Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:28])[CH2:7][CH2:6][N:5]([C@H](C2C=CC=CC=2)C)[CH:4]([CH2:16][N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])[CH2:3]1>C(O)(=O)C.[Pd]>[F:28][C:2]1([F:1])[CH2:7][CH2:6][NH:5][CH:4]([CH2:16][N:17]2[C:18](=[O:27])[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]2=[O:26])[CH2:3]1
Reactant: C[C@@H](c1ccccc1)N1CCC(F)(F)CC1CN1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CC1CC(F)(F)CCN1
Yield: 89.8 %

Procedure:
To a solution of 2-((4,4-difluoro-1-((S)-1-phenylethyl)piperidin-2-yl)methyl)isoindoline-1,3-dione (1.1 g, 2.86 mmol) in acetic acid (10 mL) was added 10% Pd/C (200 mg). The reaction was then stirred under H2 until HPLC indicated complete removal of the phenethyl group. The reaction was the filtered through diatomaceous earth and concentrated. The crude residue was then dissolved in EtOAc and washed with saturated NaHCO3, brine, dried (MgSO4), and concentrated to yield the title compound as an orange oil (720 mg, 90%).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[CH:15][CH:16]=2)[O:11]1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:23]1([S:20]([C:14]2[CH:13]=[C:12]3[C:17]([CH2:18][CH2:19][CH:10]([CH2:9][NH:7][CH3:6])[O:11]3)=[CH:16][CH:15]=2)(=[O:22])=[O:21])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(CC1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCC1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.1 %

Procedure:
To a solution of (7-benzenesulfonyl-chroman-2-ylmethyl)-methyl-carbamic acid tert-butyl ester (125 mg, 0.299 mmol) in DCM (25 mL) was added TFA (0.5 mL). The reaction was stirred for 4 h at RT, then concentrated in vacuo. The residue was recrystallized from acetone/hexane plus EtOAc to give (7-benzenesulfonyl-chroman-2-ylmethyl)-methyl-amine (76 mg, 80% yield) as white needles: Mp 196.2-198.2° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1C#N)=[CH:9][CH:8]=[C:7]([Br:14])[CH:6]=2.OS(O)(=O)=O.[OH-].[Na+]>O>[Br:14][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([NH2:1])[N:3]=[CH:4]2)=[CH:9][CH:8]=1
Reactant: N#Cc1c(N)ncc2cc(Br)ccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc2ccc(Br)cc2cn1
Temperature: 115 °C
Yield: 18.6 %

Procedure:
To a stirred solution of 3-amino-7-bromoisoquinoline-4-carbonitrile (25 g, 101 mmol) in water (100 mL) was added H2SO4 (100 mL) dropwise while cooling in an ice-water bath. Then the mixture was stirred and heated to 115° C. for 3 days. After that, the reaction was cooled down to 0° C. 10 M aqueous NaOH was added to adjust to pH>12. The resulting solid precipitate was collected by filtration, washed with water, and dried under vacuum to yield 4.2 g (19%) of 7-bromo-isoquinolin-3-amine. LCMS (ESI): M+H=222.8; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.00 (t, J=0.8 Hz, 1H), 7.49-7.48 (m, 2H), 6.58 (s, 1H), 6.06 (s, 1H).
Reaction SMILES: [C:1]1([CH2:9][OH:10])[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.CN(C)C=O.[H-].[Na+]>O>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:8][CH2:7][C:4]1[CH:5]=[CH:6][C:1]([CH2:9][OH:10])=[CH:2][CH:3]=1
Reactant: Fc1ccccn1
Reactant: OCc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1ccc(COc2ccccn2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a mixture of 1,4-benzenedimethanol (5.5 g, 40 mmol), 2-fluoropyridine (1.3 g, 13 mmol) and N,N-dimethylformamide (15 mL) was added sodium hydride (1.4 g, 40 mmol, 66% in oil) at 0° C., which was stirred for 20 minutes at room temperature and for 1 hour at 70° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1) to obtain the title compound (1.9 g, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([S:17][CH2:18][C:19]#[N:20])[N:11]=2)=[CH:5][CH:4]=1.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([S:17][CH2:18][C:19](=[N:22][OH:23])[NH2:20])[N:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Nc2cc(C)nc(SCC#N)n2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Nc2cc(C)nc(SCC(N)=NO)n2)cc1
Yield: 29 %

Procedure:
A mixture of 11.20 g (0.04 mole) of [4-(p-anisidino)-6-methyl-2-pyrimidinylthio]acetonitrile, 5.52 g (0.08 mole) of hydroxylamine hydrochloride and 16.90 g (0.16 mole) of sodium carbonate in 150 ml of N,N-dimethylformamide was heated on a steam bath for three and one-half hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was dissolved in ethyl acetate, diluted with petroleum ether and was cooled in ice. The precipitate which formed was collected and recrystallized from a mixture of ethanol-petroleum ether to afford 3.7 g of product, m.p. 189°-191° d.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[NH2:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C.C(OCC)C>C(Cl)Cl>[C:19]([C:18]1[CH:17]=[C:16]([NH:15][S:2]([C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3])[CH:26]=[CH:25][CH:24]=1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cccc(NS(=O)(=O)c2ccccc2C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-(chlorosulfonyl)-benzoate (2.25 g, 8.73 mmol) in methylene chloride (20 mL) was added dropwise to a solution of ethyl 3-aminobenzoate (1.44 g, 8.73 mmol) and triethylamine (1.21 mL, 8.73 mmol) in methylene chloride (10 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with water (20 mL), aqueous HCl (1 M, 20 mL) and aqueous NaOH (1 M, 20 mL), dried (MgSO4—, filtered and concentrated in vacuo to give an orange oil. Trituration with ethyl ether gave N-(3′-carboethoxyphenyl)-2-(carbomethoxy)benzenesulfonamide as white solid. 1H NMR (200 MHz, CDCl3): δ1.31, t, J=6.0 Hz, 3H; 4.00, s, 3H; 4.29, q, J=6.0 Hz, 2H; 7.23-7.61, m, 5H; 7.66-7.92, m, 3H; 8.26, br s , 1H.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([N:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:18]([F:21])([F:20])[F:19])[C:10]1=[O:22])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[CH3:7][CH:6]([CH3:8])[CH2:5][C@H:4]([N:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:18]([F:21])([F:19])[F:20])[C:10]1=[O:22])[C:3]([OH:23])=[O:2]
Reactant: COC(=O)[C@H](CC(C)C)N1Cc2c(cccc2C(F)(F)F)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A solution of (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid methyl ester (274 mg, 0.83 mmol) in tetrahydrofuran/water (12 mL, 1:1) was treated with lithium hydroxide monohydrate (70 mg, 1.66 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 2 h. After this time, the reaction mixture was concentrated in vacuo to remove the tetrahydrofuran. The resulting material was then diluted with a 1N aqueous hydrochloric acid solution (10 mL) and then extracted with ethyl acetate. The organic layers were combined and then dried over magnesium sulfate, filtered to remove the drying agent, and the filtrate was concentrated in vacuo to afford (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid (254 mg, 97%) as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[C:4]([C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)[C:5]#[N:6].C(CCCC[Sn]([O:28][CH2:29][CH3:30])(CCCC)CCCC)=C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:29]([C:2]1[C:3]([CH3:12])=[C:4]([C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)[C:5]#[N:6])(=[O:28])[CH3:30]
Reactant: COc1ccc(Br)c(C)c1C#N
Reactant: C=CCCCC[Sn](CCCC)(CCCC)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)=O)c(C)c1C#N
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a 20 mL microwave tube was added a stir bar, 3-bromo-6-methoxy-2-methylbenzonitrile (4.0 g, 18 mmol), vinyl ethoxy tributyltin (9.5 g, 26 mmol), palladium tetrakis (1.0 g, 0.88 mmol), and anhydrous toluene (15 mL). The tube was capped, degassed and purged with N2. The reaction mixture was heated to 110° C. for 12 hours. The tube was cooled to room temperature and treated with 4 M HCl (10 mL) and stirred for 1 hour. The crude product was extracted with EtOAc. The extraction was washed with brine, dried with Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (Hexanes:EtOAc=1:1) to afford the title product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:29]([O:31]C)=[O:30])[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:29]([OH:31])=[O:30])[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)c1cc2ccccc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)O)cc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
To a mixture of methyl N5-[(benzyloxy)carbonyl]-N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithinate (13.2 g), THF (65 ml), and methanol (65 ml) was added a 1 M aqueous sodium hydroxide solution (60 ml) under ice-cooling, followed by stirring at room temperature for 3 hours. To the reaction mixture was added 1 M hydrochloric acid (60 ml) under ice-cooling, and the solvent was removed by evaporation under reduced pressure. The residue was stirred at room temperature for 14 hours, and the solid precipitated was collected by filtration and washed with water to obtain N5-[(benzyloxy)carbonyl]-N2-[(1-methyl -1H-indol-2-yl)carbonyl]-L-ornithine (11.6 g).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[C:17]([CH2:20][CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:19])=[O:18].CC(C)([O-])C.[K+]>O1CCCC1>[O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:15]=[CH:14][C:11](/[CH:12]=[CH:21]/[CH2:20][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)[CH:4]=[CH:3]1
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(-n2ccc(=O)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)C/C=C/c1ccc(-n2ccc(=O)cc2)cc1
Temperature: -5 °C
Reaction time: 14 h
Yield: 67.9 %

Procedure:
4.0 g of 4-(1,4-dihydro-4-oxo-1-pyridyl)benzaldehyde and 8.2 g of β-carboxyethyltriphenylphosphonium chloride were suspended in 40 ml of tetrahydrofuran in a nitrogen atmosphere. The obtained suspension was cooled to -5° C., followed by the gradual addition of a solution of 4.96 g of potassium tertbutoxide in 30 ml of tetrahydrofuran. The temperature of the mixture was gradually raised to a room temperature. The resulting mixture was stirred for 14 hours, followed by the addition of ice-water. The obtained aqueous phase was washed with chloroform. The pH of the aqueous phase was adjusted with concentrated hydrochloric acid to about 3 to precipitate a crystal. This crystal was recovered by filtration and washed with water and methanol successively to obtain 3.48 g of the title compound as a pale yellow powder (yield: 68%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH2:13]1[C@@H:17]2[CH2:18][CH2:19][C@@H:20]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)(=[O:24])=[O:23])[C@@H:16]2[CH2:15][NH:14]1.C1(C(C2CCCCC2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)CCCCC1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:2]([F:12])([F:11])[F:1])[CH:10]=1)[CH2:6][N:14]1[CH2:15][C@H:16]2[C@H:20]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)(=[O:24])=[O:23])[CH2:19][CH2:18][C@H:17]2[CH2:13]1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: O=S(=O)(N[C@@H]1CC[C@H]2CNC[C@H]21)c1cccc(C(F)(F)F)c1
Agent: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Product: O=S(=O)(N[C@@H]1CC[C@H]2CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]21)c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared by substituting 3,5-bis(trifluoromethyl)benzaldehyde for 3-(trifluoromethyl)benzaldehyde and N-((3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl)-3-(trifluoromethyl)benzenesulfonamide from Example 191 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 9.53 (d, J=7.4, 1H), 8.42 (s, 1H), 8.30 (d, J=7.9, 1H), 8.03 (s, 1H), 7.96 (s, 2H), 7.81 (d, J=7.8, 1H), 7.60 (t, J=7.9, 1H), 3.82-3.74 (m, 1H), 3.59 (s, 2H), 2.68-2.64 (m, 1H), 2.59-2.49 (m, 2H), 2.38-2.33 (m, 1H), 2.23 (dt, J=5.9, 8.9, 2H), 1.97-1.81 (m, 2H), 1.59 (ddd, J=8.2, 11.8, 13.0, 1H), 1.35-1.24 (m, 1H); MS (ESI+) m/z 561 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=2)[CH:9]=1)[C:4](=[O:7])[CH2:5][CH3:6])[CH3:2].[NH2:21][NH:22][C:23]([NH2:25])=S>C(O)C>[CH2:1]([N:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]3[N:16]([C:23]([NH2:25])=[N:22][N:21]=3)[N:15]=2)[CH:9]=1)[C:4](=[O:7])[CH2:5][CH3:6])[CH3:2]
Reactant: NNC(N)=S
Reactant: CCC(=O)N(CC)c1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCO
Product: CCC(=O)N(CC)c1cccc(-c2ccc3nnc(N)n3n2)c1
Yield: 44.8 %

Procedure:
A solution of 5.0 g N-ethyl-N-[3-(6-chloro-3-pyridazinyl)phenyl]propanamide and 3.2 g thiosemicarbazide in 200 ml ethanol was refluxed for 18 hours. The mixture was treated and the product chromatographed as described for Example 70. Recrystalization of the product from dichloromethane-hexane afforded 2.4 g yellow crystals, mp 199°-200° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:13]2[CH:14]=[C:15]([CH:34]=[CH:35][CH:36]=2)[O:16][C@@H:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C@@H:18]2[NH:26][C:27](OC(C)(C)C)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[ClH:37]>O1CCCC1>[ClH:37].[C:7]1([C:13]2[CH:14]=[C:15]([CH:34]=[CH:35][CH:36]=2)[O:16][C@@H:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C@@H:18]2[NH:26][CH3:27])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1cccc(-c2ccccc2)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN[C@H]1Cc2ccccc2[C@H]1Oc1cccc(-c2ccccc2)c1

Procedure:
To a solution of LiAlH4 (1.53 g, 40 mmol) in dry tetrahydrofuran (50 ml) under argon was added dropwise a solution of (±)cis-1-(3-phenylphenoxy)-2-tert-butoxycarbonylaminoindane (3.08 g, 8 mmol) in dry tetrahydrofuran (150 ml). The reaction was heated at reflux for 3 h then cooled with an ice/water bath and quenched with the minimum of water. The reaction was filtered and dried over MgSO4. Solvents were removed in vacuo and the residue subjected to column chromatography on silica gel eluting with 5% ethanol in chloroform to afford a colourless oil (1.38 g,) which was converted to the HCl salt and crystallised to afford the title compound as a white solid. m.p. >185° C. dec. (from methanol-diethyl ether).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([S:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][NH2:17])[CH:13]=[CH:14][CH:15]=2)=[N:2]1.[F:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[C:24]([C:29](OCC)=[O:30])[NH:23][C:22]2=[O:34].C(N(C(C)C)CC)(C)C.C(O)C>C1COCC1>[F:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[C:24]([C:29]([NH:17][CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][S:6][C:3]3[N:4]=[CH:5][NH:1][N:2]=3)[CH:11]=1)=[O:30])[NH:23][C:22]2=[O:34]
Reactant: NCc1cccc(OCCSc2nc[nH]n2)c1
Reactant: CCOC(=O)c1nc2ccc(F)cc2c(=O)[nH]1
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccc(OCCSc2nc[nH]n2)c1)c1nc2ccc(F)cc2c(=O)[nH]1
Temperature: 90 °C
Reaction time: 48 h
Yield: 25 %

Procedure:
A suspension of 1-(3-{[2-(1H-1,2,4-triazol-3-ylthio)ethyl]oxy}phenyl)methanamine obtained in Reference Example 3 (318 mg, 1.27 mmol), ethyl 6-fluoro-4-oxo-3,4-dihydroquinazoline-2-carboxylate obtained in Reference Example 52 (100 mg, 0.423 mmol) and diisopropylethylamine (0.442 mL, 2.54 mmol) in THF (9 mL)-ethanol (3 mL) was stirred at 90° C. for 2 days. The reaction solvent was evaporated under reduced pressure, and the residue was extracted with 0.1N hydrochloric acid and THF-ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was crystallized from toluene-ethanol, and the obtained crude crystals were recrystallized from THF-IPE to give the title compound as a white powder (45.7 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][C:16]([C:18]2([NH:33]C(=O)OC(C)(C)C)[CH2:23][CH2:22][N:21]([C:24]3[C:25]4[CH:32]=[CH:31][NH:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[NH2:33][C:18]1([C:16]([NH:15][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][NH:10][S:11]([CH3:14])(=[O:12])=[O:13])=[O:17])[CH2:19][CH2:20][N:21]([C:24]2[C:25]3[CH:32]=[CH:31][NH:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CNS(C)(=O)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
Tert-butyl 4-(1-(4-chlorophenyl)-2-(methylsulfonamido)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 76) (100 mg, 0.17 mmol) was treated with trifluoroacetic acid (2 mL). The solution was stirred for 1 hour at room temperature. The mixture was concentrated under reduced pressure. The crude product was purified by ion exchange chromatography, using an SCX column. The residue was loaded onto the column in methanol and washed with methanol. The desired product was eluted from the column using 2M ammonia in methanol and pure fractions were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-2-(methylsulfonamido)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (79 mg, 95%) as a colourless solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH2:29][CH3:30])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:29]([N:28]1[C:24]([C@H:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C@@H:18]2[O:17][C:13]2[C:14]([F:16])=[CH:15][C:10]([S:7]([NH:6][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)(=[O:8])=[O:9])=[C:11]([F:31])[CH:12]=2)=[CH:25][CH:26]=[N:27]1)[CH3:30]
Reactant: CCn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)cc1F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 96.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (220 mg, 0.359 mmol) prepared in Example 28a, triethylsilane (0.30 mL), trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield the title compound (160 mg, 96%) as a colorless solid.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:19]=1[CH:20]=[N+:21]([CH3:23])[CH3:22].ClC1C=CC=C(F)C=1C=O.CNC>>[Cl:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:19]=1[CH:20]([N:21]([CH3:23])[CH3:22])[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[N+](C)=Cc1c(F)cccc1Cl
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: CNC
Agent: O=Cc1c(F)cccc1Cl
Agent: [Cl-]
Product: CN(C)C(c1c(F)cccc1Cl)c1c(-c2ccccc2)[nH]c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-phenylindole and (2-chloro-6-fluoro-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 2-chloro-6-fluoro-benzaldehyde and dimethylamine.
Reaction SMILES: C([O-])(=O)C.[NH4+].Cl.[CH3:7][NH:8][C:9]1[C:10]([O:19][CH3:20])=[C:11]([NH2:18])[C:12]([O:16][CH3:17])=[C:13]([Cl:15])[CH:14]=1.C1N2CCN(CC2)C1.Cl>[Pd].O.C(OCC)(=O)C.C(O)C.C(O)=O>[ClH:15].[CH3:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[C:11]([NH2:18])[C:10]=1[O:19][CH3:20]
Reactant: CNc1cc(Cl)c(OC)c(N)c1OC
Agent: [Pd]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=CO
Product: CNc1ccc(OC)c(N)c1OC
Temperature: 70 °C

Procedure:
The mixture consisting of 8.5 g of ammonium acetate, 7.5 g of 10% palladium on charcoal, 0.05 mole (15 g) of 5-methylamino-3-amino-2,4-dimethoxychlorobenzene hydrochloride in 14 ml of water containing 90 ml of ethanol and 15.2 g of triethylenediamine, was heated to 70° C. with stirring, and then 6.44 g of formic acid were added dropwise. Heating was maintained for 1 hour after completion of the addition. The catalyst was removed by filtration. The solids content obtained by evaporation of the filtrate under vacuum was dissolved in ethyl acetate. A 7N hydrochloric acid solution in absolute ethanol was added to the ethyl acetate which had been dried over sodium sulphate, in order to precipitate the expected product. The latter was recrystallized while hot from an aqueous-alcoholic solution of hydrochloric acid.