Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C(NC(C)C)(C)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][OH:28])=[CH:21][CH:20]=1.[Cl-].[NH4+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:19]1([CH3:29])[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][O:28][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])=[CH:23][CH:24]=1
Reactant: Cc1ccc(CCCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: Cc1ccc(CCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 6 h
Yield: 66.1 %

Procedure:
2.46 g of tosyl chloride (13 mmol), 3.4 ml of diisopropylamine (19.4 mmol) and 158 mg of 4-(dimethylamino)pyridine (1.29 mmol) were added to reaction solution (6.46 mmol) dissolving 971 mg of 3-p-tolyl-propane-1-ol (40ac) prepared by above step 3 in methylene chloride at 0° C. under Ar atmosphere with stirring for 6 hrs, and the reaction mixture was stirred for 12 hrs at room temperature. After the reaction mixture was neutralized with ammonium chloride, the mixture was extracted with ethyl acetate, washed with saturated NaCl solution, dried over MgSO4, filtered, and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:7) as an eluant to give 1.3 g of toluene-4-sulfonate-3-p-tolyl-propyl ester (40ad) (yield: 70%).
Reaction SMILES: [Na].FC(F)(F)S(O[C:8]1[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][C:11]([Cl:17])=[C:10]([CH3:18])[C:9]=1[Br:19])(=O)=O.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>O.C1(C)C=CC=CC=1.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:19][C:9]1[C:8]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([F:22])[CH:28]=2)=[C:13]([C:14](=[O:16])[CH3:15])[CH:12]=[C:11]([Cl:17])[C:10]=1[CH3:18]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Cl)c(C)c(Br)c1-c1cccc(F)c1
Temperature: 80 °C
Yield: 90.1 %

Procedure:
To a solution of sodium hydrogenecarbonate (0.21 g, 2.5 mmol) in water (5 mL) was added a solution of 6-acetyl-2-bromo-4-chloro-3-methylphenyl trifluoromethanesulfonate (0.50 g, 1.3 mmol) in toluene (5 mL) followed by (3-fluorophenyl)boronic acid (0.21 g, 1.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.065 mmol). The mixture was bubbled with N2 for 5 min and then heated at 80° C. overnight. The reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated and purified on silica gel (eluting with 0-20% of ethyl acetate in hexanes) to give the desired product (0.40 g, 93%). LCMS calculated for C15H12BrClFO (M+H)+: m/z=341.0. found: 341.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Yield: 68.7 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (80 mg, 0.26 mmol), 3-(trifluoromethyl)benzoic acid (54 mg, 0.29 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (55 mg, 0.29 mmol), 1-hydroxybenzotriazole (39 mg, 0.29 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 318, the title compound (86 mg, 69%) was obtained as a white powder.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:16]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[N:15]=[CH:14][CH:13]=1.[Br:23]N1C(=O)CCC1=O>ClCCl>[Br:23][C:13]1[CH:14]=[N:15][N:16]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:12]=1[C:3]1[C:4]([F:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccnn2C2CCCCO2)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)c(-c2c(Br)cnn2C2CCCCO2)c1F

Procedure:
A solution of 5-(2,6-difluoro-3-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1.23 g, 4 mmol) and N-bromosuccinimide (1.25 g, 7 mmol) in dichloromethane (10 mL) was stirred at room temperature for 18 h. The solution was washed with water, dried over anhydrous sodium sulfate and concentrated. Crude 4-bromo-5-(2,6-difluoro-3-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole was obtained.
Reaction SMILES: CN(C)[CH:3]=[O:4].O=P(Cl)(Cl)Cl.[CH2:11]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>O>[CH2:11]([C:17]1[S:18][C:19]([CH:3]=[O:4])=[CH:20][CH:21]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCc1cccs1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCCCCCc1ccc(C=O)s1
Temperature: 5 °C
Yield: 85 %

Procedure:
In a 3 liter-four-necked flask, 173.7 (2.38 mol) of N,N-dimethylformamide was placed and cooled to 5° C., followed by addition of 201.4 g (1.31 mol) of POCl3 in 15 min. below 10° C. under stirring. After stirring for 30 min. below 10° C., 200 g (1.19 mol) of 2-hexylthiophene was added dropwise to the mixture in 10 min. at room temperature, followed by stirring for 1.5 hours and further stirring for 2 hours at 60° C. After the reaction, the reaction mixture was poured into 5 liter of iced water, subjected to 3 times of extraction with 2 liter of chloroform and washed 6 times with 2 liter of water. The organic layer was dried with CaCl2, followed by distilling-off of the solvent and reduced-pressure distillation in an atmosphere of nitrogen to obtain 199.2 g of a product (yield: 85.0%). Then, 20 g of the product obtained was purified by silica gel column chromatography with the use of an n-hexane/ethyl acetate=20/1 mixture solvent to obtain 18.2 g of a pure product (yield: 91.0%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[C:9]([CH3:11])[NH:8][C:6]=2[N:7]=1.[CH:13]1([NH2:17])[CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH3:11])[NH:8][C:6]=2[N:7]=1
Reactant: Cc1cc2c(Cl)nc(Cl)nc2[nH]1
Reactant: NC1CCC1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Cc1cc2c(NC3CCC3)nc(Cl)nc2[nH]1
Yield: 44.9 %

Procedure:
A solution of 2,4-dichloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine (190 mg, 0.94 mmol), cyclobutylamine (0.160 mL, 1.88 mmol) and triethylamine (0.200 mL, 1.44 mmol) in nBuOH (6 mL) was stirred at 70° C. overnight. It was then purified by HPLC to give 2-chloro-N-cyclobutyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg).
Reaction SMILES: [N+:1]([C:4]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]=1[C:16]([OH:18])=O)([O-:3])=[O:2].[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:30]([NH2:36])[CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH3:20]>C1(C)C=CC=CC=1>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:30]([N:36]2[C:16](=[O:18])[C:5]3[C:6](=[CH:10][CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:4]=3[N+:1]([O-:3])=[O:2])[C:7]2=[O:9])[CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH3:20]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1C(=O)O
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Solvent: Cc1ccccc1
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3ccc([N+](=O)[O-])c([N+](=O)[O-])c3C2=O)ccc1OC
Yield: 48.8 %

Procedure:
A mixture of 3,4-dinitrophthalic acid (4.63 g, 18.1 mmol) and 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (4.94 g, 18.1 g) in toluene (70 mL) was heated to reflux for 15 hours. The water was removed by a Dean-Stark trap. To the reaction mixture was added ethyl acetate (150 mL). The organic layer was extracted with water, sodium hydrogen carbonate (sat), brine (100 mL each), and dried over magnesium sulfate. The solvent was removed in vacuo to give a solid. The solid was recrystallized from ethanol (300 mL) to give 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4,5-dinitroisoindoline-1,3-dione as an orange solid (4.35 g, 49% yield): mp, 122.0-124.0° C.; 1H NMR (CDCl3) δ1.47 (t, J=6.9 Hz, 3H, CH3), 2.93 (s, 3H, CH3), 3.65 (dd, J=3.9, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.10 (q, J=6.9 Hz, 2H, CH2), 4.56 (dd, J=11.4, 14.1 Hz, 1H, CHH), 5.90 (dd, J=3.9, 11.1 Hz, 1H, NCH), 6.84 (d, J=8.0 Hz, 1H, Ar), 7.07-7.11 (m, 2H, Ar), 8.16 (d, J=8.2 Hz, 1H, Ar), 8.60 (d, J=7.9 Hz, 1H, Ar); 13C NMR (CDCl3) δ14.66, 41.66, 49.57, 53.38, 55.98, 64.61, 111.61, 112.42, 120.64, 123.93, 126.18, 127.85, 131.93, 136.74, 138.10, 142.45, 148.77, 150.17, 161.57, 163.47; Anal Calcd for C20H19N3O10S+0.1 ethyl acetate: C, 48.78; H, 3.97; N, 8.37. Found: C, 48.50; H, 3.77; N, 8.07. (HNMR showed the sample contained ˜10% eq of ethyl acetate).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][NH:22][CH2:23][CH2:24][CH:25]1[O:30][CH2:29][CH2:28][NH:27][CH2:26]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]4[CH2:28][CH2:29][O:30][CH:25]([CH2:24][CH2:23][NH:22][CH3:21])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CNCCC1CNCCO1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Product: CNCCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCO1

Procedure:
By the use of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(2-methylaminoethyl)morpholine, the reaction is similarly carried out as Example 11 to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-[2-(2-methylaminoethyl)morpholino]-4-oxoquinoline-3-carboxylic acid 1/4 hydrate, melting at 243°-251° C. with decomposition.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Br:14][CH2:15][C:16](Cl)=[O:17]>>[Br:14][CH2:15][C:16]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:17]
Reactant: O=C(Cl)CBr
Reactant: CC(C)Nc1ccc([N+](=O)[O-])cc1
Product: CC(C)N(C(=O)CBr)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-isopropylamino-nitrobenzene and bromoacetyl chloride
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH:6]=[CH:7][C:8]=1[N:9]=[CH:10][N:11](C)C)#[N:2].Cl.Cl.[CH3:22][N:23]([CH3:31])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26](N)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.C(#N)C>[CH3:22][N:23]([CH3:31])[C:24]1[CH:25]=[C:26]([NH:2][C:1]2[C:3]3[C:8](=[CH:7][CH:6]=[C:5]([NH:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH:4]=3)[N:9]=[CH:10][N:11]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: CC#CC(=O)Nc1ccc(N=CN(C)C)c(C#N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC#CC(=O)Nc1ccc2ncnc(Nc3cccc(N(C)C)c3)c2c1
Yield: 58.5 %

Procedure:
A mixture of 2.54 grams (0.01 moles) of but-2-ynoic acid [3-cyano-4-(dimethylamino-methyleneamino)-phenyl]-amide, 2.40 grams (0.0115 moles) of N, N-dimethyl-1,3-phenylenediamine dihydrochloride, and 1.59 grams (0.0115 moles) of potassium carbonate in 2.5 mL of glacial acetic acid and 5 mL of acetonitrile was refluxed for an hour. On cooling the solid was filtered and recrystallized from methyl cellusolve to give 2.02 grams (58%) of the desired product, which melted at 252-254° C. MS M+H=346.1.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24](Cl)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH3:37][C:38]1[C:43]([NH2:44])=[CH:42][CH:41]=[C:40]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[CH3:51])[CH:39]=1>O1CCCC1>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([NH:44][C:43]4[CH:42]=[CH:41][C:40]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=5[CH3:51])=[CH:39][C:38]=4[CH3:37])=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2
Reactant: Cc1cc(-c2ccccc2C)ccc1N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccccc2C)ccc1NC(=O)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 10-[2-(4-chloro-phenoxy)-acetyl]-10,11-dihydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-3-carbonyl chloride of step B (0.415 mmol) in anhydrous tetrahydrofuran (3 mL) was added triethylamine (0.829 mmol) and 3,2′-dimethylbiphen-4-ylamine hydrochloride (0.415 mmol). The solution was stirred for 18 hours at ambient temperature. The solvent was evaporated, the residue was taken up in dichloromethane, washed with water, dried over anhydrous sodium sulfate, and evaporated. Chromatography on silica gel using 55:23:22 hexane/ethyl acetate/dichloromethane as eluant gave the title compound as an amorphous solid. This was crystallized from ethyl acetate/hexane to afford 0.17 g of the title product (71% yield), m.p. 159-161° C. MS [(+)ESI, m/z]: 576 [M+H]+ Anal. Calcd for C35H30CIN3O3: C, 72.97; H, 5.25; N, 7.29. Found: C, 72.59; H, 5.28; N, 7.24.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[N+:11]([O-:16])[CH:12]=[C:13](Br)[CH:14]=1.[C-:17]#[N:18].[Na+]>CN(C=O)C.O>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[N+:11]([O-:16])[CH:12]=[C:13]([C:17]#[N:18])[CH:14]=1
Reactant: CN1CCC[C@H]1COc1cc(Br)c[n+]([O-])c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC[C@H]1COc1cc(C#N)c[n+]([O-])c1

Procedure:
A sample of 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5bromo-pyridine-N-oxide, from Example 98a above, is reacted with sodium cyanide in DMF and water according to standard procedures. The solvents are removed, and the product is extracted, then purified by chromatography on silica gel.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:10]([CH3:11])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][N:7]=1.C1C(=O)N([Br:24])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:24][C:5]1[O:1][C:2]([C:6]2[C:10]([CH3:11])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][N:7]=2)=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1onc(-c2ccco2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1onc(-c2ccc(Br)o2)c1C
Yield: 21.6 %

Procedure:
Ethyl 3-(furan-2-yl)-4-methylisoxazole-5-carboxylate (5.8 g, 26.2 mmol), NBS (5.6 g, 31.5 mmol), and benzoyl peroxide (0.64 g, 2.62 mmol) were added to 150 mL of carbon tetrachloride and the mixture was refluxed for 16 h. Reaction mixture was filtered and concentrated. The residue was purified by flash chromatography (0-30% EtOAc/hexanes) to give 1.7 g of the title compound. MS: (+) m/z 300.31, 322.28 (M+1, 79Br/81Br).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[CH3:6][C:7]([C:10]1[C:15]([OH:16])=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:13]=[C:12]([NH:21][C:22]([NH2:24])=[S:23])[N:11]=1)([CH3:9])[CH3:8].O.C([O-])(O)=O.[Na+]>C(O)C>[CH3:9][C:7]([C:10]1[C:15]([OH:16])=[C:14]([C:17]([CH3:18])([CH3:20])[CH3:19])[N:13]=[C:12]([NH:21][C:22]2[S:23][CH:2]=[C:3]([CH3:4])[N:24]=2)[N:11]=1)([CH3:6])[CH3:8]
Reactant: CC(=O)CCl
Reactant: CC(C)(C)c1nc(NC(N)=S)nc(C(C)(C)C)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1csc(Nc2nc(C(C)(C)C)c(O)c(C(C)(C)C)n2)n1
Yield: 45 %

Procedure:
Chloroacetone (0.17 g, 1.9 mmol) is added to a solution of N-[4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]thiourea in 25 mL of ethanol. The reaction mixture is warmed to reflux for 18 hours. The solution is poured into 100 mL of water and the pH is adjusted to 4 with saturated NaHCO3. The resulting precipitate is collected by filtration. Recrystallization from hexane gives 0.26 g (45%) of 4,6-bis(1,1-dimethylethyl)-2-[(4-methyl-2-thiazolyl)amino]-5-pyrimidinol; mp 171°-173° C.
Reaction SMILES: C(=O)([O-])O.[Na+:5].[O:6]=[C:7]1[NH:12][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[N:10][CH:9]=[C:8]1[C:24]([OH:26])=[O:25].C(O)C>O>[O:6]=[C:7]1[NH:12][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=2)=[N:10][CH:9]=[C:8]1[C:24]([O-:26])=[O:25].[Na+:5]
Reactant: O=C(O)c1cnc(Nc2cccc(C(F)(F)F)c2)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C([O-])c1cnc(Nc2cccc(C(F)(F)F)c2)[nH]c1=O
Reaction time: 8 h
Yield: 76.6 %

Procedure:
Sodium hydrogen carbonate (0.82 g) is dissolved in water (50 ml), and thereto is added 1,6-dihydro-6-oxo-2-(3-trifluoromethylanilino)-5-pyrimidinecarboxylic acid (3 g), and the mixture is heated. After foaming is finished, ethanol is added to the reaction mixture, and the solution is allowed to stand overnight. The precipitate is collected by filtration and recrystallized from a mixture of methanol and water to give sodium 1,6-dihydro-6-oxo-2-(3-trifluoromethylanilino)-5-pyrimidinecarboxylate (2.4 g). M.p. 256°-259° C.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[Na].Br[CH:7]([CH2:19][CH2:20][CH2:21][CH:22]([O:28][C:29](=[O:31])[CH3:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>CO>[OH:4][CH2:3][CH2:2][S:1][CH:7]([CH2:19][CH2:20][CH2:21][CH:22]([O:28][C:29](=[O:31])[CH3:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: OCCS
Reactant: CCCCCC(CCCC(Br)CCCCCCC(=O)OCC)OC(C)=O
Agent: [Na]
Solvent: CO
Product: CCCCCC(CCCC(CCCCCCC(=O)OCC)SCCO)OC(C)=O

Procedure:
2-Mercaptoethanol (31.2 g., 0.4 mole) is dissolved in a solution of sodium (9.2 g., 0.4 mole) in methanol (300 ml.). Ethyl 8-bromo-12-acetoxy-heptadecanoate (Example 1, Step E) (43.5 g., 0.1 mole) is added and the resulting solution is heated at reflux for 5 hours. Most of the methanol is then removed by evaporation in vacuo. Water (350 ml.) is added to the residue and the oily product taken up in ether, washed with water and brine and dried over sodium sulfate. Evaporation of the ether leaves the title compound as a yellow residual oil which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CCCCCC.C(OCC)(=O)C>C(OCC)(=O)C.[Pt]>[CH2:28]([O:27][C:25](=[O:26])[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([F:18])[CH:11]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Pt]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(Nc1ccc(OCc2ccccc2)c(F)c1)OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 34.9 g of 1-benzyloxy-2-fluoro-4-nitrobenzene (WO 03 064413) (MW: 247.28, 141 mmol) and 340 mg of platinum (5% on activated carbon) in 350 ml of ethyl acetate was stirred at RT and normal pressure under a hydrogen atmosphere. The course of the reaction was monitored by HPLC and the reaction was terminated after 20 h. The catalyst was filtered off and the filtrate was concentrated to dryness under reduced pressure using a rotary evaporator. The oily residue was dissolved in 500 ml of acetone and 250 ml of a saturated sodium hydrogen carbonate solution and 17.5 g of sodium hydrogen carbonate (MW: 84.01, 208 mmol) were added. The mixture was cooled to 5° C. and 26.08 g of benzyl chloroformate (MW: 170.59, 152 mmol) were added dropwise. The mixture was then stirred for 2 h at RT and the course of the reaction was monitored by TLC (hexane/ethyl acetate 3:1). The acetone was removed under reduced pressure, 500 ml of water were added to the residue, and the solid material was filtered off. The crystals were washed with 500 ml of water and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:5][C:6]([N+:14]([O-])=O)=[C:7]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:8]=1>CC(O)=O.[Zn]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[N:14]=[C:10]([NH2:11])[C:9]2([CH3:13])[CH3:12]
Reactant: COc1cc(C(C)(C)C#N)c([N+](=O)[O-])cc1OCCCN1CCCC1
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1cc2c(cc1OCCCN1CCCC1)N=C(N)C2(C)C
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
2-(5-Methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-2-methylpropanenitrile (5.61 g, 16.15 mmol), from Step 1, in AcOH (100 mL) was treated with zinc (10.56 g, 161 mmol). The reaction was stirred at 90° C. for 30 min, filtered, and concentrated to dryness. The dried residue was taken into 4:1 THF:DCM and washed with saturated aqueous sodium bicarbonate solution. Aqueous washings were back-extracted with THF:DCM mixture 5 times. Organic layers were combined, dried (MgSO4), filtered and concentrated. Purification by flash chromatography (silica gel, 15-25% 1N methanolic ammonia/dichloromethane) afforded 4.95 g (97%) of 5-methoxy-3,3-dimethyl-6-(3-(pyrrolidin-1-yl)propoxy)-3H-indol-2-amine 1H NMR (400 MHz, METHANOL-D4) δ 7.17 (s, 1H), 6.90 (s, 1H), 4.16 (t, J=5.5 Hz, 2H), 3.87 (s, 3H), 3.85-3.73 (m, 2H), 3.46 (t, J=7.1 Hz, 2H), 3.13 (dt, J=10.5, 7.7 Hz, 2H), 2.31-2.23 (m, 2H), 2.19 (dd, J=14.3, 7.6 Hz, 2H), 2.12-1.99 (m, 2H), 1.55 (s, 6H); MS (ESI) m/z 318 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6]1>[Ni].CO.C1COCC1>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6]1
Reactant: CN(C)CCn1ccc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CCn1ccc(N)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 80.9 %

Procedure:
A suspension of dimethyl-[2-(3-nitro-pyrrol-1-yl)-ethyl]-amine (Step 121.2) (650 mg, 3.55 mmol) and Raney Nickel (300 mg) in MeOH/THF (1:1, v/v; 150 mL) was stirred for 7 h at rt, under a hydrogen atmosphere. The mixture was filtered through a pad of celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 98:1:1→93:6:1) to afford 440 mg of the title compound as a red oil. Title compound: ESI-MS: 154.1 [M+H]+; TLC: Rf=0.02 (DCM/MeOH, 9:1).
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.CCOC(C)=O.[ClH:34]>O1CCOCC1>[ClH:34].[ClH:34].[F:18][C:15]([F:16])([F:17])[C:14]([C:11]1[CH:10]=[CH:9][C:8]([N:7]2[CH2:6][CH2:5][NH:4][CH2:3][C@@H:2]2[CH3:1])=[CH:13][CH:12]=1)([OH:20])[CH3:19]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H]1CNCCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Yield: 70.2 %

Procedure:
A 500 mL round-bottomed flask was charged with tert-butyl (3S)-3-methyl-4-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate (8.33 g, 21.5 mmol) and 200 mL of EtOAc. To this was added 20 mL of 4N HCl (80 mmol) in dioxane. After 12 h at reflux, the resulting white precipitate was collected and dried under reduced pressure to give 1,1,1-trifluoro-2-(4-((2S)-2-methyl-1-piperazinyl)phenyl)-2-propanol dihydrochloride (5.45 g) as a white solid.