Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](O)=[O:4].B.C1COCC1>C1COCC1>[C:7]1([CH2:6][C@@H:2]([OH:1])[CH2:3][OH:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)[C@H](O)Cc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: OC[C@H](O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of (R)-2-hydroxy-3-phenylpropanoic acid (5.0 g, 30.0 mmol) in 100 mL of anhydrous THF was added slowly BH3.THF complex (90 mL, 1M in THF, 3.0 equiv.) with ice cooling under N2. The solution was stirred overnight at room temperature, and the reaction was quenched with water (Caution, copious H2 evolution). After evaporation of the solvent, the residue was diluted with water and extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford (R)-3-phenylpropane-1,2-diol (4.3 g, 94%) as a colorless oil. LC-MS (ESI) m/z 153 (M+H+). 1H NMR (CDCl3, 300 MHz) δ 7.37-7.23 (m, 5H), 4.02-3.94 (m, 1H), 3.74 (dd, 1H, J=11.1, 3.3 Hz), 3.54 (dd, 1H, J=11.1, 6.9 Hz), 2.85-2.74 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[C:22]([F:25])([F:24])[F:23])=[N:16][C:12]=3[CH:11]=[C:10]([C:34]#[N:35])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[N-:36]=[N+:37]=[N-:38].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:28][CH2:29][C@H:30]([CH3:33])[CH2:31][CH2:32]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[C:22]([F:24])([F:23])[F:25])=[N:16][C:12]=3[CH:11]=[C:10]([C:34]3[NH:38][N:37]=[N:36][N:35]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(F)(F)F)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(F)(F)F)nc3cc(-c4nnn[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 120 °C

Procedure:
A vial equipped with a stir bar was charged with 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Example 3.3, Step 1) (67 mg, 0.133 mmol), sodium azide (87 mg, 1.332 mmol), and ammonium chloride (72.0 mg, 1.345 mmol). DMF (1.3 mL) was added, and the mixture was degassed with N2. The vial was then sealed and heated at 120° C. for 16 hours. The reaction was then cooled to room temperature, diluted with EtOAc, and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by mass triggered reverse phase HPLC (C-18), eluting with acetonitrile/water containing 0.1% TFA afforded 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(1H-tetrazol-5-yl)-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine (TFA salt). MS ESI calc'd. for C25H27ClF3N9 [M+H]+ 546. found 546. 1H NMR (600 MHz, CD3OD) δ 8.86 (d, J=1.5, 1H), 8.74 (d, J=2.2 Hz, 1H), 8.38 (t, J=2.1 Hz, 1H), 8.26 (s, 1H), 5.36-5.27 (m, 1H), 3.92 (dd, J=9.0, 14.7 Hz, 1H), 3.87-3.79 (m, 1H), 3.73-3.66 (m, 1H), 3.61 (dd, J=5.5, 14.7 Hz, 1H), 2.48-2.36 (m, 1H), 2.21-2.10 (m, 2H), 2.08-1.98 (m, 1H), 1.45 (dd, J=1.4, 11.7 Hz, 2H), 1.23-1.13 (m, 1H), 1.13-1.04 (m, 1H), 1.02-0.94 (m, 1H), 0.72 (d, J=6.6 Hz, 3H), 0.71-0.56 (m, 3H), 0.57-0.46 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=1)([O-:3])=[O:2].[CH3:13]N(C)C=O.CI.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:13][N:7]1[C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[N:8]1
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)c1cc([N+](=O)[O-])nn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with methyl 5-nitro-1H-pyrazole-3-carboxylate (156a) (0.94 g, 5.5 mmol), anhydrous N,N-dimethylformamide (11 mL), methyl iodide (0.85 g, 6 mmol) and potassium carbonate (0.83 g, 6.1 mmol). The reaction was stirred at room temperature for 16 h. After this time the reaction was diluted with water (40 mL) and extracted with methylene chloride (3×25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was subjected to flash chromatography (silica, ethyl acetate/hexanes) to afford methyl 1-methyl-3-nitro-1H-pyrazole-5-carboxylate 156b in 66% yield (0.67 g) as a white solid: MS (ESI+) m/z 186.0 (M+H). Also isolated was the regioisomer methyl 1-methyl-5-nitro-1H-pyrazole-3-carboxylate in 15% yield (0.15 g) as a white solid: MS (ESI−) m/z 186.0 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:17]3[C:12]([C:13]([NH2:18])=[N:14][CH:15]=[N:16]3)=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:35](Cl)(=[O:37])[CH3:36]>>[NH2:18][C:13]1[C:12]2=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=[C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[CH2:2][NH:1][C:35](=[O:37])[CH3:36])[N:17]2[N:16]=[CH:15][N:14]=1
Reactant: NCc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Reactant: CC(=O)Cl
Product: CC(=O)NCc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Yield: 6 %

Procedure:
Using a procedure similar to that of Example 5 with 7-(3-aminomethyl-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and acetyl chloride as starting materials, 13 mg (6%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d5) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 4.10 (d, 2 H), 1.90 (s, 3 H); ES-MS m/z 488.4 [M+H]+, HPLC RT (min) 2.69.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)=[CH:6][CH:7]=[N:8]2.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:35](=[O:36])[C:34]([C:37](O)=[O:38])=[CH:33][N:32]([CH2:40][CH3:41])[C:31]2=[O:42])=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:37]([C:34]3[C:35](=[O:36])[N:30]([C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)[C:31](=[O:42])[N:32]([CH2:40][CH3:41])[CH:33]=3)=[O:38])=[CH:18][CH:17]=1)=[CH:6][CH:7]=[N:8]2
Reactant: COc1cc(OC)c2c(Oc3ccc(N)cc3)ccnc2c1
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)cc(OC)c34)cc2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [4-(5,7-dimethoxyquinolin-4-yloxy)-phenyl]-amide was synthesized using 4-(5,7-dimethoxyquinolin-4-yloxy)phenylamine and 3-(4-fluorophenyl)-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid by the method for example 38. mp=128-9° C.; LCMS m/z=557 (M+1); 1H NMR (DMSO) δ: 10.87 (s, 1H), 8.85 (s, 1H), 8.52 (m, 1H), 7.72 (m, 2H), 7.33-7.41 (m, 4H), 7.07 (m, 2H), 6.99 (m, 1H), 6.63 (m, 1H), 6.49 (m, 1H), 4.01 (m, 2H), 3.90 (s, 3H), 3.81 (s, 3H), 1.28 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C1(C)C=CC=CC=1.S(Cl)([Cl:26])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:10]=1[O:11][CH3:12])[C:5]([Cl:26])=[O:6]
Reactant: COc1c(Cl)cc(C(=O)O)cc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1c(Cl)cc(C(=O)Cl)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-chloro-4-methoxy-5-trifluoromethylbenzoic acid (300 mg), toluene (3 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.13 mL) were added, and the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (e).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([NH:13][CH:14]=[O:15])[CH3:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([NH:13][CH:14]=[O:15])[CH3:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(Cc1cccc([N+](=O)[O-])c1)NC=O
Agent: [Ni]
Solvent: CO
Product: CC(Cc1cccc(N)c1)NC=O

Procedure:
5.2 gm of 1-(3'-nitro-phenyl)-2-formylamino-propane was hydrogenated in methanol in the presence of Raney nickel at atmospheric pressure and room temperature. Thereafeter, the catalyst was filtered off, the solvent was evaporated from the filtrate, and the residue was chromatographed on a silicagel column, using methanol/chloroform (2:8) as the flow agent. The eluate was evaporated, and the residue was recrystallized from ethyl acetate, yielding 1-(3'-amino-phenyl)- 2-formylamino-propane which had a melting point of 107°-108° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH:22]([CH3:24])[CH3:23])[CH:14]=2)=[CH:9][CH:8]=1.[OH-].[Na+].CN([CH:30]=[O:31])C>O>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH:22]([CH3:24])[CH3:23])[C:14]=2[CH:30]=[O:31])=[CH:9][CH:8]=1
Reactant: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)n1c(C=O)c(-c2ccc(F)cc2)c2ccccc21
Temperature: 3 °C
Reaction time: 1.5 h

Procedure:
5.77 g (78.96 mmol) of DMF are weighed into a 100 ml three-necked round-bottomed flask, equipped with a magnetic stirrer, thermometer, dropping funnel, reflux condenser and nitrogen delivery line, and cooled, with stirring, to 3° C. 12.11 g (78.96 mmol) of phosphorus oxychloride are then slowly added dropwise so that the internal temperature does not exceed 10° C. The reaction mixture is then heated to 80° C. and 10 g (39.48 mmol) of 3-(4-fluorophenyl)-1-isopropyl-1H-indole, dissolved in 10 ml of DMF, are added dropwise in the course of 30 min. Stirring is subsequently carried out for 1.5 hours at that temperature. Cooling and dilution with 10 ml of DMF are then carried out. The reaction mixture is transferred into a dropping funnel and, with stirring, slowly added dropwise at 40° C. to 10 g (0.25 mol) of sodium hydroxide in 200 ml of water. The aqueous phase is extracted four times with 50 ml of toluene and the combined organic phases are washed six times with 100 ml of water. Subsequently, 10 g of silica gel are added, the mixture is stirred for 1 hour and filtration is carried out, followed by washing three times with 50 ml of toluene and concentration by evaporation. 10.17 g of a brown oil are obtained, which is dissolved in 100 ml of hexane under reflux. 10 g of silica gel are added, and filtration is carried out while hot, followed by washing three times with 50 ml of hot hexane. The filtrate is concentrated by evaporation and the residue is recrystallised from 94% ethanol. Slightly beige crystals having a melting point of from 89.5 to 91° C. are obtained.
Reaction SMILES: [OH-].[K+].O.[Br:4][C:5]1[N:25](S(C2C=CC=CC=2)(=O)=O)[C:8]2=[N:9][CH:10]=[C:11]([CH2:13][CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)[N:12]=[C:7]2[CH:6]=1>C1COCC1>[Br:4][C:5]1[NH:25][C:8]2=[N:9][CH:10]=[C:11]([CH2:13][CH2:14][C:15]3[CH:16]=[C:17]([O:23][CH3:24])[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=3)[N:12]=[C:7]2[CH:6]=1
Reactant: COc1cc(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
6.0 M Potassium hydroxide in water (0.50 mL, 3.0 mmol) was added to a solution of 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (0.5 g, 0.9952 mmol) (from Example 1, Step 4) in THF (10 mL) and then the mixture was stirred at 70° C. for 3 hours. Most of the solvent was removed and the residue was treated with saturated ammonium chloride. The formed precipitate was filtered, washed with water, and dried to provide the desired product (0.34 g, 94%). LCMS calculated for C16H17BrN3O (M+H)+: m/z=362.0. Found 362.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:12].O1CCOCC1.[C:19](=O)([O-:21])[O-:20].[Na+].[Na+]>O>[Cl:11][C:9]1[CH:10]=[C:2]([C:19]([OH:21])=[O:20])[CH:3]=[C:4]2[C:8]=1[NH:7][N:6]=[C:5]2[CH3:12]
Reactant: Cc1n[nH]c2c(Cl)cc(Br)cc12
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1n[nH]c2c(Cl)cc(C(=O)O)cc12
Temperature: 165 °C
Reaction time: 0.01 h
Yield: 80.4 %

Procedure:
A microwave tube was charged with 5-bromo-7-chloro-3-methyl-1H-indazole (610 mg, 2.48 mmol), dioxane (5 mL), Hermann's catalyst (119 mg, 0.12 mmol) and a solution of sodium carbonate (790 mg, 7.46 mmol) in water (10 mL). The mixture was stirred for 20 sec, heated at 165° C. for 30 minutes in a microwave reactor at very high absorption setting. The reaction was vented before handling. The mixture was filtered through diatomaceous earth and washed with EtOAc. The filtrate was concentrated, the residue was dissolved in water and acidified to pH ˜3 with conc HCl. The solids were collected by filtration and dried to afford the title compound (420 mg, 82%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[S:13][C:14]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]([CH3:22])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[CH3:22][C:17]1[C:15]2[N:16]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[S:13][C:14]=2[C:20]([CH3:21])=[CH:19][CH:18]=1
Reactant: C#CCCc1nc2c(C)ccc(C)c2s1
Reactant: Brc1ccccn1
Product: Cc1ccc(C)c2sc(CCC#Cc3ccccn3)nc12
Yield: 17.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (46 mg, 0.29 mmol) and 2-but-3-ynyl-4,7-dimethyl-benzo[d]thiazole (63 mg, 0.29 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 15 mg (52 μmol, 18%) of 4,7-dimethyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][NH:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][N:22]([C:37]([CH:34]4[CH2:36][CH2:35]4)=[O:38])[CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc2c(c1Nc1ccnc3[nH]c4c(c13)CNCC4)OCO2
Reactant: O=C(Cl)C1CC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1CC1)N1CCc2[nH]c3nccc(Nc4c(Cl)ccc5c4OCO5)c3c2C1
Temperature: 25 °C
Yield: 35.3 %

Procedure:
(5-Chloro-benzo[1,3]-dioxol-4-yl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (100 mg, 0.29 mmol) and DIEA (0.15 mL, 0.88 mmol) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature. Cyclopropanecarbonyl chloride (0.03 mL, 0.35 mmol) was added dropwise, and the reaction was stirred for 1 h at room temperature. The reaction was concentrated. The crude material was dissolved in DMSO (3 mL) and filtered. The filtrate was purified directly via prep-LC-MS to provide 68 (42 mg, 35% yield) as a white fluffy solid. LC-MS (M+H=411, obsd.=411).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7]O)=[CH:5][C:4]([CH3:9])=[N:3]1.S(Cl)([Cl:12])=O>>[Cl:12][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(CO)n(C)n1
Product: Cc1cc(CCl)n(C)n1

Procedure:
The title compound was prepared analogously to example 48b starting from (2,5-dimethyl-2H-pyrazol-3-yl)-methanol (778 mg) and thionyl chloride (2.35 ml). Yield: 900 mg.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([Sn:24]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:29][CH2:30][CH2:31][CH3:32])/[CH:25]=[CH:26]\[CH2:27]O)[CH2:21][CH2:22][CH3:23].C(Br)(Br)(Br)[Br:38]>C(Cl)Cl>[Br:38][CH2:27]/[CH:26]=[CH:25]\[Sn:24]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCC[Sn](/C=C\CO)(CCCC)CCCC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCC[Sn](/C=C\CBr)(CCCC)CCCC
Reaction time: 2.5 h
Yield: 160.6 %

Procedure:
A solution of triphenylphosphine (5.32 g) in DCM (60 mL) was added to a solution of (Z)-3-tributylstannanylprop-2-en-1-ol (Intermediate 4, 6.4 g) and carbon tetrabromide (9.18 g) in DCM (60 mL) and the mixture was stirred for 2.5 hours. The mixture was evaporated to low volume and pentane was added. The solids were removed by filtration and the filtrate was evaporated to dryness. Pentane was added and the solids were again removed by filtration and the filtrate was evaporated to dryness to give ((Z)-3-bromoprop-1-enyl)tributylstannane (12.14 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]([CH3:15])[C:12](O)=[O:13])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:34][NH2:35]>C(Cl)Cl>[OH:34][NH:35][C:12](=[O:13])[CH:11]([CH3:15])[CH:10]([S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(SC(CCCCc2ccccc2)C(C)C(=O)O)cc1
Reactant: C[Si](C)(C)ON
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(SC(CCCCc2ccccc2)C(C)C(=O)NO)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
(±)-3-(4-Methoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid (0.38 g, 1.1 mmol) is dissolved in CH2Cl2 (1 mL) and cooled to 0° C. A solution of oxalyl chloride in CH2Cl2 (0.7 mL, 1.4 mmol) is added dropwise, the bath removed and the reaction allowed to warm and stir at 23° C. for 3 hours. The reaction is then concentrated in vacuo and azeotroped with CHCl3. The resulting oil is dissolved in CH2Cl2 (3 mL), cooled to 0° C. and O-(trimethylsilyl)hydroxylamine (0.4 mL, 3.4 mmol) is added dropwise. The bath is removed and the reaction is allowed to warm to 20° C. The reaction is then partitioned between CH2Cl2 (20 mL) and 1 N HCl (10 mL). The organic layer is then separated and washed with water (10 mL), dried (MgSO4) and concentrated in vacuo to yield (±)-3-(4-methoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid hydroxyamide (0.37 g, 90%) which is used without further purification: 1H NMR (300 MHz, CDCl3) δ 7.30-7.18 (m, 4H), 7.14-7.07 (m, 3H), 7.80-7.73 (m, 2H), 3.73 (s, 1.5H), 3.72 (s, 1.5H), 3.12-3.06 (m, 0.5H), 2.97-2.90 (m, 0.5H), 2.53 (m, 2H), 2.32-2.19 (m, 1H), 1.68-1.25 (m, 6H) 1.16 (d, J=7.0 Hz, 1.5H), 1.11 (d, J=7.0 Hz, 1.5H); MS (FAB) m/e 374 (M+H)+.
Reaction SMILES: [NH2:1][OH:2].[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([Br:13])[C:11]=1[OH:12])[C:7]#[N:8]>O.C(O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([Br:13])[C:11]=1[OH:12])[C:7](=[N:1][OH:2])[NH2:8]
Reactant: N#Cc1cc(Br)c(O)c(Br)c1
Reactant: NO
Solvent: O
Solvent: CCO
Product: NC(=NO)c1cc(Br)c(O)c(Br)c1
Temperature: 25 °C
Yield: 75 %

Procedure:
Hydroxylamine (10 mL of a 50% solution in water) was added in one portion to a stirred suspension of 3,5-dibromo-4-hydroxybenzonitrile (30 g, 110 mmol) in ethanol (100 mL) at room temperature and the mixture was heated to reflux for 3 hours before cooling back down to room temperature. The solid was filtered, washed with cold ethanol and dried to yield the title compound (25.5 g, 75%) as a colourless powder. 1H NMR δ (ppm) (DMSO-d6): 5.92 (2 H, br s), 7.87 (2 H, s), 9.69 (1 H, br s), 10.19 (1 H, br s).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([F:16])=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CN(C=O)C>[F:16][C:9]1[C:8]([C:5]2[CH:4]=[N:3][C:2]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:7][CH:6]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:14][OH:15]
Reactant: OCc1cccc(-c2cnc(Cl)nc2)c1F
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Product: OCc1cccc(-c2cnc(N3CCNCC3)nc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
[3-(2-Chloropyrimidin-5-yl)-2-fluorophenyl]methanol (600 mg) was mixed with DMF (12 ml), and piperazine (2.2 g) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by stirring at 0° C. for 1 hour. The produced solid was collected by filtration, washed with water, and then dried at 50° C. under reduced pressure to obtain {2-fluoro-3-[2-(piperazin-1-yl)pyrimidin-5-yl]phenyl}methanol (697 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][S:9][CH:8]=2)=[N:4][N:3]=1.CC(N=NC(C#N)(C)C)(C#N)C.C([O-])(=O)C.[Na+].C1C(=O)N([Br:43])C(=O)C1>C(O)(=O)C.C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][Br:43])=[CH:14][CH:13]=3)=[CH:10][S:9][CH:8]=2)=[N:4][N:3]=1
Reactant: Cc1ccc(-c2cscc2-c2nnc(C)o2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: Cc1nnc(-c2cscc2-c2ccc(CBr)cc2)o1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
5-Methyl-2-(4-(4-methylphenyl)-3-thienyl)-[1,3,4]oxadiazole (3.4 g, 13.3 mmol) was dissolved into carbontetrachloride (60 ml). AIBN (0.21 g), sodium acetate (0.52 g), NBS (2.6 g, 14.6 mmol) and glacial acetic acid (0.52 ml) were added. The reaction mixture was heated at reflux temperature for 8h and then allowed to cool to ambient temperature. The reaction mixture was filtered through silica gel and the filtrate was evaporated in vacuo. The oily residue was dried in vacuo over sodium hydroxide to give 2.6 g of crude 5-methyl-2-(4-(4-bromomethylphenyl)-3-thienyl)- [1,3,4]oxadiazole.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[C:11]([CH3:25])=[C:12]([NH:17][C:18]([NH:20][C:21](=[NH:24])[NH:22][CH3:23])=[O:19])[C:13]([CH3:16])=[CH:14][CH:15]=1)C1C=CC=CC=1.Cl.CO>C(O)C.[Pd]>[ClH:1].[CH3:25][C:11]1[C:10]([OH:9])=[CH:15][CH:14]=[C:13]([CH3:16])[C:12]=1[NH:17][C:18]([NH:20][C:21](=[NH:24])[NH:22][CH3:23])=[O:19]
Reactant: CNC(=N)NC(=O)Nc1c(C)ccc(OCc2ccccc2)c1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CNC(=N)NC(=O)Nc1c(C)ccc(O)c1C
Reaction time: 0.75 h

Procedure:
1-(3-benzyloxy-2,6-dimethylphenyl)-3-methylamidinourea hydrochloride (18.2 g) and 5% Pd/C (1.0 g) in absolute ethanol (200 ml) containing HCl/methanol (50 ml) are shaken under an atmosphere of H2 (50 psi) for 45 minutes. The reaction mixture is filtered through Celite and the filtrate is concentrated. in vacuo. The resulting solid is crystallized from methanol/acetonitrile to give after drying 12.3 grams of the desired amidinourea hydrochloride salt as a white powder, M.P. 224°-5° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:27]([CH3:29])([CH3:28])[CH2:26][CH2:25][N:13]3[C:14](=[O:24])[C:15]=2[O:16]CC2C=CC=CC=2)=[O:9])=[C:4]([C:32](=[O:35])[NH:33][CH3:34])[CH:3]=1.FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:27]([CH3:29])([CH3:28])[CH2:26][CH2:25][N:13]3[C:14](=[O:24])[C:15]=2[OH:16])=[O:9])=[C:4]([C:32](=[O:35])[NH:33][CH3:34])[CH:3]=1
Reactant: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCC2(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1O)CCC2(C)C

Procedure:
Intermediate 7, N-(4-fluoro-2-(methylcarbamoyl)benzyl)-3-(benzyloxy)-8,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-2-carboxamide was treated with trifluoroacetic acid, according to Method D to provide the title compound 1H NMR (300 MHz, CDCl3) δ ppm: 12.12 (1H, br), 8.71 (1H, br), 7.47 (1H, dd, J=8.1, 5.5 Hz), 7.05–7.2 (2H, m), 6.26 (1H, br), 4.59 (2H, d, J=6.6 Hz), 3.95–4.06 (2H, m), 3.00 (3H, d, J=4.8 Hz), 1.99–2.08 (2H, m), 1.31 (6H, s); HRMS (ESI) calcd for C19H22FN4O4(M+H) 389.1625, found 389.1625.