Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=2[CH3:21])=[O:11])[CH2:3]1.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33])(=[O:25])=[O:24]>>[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([N:7]1[C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=2[CH3:21])=[O:11])[CH2:3][C@H:2]1[CH3:1])(=[O:34])=[O:33])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: COc1cccc(NC(=O)CN2C[C@@H](C)N[C@@H](C)C2)c1C
Product: COc1cccc(NC(=O)CN2C[C@@H](C)N(S(=O)(=O)c3ccccc3S(C)(=O)=O)[C@@H](C)C2)c1C

Procedure:
The title compound was prepared from the product of step (i) (0.503 mmol) and 2-methanesulphonylbenzenesulphonyl chloride (0.503 mmol) by the method of Example 58 step (ii) as a white solid. Yield: 6 mg
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([F:18])([F:17])[F:16])=[N:12]2)=[C:7]([OH:19])[C:6]=1[N+:20]([O-:22])=[O:21])=[O:4].[CH3:23]N(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.C[O+](C)C.F[B-](F)(F)F>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([F:17])([F:18])[F:16])=[N:12]2)=[C:7]([O:19][CH3:23])[C:6]=1[N+:20]([O-:22])=[O:21])=[O:4]
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: COC(=O)c1cc2nc(C(F)(F)F)ccc2c(O)c1[N+](=O)[O-]
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc2nc(C(F)(F)F)ccc2c(OC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.6 %

Procedure:
A solution of 5-Hydroxy-6-nitro-2-trifluoromethyl-quinoline-7-carboxylic acid methyl ester (1.5 g, 4.744 mmol) in methylene chloride is treated with N,N,N′,N′-Tetramethyl-1,8-naphthalendiamine (3.05 g, 14.232 mmol) and Trimethyloxonium-tetrafluorborate (2.11 g, 14.232 mmol) at 0-5° C. under argon. The reaction mixture is allowed to warm to room temperature with stirring. The reaction is complete after 2.5 hr as shown by TLC analysis. The reaction mixture is diluted with methylene chloride, and then washed successively with 2N aqueous hydrochloric acids, water, and brine. The organic phase is dried over anhydrous sodium sulphate, filtered, and concentrated in vacuo. The residue (2.9 g) is purified by flash column chromatography, eluting with 3:1 hexane:ethyl acetate. This gives the title compound (1.2 g, 76%) as yellow crystals.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]2[NH:9][NH:10][C:11](=O)[C:6]2=[CH:5][N:4]=1.P(Br)(Br)([Br:15])=O.O.[OH-].[NH4+]>CC#N>[Br:15][C:11]1[C:6]2[C:7](=[N:8][C:3]([S:2][CH3:1])=[N:4][CH:5]=2)[NH:9][N:10]=1
Reactant: O=P(Br)(Br)Br
Reactant: CSc1ncc2c(=O)[nH][nH]c2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CSc1ncc2c(Br)n[nH]c2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a suspension of 6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (0.50 g, 2.7 mmol) in CH3CN (15 mL) was added a CH3CN solution of P(O)Br3 (1.57 g, 5.5 mmol) in a pressure vessel. The mixture was sonicated for 30 min before being heated to 100° C. for 16 h (overnight). After it was cooled to 0° C., H2O and aqueous ammonium hydroxide were added to basify the mixture. The mixture was stirred at 0° C. for 1 h. The aqueous layer was extracted with EtOAc (10×). The combined EtOAc layer was dried (Na2SO4), and concentrated to give 3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine (0.51 g, 77%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.00 (s, 1H), 5.57 (s, 3H); MS m/z 245.00 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]2[CH2:23][NH:22][CH2:21][CH2:20]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>ClCCl>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([N:22]2[CH2:23][CH:19]([NH:18][S:15]([C:12]3[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=3)(=[O:17])=[O:16])[CH2:20][CH2:21]2)(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: O=S(=O)(NC1CCNC1)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(NC1CCN(S(=O)(=O)c2ccc(Cl)cc2)C1)c1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 28.9 %

Procedure:
To a solution of (2S,4R)-2-[(E and Z)-5-carboxy-1-pentenyl]-4-(4-chlorophenylsulfonylamino)pyrrolidine trifluoroacetate (7.85 g) in dichloromethane (80 ml) were added triethylamine (8.98 ml) and 4-chlorobenzenesulfonyl chloride (3.40 g) under an ice bath cooling and the mixture was stirred at the same temperature for 1.5 hours. The solution was washed successively with diluted hydrochloric acid and water and the organic phase was extracted with 1N aqueous sodium hydroxide. The aqueous phase was washed with ethyl acetate and adjusted to pH 3 with 3N hydrochloric acid. The aqueous solution was extracted with ethyl acetate and the organic phase was washed successively with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column with chloroform as an eluent to give (2S,4R)-2-[(E and Z)-5-carboxy-1-pentenyl]-1-(4-chlorophenylsulfonyl)-4-(4-chlorophenylsulfonylamino) pyrrolidine (2.03 g) as a pale yellow crystal.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>CN(C=O)C.O>[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][N:4]1[C:5]2=[N:6][CH:7]=[N:8][CH:9]=[C:10]2[C:2]([I:1])=[N:3]1
Reactant: Ic1n[nH]c2ncncc12
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccccc1Cn1nc(I)c2cncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
569 mg (2.313 mmol) of 3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 828 mg (2.544 mmol) of caesium carbonate were initially charged in 10 ml of DMF, and 481 mg (2.544 mmol) of 2-fluorobenzyl bromide dissolved in 2 ml of DMF were added. The reaction mixture was stirred at RT overnight, diluted with 50 ml of water and filtered with suction, and the residue was dried under high vacuum. 733 mg of the target compound were obtained (purity 83%; 74% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:47])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C:32]3([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:35][CH2:34][CH2:33]3)[N:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:47])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C:32]3([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:35][CH2:34][CH2:33]3)[N:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3ccccc3)n2)CC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 860 mg of 4-((S)-4-tert-Butoxycarbonyl-2-{[5-(1-ethoxycarbonyl-cyclobutoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 5 ml of DCM, 0.8 ml of TFA was added at RT. After 4 h 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 320 mg
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC1C=CC(C(C)C)=CC=1.[Pd]>[CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC1=C(c2ccccc2)CCC(=O)N1
Agent: [Pd]
Solvent: Cc1ccc(C(C)C)cc1
Product: Cc1[nH]c(=O)ccc1-c1ccccc1
Reaction time: 36 h

Procedure:
3,4-Dihydro-6-methyl-5-phenyl-2(1H)-pyridone (25.6 grams) and 5% palladium/on carbon (4.9 grams) were refluxed for about 18 hours in 750 ml p-cymene. Since little product formed upon cooling, the reaction mixture was boiled and distilled until a constant temperature of 173° C. was reached. Refluxing continued for 36 hours and then the reaction mixture was filtered hot. Upon cooling, a solid precipitate formed which was collected and washed with ether, yield 13.0 grams, m.p. 201°-208° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16][C:15]2=[O:22])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:23].BrBr>O>[Br:23][C:14]1([C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)[C:15](=[O:22])[NH:16][C:17](=[O:21])[NH:18][C:19]1=[O:20]
Reactant: O=C1NC(=O)C(c2ccc(Oc3ccccc3)cc2)C(=O)N1
Reactant: Br
Agent: BrBr
Solvent: O
Product: O=C1NC(=O)C(Br)(c2ccc(Oc3ccccc3)cc2)C(=O)N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-(4′-phenoxyphenyl)barbituric Acid (48 mg) in 0.23 ml of water, cooled at 0° C. and under stirring, are added 23 ml of 48% hydrobromic acid and successively 9 μl of bromine. After 2 hours at room temperature additional 9 μl of bromine are added and stirring is continued for 2 hours. The suspended solid is then filtered and washed with water, to give, after drying under vacuum at 60° C., 57 mg of the product, m.p. 125-127° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH:9][C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[CH:3]=1.C(O)(=O)C.[N:20](OC(C)(C)C)=O>C1COCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[N:20][N:9]([C:10]3[CH:15]=[N:14][CH:13]=[CH:12][N:11]=3)[C:4]=2[CH:3]=1
Reactant: Cc1cc(Nc2cnccn2)c(N)cn1
Reactant: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc2c(cn1)nnn2-c1cnccn1
Yield: 23.2 %

Procedure:
To a solution of 6-methyl-N4-(pyrazin-2-yl)pyridine-3,4-diamine (520 mg, 2.58 mmol) in THF (30 mL) was added acetic acid (0.44 mL, 7.75 mmol) and tert-butyl nitrite (0.51 mL, 3.88 mmol). The reaction was heated to reflux. After 30 min the reaction was cooled and filtered. The filtrate was concentrated and the residue was purified by chromatography on silica gel (0-7% [2M NH3 in MeOH]CH2Cl2) to give the desired product (127 mg, 25%). MS (ESI) mass calcd. C11H9N5, 212.08. m/z found, 213.1 [M+H]+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[NH2:16][CH2:17][CH:18]([OH:27])[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.O>CO>[OH:9][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([NH:16][CH2:17][CH:18]([OH:27])[CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NCC(O)CCN1CCOCC1
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: O
Solvent: CO
Product: OC(CCN1CCOCC1)CNC(c1ccccc1)C(O)c1ccccc1
Yield: 88.8 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mol) and 4-(4-amino-3-hydroxybutyl)morpholine (3.48 g, 0.020 mol) was heated on a steam bath for 18 hours. The resulting viscous oil was dissolved in methanol (20 mL) and the solution poured into water (150 mL). The aqueous mixture was extracted twice with 100 mL portions of methylene chloride. The extract was dried (MgSO4) and concentrated to obtain 3.29 g of the impure product as an oil. The material was chromatographed on silica gel (60 g) using increasing portions of acetone in ethyl acetate to elute the product. After combining the desired fractions and concentration under vacuum, 2.21 g (67%) of the product was obtained. The product was purified and characterized as the cyclohexyl sulfamic acid salt, mp 159°-160° C. (methanol/isopropyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.[I-].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][NH:26][CH2:27][CH2:28][CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: NCCCn1ccnc1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCNCCCn2ccnc2)ccc1Cl
Yield: 71.4 %

Procedure:
2-Chloro-5-[(2-chloroethyl)amino]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 29c, 0.200 g), N-(3-aminopropyl)-imidazole (0.957 g), triethylamine (1.2 ml), sodium iodide (0.010 g) and tetrahydrofuran (4 ml) were heated together in a sealed tube at 80° C. for 24 h. The solution was cooled, poured into saturated aqueous sodium hydrogencarbonate solution and extracted into ethyl acetate. The extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified on silica gel (eluant 19:1:0.1 dichloromethane/methanol/ammonia) to afford the title compound as a gum (0.176 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[N+]([C:13]1[S:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1)([O-])=O.O>CS(C)=O>[O:7]([C:13]1[S:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(Oc2ccccc2)s1
Reaction time: 0.5 h
Yield: 4.7 %

Procedure:
Phenol (3.3 g, 35 mmol) is added in portions to a suspension of 60% NaH (1.3 g, 35 mmol) in DMSO (100 mL). The resulting mixture is stirred for 30 min then 5-nitrothiophene-2-carboxaldehyde (5 g, 32 mmol) is added. After 1 hr the reaction mixture is poured into water (1L) and washed with ether (4×500 mL). The combined organic layers are dried over Na2SO4, filtered and evaporated to dryness. The resulting material is dissolved in MeOH and passed through a column (2.5 cm×20 cm) of Amberjet 4400 (OH− form). The eluent is dried in vacuo then evaporated twice from CH3CN. The crude product is purified by column chromatography in EtOAc-hexanes (1:1) to yield 5-phenoxy-thiophene-2-carboxaldehyde (304 mg, 5%). 1H NMR (300 MHz, CDCl3) δ 6.52, 7.20, 7.27, 7.45, 7.55, 9.75.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:11](C1C=CC(C#N)=CN=1)=[CH2:12]>>[CH3:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([CH:11]=[CH2:12])[N:9]=1
Reactant: C=Cc1ccc(C#N)cn1
Reactant: Cc1ccc(C#N)c(Cl)n1
Product: C=Cc1nc(C)ccc1C#N

Procedure:
Compound 386A was prepared from 2-chloro-6-methyl-nicotinonitrile by a route analogous to that used for the preparation of compound 384A. HPLC retention time=1.81 min. (Condition A), M+=145.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[Si:28]([O:35][CH2:36][CH:37]=[O:38])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1.CCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:37]([OH:38])[CH2:36][O:35][Si:28]([C:31]([CH3:33])([CH3:32])[CH3:34])([CH3:29])[CH3:30])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Agent: [Li]C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCCCC
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C(O)CO[Si](C)(C)C(C)(C)C)nc3N21
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
To a solution of 4.00 g (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 100 ml toluene was added drop wise at −78° C. 10.86 ml of a 1.5M solution of tert-butyllithium in pentane. The mixture was stirred at this temperature for 30 min. To the resulting solution was added 5.017 g (tert-butyldimethylsilyloxy) acetaldehyde and the mixture was stirred at −78° C. for 30 min. The reaction was quenched by addition of 10% aqueous ammonium chloride. The phases were separated and the organic phase was purified by chromatography on silica gel with heptane:ethyl acetate=4:1 to yield 2.34 g (4R,9aR)-6-[2-(tert-butyl-dimethyl-silanyloxy)-1-hydroxy-ethyl]-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester as slightly yellow oil (MS: 464.4 (M+H+))
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[O:24]1[CH2:27][C:26](=O)[CH2:25]1.[BH3-]C#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-].CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH:26]4[CH2:27][O:24][CH2:25]4)[CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: O=C1COC1
Reactant: Clc1cc(Nc2ccc(N3CCNCC3)cn2)c2nccn2c1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: Clc1cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c2nccn2c1
Reaction time: 5 h
Yield: 29.7 %

Procedure:
A mixture of 102b (0.773 g, 1.75 mmol), oxetan-3-one (0.189 g, 2.62 mmol), NaBH3CN (0.22 g, 3.5 mmol), and zinc chloride/Et2O (3.5 ml, 3.5 mmol) in methanol (40 mL) was stirred at 50˜60° C. for 5 hours. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with 5:1 CH2Cl2/methanol to afford 102c (200 mg, 30%). MS: [M+H]+ 385.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([OH:27])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl.[NH2:29][C@H:30]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:29][C@H:30]4[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:31]4)=[O:27])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)C1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and tert-butyl [(1S,3S)-3-aminocyclopentyl]carbamate hydrochloride (example C6) the title compound is obtained as pale yellow foam.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10](Cl)=O.Cl.[BH4-].[Na+].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>COCCOCCOC.O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:10][C:6]2[S:5][CH:9]=[CH:8][CH:7]=2)=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1cccs1
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [BH4-]
Solvent: COCCOCCOC
Solvent: O
Product: Fc1ccc(Cc2cccs2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
33.8 g of aluminium chloride were suspended in 200 g of fluorobenzene, and a solution of 37.8 g of thiophene-2-carbonyl chloride in 50 ml of fluorobenzene was added dropwise to this at 0° C. over the course of 30 minutes. The mixture was stirred at 0° C. for 2 hours and then slowly warmed, and heated under reflux at 85° C. for 2 hours until evolution of hydrogen chloride ceased. The solution was cooled to 70° C. and then, at this temperature, added dropwise over the course of 30 minutes to a stirred suspension of 7.2 g of of sodium borohydride in 50 ml of diglyme. The mixture was then stirred at 70° C. for 90 minutes and, after cooling, discharged into a mixture of 250 g of ice, 200 ml of water and 62.5 g of concentrated aqueous hydrochloric acid. After addition of 100 ml of fluorobenzene, the organic phase was separated off, extracted by shaking with 100 ml of water and concentrated. Yield: 58.3 g of product with a content of 61.8% by weight of 2-(4-fluorobenzyl)thiophene (GC), corresponding to a yield of 75.1% of theory. An organic phase was obtained from the aqueous mother liquor by extraction with methylene chloride and concentration and contained a further 33.7% by weight of the required product (GC), corresponding to an additional yield of 4.6% of theory. Distillation of the organic phase resulted in a 99.2% pure 2-(4-fluorobenzyl)thiophene.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[CH3:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1.C(N(CC)CC)C.O>ClCCl>[CH3:5][O:4][N:3]([CH3:2])[C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1
Reactant: CNOC
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N(C)OC)cc1
Temperature: 2.5 °C
Yield: 93.7 %

Procedure:
14.7 g (151 mmol) of N,O-dimethylhydroxylamine hydrochloride are added portionwise to a solution of 25 g (147 mmol) of 4-methoxybenzoyl chloride in 450 mL of dichloromethane, stirred at 0-5° C. under nitrogen. 51 mL (370 mmol) of triethylamine are then added slowly to the mixture stirred at 0-5° C. The orange-coloured reaction medium is stirred at room temperature for 3 hours. The mixture is hydrolysed with 250 mL of water and then extracted with dichloromethane. The organic phase is washed with 100 mL of 1N HCl, 150 mL of 1N NaOH and then with water and brine. It is dried over anhydrous sodium sulfate, filtered and evaporated to dryness. 26.9 g of an orange-coloured oil are obtained, and are purified on a column of silica, eluting with dichloromethane and then with a 95/5 dichloromethane/methanol mixture. 25.4 g of a yellow oil are obtained (89% yield).
Reaction SMILES: [I:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=1>CN(C=O)C>[I:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[CH:3]=1
Reactant: Cc1cccc(CBr)n1
Reactant: O=c1c(I)c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2cc(I)c(=O)c3ccccc32)n1
Reaction time: 3 h

Procedure:
3-iodo-1H-quinolin-4-one (1.36 g, 5 mmol, 1 equiv) in 5 mL of DMF was treated with 0.22 g of NaH (1.1 equiv) for 10 min. 2-Bromomethyl-6-methyl-pyridine (1.11 g, 1.2 equiv) was then added and stirring continued for 3 h. The reaction was quenched by slow addition of saturated aqueous solution of NH4Cl. Standard workup followed by flash chromatography gave 3-iodo-1-(6-methyl-pyridin-2-ylmethyl)-1H-quinolin-4-one as a white solid.