Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O=S(Cl)Cl.[CH3:19]O>>[F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:19])=[O:8]
Reactant: Cc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(F)cc([N+](=O)[O-])c1C
Yield: 25 %

Procedure:
To a solution of conc. H2SO4 (700 mL) was added portion-wise 5-fluoro-2-methylbenzoic acid (80 g, 520 mmol) at −5˜0° C. Then a mixture of conc. HNO3 (60.4 g, 624 mmol) in conc. H2SO4 (60 mL) was added drop-wise at −5˜0° C. in a period of about 1.5 hrs. After the addition, the mixture was stirred at this temperature for 2 hrs. TLC (petroleum ether/EtOAc=1:1) showed the reaction was complete. The mixture was poured into crash ice with vigorous stirring and the precipitate was collected by filtration. The precipitate was dissolved in EtOAc, washed with brine, dried over anhydrous Na2SO4, concentrated to give crude 5-fluoro-2-methyl-3-nitrobenzoic acid (54 g). A solution of this crude 5-fluoro-2-methyl-3-nitrobenzoic acid (54 g) in dry methanol (500 mL) was cooled to 0° C., SOCl2 (64.52 g, 542.3 mmol) was added drop-wise. After the addition, the mixture was heated to reflux for 16 hrs. TLC (petroleum ether/EtOAc=1:1) showed the reaction was complete. Solvent was removed under reduced pressure to give crude product. The crude product was purified by silica gel chromatography (petroleum ether to petroleum ether/EtOAc=50:1) to give methyl 5-fluoro-2-methyl-3-nitrobenzoate (28 g, yield 25% for two steps) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.59 (s, 3H), 3.95 (s, 3H), 7.60-7.63 (dd, 1H), 7.74-7.77 (dd, 1H); LC-MS (ESI) m/z: 214 (M+1)+, 216(M+3)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:20][CH2:19][N:11]2[C:12]3[C:17]([CH:18]=[C:10]2[CH2:9]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:20][CH2:19][N:11]2[C:12]3[C:17]([C:18]([C:23]([Cl:22])=[O:25])=[C:10]2[CH2:9]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCn2c(cc3ccccc32)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCn2c(c(C(=O)Cl)c3ccccc32)C1
Reaction time: 2 h

Procedure:
A solution of (6,7,8,9-tetrahydro-pyrido[1,2-a]indol-8-yl)-carbamic acid tert-butyl ester (400 mg, 1.40 mmol) in dry THF (5 mL) was cooled to 0° C. Triphosgene (208 mg, 0.7 mmol) dissolved in dry THF (3 mL) and triethylamine (194 μL, 1.40 mmole) were added. A precipitation was formed. The reaction was allowed to reach room temperature and after 2 h the mixture was evaporated and the crude product was used in the next step. APCI-MS m/z: 345 [MH+] (analysis performed on a sample quenched with methanol, thus the mass corresponds to the methylester).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][C:26]=3[O:28][CH3:29])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(I)c(F)ccc12
Reactant: COc1ccc(B(O)O)c(OC)c1
Product: COc1ccc(-c2c(F)ccc3c(N)c(C(=O)NC4CC4)nnc23)c(OC)c1
Yield: 59.9 %

Procedure:
Using Method A, 4-amino-7-fluoro-8-iodo-N-cyclopropyl-cinnoline-3-carboxamide (178 mg, 0.48 mmol) and 2,4-dimethoxyphenylboronic acid (175 mg, 0.96 mmol) were reacted. After purification the title compound (110 mg, 60% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.98 (d, J=4.8 Hz, 1H), 8.47 (a dd, J=5.6, 9.3 Hz, 1H), 7.70 (t, J=9.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 6.70(s, 1H), 6.63 (a d, J=8.3 Hz, 1H), 3.84 (s, 3H), 3.64 (s, 3H), 2.95 (m, 1H), 0.67 (m, 4H). MS APCI, m/z=383.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:44][CH2:45][C:46]1[C:47]([OH:54])=[N:48][C:49]([CH3:53])=[CH:50][C:51]=1[CH3:52]>ClCCl>[OH:54][C:47]1[C:46]([CH2:45][NH:44][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([CH:2]([CH2:3][CH2:4][CH3:5])[CH3:1])=[CH:14][CH:13]=2)=[C:51]([CH3:52])[CH:50]=[C:49]([CH3:53])[N:48]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CCCC(C)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(C)c1ccc(C(=O)NCc2c(C)cc(C)nc2O)cc1
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
A solution of 4-(pentan-2-yl)benzoic acid (120 mg, 0.66 mmol) in dichloromethane (40 mL) was added N-hydroxybenzotriazole (HOBT) (135 mg, 1.0 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (192 mg, 1.0 mmol), triethylamine (135 mg, 1.5 mmol), stirred for 30 minute. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (100 mg, 0.66 mmol) was added and the mixture was stirred at room temperature for 18 hours. The mixture was washed with water (30 mL), dried over anhydrous sodium sulfate, concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) and the obtained solution was freeze-dried to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(pentan-2-yl)benzamide (186 mg, 86.4%) as white solid. LRMS (M+H+) m/z: calcd 326.20. found 326. HPLC Purity (214 nm)95%. 1H NMR (300 MHz, CD3OD): δ 7.72-7.69 (d, J=11 Hz, 2H) 7.29-7.26 (d, J=8.4 Hz, 2H), 6.102 (s, 1H), 4.48 (s, 2H), 2.69-2.62 (m, 1H), 3.36 (s, 3H), 2.24 (s, 3H), 1.66-1.57 (m, 2H), 1.22-1.25 (d, J=9 Hz, 3H), 0.782-0.832 (t, J=7.5 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[CH2:16][O:17][CH2:18][CH2:19][OH:20])=[CH:10][CH:9]=2)[CH:2]=1.[CH2:21]=[C:22]1[O:26][C:24](=[O:25])[CH2:23]1>O1CCCC1.C(N(CC)CC)C>[C:24]([O:20][CH2:19][CH2:18][O:17][CH2:16]/[CH:15]=[CH:14]/[C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:9][CH:10]=1)(=[O:25])[CH2:23][C:22]([CH3:21])=[O:26]
Reactant: OCCOC/C=C/c1ccc(Cc2cccnc2)cc1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCCOC/C=C/c1ccc(Cc2cccnc2)cc1
Yield: 72 %

Procedure:
In 50 ml of tetrahydrofuran was dissolved 5.4 g of 2-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]allyloxy]ethanol, and one drop of triethylamine was added to the resulting solution. To this solution was dropwise added a mixture of 1.8 g of diketene and 4 ml of tetrahydrofuran under reflux over one hour, and then the resulting mixture was subjected to reaction at the same temperature for a further 30 minutes. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: benzene:ethyl acetate (2:1 by volume)] to obtain 5.1 g (yield 72.2%) of oily 2-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]allyloxy]ethyl acetoacetate.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([N:8]([CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:7].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)C>[Cl:25][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([Cl:24])[CH:21]=1)[CH2:17][N:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=1)[C:6](=[O:7])[C:5]1[CH:26]=[CH:27][CH:28]=[C:3]([CH2:2][NH:1][CH2:34][C:33]2[CH:36]=[CH:37][C:30]([F:29])=[CH:31][CH:32]=2)[CH:4]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NCc1cccc(C(=O)N(Cc2ccc(F)cc2)Cc2cc(Cl)cc(Cl)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C(c1cccc(CNCc2ccc(F)cc2)c1)N(Cc1ccc(F)cc1)Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
To a solution of 3-(aminomethyl)-N-(3,5-dichlorobenzyl)-N-(4-fluorobenzyl)benzamide (0.6 g, 1.44 mmol) in CH2Cl2 (6.0 mL) and 2-propanol (6.0 mL) was added 4-fluorobenzaldehyde (0.16 mL, 1.44 mmol). The resulting mixture was stirred at rt for 1.5 h. The reaction mixture was cooled to ice bath temperature and was added sodium triacetoxyborohydride (0.49 g, 2.30 mmol) under N2 atmosphere. The resulting mixture was stirred at rt for 20 h. To the reaction mixture was added saturated aq NaHCO3 solution and the mixture was stirred for 20 minutes. The mixture was concentrated, and the residue was diluted with ethyl acetate and saturated aq NaHCO3 solution. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica gel (ISCO. condition: 24 g column; eluents: 0-25% of ethyl acetate in CH2Cl2, gradient over 40 minutes) to obtain the desired product as colorless oil (0.47, 63%). 1H NMR (CDCl3): δ 7.55-7.29 (m, 7H), 7.17-7.00 (m, 8H), 4.70-4.63 (m, 2H), 4.43-4.36 (m, 2H), 3.82 (s, 2H), 3.77 (s, 2H); MS (ESI): [M+H]+=524.9.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28](O)(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CCCCC(=O)O
Agent: Cl
Product: CCCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (54 mg, 65%), MS (ISP) m/z=415.5 [(M+H)+], mp 180.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and pentanoic acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.[H-].[Na+].Br[CH2:16][CH2:17][CH3:18]>CN(C=O)C>[CH2:16]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1)[CH2:17][CH3:18]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1nc(C(=O)O)c2ccccc21
Yield: 67.3 %

Procedure:
To a solution of 1H-indazole-3-carboxylic acid (5.00 g) in DMF (40 ml) was gradually added 60% sodium hydride (1.55 g) at 0° C. with stirring, and the mixture was stirred at room temperature for one hour. Then 1-bromopropane (4.55 g) was added, and the mixture was stirred overnight. The reaction solution was distilled off, dissolved in water, and washed with ethyl acetate. The aqueous layer was made acidic with hydrochloric acid, extracted with ethyl acetate, then the extract was dried over anhydrous magnesium sulfate, and decolorized with active carbon. After the solvent was distilled off, crystallization from ether gave the title compound (4.24 g) as crystals. Yield=67%.
Reaction SMILES: [CH:1]1([NH:4][C:5]([CH:7]2[CH:9]([CH2:10][CH2:11][CH3:12])[O:8]2)=[O:6])[CH2:3][CH2:2]1.[N-:13]=[N+:14]=[N-:15].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>CO>[N:13]([CH:9]([CH2:10][CH2:11][CH3:12])[CH:7]([OH:8])[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:6])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCC1OC1C(=O)NC1CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CO
Product: CCCC(N=[N+]=[N-])C(O)C(=O)NC1CC1
Temperature: 65 °C

Procedure:
A flask equipped with an overhead stirrer, thermometer and reflux condenser was placed under a nitrogen atmosphere then charged with compound 38 (20.0 g, 118 mmol), sodium azide (NaN3; 31.0 g, 473 mmol), magnesium sulfate (MgSO4; 14.0 g, 118 mmol) and methanol (MeOH; 200 mL). The mixture was heated to 65±5° C. for 2 hours then cooled to 25±S ° C. and filtered through a pad of Celite 545. The solvent was removed under reduced pressure resulting in a thick oil which was taken up in IPAc (250 mL) then washed with water (3×250 mL). The organic phase was dried over sodium sulfate (Na2SO4), filtered and concentrated under reduced pressure to provide compound 40 as a white solid. 1H NMR (500 MHz, d6-DMSO) 7.87 (s, 1H), 5.97 (d, J=6.0, 1H), 4.02 (dt, J=6.0, 3.8 Hz, 1H), 2.70-2.65 (m, 1H), 1.60-1.20 (m, 4H), 0.88 (t, J=7.0 Hz, 3H), 0.63-0.58 (m, 2H), 0.51-0.46 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[Cl:7][C:8]1[CH:18]=[CH:17][C:11]([CH2:12][NH:13][C:14](=[S:16])[S-:15])=[CH:10][CH:9]=1.[NH4+]>CN(C)C=O>[C:5]([CH2:4][CH2:3][CH2:2][S:16][C:14](=[S:15])[NH:13][CH2:12][C:11]1[CH:17]=[CH:18][C:8]([Cl:7])=[CH:9][CH:10]=1)#[N:6]
Reactant: S=C([S-])NCc1ccc(Cl)cc1
Reactant: N#CCCCBr
Agent: [NH4+]
Solvent: CN(C)C=O
Product: N#CCCCSC(=S)NCc1ccc(Cl)cc1

Procedure:
To 37.5 g. of 4-bromobutyronitrile in 350 ml. of absolute dimethylformamide were added, while cooling with ice, 53.7 g. of ammonium (N-4-chlorobenzyl)dithiocarbamate and the mixture was stirred overnight at room temperature. After evaporation in vacuo, the product was taken up in ethyl acetate, washed with water, dried, concentrated and the residue crystallized from diethyl ether/diisopropyl ether, whereby 48.2 g. of 3-cyanopropyl(p-chlorobenzyl)dithiocarbamate having a melting point of 61°-63° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:14])=[C:4]([C:9]([Br:13])=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:15]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:13][C:9]1[C:10]([Cl:12])=[CH:11][C:2]2[NH:1][N:15]=[CH:14][C:3]=2[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=N[O-]
Reactant: COC(=O)c1c(C)c(N)cc(Cl)c1Br
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1c(Br)c(Cl)cc2[nH]ncc12
Reaction time: 24 h
Yield: 76.4 %

Procedure:
To a solution of methyl 3-amino-6-bromo-5-chloro-2-methylbenzoate (500 mg, 1.80 mmol) in acetic acid (9 mL) was added a solution of sodium nitrite (137 mg, 1.99 mmol) in water (0.9 mL) at room temperature, and the mixture was stirred for 24 hr. The organic solvent was evaporated under reduced pressure. The residual aqueous solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (398 mg, yield 76%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Cl[CH:12]([C:18]([CH3:20])=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:18]([CH3:20])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC(=S)c1ccc(O)cc1
Product: CCOC(=O)c1sc(-c2ccc(O)cc2)nc1C
Reaction time: 1 h

Procedure:
A mixture of 4-hydroxy thiobenzamide (100 g, 0.653 mol) and ethyl 2-chloroacetoacetate (118.3 g, 0.719 mol) in denatured spirit (DNS) (500 mL) was heated at about 60° C. to 65° C. for about 2.5 hours. The reaction mixture was cooled to about 0° C. to 5° C. and stirred for about 1 hour at the same temperature. The solid obtained was filtered, washed with denatured spirit and dried to obtain the title compound. (Yield: 156 g, 90.7%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])(=[O:11])=[O:10].[Cl:23][C:24]1[CH:25]=[C:26]([CH:31]([CH3:34])[CH2:32][NH2:33])[CH:27]=[CH:28][C:29]=1[Cl:30]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:31]([CH3:34])[CH2:32][NH:33][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:13]=2[NH:12][S:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])(=[O:11])=[O:10])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F
Reactant: CC(CN)c1ccc(Cl)c(Cl)c1
Product: CC(CNC(=O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F)c1ccc(Cl)c(Cl)c1

Procedure:
This compound was prepared from 2-(2,6-difluorobenzenesulfonylamino)-4-iodo-benzoic acid and 2-(3,4-dichloro-phenyl)-propylamine as in EXAMPLE 1, Part C. HPLC: RT=11.98 min. MS (ESI−): mass calcd. for C22H17Cl2F2IN2O3S, 625.3; m/z found, 624 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.63 (s, 1H), 8.02 (d, J=1.5, 1H), 7.54-7.45 (m, 1H), 7.39 (d, J=8.2, 1H), 7.34 (d, J=1.6, 1H), 7.32 (d, J=1.8, 1H), 7.09 (dd, J=8.3, 2.1, 1H), 7.02-6.94 (m, 3H), 6.34-6.32 (br m, 1H), 3.74-3.65 (m, 1H), 3.40 (ddd, J=13.7, 8.5, 5.6, 1H), 3.14-3.04 (m, 1H), 1.30 (d, J=7.0, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.[CH3:19][O:20][CH2:21]Cl>C(Cl)Cl>[CH3:19][O:20][CH2:21][O:9][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(O)c1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 12.0 g (100 mmol) of 3-methoxyphenol in 100 mL of methylene chloride at 0° C. was added 29.5 g (229 mmol) of diisopropylethylamine followed by dropwise addition of 10 g of chloromethyl methyl ether. The reaction mixture was stirred at room temperature overnight, washed with 1N HCl (3×75 mL), 1N NaOH (3×75 mL) and brine and was dried over anhydrous MgSO4. The mixture was filtered and concentrated in vacuo to give 3-methoxymethyloxy-anisole. 6.0 g (36 mmol) of 3-methoxymethyloxy-anisole was dissolved in 100 mL dry THF and was cooled to −78° C. To the solution was added dropwise 20 mL (50 mmol) of 2.5M n-butyl lithium in hexanes. The solution was stirred at −78° C. for 1 hour, the ice bath was removed and the solution stirred at room temperature for a further 1 hour. The reaction mixture was cooled to −78° C. and treated with 5.56 g (54 mmol) of trimethyl orthoborate. The solution was stirred for 1 hour and then allowed to warm to room temperature over 1 hour. The solution was treated with 30 mL of saturated NH4Cl solution and 100 mL of ethyl acetate with stirring. The pH was immediately adjusted to 5.0 by addition of aliquots of 5% citric acid solution. The aqueous phase was promptly extracted with ethyl acetate (3×50 mL). The combined ethyl acetate phases were extracted with 1N NaOH solution (3×50 mL). The combined basic extracts were acidified with rapid stirring by dropwise addition of concentrated hydrochloric acid to pH 5.0. The mixture was extracted by ethyl acetate (3×75 mL). The combined EtOAc phases were dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 2-methoxy-6-(methoxymethyloxy)phenylboronic acid.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[CH:37][C:38]=1[Cl:39].N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[CH:34]=[C:35]([S:40]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]3[C:16]([C:17]4[N:25]=[CH:24][N:23]=[C:22]5[C:18]=4[N:19]=[CH:20][N:21]5[CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)=[CH:15][CH:14]=[CH:13][N:12]=3)[C:2]=2[F:1])(=[O:41])=[O:42])[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 3,4-dichlorobenzenesulfonyl chloride (17 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 26 mg of the target compound, 3,4-dichloro-N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)benzenesulfonamide (percentage yield: 89%), was obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:13][C:5]2=[N:6][CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=[C:4]2[C:3]=1[CH3:14].[Cl-].[NH4+].C(O)C>[Fe].O>[CH3:1][C:2]1[NH:13][C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[C:3]=1[CH3:14]
Reactant: Cc1[nH]c2ncc([N+](=O)[O-])cc2c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1[nH]c2ncc(N)cc2c1C
Temperature: 110 °C
Yield: 99.9 %

Procedure:
2,3-Dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.11 g, 0.596 mmol), iron (0.40 g, 7.16 mmol) and ammonium chloride (0.13 g, 2.39 mmol) were combined with ethanol (2.8 mL) and water (0.65 mL) in a microwave vessel and heated in a microwave reactor to 110° C. for 15 minutes. The reaction mixture was filtered, saturated aqueous sodium bicarbonate was added, and the layers were separated. The aqueous layer was extracted once with ethyl acetate. The organic layers were dried with sodium sulfate, filtered and concentrated in vacuo to afford 2,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-amine (0.096 g, 100%), which was carried to the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][CH:12]=[C:11]([CH2:14]O)[CH:10]=2)=[CH:5][CH:4]=1.C(P(CCCC)CCCC)CCC.[CH2:31]([O:33][C:34](=[O:45])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([SH:43])=[CH:39][C:38]=1[CH3:44])[CH3:32]>O1CCCC1>[CH2:31]([O:33][C:34](=[O:45])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43][CH2:14][C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=3)[O:13][CH:12]=2)=[CH:39][C:38]=1[CH3:44])[CH3:32]
Reactant: OCc1coc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCOC(=O)COc1ccc(S)cc1C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(SCc2coc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of {5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol (0.15 g) in tetrahydrofuran (15 ml) stirred at 0° C. was treated with tributylphosphine (0.2 ml), as solution of ethyl(4-mercapto-2-methylphenoxy)acetate (0.150 g) in tetrahydrofuran (2 ml) and finally azodicarbonyldimorpholide (0.204 g). The reaction was allowed to warm to ambient temperature and stirred for 18 hours. The solvent was evaporated and the residue subjected to an aqueous work up using ethyl acetate and water. The organic phase was dried over magnesium sulfate. The product isolated after evaporation of the solvent was further purified by flash column chromatography using a cyclohexane:ethyl acetate (5:1) as eluent to give the title compound.