(C1)N2C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CC(C1)N2
Temperature: 25 °C
Yield: 78.5 %

Procedure:
A solution of 3-(tert-butoxycarbonyl)-6-(trifluoromethylcarbonyl)-3,6-diazabicyclo[3.1.1]heptane (4) (8.5 g, 28.9 mmol) and potassium carbonate (30.7 g, 2 eq, 57.8 mmol) in methanol (150 mL) was heated at 70° C. for 3 h. The solution was cooled to ambient temperature and the solvent was removed in vacuo. The crude material was dissolved in a 1:1 solution of methylene chloride:methanol and filtered to give 3-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane (5) (4.5 g, 79% yield) as an off-white solid.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH2:25][CH2:26][S:27]([OH:30])(=[O:29])=[O:28].C(O)C.C([BH3-])#N.[Na+]>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:24][CH2:25][CH2:26][S:27]([OH:30])(=[O:29])=[O:28])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Reactant: NCCS(=O)(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCS(=O)(=O)O)ccc3c2)CC1
Temperature: 25 °C

Procedure:
A solution of 6-(trans-4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (0.1662 g, 0.5354 mmol) and Taurine (0.06700 g, 0.5354 mmol) in anhydrous Ethanol (4.00 mL, 68.5 mmol) was refluxed for 2 hours. The mixture was cooled to room temperature and Sodium cyanoborohydride (0.04037 g, 0.6425 mmol) was added. The mixture was then refluxed overnight. The reaction mixture was cooled to room temperature and washed with Sat. aqueous citric acid (4 mL). The mixture was then concentrated to dryness under reduced pressure. The resulting solid was suspended in water and filtered. The residue was washed with water, air-dried and purified by prep HPLC to give the title compound. ESI-MS (M+H+): 420.34; 1H NMR (400 MHz, DMSO-d6) Shift 8.68 (br. s., 1H), 7.84 (br. s., 1H), 7.73-7.81 (m, 2H), 7.45 (dd, J=1.76, 8.53 Hz, 1H), 7.32-7.35 (m, 1H), 7.12 (dd, J=2.51, 8.78 Hz, 1H), 4.29-4.38 (m, 1H), 4.24 (br. s., 2H), 3.13 (d, J=13.80 Hz, 2H), 2.76 (d, J=13.55 Hz, 2H), 2.10-2.18 (m, 2H), 1.72-1.80 (m, 2H), 1.23-1.36 (m, 2H), 1.09-1.22 (m, 2H), 0.96-1.06 (m, 1H), 0.81 (s, 9H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([C:16]([CH3:36])([CH3:35])[C@@H:17]([O:27][Si](C(C)(C)C)(C)C)[CH2:18][CH2:19]2)=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7].[CH:38]1C=CC=CC=1.Cl>C(O)C>[CH2:1]([O:2][C:3](=[O:37])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C:11]([C:12]3[CH2:13][CH2:14][C@@H:15]4[C@:20]([C:22]=3[CH2:23][CH2:24]2)([CH3:21])[CH2:19][CH2:18][C@H:17]([OH:27])[C:16]4([CH3:35])[CH3:36])=[CH:10][CH2:9]1)[CH3:7])[CH3:38]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: c1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethylchola-5,7-dien-24-oic acid methyl ester (4.0 g) is suspended in a mixture of 60 ml of 96% ethanol, 10.1 ml of benzene and 10.1 ml of concentrated hydrogen chloride acid and refluxed for 3.5 hours. After aqueous work-up and column chromatography followed by crystallization from ethanol the title compound (1.37 g) is isolated. Melting point: 122-124° C. 1H-NMR (CDCl3, 300 MHz): δ=5.35 (1H, s); 4.13 (2H, q); 3.25 (1H, m). 1.25 (3H, t). MS: Calculated: 428.7. Found 428.3.
Reaction SMILES: Br[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[CH:15]1([NH2:18])[CH2:17][CH2:16]1>C1COCC1.CCOC(C)=O>[CH:15]1([NH:18][C:2]2[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: CNC(=O)c1cccc([N+](=O)[O-])c1Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1cccc([N+](=O)[O-])c1NC1CC1
Temperature: 60 °C

Procedure:
A mixture of 2-bromo-N-methyl-3-nitrobenzamide (830 mg, 3.20 mmol), cyclopropanamine (666 μL, 9.61 mmol) in THF (10 mL) under N2 was heated at 60° C. for 18 h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using DCM-EtOAc (1:1) as eluent to give 2-(cyclopropylamino)-N-methyl-3-nitrobenzamide: 1H NMR (400 MHz, DMSO-d6) δ 8.54-8.47 (m, 2H), 7.95 (dd, J=8, 4 Hz, 1H), 7.64 (dd, J=8, 4 Hz, 1H), 6.77 (dd, J=8, 4 Hz, 1H), 2.76 (d, J=8 Hz, 3H), 2.68-2.62 (m, 1H), 0.67-0.60 (m, 2H), 0.44-0.40 (m, 2H); LC-MS (ESI) m/z 236.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:9]=3[N:10]=[C:4]2[CH:3]=1.[F:22][C:23]([F:38])([F:37])[C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=2)=[CH:26][CH:25]=1>>[O:36]=[C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[N:29][C:24]([C:23]([F:38])([F:22])[F:37])=[CH:25][CH:26]=2)[CH:35]=[CH:34][N:33]1[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:9]=3[N:10]=[C:4]2[CH:3]=1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)nc2)cc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3cc(Br)ccn3c2C1
Product: CC(C)(C)OC(=O)N1CCc2nc3cc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)ccn3c2C1
Yield: 55.2 %

Procedure:
tert-Butyl 7-bromo-3,4-dihydropyrido[4′,3′:4,5]imidazo[1,2-a]pyridine-2(1H)-carboxylate (212 mg, 0.602 mmol) and 4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (145 mg, 0.604 mmol) were reacted according to Example 18 (step g) to provide the title compound (170 mg, 55%) as a white solid: ESI MS m/z 512 [M+H]+.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@H:11]([N:15]1[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:17]=[CH:16]1)[CH2:12][CH2:13][OH:14])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(N(CC)CC)C>ClCCl>[Si:1]([O:8][C@H:9]([C@H:11]([N:15]1[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:17]=[CH:16]1)[CH2:12][CH2:13][O:14][S:26]([CH3:25])(=[O:28])=[O:27])[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cn([C@H](CCO)[C@H](C)O[Si](C)(C)C(C)(C)C)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn([C@H](CCOS(C)(=O)=O)[C@H](C)O[Si](C)(C)C(C)(C)C)cn1
Reaction time: 1 h
Yield: 105.5 %

Procedure:
To a stirred mixture of ethyl 1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-hydroxy-3-pentyl]imidazole-4-carboxylate (500 mg, 1.4 mmol) and methanesulfonyl chloride (321 mg, 2.8 mmol) in dichloromethane (15 ml) was added dropwise triethylamine (284 mg, 2.8 mmol) at ice-bath temperature. After 1 h, the reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried (magnesium sulfate), and concentrated in vacuo to give ethyl 1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-methanesulfonyloxy-3-pentyl]imidazole-4-carboxylate (642 mg, 105%) as a syrup. This material was used for the next reaction without further purification.
Reaction SMILES: [CH2:1]([C:3]1(O)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[F:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[CH:20]2>>[CH2:1]([C:3]1([C:20]2[C:19]3[C:23](=[C:15]([F:14])[CH:16]=[CH:17][CH:18]=3)[NH:22][CH:21]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(O)CCc2cc(F)ccc21
Reactant: Fc1cccc2cc[nH]c12
Product: CCC1(c2c[nH]c3c(F)cccc23)CCc2cc(F)ccc21

Procedure:
Utilizing 1-ethyl-5-fluoro-indan-1-ol and 7-fluoroindole, the title compound is prepared as in example 1. 217 mg (92%). NMR (400 MHz, CDCl3): δ 0.85 (t, 3H), 2.12 (m, 1H), 2.21 (m, 1H), 2.31 (m, 1H), 2.58 (m, 1H), 2.97 (m, 2H), 6.83 (m, 4H), 6.98 (m, 3H), 8.06 (s, 1H, NH).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:20][CH3:21])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: Cc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(C)c(C(F)(F)F)c1

Procedure:
A solution of commercially available 4-methyl-3-trifluoromethylbenzoic acid (24.5 g, 120 mmol) and conc. sulfuric acid (6.5 ml) in dry ethanol (245 ml) is refluxed for 23 h. After reaching room temperature the solvent is evaporated and the residue is neutralized by addition of saturated aqueous NaHCO3 solution. The mixture is extracted with ethyl acetate (3×40 ml). The organic extracts are combined, dried over Na2SO4 and evaporated to dryness to afford a pale yellow oil: HPLC: tR=7.15 min (purity: >96%, gradient A), ESI-MS: 233.3 [MH]+.