Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@:12]2([CH3:13])[C@H:7]([C:8]([CH3:15])([CH3:14])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][C@@:4]1([CH3:17])[OH:16].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>CN(C=O)C>[CH3:25][S:26]([O:1][CH2:2][C@@H:3]1[C@:12]2([CH3:13])[C@H:7]([C:8]([CH3:15])([CH3:14])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][C@:4]1([OH:16])[CH3:17])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CCC[C@]2(C)[C@@H](CO)[C@](C)(O)CC[C@@H]12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CCC[C@]2(C)[C@@H](COS(C)(=O)=O)[C@](C)(O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
A solution of (1S,2R,4aS,8aS)-1-(hydroxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (3) (12 g, 50 mmol) in anhydrous DMF (100 mL) was cooled with an ice bath under N2. To this mixture, triethylamine (15 mL, 110 mmol) and methanesulfonyl chloride (5.0 mL, 60 mmol) was added. The ice bath was removed and the mixture stirred at room temperature for 3 h. The reaction was diluted with diethyl ether and washed with 1 M HCl, saturated aqueous sodium bicarbonate and brine. The organic layer was concentrated to dryness to yield [(1S,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalen-1-yl]-methyl methanesulfonate (12) (15 g, 97% yield) as an orange solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:30][CH3:31])=[C:11]([OH:29])[C:12]([O:15][C:16]2[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[C:21]3[C:17]=2[CH2:18][CH2:19][CH2:20]3)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]1([CH2:38][CH2:39]O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[C:21]3[C:17]=2[CH2:18][CH2:19][CH2:20]3)=[C:11]([O:29][CH2:39][CH2:38][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:10]=1[CH2:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCC1CCCCC1
Reactant: CCc1c(OCc2ccccc2)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1O
Product: CCc1c(OCc2ccccc2)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1OCCC1CCCCC1

Procedure:
The title compound was prepared in a similar manner to those described in Example 2 using 3-benzyloxy-2-ethyl-6-(5-methyl-7-nitroindan-4-yloxy)phenol instead of ethyl N-[7-(3-ethyl-2-hydroxy-4-trifluoromethanesulfonyloxyphenoxy)-6-methylindan-4-yl]malonamate and using 2-cyclohexylethanol instead of 4-fluorobenzylalcohol.
Reaction SMILES: C.CC.[CH3:4]CC.[CH3:7][CH2:8]CC.[CH2:11]([S:19]([OH:22])(=[O:21])=[O:20])[CH2:12][CH2:13][CH2:14]CCCC>CCCCCC>[CH4:4].[CH3:7][CH3:8].[CH3:11][CH2:12][CH3:13].[CH2:11]([S:19]([OH:22])(=[O:21])=[O:20])[CH2:12][CH2:13][CH3:14]
Reactant: CCCC
Reactant: CCCCCCCCS(=O)(=O)O
Agent: C
Agent: CC
Solvent: CCCCCC
Solvent: CCC
Product: CCCCS(=O)(=O)O

Procedure:
In a Gotte foam beater (DIN 53 902, Part 1), methane, ethane, propane, butane, n-hexane and n-octane sulfonic acid were tested for their foaming behavior in 0.5% aqueous solution (0° Gh) at 40° C. The solutions of methane, ethane, propane and butane sulfonic acid did not produce any foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:15][CH2:16][C:17]([OH:19])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]=1[CH3:7].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:15][CH2:16][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[C:6]=1[CH3:7]
Reactant: Cc1c(Br)cnn1CC1(OCC(=O)O)CCCCC1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(Br)cnn1CC1(OCC(=O)N2CCOCC2)CCCCC1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 174B (331 mg) in dichloromethane (10 mL) was added morpholine (174 mg), 4-dimethylaminopyridine (122 mg) and 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (287 mg). The mixture was stirred overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with water and brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the crude title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24].O>C1COCC1>[N+:32]([C:29]1[CH:28]=[CH:27][C:26]([O:25][C:23]([N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])=[CH:12]2)=[O:24])=[CH:31][CH:30]=1)([O-:34])=[O:33]
Reactant: O=C(OCc1ccccc1)c1c[nH]c2ccccc12
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)c1cn(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1H-indole-3-carboxylic acid benzyl ester (100 mg, 0.398 mmol) in dry THF (2 mL) at 0° C. under nitrogen was added NaH (60% in mineral oil, 32 mg, 0.796 mmol). The resulting solution was stirred at 0° C. for 10 min, and added dropwise to a stirred solution of 4-nitrophenyl chloroformate (160 mg, 0.796 mmol) in dry THF (2 mL) cooled at 0° C. The resulting solution was stirred at RT under nitrogen for 48 h. The mixture was poured into water and extracted twice with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude residue was successively purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 7:3) and by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19×50 mm, 20% CH3CN/H2O 2.5 min, 20-100% CH3CN/H2O in 10 min, CH3CN/H2O containing 0.1% HCOOH flow: 20 mL/min) to give after extraction of the pure fractions the desired compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.8; MS (LC/MS): 439.0 [M+Na]+; tR (HPLC conditions a): 4.58 min.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1.[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30])=[CH2:23].C(=O)([O-])O.[K+].ClN1C(=O)CCC1=O>C(OCC)(=O)C.O>[OH:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH:22]1[O:1][N:2]=[C:3]([C:4]2[N:5]=[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[S:7][CH:8]=2)[CH2:23]1
Reactant: C=Cc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4O)C3)cs2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-{4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (3.46 g) and 2-vinylphenol (1.60 g) in ethyl acetate (50 ml) were added, at room temperature, potassium hydrogencarbonate (5.55 g) and N-chlorosuccinimide (1.78 g), and then one drop of water. After stirring at 60° C. overnight, the reaction mixture was admixed with ethyl acetate and water and extracted with ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave tert-butyl 4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (1.70 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[C:20]([CH3:24])([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[CH3:22][N:21]1[C:14]2[N:15]([C:16](=[O:18])[N:17]=[C:12]([O:1][CH2:2][C:3]3[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=3)[C:6]#[N:7])[CH:13]=2)[CH2:19][C:20]1([CH3:24])[CH3:23]
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: N#Cc1cccc(CO)c1
Product: CN1c2cc(OCc3cccc(C#N)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 3-(hydroxymethyl)benzonitrile and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo-[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[O:25])[C:6]1=[O:32].[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:30]([O:29][CH2:28][CH2:27][NH:26][C:24]([C:7]1[C:6](=[O:32])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:38]([C:34]2[O:33][CH:37]=[CH:36][CH:35]=2)=[O:39])[C:14]2[C:9]([C:8]=1[OH:23])=[N:10][CH:11]=[C:12]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH:13]=2)=[O:25])[CH3:31]
Reactant: O=C(Cl)c1ccco1
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCNC(=O)c2ccco2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(3-aminopropyl)-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (25 mg, 0.057), 2-furancarbonyl chloride (5.8 μL, 0.059 mmol) and DIEA (49 μL, 0.282 mmol) was combined in anhydrous DMF (1.5 mL). After stirring under nitrogen at ambient temperature for 0.5 hrs, the reaction mixture was evaporated in vacuo and partitioned between EtOAc and 1N NaHSO4. The aqueous layer was separated and back-extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The product was crystallized from MeOH/Et2O and collected by filtration providing a white solid: ES+ MS: 537 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[OH:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:37][NH:36][CH2:35][CH2:34][NH:33]2)=[CH:28][CH:27]=1.O>CS(C)=O>[F:1][C:2]1[C:20]([N:36]2[CH2:35][CH2:34][NH:33][CH:32]([C:29]3[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][OH:22])=[CH:31][CH:30]=3)[CH2:37]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: OCCOc1ccc(C2CNCCN2)cc1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Solvent: O
Solvent: CS(C)=O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5ccc(OCCO)cc5)C4)cc3nc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
A suspension of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.015 g) and (RS)-2-[4-(2-hydroxyethoxy)phenyl]-piperazine (1.7 g) in dimethyl sulphoxide (15 cc) is heated with stirring to a temperature in the region of 100° C. for 2 hours and a half. After cooling to approximately 20° C., the suspension is treated with water (30 cc), drained and washed with water (3×10 cc). After one recrystallization in dimethylformamide (15 cc), (RS)-7-fluoro-8-{3-[4-(2-hydroxyethoxy)phenyl]-1-piperazinyl}-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.2 g)is obtained in the form of a yellow solid, m.p. 276° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].ClC(=O)[C:31]([O:33]C)=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](=[O:21])[C:31]([OH:33])=[O:32]
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: COC(=O)C(=O)Cl
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)C(=O)O)c(=O)n(C)c1=O

Procedure:
The title compound was synthesized following a similar procedure described in the synthesis of compound 2A from reaction of Example 1 with methyl 2-chloro-2-oxoacetate (hydrolysis of the crude upon column chromatography afforded Example 31). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.95 (s, 3 H) 3.17 (s, 3 H) 7.28 (s, 1 H) 7.61 (m, 1 H) 7.84 (m, 1 H) [M+H] calc'd for C14H11FIN3O5, 448; found, 448.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:15]([CH:16]2[CH2:18][CH2:17]2)[C:14](=[O:19])[C:13]2[C:8](=[C:9](I)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C@@H:22]1[C:26]2[NH:27][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:29][C:25]=2[C:24](=[O:39])[NH:23]1>>[C:1]([NH:5][C:6]1[N:15]([CH:16]2[CH2:18][CH2:17]2)[C:14](=[O:19])[C:13]2[C:8](=[C:9]([C:28]3[NH:27][C:26]4[C@@H:22]([CH3:21])[NH:23][C:24](=[O:39])[C:25]=4[CH:29]=3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: CC(C)(C)Nc1nc2c(I)cccc2c(=O)n1C1CC1
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(C5CC5)c(NC(C)(C)C)nc34)[nH]c21
Yield: 58.3 %

Procedure:
This compound (73 mg, 57% yield) as a tan amorphous solid was prepared according to the procedure described for Example 448, using 2-(tert-butylamino)-3-cyclopropyl-8-iodoquinazolin-4(3H)-one (718) (125 mg, 0.32 mmol) and (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705) (85 mg, 0.32 mmol) as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.99 (1H, br. s.), 7.89 (1H, d, J=7.4 Hz), 7.85 (1H, d, J=7.8 Hz), 7.65 (1H, s), 7.16 (1H, t, J=7.7 Hz), 6.74 (1H, s), 6.15 (1H, s), 4.48-4.59 (1H, m), 2.88 (1H, br. s.), 1.54 (9H, s), 1.38 (3H, d, J=6.5 Hz), 1.27 (2H, d, J=6.7 Hz), 0.78 (2H, br. s.). m/z (ESI, +ve) 392.0 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN.[C:17]([BH3-])#[N:18].[Na+]>CO.C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:18][CH3:17])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CN
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 79.1 %

Procedure:
Amine preparation: To a solution of 1-BOC-4-piperidone (1.0 g) in MeOH (10 mL) was added a solution of freshly prepared methylamine in MeOH (1.0 mL). The reaction mixture was stirred for 1 h and then sodium cyanoborohydride (0.315 g) was added. After stirring for 24 h the reaction mixture was then diluted with DCM, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester (0.85 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[S:37]1(=[O:45])(=[O:44])[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1.[Na].C(O)(=O)C>>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][CH:40]1[CH2:41][CH2:42][S:37](=[O:45])(=[O:44])[CH2:38][CH2:39]1)=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1CCS(=O)(=O)CC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: [Na]
Solvent: CC(=O)O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC4CCS(=O)(=O)CC4)nc32)[C@H](O)[C@@H]1O
Yield: 42.8 %

Procedure:
The title compound was prepared by a similar method to example 6 using (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (305 mg, 0.60 mmol) (example 1), tetrahydro-1λ6-thiopyran-1,1,4-trione (88 mg, 0.60 mmol), sodium triacetoxyborohydrde (200 mg, 0.90 mmol) and acetic acid (43 mg, 0.72 mmol). The product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (96:4:0.2) to give the title compound (160 mg) as a foam. MS: 623 (MH+).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[C:25]1[N:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]=1>O>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:25]3[N:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1ncc(Br)cn1
Reactant: C1CCN(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cnc(N2CCC(N3CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
4-(Piperidin-1-yl)piperidine (342 mg, 2.03 mmols) and cesium carbonate (764 mg, 2.34 mmols) were added to DMF solution (10 ml) of 2-chloro-5-bromopyrimidine (300 mg, 1.56 mmols), and stirred at room temperature for 16 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, chloroform/methanol=100/3) to obtain the entitled compound (349 mg, 69%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[O:13][C:14](=[O:16])[CH3:15].N1C2C(=CC=CC=2)C=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[O:13][C:14](=[O:16])[CH3:15]
Reactant: COCCC#Cc1ccncc1OC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: COCCCCc1ccncc1OC(C)=O

Procedure:
To a degassed solution of 9.9 mmol acetic acid 4-(4-methoxy-but-1-ynyl)-pyridin-3-yl ester and 0.51 mmol quinoline in 230 ml ethyl acetate is added 0.56 mmol 10% Pd/C. The suspension is vigorously stirred under an atmospheric pressure of hydrogen for 2 hours. The catalyst is removed by filtration and the solvent is evaporated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) and identified based on its Rf value.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:42])C=1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19]([CH3:20])=[O:42])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(C(F)(F)F)cc3)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cccc2c(C(c3ccc(F)cc3)c3ccc(C(F)(F)F)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
75 mg (0.18 mmol) of the compound from Example 99 were introduced into 25 ml of dichloromethane at 0° C., 43 mg (0.18 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was purified twice by preparative HPLC (mobile phase: acetonitrile/water gradient). 65 mg (84% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]=1[C:13]1[C:14]2[NH:21][CH:20]=[C:19]([C:22]([OH:24])=O)[C:15]=2[N:16]=[CH:17][N:18]=1)[CH3:2].[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][C@@H:34]([NH:37][C:22]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:5]4[C:6]5[O:10][CH2:9][O:8][C:7]=5[CH:11]=[CH:12][C:4]=4[O:3][CH2:1][CH3:2])[C:14]=3[NH:21][CH:20]=2)=[O:24])[CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: CCOc1ccc2c(c1-c1ncnc3c(C(=O)O)c[nH]c13)OCO2
Product: CCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-ethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A69) and commercially available (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[NH:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=O.N1CCCCC1>CO>[NH:11]1[CH:15]=[CH:14][CH:13]=[C:12]1/[CH:16]=[C:3]1\[C:2](=[O:10])[NH:1][C:9]2[C:4]\1=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=Cc1ccc[nH]1
Reactant: O=C1Cc2ccccc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2/C1=C/c1ccc[nH]1
Yield: 96.1 %

Procedure:
A mixture of oxindole (137 mg, 1.03 mmol), pyrrole-2-carboxaldehyde (115.1 mg, 1.21 mmol) and piperidine (40 μL, 0.404 mmol) in 2.0 mL MeOH was heated at reflux for 3 h. The mixture was cooled in an ice bath and the solid which formed was collected by filtration to give the title compounds (208 mg, 96%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15](I)=[CH:14][N:13](S(C3C=CC=CC=3)(=O)=O)[C:10]2=[N:11][CH:12]=1)=[O:5].[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[F:45].C([O-])([O-])=O.[K+].[K+].C(#N)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.O>[F:38][C:39]1[CH:40]=[C:41]([C:15]2[C:9]3[C:10](=[N:11][CH:12]=[C:7]([NH:6][C:4](=[O:5])[C:3]4[C:26]([F:37])=[CH:27][CH:28]=[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[C:2]=4[F:1])[CH:8]=3)[NH:13][CH:14]=2)[CH:42]=[CH:43][C:44]=1[F:45]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccccc2)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(-c4ccc(F)c(F)c4)c3c2)c1F
Temperature: 160 °C
Yield: 44.2 %

Procedure:
2,6-Difluoro-N-(3-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.025 g, 0.038 mmol), 3,4-difluorophenylboronic acid (0.0090 g, 0.057 mmol), K2CO3 (0.026 g, 0.19 mmol), and Pd(PPh3)4 (0.0022 g, 0.0019 mmol) were taken up in 4:1 acetonitrile (“ACN”)/water (1.5 mL) and degassed with argon for 10 minutes. The reaction mixture was heated to 160° C. for 10 minutes under microwave irradiation. The solution was partitioned between water and EtOAc. The organic portion was washed with water (3×), brine, dried over Na2SO4 and concentrated to an oil. DCM was added to the oil, and a solid precipitated out, which was collected by filtration giving N-(3-(3,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (8.5 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ 12.08 (br s, 1H), 10.97 (s, 1H), 9.80 (br s, 1H), 8.66 (br s, 1H), 8.52 (br s, 1H), 7.99 (br s, 1H), 7.69-7.75 (m, 1H), 7.51-7.59 (m, 3H), 7.25-7.30 (m, 1H), 3.11-3.15 (m, 2H), 1.74-1.80 (m, 2H), 0.98-1.02 (m, 3H); m/z (APCI-pos) M+1=505.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH:28]=O)[CH:22]=1>>[CH3:30][C:21]1[CH:22]=[C:23]([C:27]2[CH:28]=[N:1][C:2]3[C:3]([C:12]=2[C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]([F:11])([F:10])[F:9])[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Reactant: Cc1cccc(CC=O)c1
Product: Cc1cccc(-c2cnc3c(C(F)(F)F)cccc3c2-c2cccc(O)c2)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and m-Tolyl-acetaldehyde following the procedure of Example 457: MS (ES) m/z 378.0; HRMS: calcd for C23H16F3NO+H+, 380.12567; found (ESI, [M+H]+), 380.1263.