Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](=[O:13])[N:10]([CH3:14])[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17][Si:18]([CH3:25])([CH3:24])[CH2:19][CH2:20][O:21][CH2:22]Cl.CCOC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:22][O:21][CH2:20][CH2:19][Si:18]([CH3:25])([CH3:24])[CH3:17])[C:11](=[O:13])[N:10]([CH3:14])[N:9]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cn1nc(-c2ccc(Br)cc2)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccc(Br)cc2)n(COCC[Si](C)(C)C)c1=O
Reaction time: 0.33 h

Procedure:
To a solution of compound 51b (1.0 g, 3.9 mmol) in DMF (5 mL) was added sodium hydride (0.2 g, 5.0 mmol) in portions at 0° C. The mixture was stirred for 20 min, then 2-(trimethylsilyl)ethoxymethyl chloride (0.73 g, 4.4 mmol) was added dropwise. The reaction mixture was stirred at rt for 2 h. EtOAc (100 mL) was added. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:5 v/v)) to afford compound 51c as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C15H22BrN3O2Si: 384.1 (M+H). Found 384.1.
Reaction SMILES: Br[C:2]1[CH2:6][C:5](C)(C)[CH2:4][C:3]=1[Br:9].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)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>[Br:9][C:3]1[CH2:4][CH2:5][CH2:6][C:2]=1[C:14]1[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC1(C)CC(Br)=C(Br)C1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1ccc(C2=C(Br)CCC2)cc1
Yield: 24.1 %

Procedure:
Under nitrogen, 1.3 g (5.1 mmol) of 1,2-dibromo-4,4-dimethylcyclopentene (Step 8) was reacted with 600 mg (4.3 mmol) of 4-fluorophenylboronic acid (Lancaster) in 23 mL of toluene, 15 mL of ethanol, and 10 mL of 2M Na2CO3 in the presence of 250 mg (5 mol %) of Pd(PPh3)4. The reaction was vigorously stirred at reflux overnight and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, dried (Na2SO4), and reconcentrated. Purification by silica gel chromatography (MPLC) with hexane gave 250 mg of 1-(2-bromocyclopenten-1-yl)-4-fluorobenzene (38 in Synthetic Scheme X when R1 and R2 =CH3, R5 =F, R3, R4, R6, and R7 =H) as a pale yellow oil which was reacted with 200 mg (1.2 mmol) of 4-methylthiophenylboronic acid (Example 1, Step 1) in 5.2 mL of toluene, 3.4 mL of ethanol, and 2.2 mL of 2M Na2CO3 in the presence of 40 mg (5 mol %) of Pd(PPh3)4. The reaction was vigorously stirred at reflux for 6 h and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, dried (Na2SO4), and reconcentrated. Purification by silica gel chromatography (MPLC) with hexane gave 120 mg of 1-[2-(4-fluorophenyl)-4,4-dimethyl cyclopenten-1-]-4-(methylthio)benzene (41 in Synthetic Scheme X when R1 and R2 =CH3, R5 =F, R10 =SCH3, R3, R4, R6, R7, R8, R9, R11, and R12 =H) as an oil: NMR (CDCl3) d 1.20 (s, 6HO0, 2.42 (s, 3H), 2.63 (s, 4H) , 6.90 (t, J=8 Hz, 2H) , 7.00-7.18 (m, 4H) , 7.30-7.60 (m, 2H) .
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C@H:12]3[CH2:15][CH2:16][CH2:17][C@H:11]3[N:10]([C:18](=[O:31])[CH2:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[C:9]3[CH:32]=[CH:33][CH:34]=[CH:35][C:8]2=3)=[CH:4][CH:3]=1.[C:38]1([C@@H:44]([N:46]=[C:47]=[O:48])[CH3:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(OCC)(=O)C.C(OCC)C>[C:38]1([C@@H:44]([NH:46][C:47](=[O:48])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:13](=[O:14])[C@H:12]4[CH2:15][CH2:16][CH2:17][C@H:11]4[N:10]([C:18](=[O:31])[CH2:19][N:20]4[C:21](=[O:30])[C:22]5=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]5[C:24]4=[O:25])[C:9]4[CH:32]=[CH:33][CH:34]=[CH:35][C:8]3=4)=[CH:36][CH:37]=2)[CH3:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: C[C@H](N=C=O)c1ccccc1
Reactant: Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C[C@H](NC(=O)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1)c1ccccc1
Yield: 53 %

Procedure:
Using (3aR*,10aS*)-9-(4-aminobenzyl)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one and (S)-1-phenylethyl isocyanate, the title compound was synthesized in otherwise the same manner as Example 26. Yield 53%, m.p. 156°-160° C. (ethyl acetate-diethyl ether).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][NH:21][C:20](=[S:23])[C@H:19]([NH:24][C:25](=[O:31])OC(C)(C)C)[CH2:18][CH2:17]1.[O:32]=[C:33]1[NH:41][C:36]2=[N:37][CH:38]=[CH:39][CH:40]=[C:35]2[N:34]1[CH:42]1[CH2:47][CH2:46][N:45](C(Cl)=O)[CH2:44][CH2:43]1>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][NH:21][C:20](=[S:23])[C@H:19]([NH:24][C:25]([N:45]2[CH2:44][CH2:43][CH:42]([N:34]3[C:35]4[C:36](=[N:37][CH:38]=[CH:39][CH:40]=4)[NH:41][C:33]3=[O:32])[CH2:47][CH2:46]2)=[O:31])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S
Reactant: O=C(Cl)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.5 %

Procedure:
Triethylamine (0.45 mL, 3.25 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-thioxoazepan-3-ylcarbamate (416 mg, 1.62 mmol) and 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carbonyl chloride (466 mg, 1.66 mmol) in dichloromethane (70 mL) and the mixture heated to reflux. After 18 h, the mixture was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography (100% dichloromethane o 95% dichloromethane/methanol) gave the title compound (685 mg). MS 501.0 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:13][CH:12]=1
Reactant: COc1ccc(CN)cc1
Reactant: CN1CCC(=O)CC1
Product: COc1ccc(CNC2CCN(C)CC2)cc1

Procedure:
1-Methyl-4-piperidone (1.13 g, 10.0 mmol, 1.0 eq.), 4-methoxybenzylamine (1.37 g, 1.0 eq.).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH2:6]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:13][CH2:12]2)[CH3:7]>ClCCl>[CH2:6]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[S:2]([Cl:1])(=[O:5])=[O:3])[CH2:15][N:14]([C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[CH2:13][CH2:12]2)[CH3:7]
Reactant: O=S(=O)(O)Cl
Reactant: CCOc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2
Solvent: ClCCl
Product: CCOc1cc2c(cc1S(=O)(=O)Cl)CN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of chlorosulfonic acid (0.48 mL) in dichloromethane (5 mL) at 0° C. was added dropwise a solution of 1-(6-ethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone (0.39 g, 1.43 mmol). The mixture was stirred at room temperature overnight before partitioning between water and dichloromethane. The organic layer was removed, dried over sodium sulfate, filtered and evaporated to dryness yielding the subtitled compound as a clear oil (0.34 g). 1H NMR δ (CDCl3) 1.46-1.63 (3H, t), 2.95-3.06 (2H, m), 3.80-3.95 (2H, m), 4.18-4.32 (2H, m), 4.69-4.80 (2H, d), 6.84-6.93 (1H, d), 7.70-7.79 (1H, d).
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:14])[CH2:8][CH2:9][C:10]([O:12]C)=O.[CH3:21][C:22]1[S:23][CH:24]=[C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)[N:26]=1>>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[N:14]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:25]3[N:26]=[C:22]([CH3:21])[S:23][CH:24]=3)[CH:28]=2)[C:10](=[O:12])[CH2:9][CH2:8]1
Reactant: COC(=O)CCC(N)c1ccccc1-c1ccccc1
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Product: Cc1nc(-c2cccc(CN3C(=O)CCC3c3ccccc3-c3ccccc3)c2)cs1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-([1,1′-biphenyl]-2-yl)-4-aminobutanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: 425.01 g/mol.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH:11]=[O:12].C1(C)C=CC=CC=1.[OH-:20].[Na+].OO>O>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:9])[F:10])[C:3]=1[C:11]([OH:20])=[O:12]
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1nc(C(F)F)c(C(=O)O)c1Cl
Temperature: 50 °C
Reaction time: 7 h
Yield: 49 %

Procedure:
In a 500 mL flask, 6.0 g (31 mmol) of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde are added to 30 mL of toluene. A solution of 2.4 g (62 mmol) of sodium hydroxide in 6 ml of water is added to the reaction mixture, followed by 103 mL of a 30% solution of hydrogen peroxide in water, whilst keeping the temperature below 37° C. After the end of the addition, the reaction mixture is stirred at 50° C. for 7 hours. Once the reaction mixture is back to room temperature, the two phases are separated and the organic phase is extracted with 100 mL of water. The combined aqueous phases are acidified to pH 2 with aqueous hydrochloric acid. The resulting white precipitate is filtered, washed twice with 20 mL of water, and dried to yield 3.2 g of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 3.78 (s, 3H); 7.12 (t, 1H, JHF=53.60 Hz); 13.19 (s, 1H); IR (KBr): 1688 cm−1 (C═O); 2200-3200 cm−1 broad (hydrogen bond).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2Cl)=[O:4].[CH3:20][C:21]1[CH:22]=[C:23]([NH2:34])[CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>CC(O)(C)C.ClCCCl>[Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:34][C:23]1[CH:24]=[CH:25][C:26]([O:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[C:21]([CH3:20])[CH:22]=1)=[O:4]
Reactant: Cc1cc(N)ccc1Oc1cccnc1
Reactant: O=C(CCl)NCC#Cc1ccc2ncnc(Cl)c2c1
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: Cc1cc(Nc2ncnc3ccc(C#CCNC(=O)CCl)cc23)ccc1Oc1cccnc1
Yield: 88.8 %

Procedure:
A mixture of 2-Chloro-N-[3-(4-chloro-quinazolin-6-yl)-prop-2-ynyl]-acetamide (0.90 g, 3.05 mmol) and 3-Methyl-4-(pyridin-3-yloxy)-phenylamine (0.61 g, 3.05 mmol) in tBuOH/DCE (5.0/5.0 mL) was refluxed under nitrogen for 40 minutes and concentrated. The residue was dissolved in MeOH (2.0 mL) and added to EtOAc with vigorous stirring to precipitate the HCl salt product as tan solid which was collected by vacuum-filtration, rinsed with EtOAc, and further dried to give 1.24 g (82%) of 2-Chloro-N-(3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide: 1H NMR (CD3OD) δ 2.27 (s, 3H), 4.09 (s, 2H), 4.29 (s, 2H), 7.07 (d, 1H), 7.51 (m, 2H), 7.60 (d, 1H), 7.70 (s, 1H), 7.78 (d, 1H), 8.05 (d, 1H), 8.32 (m, 2H), 8.67 (s, 1H), 8.75 (s, 1H); MS m/z (MH+) 458.0.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13].[OH-].[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O>[CH2:23]([O:22][C:20]([NH:13][C@H:12]([C:14]([OH:16])=[O:15])[CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(N[C@@H](Cc1ccc2ccccc2c1)C(=O)O)OCc1ccccc1
Reaction time: 2 h

Procedure:
5 g of 3-(2-naphthyl)-L-alanine and 0.93 g of sodium hydroxide in 12 ml of water were cooled to 0° C. and stirred while a solution of 1.4 g of sodium hydroxide in 9 ml of water and 5 ml of benzyl chloroformate were added simultaneously during 10 minutes. Stirring was continued for 2 hours and the mixture was allowed to come to room temperature. The mixture was diluted with water and then extracted with diethyl ether. The aqueous layer was acidified with 4 ml of concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extracts were back-washed with water. The combined ethyl acetate extracts were dried over sodium sulphate, filtered, evaporated and triturated with petroleum ether (boiling point 40°-60° C.) to give 7.5 g of N-(benzyloxycarbonyl)-3-(2-naphthyl)-L-alanine of melting point 109°-111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([OH:18])=O)[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:19][C:20]1[CH:21]=[C:22]([C:30]([O:32][CH3:33])=[O:31])[CH:23]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:19][C:20]3[CH:21]=[C:22]([C:30]([O:32][CH3:33])=[O:31])[CH:23]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:25]=3)=[O:18])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: Cc1c(C(=O)O)nnn1Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)cc(C(=O)OC)c1
Temperature: 45 °C
Reaction time: 24 h

Procedure:
A mixture of 1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (Intermediate 11) (0.4 g, 1.3 mmol), dimethyl 5-amino-1,3-benzenedicarboxylate (0.29 g, 1 eq), HATU (0.69 g, 1.3 eq) and DIPEA (0.34 mL, 1.3 eq) in DMF (10 mL) was stirred at 45° C. for 24 hours. The solvent was evaporated and the residue was washed with water and extracted with DCM. The organic phase was dried over sodium sulphate and concentrated. The title compound was obtained as a white solid (650 mg, 95%) after recrystallisation from acetonitrile. LC/MS: m/z 477 (M+H)+, Rt: 3.81 min.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[N:15]1[CH:20]=[C:19](B(O)O)[CH:18]=[N:17][CH:16]=1>>[C:9]1([C:6]2[N:5]=[CH:4][C:3]([CH2:2][C:19]3[CH:20]=[N:15][CH:16]=[N:17][CH:18]=3)=[CH:8][N:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1cncnc1
Reactant: BrCc1cnc(-c2ccccc2)nc1
Product: c1ccc(-c2ncc(Cc3cncnc3)cn2)cc1
Reaction time: 0.5 h

Procedure:
Synthesized using compound 64a (102 mg, 0.41 mmol) and pyrimidine-5-boronic acid (76 mg, 0.61 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (1:2) as eluent. After flash chromatography the product was solved in ethyl acetate and a few drops of conc. HCl and water were added. After stirring for 30 minutes the phases were separated and water phase was neutralized with aqueous Na2CO3-solution (2M). After extraction with ethyl acetate and drying over MgSO4 the solvent was removed under vacuum. White solid. Yield: 41 mg, 40%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=4.00 (s, 2H), 7.46-7.55 (m, 3H), 8.39-8.47 (m, 2H), 8.63-8.71 (m, 4H), 9.15 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=31.1, 128.1, 128.6, 129.1, 130.9, 132.2, 137.0, 156.9, 157.2, 157.6, 163.7; (ESI): m/z=248.83 [M+H]+.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[C:8]([C:12]1[CH:19]=[CH:18][C:15](C=O)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].N1CCCCC1.Cl>N1C=CC=CC=1>[C:8]([C:12]1[CH:19]=[CH:18][C:15](/[CH:1]=[CH:2]/[C:3]([OH:5])=[O:4])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C(O)CC(=O)O
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(/C=C/C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48051.9 %

Procedure:
19.20 g (0.185 mol) of malonic acid were dissolved in pyridine (33 ml) and stirred for 15 minutes at RT. 25.00 g (0.154 mmol) of para-tert.-butylbenzaldehyde and 1.50 ml (0.020 mol) of piperidine were then added. The reaction mixture was heated for 8 hours at 100° C., with stirring. After pouring the reaction solution into a mixture of concentrated hydrochloric acid and ice, stirring was continued for a further two hours at room temperature. The resulting precipitate was filtered out with suction. Recrystallisation of the precipitate from methanol yielded 15.20 g (0.074 mol, 48% of theory) of para-tert.-butyl-trans-cinnamic acid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=2)[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1cccc(C2CCN(C(=O)c3cnc4c(C(=O)O)cnn4c3NCc3ccccc3)CC2)c1
Product: Cc1cccc(C2CCN(C(=O)c3cnc4c(C(=O)NS(C)(=O)=O)cnn4c3NCc3ccccc3)CC2)c1
Yield: 38.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(3-methylphenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.09 g, 0.19 mmol) obtained in step 2 and methanesulfonamide (0.090 g, 0.950 mmol), the title compound (0.04 g, 38%) was obtained.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][NH2:11])[CH3:8])([CH3:4])[CH3:3].Cl[C:14]1[N:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1.C(N(CC)C(C)C)(C)C.C([O-])([O-])=O.[K+].[K+]>>[CH3:4][C:2]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][NH:11][C:14]1[N:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1)[CH3:8])([CH3:1])[CH3:3]
Reactant: Clc1ncc(Br)cn1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCNc1ncc(Br)cn1)C(=O)OC(C)(C)C
Yield: 72.5 %

Procedure:
The title compound (2.40 g, 73%) was prepared from (2-amino-ethyl)-methyl-carbamic acid dimethyl-ethyl ester (1.74 g, 10 mmol), 2-chloro-5-bromo-pyrimidine (1.93 g, 10 mmol), N,N-diisopropylethylamine (3.87 g, 30 mmol) and K2CO3 (2.76 g, 20 mmol) according to the procedure described for Description 1.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[CH3:24][O:25][C:26](=[O:30])[CH2:27][C:28]#[N:29].[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:24][O:25][C:26](=[O:30])[CH2:27][C:28]1[N:29]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)[C:3]2[C:2](=[CH:19][C:18]([O:20][CH3:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[N:1]=1
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: COC(=O)CC#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: COC(=O)Cc1nc(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2n1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (6.3 g) and cyanoacetic acid methyl ester (23 ml), powdered aluminum chloride (5.3 g) was added, followed by stirring at 100° C. for 2.5 hours. The reaction mixture was poured over water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (4:1, v/v) to yield 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinazoline-2-acetic acid methyl ester (4.4 g, 55%), which was then recrystallized from isopropyl ether to yield a colorless needle crystal having a melting point of 152° to 153° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12]Br.[CH3:14][OH:15]>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:15][CH3:14]
Reactant: CO
Reactant: COC(=O)c1ccc(Br)c(CBr)c1
Product: COCc1cc(C(=O)OC)ccc1Br
Yield: 94 %

Procedure:
A solution of methyl 4-bromo-3-(bromomethyl)benzoate (38 g; 122 mmol) in MeOH (1.1 L) was refluxed for 4 days. After concentration, the mixture was partitioned between EtOAc (500 mL) and water (200 mL). The organic layer was washed with a 5% NaHCO3 aqueous solution (200 mL), brine (200 mL), dried over MgSO4 and concentrated affording the title compound as a beige solid (30 g, 94%). 1H NMR (DMSO-d6, 300 MHz) δ 8.06-8.05 (m, 1H), 7.83 (m, 2H), 4.54 (m, 2H), 3.90 (s, 3H), 3.45 (s, 3H). LC/MS (Method B): 227.2 (M−H)−. HPLC (Method A) Rt 4.42 min (Purity: 93.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([N+:24]([O-])=O)=[C:13]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=2)=[CH:5][CH:4]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:24][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]2[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:14][C:13]=1[CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: COc1ccc(COc2ccc([N+](=O)[O-])c(CNC(=O)OC(C)(C)C)c2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1ccc(COc2ccc(N)c(CNC(=O)OC(C)(C)C)c2)cc1
Yield: 100.1 %

Procedure:
A solution of tert-butyl {5-[(4-methoxybenzyl)oxy]-2-nitrophenyl}methylcarbamate produced in Example (1a) (209 g, 538 mmol), iron powder (150 g, 2.69 mol) and ammonium chloride (15.0 g, 280 mmol) in ethanol (1.2 L) and water (1 L) was stirred with heating under reflux for five hours. After leaving to cool, the reaction mixture was filtered through celite. The filtrate was concentrated to about half volume under reduced pressure, and the concentrated residue was extracted with toluene (1 L) twice. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (193 g, 99%) as a brown oil.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1.[N-:25]=[N+:26]=[N-:27].[Na+].CN(C=O)C>O>[N:25]([C:7]1[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:20])([F:22])[F:21])[N:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+:26]=[N-:27]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1N=[N+]=[N-]
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A mixture of 15.13 g (0.040 mol) of product of Example 27, 2.85 g (0.040 mol) of sodium azide and 175 ml of DMF was stirred for 1 hour and poured into 500 ml of water. The mixture was extracted with ether. The ether was extract was washed several times with water, dried (MgSO4) and concentrated to give 14.4 g (93.7%) of product; mp 46°-47° C.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[S:24][C:23]3[C:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:21][C:20]([C:31]4[CH:39]=[CH:38][CH:37]=[C:36]5[C:32]=4[CH:33]=[CH:34][NH:35]5)=[N:19][C:18]=3[CH:17]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>>[NH:35]1[C:36]2[C:32](=[C:31]([C:20]3[N:21]=[C:22]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)[C:23]4[S:24][C:16]([CH2:15][N:12]5[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]5)=[CH:17][C:18]=4[N:19]=3)[CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:34]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc3nc(-c4cccc5[nH]ccc45)nc(N4CCOCC4)c3s2)CC1
Agent: Cl
Product: c1cc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)c2cc[nH]c2c1

Procedure:
Via ethereal HCl-mediated BOC-group cleavage of 4-[2-(1H-Indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]piperazine-1-carboxylic acid tert-butyl ester.