Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:23][CH:24]([O:30][CH2:31][CH3:32])[C:25]1[N:29]=[CH:28][NH:27][N:26]=1)[CH3:22].C(N(CC)CC)C>ClCCl>[CH2:31]([O:30][CH:24]([O:23][CH2:21][CH3:22])[C:25]1[N:29]=[CH:28][N:27]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:26]=1)[CH3:32]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(OCC)c1nc[nH]n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(OCC)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 3 h
Yield: 42.3 %

Procedure:
A solution of trityl chloride (43.4 g) in dichloromethane (120 ml) was added dropwise, over thirty minutes, to a stirred solution of 1,2,4-triazole-3-carboxaldehyde diethyl acetal (21.67 g, prepared as described by Mukahami et al, Heterocycles, 1981, 15, 301) and triethylamine (25 ml) in dichloromethane (200 ml). After stirring for a further three hours, the mixture was washed with water, dried over magnesium sulphate and evaporated under reduced pressure. A solution of the residual oil in ether (250 ml) crystallised to give 1-trityl-1,2,4-triazole-3-carboxaldehyde diethyl acetal (22.14 g, m.p. 120-124° C.). Trimethylsilyl bromide (14 ml) was added rapidly to a stirred solution of this acetal (6.2 g) in toluene (80 ml). After a further fifteen minutes, the solution was poured into a rapidly-stirred mixture of saturated sodium carbonate solution (200 ml), solid sodium carbonate (10 g) and ethyl acetate (150 ml). The mixture was stirred rapidly for ten minutes, the phases separated and the organic layer washed with water, dried over magnesium sulphate, and evaporated under reduced pressure. The residual oil was chromatographed on silica, using dichloromethane-ether (25:1) as eluant, to give the title compound (2.57 g). The deacetalation can also be carried out using pyridinium p-toluenesulphonate in acetone.
Reaction SMILES: O.[OH-].[Li+].[N:4]1[C:5]([CH2:13][O:14][C:15]2[CH:36]=[CH:35][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)\[CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:17][CH:16]=2)=[CH:6][N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12.O.Cl>O1CCCC1.CO>[N:4]1[C:5]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)\[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:35][CH:36]=2)=[CH:6][N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2cn3ccccc3n2)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC/C(=N\OCc1ccc(OCc2cn3ccccc3n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
Lithium hydroxide monohydrate (53.0 mg) was added to a solution of methyl E-4-[4-(imidazo[1,2-α]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyrate (280 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 2 hours. 1N hydrochloric acid (1.3 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[4-(imidazo[1,2-α]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyric acid (206 mg, yield 76%) as colorless crystals. m.p. 180-182° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].Cl[S:24]([C:27]1[CH:39]=[CH:38][C:30]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:29]([CH3:40])[CH:28]=1)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:5]([C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)[S:24]([C:27]1[CH:39]=[CH:38][C:30]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:29]([CH3:40])[CH:28]=1)(=[O:26])=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1C
Reactant: CCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCN(c1cccc(-c2ccc(C(F)(F)F)cc2)c1C)S(=O)(=O)c1ccc(OCC(=O)OCC)c(C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 14 %

Procedure:
To a solution of N-butyl-N-[2-methyl-4′-(trifluoromethyl)-1,1′-biphenyl-3-yl)amine (58 mg, 0.19 mmol) in anhydrous CH2Cl2 (5 mL) was added ethyl [4-(chlorosulfonyl)-2-methylphenoxy]acetate (83 mg, 0.28 mmol) and triethylamine (0.052 mL, 0.38 mmol). The resulting solution was stirred 20 h at room temperature under nitrogen. The reaction was diluted with CH2Cl2 (50 mL), and the organic solution washed with aq. sat. NaHCO3 (10 mL) and brine (10 mL). The organic extract was separated by hydrophobic frit and evaporated. Purification by mass directed autoprep afforded the title compound as a colourless oil (15 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=1[N:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.C(N(CC)CC)C>S(Cl)(Cl)=O.ClCCl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:16][C:15]=1[N:21]1[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=C(O)Cc1ccc(Br)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)Cc2ccc(Br)cc2)cc1N1CCN(C)CC1
Reaction time: 1 h
Yield: 53 %

Procedure:
4Bromophenylacetic acid (0.300 g, 1.40 mmol) was suspended in thionyl chloride (10 ml) and heated to reflux with stirring. After 1 h, the reaction mixture was allowed to cool and was evaporated under reduced pressure to give a yellow oil. The oil was then azeotroped with toluene, and the residue dried in vacuo to give the crude acid chloride. Meanwhile 4-methoxy-3-(4-methyl-1-piperazinyl)benzeneamine (EP 0533 267 A1) (0.293 g, 1.33 mmol) was dissolved in dichloromethane (10 ml) and treated with triethylamine (0.195 ml, 1.40 mmol), followed by dropwise addition of a solution of the crude acid chloride in dichloromethane (3 ml). The mixture was stirred at room temperature overnight before being washed with NaHCO3 solution. The organic layer was then dried (Na2SO4), and was evaporated under reduced pressure to give a brown oil. The oil was purified by silica-gel chromatography (5% MeOH/CH2Cl2 as eluant) to give the title compound as a pale yellow oil (0.295 g, 50%), which was converted to its oxalate salt.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1COCC1.CCOC(C)=O>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([NH:1][C:10](=[O:12])[CH3:11])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(CO)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(CO)c1
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a chilled suspension of 3-aminobenzyl alcohol (9.24 g, 75 mmol) in THF (50 mL) was added neat acetic anhydride (8.1 mL, 86 mmol). The reaction mixture was stirred cold for 1 hr, diluted with EtOAc, washed with aq. NaOH and brine, and concentrated in vacuo to give N-[3-(hydroxymethyl)phenyl]acetamide (10.5 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([S:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:27][C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([OH:28])[CH:25]=3)[CH2:20]2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(C)C=CC(S(O[CH2:49][CH2:50][Cl:51])(=O)=O)=CC=1>>[Cl:51][CH2:50][CH2:49][O:28][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[CH2:20][N:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([S:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1)[C:12]#[N:13])[CH2:27]2
Reactant: COc1cc2c(cc1O)CN(CCCCCC(C#N)(Sc1ccc(C)cc1)c1ccc(OC)c(OC)c1)C2
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Product: COc1ccc(C(C#N)(CCCCCN2Cc3cc(OC)c(OCCCl)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 73 %

Procedure:
The procedure of Example of 32 is used with 0.45 g of α-(3,4-dimethoxyphenyl)-1,3-dihydro-5-hydroxy-6-methoxy-α-[(4-methylphenyl)thio]-2H-isoindole-2-heptanenitrile and 0.65 g of 2-chloroethyl p-toluenesulfonate. This affords 0.367 g of the desired product as a light brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([OH:9])[C:3]=1[OH:10].[C:11](=O)([O-])[O-].[Cs+].[Cs+].BrCCl.O>CN(C)C=O.C(OCC)C>[F:1][C:2]1[C:3]2[O:10][CH2:11][O:9][C:4]=2[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Oc1cc(F)cc(F)c1O
Reactant: O=C([O-])[O-]
Agent: ClCBr
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Fc1cc(F)c2c(c1)OCO2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 27.5 %

Procedure:
3,5-Difluorobenzene-1,2-diol (10 g, 69 mmol) was dissolved in dry N,N-dimethylformamide (100 mL), treated with cesium carbonate (56 g, 170 mmol) and stirred for 30 min at 20° C. Bromochloromethane (12 g, 90 mmol) was added and the mixture was heated and stirred at 60° C. for 19 h. After cooling, the mixture was shaken with water (100 mL) and diethyl ether (100 mL). The aqueous phase was extracted again with ether (50 mL). The combined extracts were washed with water (2×20 mL), washed with saturated NaCl (1×10 mL) and dried (Na2SO4). The bulk of the ether was removed by atmospheric distillation through a 300 mm Vigreux column. The pressure was reduced to 75 mmHg and the product was distilled at 70-90° C. to give the title compound as a thick oil (3.0 g, 28%): 1H NMR (400 MHz, CDCl3) δ 6.45 (m, 1H), 6.42 (d, J=2.4 Hz, 1H), 6.39 (d, J=2.4 Hz, 1H), 6.02 (s, 2H); 19F NMR (376 MHz, CDCl3) δ −117.99, −135.90; EIMS m/z 158.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([SH:10])[CH:7]=[CH:8][CH:9]=1.[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16](F)[C:13]=1[C:14]#[N:15]>CN(C=O)C>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([S:10][C:6]2[CH:5]=[C:4]([CH3:3])[CH:9]=[CH:8][CH:7]=2)[C:13]=1[C:14]#[N:15]
Reactant: Cc1cccc(S)c1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Sc2cccc(F)c2C#N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
To a cold (ice water) suspension of sodium hydride (316 mg; 7.9 mmol) in anhydrous DMF (10 mL) is added a solution of 3-methylbenzenethiol (941 uL; 7.9 mmol) in anhydrous DMF (5 mL) over 10 minutes. After allowing to room temperature over 30 minutes, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (1 g; 7.2 mmol) in anhydrous DMF (15 mL), and allowed to room temperature over 3 hours. The reaction mixture is poured into ice water with vigorous stirring and the resulting precipitate is removed by filtration and dried under vacuum overnight to give 1.74 grams of 2-fluoro-6-m-tolylsulfanylbenzonitrile.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]4[CH2:19][NH:20][CH2:21][CH2:22][C:12]([C:13]=34)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:25](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>COCCOC>[CH3:25][N:20]1[CH2:21][CH2:22][C:12]2=[CH:11][N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:13]=32)[CH2:19]1
Reactant: CC(=O)O
Reactant: O=S(=O)(c1ccccc1)n1cc2c3c(cccc31)CNCC2
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COCCOC
Product: CN1CCc2cn(S(=O)(=O)c3ccccc3)c3cccc(c23)C1
Temperature: 25 °C

Procedure:
1-(Phenylsulfonyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol, Example 15 (34.4 mg, 0.11 mmol) was dissolved in DME (2 mL) and added formaldehyde (37% Wt. solution in water, 0.1 mL, 1.1 mmol), acetic acid (0.05 mL, 0.7 mmol) and sodium triacetoxyborohydride (156 mg, 0.7 mmol). The reaction mixture was stirred at room temperature for 24 H. The reaction was quenched by adding 1 M NaOH (5 mL). Aqueous phase (pH about 14) was separated and was then extracted with DCM (3×5 mL). The combined organic phases was washed with water and brine, and dried with MgSO4. The solvent was removed under vacuum. 20 mg pure product was obtained as an off-white solid. MS m/z 327 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][S:7](=[O:10])(=[O:9])[CH2:8][C:4]=2[CH:3]=1.[F:13][C:14]([F:24])([F:23])[C:15]1[CH:16]=[CH:17][C:18]([CH:21]=[CH2:22])=[N:19][CH:20]=1>>[O:9]=[S:7]1(=[O:10])[CH2:8][C:4]2[CH:3]=[C:2]([NH:1][CH2:22][CH2:21][C:18]3[CH:17]=[CH:16][C:15]([C:14]([F:24])([F:13])[F:23])=[CH:20][N:19]=3)[CH:12]=[CH:11][C:5]=2[CH2:6]1
Reactant: C=Cc1ccc(C(F)(F)F)cn1
Reactant: Nc1ccc2c(c1)CS(=O)(=O)C2
Product: O=S1(=O)Cc2ccc(NCCc3ccc(C(F)(F)F)cn3)cc2C1

Procedure:
In analogy to the procedure described for the synthesis example 25 (step 1), the title compound (2,2-dioxo-2,3-dihydro-1H-2lambda(6)-benzo[c]thiophen-5-yl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 357.1 [M+H]+) was prepared from 5-amino-2,3-dihydro-1H-2lambda(6)-benzo[c]thiophene-2,2-dione instead of 3,4-dimethylaniline and 5-trifluoromethyl-2-vinyl-pyridine.
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2].[C:26](OC(C)=C)(=[O:29])[CH2:27][CH3:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16]([O:23][C:26](=[O:29])[CH2:27][CH3:28])=[CH:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Reactant: C=C(C)OC(=O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Product: CCC(=O)OC1=CC[C@H]2[C@@H]3CCc4cc(OC)cc(OC(C)=O)c4[C@H]3CC[C@]12C

Procedure:
A solution of 1-acetoxy-3-methoxyestra-1,3,5(10)-trien-17-one (0.884 g, 26 mM), isopropenyl propionate (15.1 g, 123 mM) and p-toluenesulfonic acid monohydrate (0.134 g, 0.7 mM) is heated at 120° on a set-up employing a Vigreaux column as described in Example 9. After heating at 120° for 12 hrs, the temperature is raised to 150° for 1 hr. The pot residue is poured into ether. The ethereal solution is extracted with saturated sodium bicarbonate solution, cold H2O and dried over MgSO4. Evaporation of the solvent gives a residue which upon chromatography on neutral silica gel affords 1-acetoxy-3-methoxy-17-propionyloxyestra-1,3,5(10),16-tetraene.
Reaction SMILES: [Br:1][CH:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[S:4][CH2:3]1.[BH4-].[Na+]>CO>[Br:1][CH:2]1[CH:11]([OH:12])[C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[S:4][CH2:3]1
Reactant: O=C1c2ccc(Cl)cc2SCC1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1c2ccc(Cl)cc2SCC1Br
Temperature: 0.5 °C

Procedure:
Suspend 3-bromo-7-chlorothiochroman-4-one (59.6 gms., 215 mmols) in methanol (500 ml.), cool to 0.5° C., and with stirring add sodium borohydride (8.18 gms., 215 mmols) in three portions. Continue stirring the reaction mixture at room temperature for three hours, then pour into ice water (4 liters) and extract with chloroform (2 liters). Dry the chloroform solution over anhydrous magnesium sulfate, filter and evaporate in vacuo to a residue. Triturate the residue with chloroform/hexane to give 3-bromo-7-chlorothiochroman-4-o1, m.p. 141°-142° C.
Reaction SMILES: [N:1]1([C:6]2[CH:21]=[CH:20][C:9]([CH2:10][CH:11]([C:16](=O)[CH2:17][CH3:18])[C:12]([O:14]C)=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Br:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][C:11]3[C:16]([CH2:17][CH3:18])=[N:27][C:26]4[C:28]([C:12]=3[OH:14])=[CH:29][C:23]([Br:22])=[CH:24][CH:25]=4)=[CH:20][CH:21]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)OC
Reactant: Nc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1nc2ccc(Br)cc2c(O)c1Cc1ccc(-n2cccn2)cc1
Temperature: 220 °C
Reaction time: 2 h

Procedure:
A mixture containing methyl 2-(4-(1H-pyrazol-1-yl)benzyl)-3-oxopentanoate (2.7 g, 9.4 mmol, Intermediate 32: step b), 4-bromoaniline (1.6 g, 9.4 mmol), and para-toluenesulfonic acid monohydrate (162 mg, 0.943 mmol) in diphenyl ether (31 mL) was heated to 220° C. After 2 hours, the flask was cooled to 23° C. Diethyl ether (50 mL) was added resulting in the formation of a solid. The heterogeneous mixture was stirred at 23° C. After 30 minutes, the mixture was filtered through filter paper and the filter cake was rinsed with diethyl ether. The solids were collected and dried to afford the title compound which was taken onto the next step without further purification.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][N+:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6])[CH3:3].[F:14][C:15](F)=[CH:16]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>CN(C)C=O.O>[CH2:2]([O:4][C:5]([C:7]1[N:8]2[C:13]([CH:12]=[CH:11][CH:10]=[CH:9]2)=[CH:16][C:15]=1[F:14])=[O:6])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OC=C(F)F)cc1
Reactant: CCOC(=O)C[n+]1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(F)cc2ccccn12
Temperature: 70 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a solution of 1-ethoxycarbonylmethylpyridinium bromide (4.8 g) in N, N-dimethylformamide (50 mL) were added toluene-4-sulfonic acid 2, 2-difluorovinyl ester (4.6 g), potassium carbonate (4.0 g) and triethylamine (3.0 g), and the mixture was stirred at 70° C. overnight. After cooling to room temperature, to the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give 2-fluoroindolizine-3-carboxylic acid ethyl ester (1.9 g). To a solution of the obtained. compound (1.9 g) in dichloromethane (30 mL) was added N-bromosuccinimide (1.8 g), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1 mol/L sodium thiosulfate aqueous solution, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give 1-bromo-2-fluoroindolizine-3-carboxylic acid ethyl ester (1.3 g). To a mixed solution of the obtained compound (1.3 g) in tetrahydrofuran (20 mL), ethanol (7 mL) and water (7 mL) was added lithium hydroxide monohydrate (0.29 g), and the mixture was stirred at room temperature overnight. To the reaction mixture were added 1 mol/L hydrochloric acid and water. The precipitated solid was collected by filtration, washed with water and n-hexane, and dried under reduced pressure at 50° C. to give 1-bromo-2-fluoroindolizine-3-carboxylic acid (0.76 g). To a suspension of the obtained compound (0.56 g) and quinoline (5 mL) was added copper (0.03 g), and the mixture was stirred at 220° C. for 30 minutes. After cooling to room temperature, to the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.47 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[S:10]([OH:12])=[O:11].C(N(CC)CC)C.I[CH:21]([CH3:23])[CH3:22]>CN(C=O)C>[F:9][C:6]1[CH:5]=[CH:4][C:3]([S:10]([CH:21]([CH3:23])[CH3:22])(=[O:12])=[O:11])=[C:2]([F:1])[C:7]=1[F:8]
Reactant: O=S(O)c1ccc(F)c(F)c1F
Reactant: CC(C)I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 20.4 mmol 2,3,4-trifluoro-benzenesulfinic acid (prepared in analogy to example 2.20(a) from 2,3,4-trifluoro-benzenesulfonyl chloride) and 61.2 mmol triethylamine in 20 ml DMF was added 40.8 mmol 2-iodopropane, and the mixture stirred at room temperature for 16 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed twice with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:4) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.C(N(CC)CC)C.[CH:22]1([C:25]2[CH:26]=[C:27]([NH2:30])[NH:28][N:29]=2)[CH2:24][CH2:23]1>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:30][C:27]2[NH:28][N:29]=[C:25]([CH:22]3[CH2:24][CH2:23]3)[CH:26]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: Clc1ncc(-c2ccccc2)c(Cl)n1
Reactant: Nc1cc(C2CC2)n[nH]1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Clc1ncc(-c2ccccc2)c(Nc2cc(C3CC3)n[nH]2)n1
Yield: 60 %

Procedure:
To 2,4-Dichloro-5-phenyl-pyrimidine (187 mg, 0.83 mmol) and triethylamine (255 μL, 1.83 mmol) in ethanol (25 mL) was added 5-Cyclopropyl-2H-pyrazol-3-ylamine (142 mg, 1.16 mmol) and the solution was heated to 80 C for 14 h. The solvent was removed in vacuum, and the title compound was obtained by flash chromatography (0-2% methanol in dichloromethane) to give: 150 mg (60% yield). HPLC tr=6.68 min (87%), LCMS m/e 312.1 (M+H), 310.0 (M-H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:17][CH:18]1[CH2:20][CH2:19]1)[C:9]([CH3:16])=[N:10]2)=[O:4].[C:21]([O:25][C:26]([NH:28][C:29]1([C:32](=[O:39])[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C([O-])(O)=O.[Na+].C(Cl)(Cl)Cl>[C:21]([O:25][C:26]([NH:28][C:29]1([C:32]([CH:33]([CH2:2][C:3]([C:5]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]3[C:6]=2[N:7]=[C:8]([NH:17][CH:18]2[CH2:20][CH2:19]2)[C:9]([CH3:16])=[N:10]3)=[O:4])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:39])[CH2:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1nc2ccc(F)c(C(=O)CBr)c2nc1NC1CC1
Reactant: CCOC(=O)CC(=O)C1(NC(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(CC(=O)c1c(F)ccc2nc(C)c(NC3CC3)nc12)C(=O)C1(NC(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 37.2 %

Procedure:
At RT, to a mixture of 2-bromo-1-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanone (283c) (1.18 g, 3.49 mmol) and ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-3-oxopropanoate (604) (1.14 g, 4.19 mmol) dissolved in DMF (10.26 mL) was added K2CO3 (1.21 g, 8.72 mmol). The overall mixture was stirred overnight. The mixture was diluted with saturated NaHCO3 (100 mL) and CHCl3 (100 mL). The layers were separated and the aq. layer was extracted with CHCl3 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by chromatography through an Interchim puriFlash UP (25 micron) pre-packed silica-gel column (80 grams), eluting with a gradient of 0-30% EtOAc in DCM, to provide ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropanecarbonyl)-4-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-4-oxobutanoate (0.69 g, 1.30 mmol, 37% yield) as a yellow oil. The yellow oil was put into a sealed tube with 2:1 mixture of EtOH/AcOH (3 mL) and NH4OAc (Sigma) (0.80 g, 10.5 mmol) was added and the mixture was stirred at 60° C. overnight. The precipitate solid was filtered and washed with Et2O (3×2 mL) to give ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (0.41 g, 23% yield) as a yellow solid. m/z (ESI, +ve) 510 (M+H).