Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13]([O:17][C:18]([NH:20][C@H:21]([CH:26]=O)[C@H:22]([CH2:24][CH3:25])[CH3:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]1([CH2:11][NH:12][CH2:26][C@@H:21]([NH:20][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[C@@H:22]([CH3:23])[CH2:24][CH3:25])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@H](C)[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: NCc1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC[C@H](C)[C@@H](CNCc1cccc2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a slurry of 1-naphthylmethylamine (5.84 g, 37.2 mmol), crushed 3A molecular sieves (10 g), and N-t-butoxycarbonyl-isoleucinal (8.0 g, 37.2 mmol) in 1,2-dichloroethane (50 ml) was added sodium triacetoxyborohydride (15.8 g, 74.3 mmol) at 0° C. The reaction was allowed to warm slowly to RT and stirred for 48 hrs. The reaction was cooled to 0° C. and quenched with sat. aq. NaHCO3 and stirred for 30 min. The organic layer was separated, washed with saturated brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (SiO2, 25% ethyl acetate in hexanes) to provide the title compound as an oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:33]([NH:36][CH2:37][CH2:38][CH2:39][NH2:40])([CH3:35])[CH3:34].F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH2:39][CH2:38][CH2:37][NH:36][CH:33]([CH3:35])[CH3:34])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)NCCCN
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C(=O)NCCCNC(C)C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 18 h
Yield: 19.2 %

Procedure:
A mixture of 0.100 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.039 g (0.33 mmole) of N-isopropyl-1,3-propanediamine, 0.102 g (0.27 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.036 g (0.27 mmole) of 1-hydroxybenzotriazole, 0.195 mL (1.12 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient, 20:80-100:0) to give 0.023 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-isopropylamino-propyl)-3-methoxy-benzamide (I-46) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([I:15])[C:13]=1[OH:14])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.[CH3:21]O>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([I:15])[C:13]=1[OH:14])[C:8]([O:10][CH3:21])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(I)c1O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: COC(=O)c1cc(I)c(O)c(C(C)(C)C)c1
Yield: 94 %

Procedure:
24.7 g (77 mmol) of 3-tert-Butyl-4-hydroxy-5-iodobenzoic acid are dissolved in 500 mL of methanol and 50 mL of THF. 5 mL of concentrated sulfuric acid are added and the reaction medium is refluxed for 18 hours. The reaction medium is concentrated under reduced pressure and then diluted in a dichloromethane/water mixture. The organic phase is washed with water and then concentrated under reduced pressure. A yellow solid is obtained (m=24.1 g; yield=94%; m.p.=67° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([NH2:17])=O)[CH:13]=2)[C:8]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])=[CH:7]1.CCN(CC)CC.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:17])[CH:13]=2)[C:8]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])=[CH:7]1
Reactant: NC(=O)c1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cc(F)cc(F)c3)c2c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cc(F)cc(F)c3)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a cooled (0° C.) suspension of 1-(3,5-Difluoro-benzyl)-3-(2-nitro-phenylsulfanyl)-1H-indole-6-carboxylic acid amide (15 mg, 0.034 mmol) and Et3N (10 μL, 0.072 mmol) in CH2Cl2 (1.5 mL) was added Tf2O (13 μL, 0.077 mmol). The mixture was stirred at 0° C. for 2 h and then at room temperature for 20 h. Water (25 mL) was added and the mixture was extracted with CH2Cl2 (2×25 mL). The combined organic phases were dried (Na2SO4) and concentrated to give the title compound as a yellow solid (13 mg, yield: 91%).
Reaction SMILES: [C:1]([C:3]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)([CH:20]([CH3:22])[CH3:21])[CH2:4][CH2:5][CH2:6][N:7]([CH3:19])[CH2:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])#[N:2].[C:33](N1C=CN=C1)(N1C=CN=C1)=O.CO>C1COCC1>[C:1]([C:3]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)([CH:20]([CH3:22])[CH3:21])[CH2:4][CH2:5][CH2:6][N:7]([CH3:19])[CH2:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:14][CH3:33])=[O:13])#[N:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(C(C#N)(CCCN(C)CCc2ccccc2C(=O)O)C(C)C)cc1OC
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccccc1CCN(C)CCCC(C#N)(c1ccc(OC)c(OC)c1)C(C)C
Temperature: 22 °C
Reaction time: 16 h

Procedure:
To 331 mg (0.839 mmol) of 2-(3,4-dimethoxyphenyl)-2-isopropyl-5-(methyl(phenethyl)amino)pentanenitrile in 8.3 mL of benzene was added 226 mg (1.01 mmol) of palladium(II)acetate and the mixture was stirred for 72 h at 22° C. under nitrogen. The solution was transferred into a pressure flask, 10 mL of methanol was added and the mixture was treated with carbon monoxide at 40 psi for 24 h. After addition of 175 μL (1.26 mmol) of triethylamine, the mixture was filtered through a pad of celite and evaporated to give a crude mixture of 3au and 2-(3,4-dimethoxyphenyl)-2-isopropyl-5-(methyl(phenethyl)amino)pentanenitrile. In order to afford purification, a solution of 57 mg of the crude product was dissolved in 1 mL of methanol and treated with 63 μL of 10 N NaOH. After stirring for 1 h at 22° C., an additional 1264 of 10 N NaOH and 2 mL of methanol was added. The solution was heated to 50° C. then cooled to 22° C., evaporated and partitioned between ether and 0.5 N NaOH. The aqueous layer was acidified to about pH 6 with 12 N HCl then extracted with ethyl acetate (3×). The combined organic layers were dried (Na2SO4) and evaporated to give 2-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoic acid. The carboxylic acid was esterified by treating with 44 mg (0.24 mmol) of carbonyldiimidazole in 1 mL of THF for 3 h at 22° C. followed by addition of 8 mL of methanol and continued stirring for about 16 hours at 22° C. The solvent was evaporated and the residue was purified by flash chromatography on silica gel, eluting first with dichloromethane and then gradually increasing to 3% methanol/dichloromethane to give 3au. MS found M+H=453. Substitution of the ester group in the indicated ortho-position of the phenyl ring was confirmed by 1H NMR analysis.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([C@H:25]([O:28]C(=O)[C@H](OC)C3C=CC=CC=3)[CH2:26][CH3:27])=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]3)[N:13]=2)=[CH:5][CH:4]=1.[OH-].[Na+].Cl>O1CCCC1.C(O)C.O>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([C@H:25]([OH:28])[CH2:26][CH3:27])=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:23])([F:22])[F:24])[CH2:17][CH2:16]3)[N:13]=2)=[CH:5][CH:4]=1
Reactant: CC[C@@H](OC(=O)[C@H](OC)c1ccccc1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC[C@@H](O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
To a solution of 0.67 g of (R)-methoxy-phenyl-acetic acid (R)-1-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-yl]-propyl ester in 2.5 mL of tetrahydrofuran and 2.5 mL of ethanol at 0° C. was dropwise added 3.5 mL of a molar solution of sodium hydroxide in 2.7 mL of water. The resulting mixture was stirred at 0° C. for 15 minutes then 0.6 mL of a 5N solution of hydrochloric acid in 2.7 mL of water was added. After removal of the organic solvents under vacuum, the mixture was extracted with dichloromethane, filtered through a silicone treated filter and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane 90/ethyl acetate 10) to give 270 mg of (R)-1-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-yl]-propan-1-ol.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[C:15]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[C:26]1[N:27]([CH3:42])[CH:28]=[C:29]([C:31](=[O:41])[N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[N:30]=1)[C:20](O)=[O:21])=[O:16])=[N+:2]=[N-:3].[I:43][C:44]1[CH:45]=[CH:46][CH:47]=[C:48]2[C:53]=1[CH:52]=[C:51]([S:54]([NH2:57])(=[O:56])=[O:55])[CH:50]=[CH:49]2>>[N:1]([CH2:4][C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[C:15]([C:17]1[CH:18]=[C:19]([C:20](=[O:21])[NH:57][S:54]([C:51]2[CH:50]=[CH:49][C:48]3[C:53](=[C:44]([I:43])[CH:45]=[CH:46][CH:47]=3)[CH:52]=2)(=[O:56])=[O:55])[CH:23]=[CH:24][C:25]=1[C:26]1[N:27]([CH3:42])[CH:28]=[C:29]([C:31]([N:32]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:37][CH2:38][CH2:39][CH3:40])=[O:41])[N:30]=1)=[O:16])=[N+:2]=[N-:3]
Reactant: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)O)cc2C(=O)N2Cc3ccccc3C[C@H]2CN=[N+]=[N-])n1
Reactant: NS(=O)(=O)c1ccc2cccc(I)c2c1
Product: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(I)c4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CN=[N+]=[N-])n1
Yield: 40.8 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 271, 3-((S)-3-(azidomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-(4-(dibutylcarbamoyl)-1-methyl-1H-imidazol-2-yl)benzoic acid (Intermediate 281D, 120 mg, 0.21 mmol) and 8-iodonaphthalene-2-sulfonamide (Intermediate 8, 139 mg, 0.42 mmol) were converted to the title compound (76 mg, 41%). MS(ESI−) m/z 885.8 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1/[C:5](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)/[C:6]2[C:11]([C:12]=1[CH3:13])=[CH:10][CH:9]=[CH:8][CH:7]=2.N1C=CC=CC=1.CCOCC>ClCCl.[O-2].[O-2].[O-2].[Cr+6]>[CH3:13][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:5](=[CH:14]\[C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)/[C:4]=1[CH2:3][CH:2]=[O:1]
Reactant: CSc1ccc(/C=C2/C(CCO)=C(C)c3ccccc32)cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CSc1ccc(/C=C2/C(CC=O)=C(C)c3ccccc32)cc1
Reaction time: 1.5 h

Procedure:
A solution of the primary alcohol from Step 4 (1 g, 3.25 mmol) in dichloromethane (10 mL) was added dropwise to a mixture of chromium trioxide (3.3 g, 32 mmol, 10 eq.) in dichloromethane (50 mL) at 0° C. containing pyridine (5.1 mL, 63 mmol, 20 eq.). After 1.5 hour, ether was added to precipitate the chromium salts and the heterogenous mixture was filtered through silica gel and washed with ether. After evaporation to dryness, the residue was purified by chromatography on silica gel eluting with a 15:85 mixture of ethyl acetate-hexane to yield the title compound as a yellow oil.
Reaction SMILES: C(OC([C:6]1[C:11](=[O:12])[NH:10][C:9]2[S:13][CH:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[C:7]=1[OH:22])=O)C>[Na]>[OH:22][C:7]1[C:8]2[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][S:13][C:9]=2[NH:10][C:11](=[O:12])[CH:6]=1
Reactant: CCOC(=O)c1c(O)c2c(-c3ccccc3)csc2[nH]c1=O
Agent: [Na]
Product: O=c1cc(O)c2c(-c3ccccc3)csc2[nH]1
Temperature: 0 °C

Procedure:
4-Hydroxy-6-oxo-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester (1.5 g, 4.76 mmol) was refluxed in 2 M sodium hydrxide (50 ml) for 5 hr, filtered while still hot, then cooled to 0° C. and acidified to pH 1 by addition of conc. HCl. The resultant white precipitate was filtered and dried to give 4-hydroxy-3-phenyl-7H-thieno[2,3-b]pyridin-6-one as a white solid. Yield=1.05 g (90.7%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([C:19]([OH:21])=O)=[CH:12]2)([CH3:4])([CH3:3])[CH3:2].Cl.[C:24]([N:28]1[CH:41]=[C:40]2[C:30]([C:31](=[O:42])[CH2:32][C:33]3([CH2:39]2)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[N:29]1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([N:28]1[CH:41]=[C:40]2[C:30]([C:31](=[O:42])[CH2:32][C:33]3([CH2:39]2)[CH2:38][CH2:37][N:36]([C:19]([C:13]2[CH:14]=[N:15][C:16]4[C:11]([CH:12]=2)=[CH:10][C:9]([O:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:22])=[CH:18][CH:17]=4)=[O:21])[CH2:35][CH2:34]3)=[N:29]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)COc1ccc2ncc(C(=O)O)cc2c1
Reactant: CC(C)(C)n1cc2c(n1)C(=O)CC1(CCNCC1)C2
Agent: Cl
Product: CC(C)(C)OC(=O)COc1ccc2ncc(C(=O)N3CCC4(CC3)CC(=O)c3nn(C(C)(C)C)cc3C4)cc2c1

Procedure:
The title compound was prepared by a method analogous to that described for Example 3, using 6-(2-tert-butoxy-2-oxoethoxy)quinoline-3-carboxylic acid and 2-tert-butyl-4,6-dihydrospiro[indazole-5,4′-piperidin]-7(2H)-one hydrochloride salt. +ESI (M+H) 547.3; 1H NMR (400 MHz, CDCl3, δ): 8.77 (d, J=2.0 Hz, 1 H), 8.10 (d, J=1.6 Hz, 1 H), 8.06 (d, J=9.2 Hz, 1 H), 7.50 (dd, J=9.3, 2.8 Hz, 1 H), 7.41 (s, 1 H), 7.02 (d, J=2.7 Hz, 1 H), 4.64 (s, 2 H),3.68-3.93 (m, 2 H), 3.41-3.51 (m, 2 H), 2.78 (s, 2 H), 2.65 (s, 2 H), 1.53-1.76 (m, 4 H), 1.61 (s, 9 H), 1.49 (s, 9 H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[N:10]=[CH:9][N:8]=[C:7]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[NH:20][C:19]4=[O:27])[CH2:14][CH2:13]3)[C:6]=2[N:5]=[C:4]([O:28][CH3:29])[C:3]1=[O:30].Cl[C:32]1[C:41]2N=C(OC)C(=O)N(C3CC3)C=2N=CN=1.N1CCC(N2C3C=CC=CC=3NC2=O)CC1.C(N(CC)CC)C>C(O)CCC>[CH:1]1([N:2]2[C:11]3[N:10]=[CH:9][N:8]=[C:7]([N:12]4[CH2:13][CH2:14][CH:15]([N:18]5[C:22]6[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=6[NH:20][C:19]5=[O:27])[CH2:16][CH2:17]4)[C:6]=3[N:5]=[C:4]([O:28][CH3:29])[C:3]2=[O:30])[CH2:41][CH2:32]1
Reactant: COc1nc2c(Cl)ncnc2n(C2CC2)c1=O
Reactant: COc1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n(C)c1=O
Agent: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n(C2CC2)c1=O

Procedure:
8-Cyclopropyl-6-methoxy-4-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]pteridin-7(8H)-one was prepared in the same manner as 8-methyl-6-methoxy-4-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]pteridin-7(8H)-one. The reaction of 4-chloro-8-cyclopropyl-6-methoxypteridin-7(8H)-one (0.59 g, 2.33 mmol), 1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (0.507 g, 2.33 mmol, triethylamine (0.708 g, 7.99 mmol, 0.98 mL). anhydrous n-butanol (8 mL) at 80° C. for 16 hours gave rise to 0.856 g of 8-cyclopropyl-6-methoxy-4-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]pteridin-7(8H)-one as a light brown solid, which was used without any further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.[Br:19]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:19][CH2:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(=O)c3ccc(C)cc3ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Product: Cc1ccc2c(=O)c3ccc(CBr)cc3ccc2c1

Procedure:
The product of step (i) (2.0 g) and N-bromosuccinimide (1.52 g) in ethyl acetate (80ml) was irradiated with a 500 W halogen lamp for 4 hours. The reaction mixture was washed with brine, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with toluene. Used directly in the next step.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.[F:10][C:11]([F:37])([F:36])[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[NH:32][CH2:31][CH2:30]4)(=[O:26])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>ClCCl>[F:36][C:11]([F:10])([F:37])[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][N:21]([S:24]([C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[NH:32][CH:31]=[CH:30]4)(=[O:26])=[O:25])[CH2:22][CH2:23]2)=[CH:14][CH:13]=1
Reactant: O=S(=O)(c1ccc2c(c1)CCN2)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: c1ccc2[nH]ccc2c1
Solvent: ClCCl
Product: O=S(=O)(c1ccc2[nH]ccc2c1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
5-|4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl|-1H-indole: 5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-1H-indole (180 mg, 0.44 mmol) was dissolved in dichloromethane (10 mL). DDQ (100 mg, 0.44 mmol) was added and stirred at room temperature for 4 h. The reaction was concentrated and purified by silica gel flash column chromatography (45% ethyl acetate in hexanes) to provide 5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-1H-indole (70%) as a white solid. 1H NMR (400 MHz, DMSO-D6) δ 11.72 (s, 1H), 8.07(s, 1H) 7.65 (d, 1H), 7.62-7.61 (m, 1H), 7.52-7.48 (m, 3H), 7.04 (d, 2H), 6.71 (m, 1H), 3.40-3.36 (m, 4H), 3.02-2.99 (m, 4H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)=O.[OH:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:34][CH2:35][OH:36])[CH:25]1[CH2:30][CH2:29][N:28]([C:31](=[S:33])[NH2:32])[CH2:27][CH2:26]1>>[OH:36][CH2:35][CH2:34][N:24]([CH:25]1[CH2:26][CH2:27][N:28]([C:31]2[S:33][CH:2]=[C:3]([C:5]3[CH:14]=[CH:13][C:12]4[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=4[CH:6]=3)[N:32]=2)[CH2:29][CH2:30]1)[CH2:23][CH2:22][CH2:21][CH2:20][OH:19]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CBr)ccc21
Reactant: NC(=S)N1CCC(N(CCO)CCCCO)CC1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N(CCO)CCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 800 mg (1.01 mmol) of 2-bromo-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone and 452 mg (1.01 mmol) of 4-[(4-hydroxybutyl)-(2-hydroxyethyl)amino]-piperidine-1-carbothioic acid amide from step d. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: C[O-].[Na+].[N+:4]([C:7]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:8]=1[CH:9]=O)([O-:6])=[O:5]>C(O)C>[N+:4]([C:7]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:8]=1/[CH:9]=[CH:9]/[C:8]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:7]=1[N+:4]([O-:6])=[O:5])([O-:6])=[O:5]
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cc(Cl)ccc1/C=C/c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 74 %

Procedure:
In a solution of 1.1 g. of sodium methylate in 32 ml. of ethanol, 6.2 g. of diethyl 2-nitro-4-chlorobenzyl phosphonate was dissolved. A solution of 3.7 g. of 2-nitro-4-chlorobenzaldehyde in 32 ml. of ethanol was dropwise added to said solution with stirring at ambient temperature. After the solution was stirred for 1 hour, the yellow crystalline materials formed were filtered and washed with a small amount of ethanol to give 5 g. (74% yield) of trans-2,2'-dinitro-4,4'-dichlorostilbene. Its recrystallization from glacial acetic acid gave a product having a melting point of 247° to 248° C.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[C:15]3[CH:14]=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl[C:29]([O:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:30].C(N(CC)CC)C>CN(C=O)C>[CH3:34][C:33]([CH3:36])([CH3:35])[CH2:32][O:31][C:29]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]3[N:12]([C:9]4[CH:10]=[CH:11][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=4)[N:13]=[CH:14][C:15]=23)[CH2:23][CH2:24]1)=[O:30]
Reactant: CC(C)(C)COC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)COC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
1-(4-Methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (0.17 mmol, 70 mg), neopentyl chloroformate (0.25 mmol, 37 μL) and triethylamine (0.51 mmol, 72 μL) were dissolved in DMF (2 mL) and stirred for 60 minutes at room temperature. Progress of the reaction was monitored by TLC and LCMS. The reaction mixture was quenched with water. The product was extracted with ethyl acetate. Removal of organic solvents in vacuo and purification by HPLC provided Compound A124 as a white solid (28 mg, 27%). Exact mass calculated for C23H29N5O5S 487.57, found 488.20 (MH+).