Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][N:30]3[CH2:31][CH2:32][N:27]([CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:28][CH2:29]3)[O:13][N:12]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1ccc(-c2cc(CCC=O)on2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cc(CCCN3CCN(Cc4ccccc4)CC3)on2)cc1OC
Yield: 142.9 %

Procedure:
About 2 min after dissolving 3-[3-(3,4-dimethoxyphenyl)isoxazol-5-yl]propanal (20 mg, 0.08 mmol) and 1-benylpiperazine (13.4, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (48 mg, 0.23mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 20 hr and followed the same processes as in Example 1 to obtain 24.1 mg (74.6%) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Br[C:57]1[CH:64]=[CH:63][C:60]([C:61]#[N:62])=[C:59]([F:65])[CH:58]=1>C1(C)C=CC=CC=1>[F:65][C:59]1[CH:58]=[C:57]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[C:10]([F:11])([F:12])[F:13])[CH:64]=[CH:63][C:60]=1[C:61]#[N:62]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: COc1ccc(N)c(C(F)(F)F)c1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2ccc(C#N)c(F)c2)c(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
2-Amino-5-methoxy-benzotrifluoride (10.46 mmol), K3PO4 (15.7 mmol), Xphos (1.05 mmol) and Pd4(dba)3 (0.314 mmol) were added under nitrogen to a solution of 4-bromo-2-fluoro-benzonitrile (10.46 mmol) in 50 mL toluene and the mixture was stirred for 20 hours at a bath temperature of 110° C. Then the mixture was filtered through a glass fibre filter, then the filtrate was extracted with 150 mL water. The organic phase was dried on sodium sulphate and evaporated down. In this way the product was obtained in a yield of 87% of theory.
Reaction SMILES: [Br:1][CH:2]([CH:5]=O)[CH:3]=O.[NH2:7][C:8]1[CH:12]=[CH:11][NH:10][N:9]=1>C(O)(=O)C>[Br:1][C:2]1[CH:5]=[N:7][C:8]2[N:9]([N:10]=[CH:11][CH:12]=2)[CH:3]=1
Reactant: O=CC(Br)C=O
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Product: Brc1cnc2ccnn2c1
Yield: 11.2 %

Procedure:
Dissolve bromomalonaldehyde (Aldrich; 2.5 g, 16.5 mmol) and 3-aminopyrazole (Aldrich; 1.38 g, 16.5 mmol) in glacial acetic acid (25 mL) and reflux the resulting mixture under nitrogen for 2 h. Concentrate under reduced pressure. Dissolve the residue in absolute methanol (150 mL), vacuum filter through a pad diatomaceous earth and concentrate under reduced pressure. Chromatograph on flash silica using a gradient from neat hexane to 50% ethyl acetate/50% hexane to obtain 365 mgs (11%) of the subtitled compound as a light yellow solid. High Resolution Mass Spectrum: 197.9674 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][F:22])[CH:14]=1)[C:5]2=O.O.[NH2:25][NH2:26]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][F:22])[CH:14]=3)=[CH:7][NH:26][N:25]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: NN
Reactant: O=c1c(-c2cccc(OCCF)c2)coc2cc(O)c(Cl)cc12
Solvent: CCO
Solvent: O
Product: Oc1cc(O)c(-c2n[nH]cc2-c2cccc(OCCF)c2)cc1Cl

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-3-[3-(2-fluoro-ethoxy)-phenyl]-7-hydroxy-chromen-4-one (0.2 g, 0.6 mmol), hydrazine hydrate (2.5 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give an oil which was purified by column chromatography to give 4-Chloro-6-{4-[3-(2-fluoro-ethoxy)-phenyl]-1H-pyrazol-3-yl}-benzene-1,3-diol as an off white solid (0.12 g, 57.3%); Rf 0.5 cf SM 0.85 ethyl acetate/hexane (80/20).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][C:11]1[CH:15]=[C:14]([CH:16]2[CH2:18][CH2:17]2)[NH:13][N:12]=1.C(N(CC)CC)C>CCO>[CH:16]1([C:14]2[CH:15]=[C:11]([NH:10][C:6]3[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([Cl:1])[N:7]=3)[NH:12][N:13]=2)[CH2:18][CH2:17]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1cc(Nc2cc(C3CC3)n[nH]2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.8 %

Procedure:
To a solution of 2,4,6-trichloropyrimidine (60 mg, 3.27 mmol) and 3-amino-5-cyclopropylpyrazole (403 mg, 3.27 mmol) in EtOH (10 mL) was added triethylamine (456 μL, 3.27 mmol) and the reaction mixture was stirred for 15 hours at room temperature. The solvent was evaporated and the residue was purified by flash chromatography (SiO2, Hexane/AcOEt gradient) to afford (5-cyclopropyl-2H-pyrazol-3-yl)-(2,6-dichloropyrimidin-4-yl)-amine (705 mg, 80%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.Cl[C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([O:21][CH3:22])[N:14]=1>>[CH3:22][O:21][C:15]1[N:16]=[C:17]([O:19][CH3:20])[N:18]=[C:13]([CH:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[N:14]=1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: COc1nc(Cl)nc(OC)n1
Product: COc1nc(OC)nc(C2C(=O)Nc3ccc(F)cc32)n1

Procedure:
5-Fluoro-1,3-dihydro-2H-indol-2-one (10 g) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (15.5 g) are reacted analogously to Example 1 Variant A. This gives the title compound as solid in an HPLC purity of 92% area (19 g, 91% of theory).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[N:8]([CH2:22][CH2:23][CH3:24])[C:7]=2[CH:25]=1.C(OC)(OC)OC.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O.[BH4-].[Na+]>CO>[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:38][NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[N:8]([CH2:22][CH2:23][CH3:24])[C:7]=2[CH:25]=1
Reactant: CCCN(CCC)CCCCc1nc2ccc(CN)cc2n1CCC
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN(CCC)CCCCc1nc2ccc(CNCc3ncc[nH]3)cc2n1CCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
The compound (130 mg) obtained in Example 125-6 was dissolved in methanol (3.0 ml) and added with trimethyl orthoformate (0.130 ml) and 2-imidazole carboxaldehyde (37.3 mg), followed by stirring for 1 hour. Then, the solution was cooled to 0° C. The solution was added with sodium borohydride (21.5 mg) and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. The solution was washed with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Then, the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (64.0 mg) as a pale-yellow viscous substance.
Reaction SMILES: Cl.[CH:2]1([CH2:5][C:6]2([C:12]#[N:13])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH2:23]([S:25](Cl)(=[O:27])=[O:26])[CH3:24]>C(Cl)Cl>[CH:2]1([CH2:5][C:6]2([C:12]#[N:13])[CH2:7][CH2:8][N:9]([S:25]([CH2:23][CH3:24])(=[O:27])=[O:26])[CH2:10][CH2:11]2)[CH2:4][CH2:3]1
Reactant: N#CC1(CC2CC2)CCNCC1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(C#N)(CC2CC2)CC1
Reaction time: 2 h

Procedure:
A suspension of 4-(cyclopropylmethyl)piperidine-4-carbonitrile hydrochloride (I-3, 2.5 g, 12.5 mmol) in CH2Cl2 (130 mL) at 0° C. was treated with i-Pr2NEt (8.7 mL, 50 mmol) and EtSO2Cl (1.8 mL, 18.7 mmol) dropwise. After 2 h, the reaction was quenched with the addition of 1 M aqueous NaOH (40 mL) and stirred 18 h before being extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford 4-(cyclopropylmethyl)-1-(ethylsulfonyl)piperidine-4-carbonitrile (I-4, M+H+=256.1) as an off-white amorphous solid. This material was used in subsequent reactions without further purification.
Reaction SMILES: [OH-].[CH2:2]([N+:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].[C:19]([OH:30])(=[O:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1.C(O)C>C1C=CC=CC=1>[C:19]([O-:30])(=[O:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([O-:26])=[O:25])=[CH:22][CH:21]=1.[CH2:15]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18].[CH2:15]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCO
Product: O=C([O-])c1ccc(C(=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a clean, dry 500 mL round bottom flask equipped with a stir bar, Dean-Starke adapter, condenser, drying tube, and nitrogen inlet, was added 10.0 mL (0.015411 mol) of a 40 wt % aqueous solution of tetrabutylammonium hydroxide, 1.2801 (0.007705 mol) terephthalic acid, 100 mL ethanol, and 150 mL benzene. Lowered apparatus into an oil bath and heated to reflux for 6 hours. The azeotrope distilled at 64.9° C. and the reaction was allowed to remove water overnight. The reaction was cooled to room temperature, and the solvent was removed via rotary evaporation. A sample of the crude product was shown to be very soluble in water, and an NMR was taken which showed the absence of terephthalic acid. The wax-like solid was recrystallized from ethanol/ether to give white crystals, 3.9104 g (78%). Calculated for C40H76N2O4: C, 740219%; H, 11.8019%; N, 4.3161%. Found: C, 69.16; H, 11.74%; N, 4.02%. 1H NMR (CDCl3 300 MHZ): δ 0.92(t 24H), δ 1.30-1.50 (mm 32H), δ 3.10 (t 16H), 6 8.00 (m 4H). Melting point 135-137° C.
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:30])[C:17]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][C:25](=[O:27])[N:24]([CH3:28])[C:23]=3[CH:29]=2)=[O:18])=[C:12]([Cl:31])[CH:11]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:30])[C:17]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][C:25](=[O:27])[N:24]([CH3:28])[C:23]=3[CH:29]=2)([OH:18])[C:2]([F:4])([F:3])[F:1])=[C:12]([Cl:31])[CH:11]=1
Reactant: CC(C(=O)c1ccc2oc(=O)n(C)c2c1)c1ccc(Br)cc1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
Trifluoromethyltrimethylsilane (2M in THF, 1.13 mL) was added at 0° C. to a solution of 5-[2-(4-bromo-2-chloro-phenyl)-propionyl]-3-methyl-3H-benzooxazol-2-one (404 mg) in THF (8 mL) followed by the addition of tetrabutylammonium fluoride trihydrate (65 mg). Stirring was continued for 2 hours at 0° C. More tetrabutylammonium fluoride (1M in THF, 0.82 mL) was added to the reaction mixture and stirring was continued for 1 hour at 0° C. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, CH2Cl2:MeOH=100:0 to 96:4) to give the title compound as a colorless foam (320 mg, 67%). MS (m/e)=466.1 [M+H+].
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:22])[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCC[O:25]C1.[O-][Mn](=O)(=O)=O.[K+]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:22])[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:11](=[O:25])[C:10]=3[C:5]2=[CH:4][CH:3]=1
Reactant: Cn1c2c(c3ccc(Br)nc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cn1c2c(c3ccc(Br)nc31)C(=O)N(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 17 h
Yield: 176.2 %

Procedure:
To a stirred solution of tert-butyl 2-bromo-9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (732 mg, 2.0 mmol) in CH2Cl2 (20 mL) at room temperature was added 18-crown-6 (53 mg, 0.20 mmol) followed by addition of KMnO4 (474 mg, 3.0 mmol) in small portions over 20 min. The reaction mixture was stirred at room temperature for 17 h, quenched with saturated sodium metabisulfite solution (20 ml) and extracted with CH2Cl2 (3×20 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated. Flash chromatography (40 g ISCO column, 100:0 to 65:35 hexanes/EtOAc gradient) gave the title compound (134 mg, 18%) as an orange solid: 1H NMR (500 MHz, DMSO-d6) δ 8.30 (d, J=8.1 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 4.22 (t, J=6.4 Hz, 2H), 3.80 (s, 3H), 3.05 (t, J=6.4 Hz, 2H), 1.59 (s, 9H); ESI MS m/z 380 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:12]1[CH:13]=[CH:14][C:15]([OH:23])=[C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=1)[O:4][Si:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7].[Br:24][C:25]1[CH:42]=[CH:41][C:28]([O:29][CH2:30][C:31](ON2C(=O)CCC2=O)=[O:32])=[CH:27][CH:26]=1>O1CCCC1>[Br:24][C:25]1[CH:42]=[CH:41][C:28]([O:29][CH2:30][C:31]([NH:1][CH2:2][C@@H:3]([C:12]2[CH:13]=[CH:14][C:15]([OH:23])=[C:16]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])[CH:17]=2)[O:4][Si:5]([CH2:6][CH3:7])([CH2:10][CH3:11])[CH2:8][CH3:9])=[O:32])=[CH:27][CH:26]=1
Reactant: CC[Si](CC)(CC)O[C@@H](CN)c1ccc(O)c(NS(C)(=O)=O)c1
Reactant: O=C(COc1ccc(Br)cc1)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)O[C@@H](CNC(=O)COc1ccc(Br)cc1)c1ccc(O)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of N-[5-((R)-2-azido-1-triethylsilyloxyethyl)-2-benzyloxyphenyl]methanesulfonamide (1.84 g) and 10% palladium-carbon (0.18 g) in methanol (15 mL) /methylene chloride (15 mL) was stirred at room temperature for 5 hrs under an atmosphere of hydrogen. The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure to afford N-[5-((R)-2-amino-1-triethylsilyloxyethyl)-2-hydroxyphenyl]methanesulfonamide as a crude product. The crude N-[5-((R)-2-amino-1-triethylsilyloxyethyl)-2-hydroxyphenyl]methanesulfonamide was dissolved in tetrahydrofuran (40 mL), and 2,5-dioxopyrrolidin-1-yl (4-bromophenoxy)acetate (1.39 g) was added to the solution. After being stirred at room temperature for 3 hrs, the reaction mixture was concentrated in vacuo, and the residue was purified by medium-pressure silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to afford the title compound (1.01 g).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[C:22]([F:28])[CH:21]=1.[Si]([C:33]([F:36])([F:35])[F:34])(C)(C)C.Cl>C1COCC1>[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]([OH:25])[C:33]([F:36])([F:35])[F:34])=[C:22]([F:28])[CH:21]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.9 %

Procedure:
TBAF (0.1 ml) was added to a solution of 4-bromo-2-fluoro-benzaldehyde (2.03 g, 10 mmol) and TMSCF3 (20 ml, 12 mmol) in 10 ml THF at 0° C. The formed mixture was warmed up to room temperature and stirred for 4 hours. The reaction mixture was then treated with 12 ml of 3M HCl and stirred overnight. The product was extracted with ethyl acetate (3×20 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 2.4 g of 1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethanol (yield: 90%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:17]([F:20])([F:19])[F:18])=[O:5])[CH3:2].[H-].[Na+].[CH3:23]I>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[N:8]([CH3:23])[C:7]=1[C:17]([F:20])([F:18])[F:19])=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1c(C(F)(F)F)[nH]c2cc(OC)ccc12
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(C(F)(F)F)n(C)c2cc(OC)ccc12
Yield: 87.4 %

Procedure:
This material was prepared from 6-methoxy-2-trifluoromethyl-1H-indole-3-carboxylic acid ethyl ester 76d (1.64 g, 5.7 mmole) by treatment with NaH (274 mg, 60% in mineral oil, 6.84 mmole) and methyl iodide (1.21 g, 8.55 mmole) and NaH in a manner as previously described for example 16b to give 1.5 g product (87% yield). 1H NMR (300 MHz, CDCl3) δ 7.96 (1H, dd, J=3.7, 8.8 Hz), 6.94 (1H, dd, J=2.3, 9.1 Hz), 6.77 (1H, d, J=2.1 Hz), 4.40 (2H, m), 3.89 (3H, s), 3.86 (3H, s), 1.41 (3H, m).
Reaction SMILES: Cl[C:2]([N:4]1[CH2:7][CH:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH2:5]1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.C1C=CC=CC=1>[F:16][C:15]([F:18])([F:17])[C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH:6]1[CH2:7][N:4]([C:2]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:3])[CH2:5]1
Reactant: C1CCNCC1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: O=C(N1CCCCC1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: -70 °C

Procedure:
A solution of 5.6 g (0.02 mole) of 1-chlorocarbonyl-3-[3-(trifluoromethyl)phenoxy]azetidine in 50 ml of tetrahydrofuran was treated with 3 g (0.022 mole) of potassium carbonate and while stirring, 1.9 g (0.022 mole) of piperidine was added dropwise. The mixture was then treated with 10 g of ice and stirred for 2 hr. The tetrahydrofuran was decanted then concentrated on a rotary evaporator to yield an amber oil, 6.0 g. The oil was dissolved in benzene, washed with dilute acid then water, dried over magnesium sulfate and concentrated in vacuo. This oil crystallized when cooled to -70° C. and was recrystallized from hexane with charcoal treatment at 0° C. yielding pale tan crystals, 4.5 g (68.5%), m.p. 50°-52° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([Br:18])=[N:9][N:10]([CH:15]([CH3:17])[CH3:16])[C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O.Cl>CCO.O.[Fe]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([Br:18])=[N:9][N:10]([CH:15]([CH3:16])[CH3:17])[C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: CC(C)n1nc(Br)c2ccc([N+](=O)[O-])cc2c1=O
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)n1nc(Br)c2ccc(N)cc2c1=O
Temperature: 80 °C
Yield: 99.2 %

Procedure:
7-Nitro-2-Isopropyl-4-bromo-2H-phthalazin-1-one (4.6 g, 0.015 mol) was dissolved in a 5:1 mixture of EtOH and water (150 ml). To this solution was added iron powder (2.14 g, 0.039 mol) and concentrated HCl (1 ml), the mixture was heated to 80° C. for three hours. After this time, the reaction mixture was cooled to RT and filtered through a pad of celite, the celite was washed with EtOH (100 ml), and the solution was concentrated under vacuum to give the title compound (4.2 g, 98% yield) as a white solid. 1H-NMR: (400 MHz, D6-DMSO), 7.56 (1H, d), 7.28 (1H, s), 7.13 (1 H, d), 6.47 (2H, s), 5.24-5.09 (1H, m), 1.23 (6H, d); MS (ESI+)=(M+H)+ 282, 284
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[N+:22]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1N

Procedure:
Prepared from (4′-cyano-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example C13) by reduction with SnCl2.2H2O according to the general procedure G (method b). Obtained as a yellow solid (360 mg).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[N:8]=[C:9]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:10]3[N:15]=[C:14]([CH:16]=O)[S:13][C:11]=3[N:12]=2)[C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=2[N:3]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([C:34]([OH:37])([CH3:36])[CH3:35])[CH2:29]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][C:2]1[N:6]([C:7]2[N:8]=[C:9]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:10]3[N:15]=[C:14]([CH2:16][N:28]4[CH2:33][CH2:32][CH2:31][CH:30]([C:34]([OH:37])([CH3:36])[CH3:35])[CH2:29]4)[S:13][C:11]=3[N:12]=2)[C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)sc2n1
Reactant: CC(C)(O)C1CCCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCCC(C(C)(C)O)C3)sc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-(2-methylbenzoimidazol-1-yl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine-2-carbaldehyde (78 mg, 0.2 mmol), 2-piperidin-3-yl-propan-2-ol (43 mg, 0.3 mmol) trimethyl orthoformate (0.109 mL, 1.0 mmol) and glacial acetic acid (0.017 mL, 0.3 mmol) in 1,2-dichloroethane (2 mL) was stirred at RT under nitrogen atmosphere for 1 h. Sodium triacetoxyborohydride (85 mg, 0.4 mmol) was added and the resulting reaction mixture was stirred at RT for 16 h. The solvent was reduced in vacuo and the residue was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The residue was purified by column chromatography (Si—PCC, acetone:cyclohexane: 10:90 to 35:65 by volume). Solvents were reduced in vacuo to afford the title compound as a white solid. The resulting solid was further purified by reverse phase HPLC (MeOH: H2O+0.1% HCCOH, gradient 10:90 to 90:10 over 25 min). The solvent was reduced in vacuo and the aqueous residue freeze dried to afford 362 as a white solid (23 mg, 23%). LCMS (Method G): RT 6.73 min, [M+H]+ 508. 1H NMR (400 MHz, CDCl3): δ 8.18 (1 H, s), 8.04-8.03 (1 H, m), 7.70-7.69 (1 H, m), 7.27-7.26 (2 H, m), 4.38 (4 H, br s), 3.90 (2 H, s), 3.85 (4 H, t, J=4.74 Hz), 3.18 (2 H, m), 2.91 (5 H, m), 2.28-2.15 (2 H, m), 1.81 (2 H, m), 1.75-1.60 (2 H, m), 1.20 (3 H, s), 1.15 (3 H, s)
Reaction SMILES: Cl[CH:2]1[NH:7][C:6]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:10][C:5]=2[C:4](=[O:17])[N:3]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.[CH3:25][NH:26][CH3:27].C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:3]2[C:4](=[O:17])[C:5]3[S:10][CH:9]=[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:6]=3[N:7]=[C:2]2[N:26]([CH3:27])[CH3:25])=[CH:19][CH:20]=1
Reactant: O=C1c2scc(-c3ccccc3)c2NC(Cl)N1c1ccc(Cl)cc1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1nc2c(-c3ccccc3)csc2c(=O)n1-c1ccc(Cl)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
The thus synthesized compound 2-chloro-3-(4-chlorophenyl)-7-phenyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (22.7 mg, 0.06 mmol) was mixed with a solution of N,N-dimethylamine (3 ml) and diisopropylethylamine (0.01 ml, 0.06 mmol) in THF. The mixture was heated with stirring at 65° C. overnight. After the completion of the reaction was confirmed by TLC, the reaction mixture was cooled to room temperature and separated with water and dichloromethane. The extracted organic layer was washed with brine, dried over anhydrous MgSO4, and filtered. The filtrate was distilled under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc:Hex=1:5) to give 14.1 mg (0.037 mmol, 62% yield) of the title compound.