Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[C:26]([CH:29]=[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40](=[O:56])/[CH:41]=[CH:42]/[C:43]3[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH2:51][CH2:52][CH3:53])=[C:45]([O:54][CH3:55])[CH:44]=3)[CH:31]=2)[CH2:27]O)=[O:15])=[CH:8][C:7]=1[O:57][CH3:58])[CH2:2][CH2:3][CH3:4].[Br:59]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[C:26]([CH:29]=[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40](=[O:56])/[CH:41]=[CH:42]/[C:43]3[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH2:51][CH2:52][CH3:53])=[C:45]([O:54][CH3:55])[CH:44]=3)[CH:31]=2)[CH2:27][Br:59])=[O:15])=[CH:8][C:7]=1[O:57][CH3:58])[CH2:2][CH2:3][CH3:4]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCOc1ccc(/C=C/C(=O)OCCCCCCOc2cc(CO)cc(OCCCCCCOC(=O)/C=C/c3ccc(OCCCC)c(OC)c3)c2)cc1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCOc1ccc(/C=C/C(=O)OCCCCCCOc2cc(CBr)cc(OCCCCCCOC(=O)/C=C/c3ccc(OCCCC)c(OC)c3)c2)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5.00 g (5.88 mmol) 3,5-bis[(6-{[(2E)-3-(4-butoxy-3-methoxyphenyl)-2-propenoyl]oxy}hexyl)oxy]benzyl alcohol, (6.47 mmol) tetrabromomethane were dissolved in 100 ml dichloromethane. The solution was subsequently cooled to 0° C. and a solution of 1.85 g (7.05 mmol) triphenylphosphine in 20 ml dichloromethane was added dropwise thereto over a period of 1 hour. The reaction mixture was reduced in volume by evaporation. Chromatography of the residue yield 3,5-bis[(6-{[(2E)-3-(4-butoxy-3-methoxy-phenyl)-2-propenoyl]oxy}hexyl)oxy]benzyl bromide.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[CH:9]=1)[C:4]([OH:6])=[O:5]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:24][CH:25]=2)[CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: COC(Cc1cccc(C#CCCCOc2ccc(Oc3ccccc3)cc2)c1)C(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(Cc1cccc(CCCCCOc2ccc(Oc3ccccc3)cc2)c1)C(=O)O

Procedure:
The title compound was prepared from 2-Methoxy-3-{3-[5-(4-phenoxy-phenoxy)-pent-1-ynyl]-phenyl}-propionic acid of Example 155, Step E, and treated with Pd—C (0.1 eq) in ethyl acetate and H2. Filtered through celite and concentrated to give the compound. MS (ES) for C27H30O5 [M+H]+: 435.2, [M+NH4]+: 452.2. 1H-NMR (CDCl3, 200.15 MHz): 7.34–7.19 (m, 3H), 7.09–6.84 (m, 10H), 4.02 (dd, 1H, J=7.5, 4.6), 3.94 (t, 2H, J=6.5), 3.39 (s, 3H), 3.13 (dd, 1H, J=14.0, 4.3), 3.00 (dd, 1H, J=14.0, 7.5), 2.63 (t, 2H, J=7.8), 1.88–1.45 (m, 6H)ppm.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[C:21]([C:22](=[O:24])N)=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:13]=2)[N:8]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=2)[C:7]=1[CH2:35][C:36]([O:38]CC)=[O:37])=[O:5])C.[OH-:41].[Na+]>CCO>[C:4]([CH2:6][C:7]1[N:8]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH:32]([CH3:33])[CH3:34])=[CH:29][CH:30]=2)[C:9]2[C:14]([C:35]=1[C:36]([OH:38])=[O:37])=[CH:13][C:12]([O:15][C:16]1[C:21]([C:22]([OH:24])=[O:41])=[CH:20][CH:19]=[CH:18][N:17]=1)=[CH:11][CH:10]=2)([OH:3])=[O:5]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ncccc3C(N)=O)ccc2n1-c1ccc(OC(C)C)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)Oc1ccc(-n2c(CC(=O)O)c(C(=O)O)c3cc(Oc4ncccc4C(=O)O)ccc32)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(3-carbamoylpyridin-2-yloxy)-2-ethoxycarbonylmethyl-1-(4-isopropoxyphenyl)indole-3-carboxylic acid ethyl ester (63 mg, 0.12 mmol, see step (a) Example 65), NaOH (aq, 2M, 0.35 mL) and EtOH (2 mL) was stirred at 90° C. for 8 h, concentrated, diluted with MeOH and filtered through Celite®. EtOAc was added to the filtrate which was cooled for 4 h at 5° C. The solid was collected and dissolved in H2O. The mixture was acidified to pH 4 with HCl (aq, 2 M). The solid was filtered off and dried for 4 h at 60° C. to give the title compound. Yield 34 mg (60%), mp 212-214° C. after recrystallisation from EtOAc/MeOH.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C1(C)C=CC=CC=1>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=2)[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)c(Cl)cc2Cl)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
To a mixture of 2,3,5,6-tetrachloropyridine (6.51 g), 1-Boc-piperazine (6.71 g) and potassium carbonate (9.95 g) were added dimethylformamide (15 mL) and toluene (30 mL), and the mixture was stirred at 100° C. for 2 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (ethyl acetate:hexane) to give the title compound (9.42 g).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH2:34][C:35](Cl)=[O:36]>C1(C)C=CC=CC=1.O>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:35](=[O:36])[CH2:34][C:30]4[S:29][CH:33]=[CH:32][CH:31]=4)[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Cc1cccs1)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 50 °C
Yield: 53.5 %

Procedure:
(R)—N2-indan-1-yl-quinoline-2,6-diamine (0.10 g, 0.36 mmol), triethylamine (0.055 mL, 0.4 mmol) and 2-thiophenacetyl chloride (0.049 mL, 0.4 mmol) were dissolved in toluene (3.0 mL). The reaction mixture was heated to 50° C. for 10 h. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined organic phases were dried on sodium sulfate and evaporated. The crude product was purified by column chromatography (silica gel, heptane ethyl acetate 4:1/2:1/1:1/1:2). The title compound (0.077 g, 53%) was obtained as a yellow solid; MS: m/e=400.6 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]1[CH2:33][C@H:32]2[CH2:34][C@@H:29]1[CH2:30][N:31]2[C:35]([C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[CH:41][CH:42]=1)=[O:36])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][C@H:32]2[CH2:34][C@@H:29]1[CH2:30][N:31]2[C:35]([C:37]1[CH:38]=[N:39][C:40]([NH:43][C:10]2[N:11]=[CH:12][C:7]3[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[C:8]=3[N:9]=2)=[CH:41][CH:42]=1)=[O:36])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@H]1CN2C(=O)c1ccc(N)nc1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4C[C@H]5C[C@@H]4CN5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Yield: 25.5 %

Procedure:
Following general N—C coupling procedure 1, 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (200 mg, 0.683 mmol, 1.0 eq) was combined with 5-(6-Amino-pyridine-3-carbonyl)-(R,R)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (217 mg, 0.683 mmol, 1.0 eq) which gave 5-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-(R,R)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (100 mg) in 25% yield. 1H NMR (400 MHz, CDCl3-d) δ ppm 1.47 (br. s., 5H) 1.52 (br. s., 5H) 1.69-1.83 (m, 2H) 1.83-2.00 (m, 2H) 2.06-2.20 (m, 4H) 2.59 (br. s., 2H) 3.18 (s, 6H) 3.38-3.58 (m, 2H) 3.58-3.82 (m, 3H) 4.56 (br. s., 1H) 4.75-4.91 (m, 1H) 6.50 (s, 1H) 7.96 (br. s., 1H) 8.35 (br. s., 1H) 8.52 (br. s., 1H) 8.59 (br. s., 1H) 8.78 (s, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:11][C:10]3=[O:18].CC1C=CC(S(O[CH2:32][C@H:33]2[CH2:37][CH2:36][CH2:35][O:34]2)(=O)=O)=CC=1.BrCC1CCCCO1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:11]([CH2:32][C@H:33]1[CH2:37][CH2:36][CH2:35][O:34]1)[C:10]3=[O:18]
Reactant: COc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: BrCC1CCCCO1
Product: COc1ccc2c(c1)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 6-methoxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (54%) as a colorless liquid: 1H NMR (300 MHz, CDCl3) (diastereomers) δ 7.32-7.25 (m, 1H), 7.16-6.99 (m, 3H), 6.61 (d, J=8.1 Hz, 1H), 6.52 (d, J=2.1 Hz, 1H), 6.36 (dd, J=8.1, 2.1 Hz, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.69 (d, J=9.0 Hz, 1H), 4.32-4.22 (m, 1H), 4.00-3.66 (m, 4H), 3.77 (s, 3H), 2.10-1.66 (m, 4H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ178.0, 177.9, 162.0, 161.4, 142.9, 142.8, 132.4, 132.3, 128.7, 128.6, 123.6, 123.5 (2C), 123.4, 123.2, 121.0, 120.9, 109.6, 109.3, 107.4 (2C), 96.5, 80.5, 80.4, 76.8, 76.7, 68.2, 68.1, 57.5, 55.5, 44.5 (2C), 29.2, 28.9, 25.6, 25.5; MS (ES+) m/z 352.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].CC([O-])(C)C.[K+].CS([C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=1)(=O)=O.O>C1COCC1>[CH3:29][S:26]([C:23]1[CH:24]=[CH:25][C:20]([O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[N:21][CH:22]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Reactant: N#Cc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc(C#N)cc2)nc1

Procedure:
To 3.04 g of 4-cyanophenol dissolved in a 15 ml THF/15 ml DMSO mixture was added 2.86 g of t-BuOK and then 6 g of 2,5-bis(methylsulfonyl)pyridine, and the resulting mixture heated at 60° C. for 11/2 hrs. After cooling, the reaction mixture was poured into water and the solid which formed collected. Recrystallization from acetonitrile gave purified 4-((5-(methylsulfonyl)-2-pyridinyl)oxy)benzonitrile, m.p. 195°-196° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9].[NH2:16][C:17]1[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=1>>[NH2:16][C:17]1[C:18]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccccc1C(=O)c1ccccn1
Reactant: Nc1cccnc1Cl
Product: Nc1cccnc1Nc1ccccc1C(=O)c1ccccn1

Procedure:
The title compound is prepared by reacting (2-aminophenyl)(2-pyridinyl)methanone, as prepared by Schofield, K., J. Chem. Soc. 1949, 2408-12, with 3-amino-2-chloropyridine.
Reaction SMILES: [Br-:1].[Li+].[CH3:3][O:4][N:5]=[CH:6][C@@H:7]([F:37])[C@H:8]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:9](OC1C=C(Cl)C(Cl)=CC=1Cl)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C.O>O1CCCC1.CN1CCN(C)C1=O>[CH3:3][O:4][N:5]=[CH:6][C@H:7]([F:37])[C@H:8]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:9]([Br:1])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [Br-]
Reactant: CON=C[C@@H](F)[C@H](OCc1ccccc1)[C@@H](COCc1ccccc1)Oc1cc(Cl)c(Cl)cc1Cl
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Product: CON=C[C@H](F)[C@H](OCc1ccccc1)[C@@H](Br)COCc1ccccc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 56.3 %

Procedure:
430 mg of lithium bromide was added to a solution of 1.50 g of (2R,3R,4R)-2-fluoro-3,5-bis(benzyloxy)-4-(2,4,5-trichlorophenoxy)pentanal O-methyloxime in 6 mL of tetrahydrofuran and 5.4 mL of 1,3-dimethyl-2-imidazolidinone, and the obtained mixture was then stirred at 60° C. for 6 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated. The obtained organic layer was washed with a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 75/25), so as to obtain 662 mg of (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis(benzyloxy)pentanal O-methyloxime in the form of a colorless oily product.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:20]1([C@@H:26]([NH2:28])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C@@H:26]([NH:28][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: C[C@H](N)c1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1ccccc1
Reaction time: 8 h
Yield: 57 %

Procedure:
A solution of 2-methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine (0.203 g, 0.74 mmol) and (S)-1-phenylethylamine (0.15 mL, 1.16 mmol) in 2 mL of xylenes was heated to 100° C. After 8 h, the reaction mixture was concentrated and purified by chromatography (silica, 1:1 hexanes: EtOAc, then 1:1 CH2Cl2: EtOAc) to give 0.133 g of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.49 (br s, 1H); 8.39 (d, J=5.5 Hz, 1H); 7.83 (d, J=8.0 Hz, 1H); 7.3-7.5 (m, 8H); 6.79 (d, J=5.5 Hz, 1H); 5.75 (br s, 1H); 5.21 (br s, 1H); 1.65 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)=O.[NH2:15][CH2:16][CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[K+].[K+]>ClCCCl>[NH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([CH2:17][CH2:16][NH:15][CH2:1][C:3]2[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)=[CH:19]1
Reactant: COC(=O)C=Cc1ccc(C=O)cc1
Reactant: NCCc1c[nH]c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: COC(=O)C=Cc1ccc(CNCCc2c[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 39 h
Yield: 83.3 %

Procedure:
To a stirred solution of 1 (3.00 g, 15.77 mmol) and tryptamine (2.78 g, 17.35 mmol) in anhydrous 1,2-dichloroethane (200 mL) under nitrogen was added NaBH(OAc)3 (3.87 g, 17.35 mmol) at room temperature. The reaction mixture was stirred at room temperature for 39 hours, poured into 10% solution of K2CO3 and extracted with CH2Cl2. The organic layer was concentrated to form a residue which was purified by flash chromatography on silica gel (MeOH/CH2Cl2, 10/90) and co-precipitated in a mixture of AcOEt/hexane to afford the title compound 2 (4.39 g, 13.13 mmol, 83% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.78 (s, 1H), 7.70-7.62 (m, 3H), 7.49 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.2 Hz, 2H), 7.33 (dt, J=8.0, 0.9 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 7.06 (ddd, J=7.0, 7.0, 1.2 Hz, 1H), 6.96 (ddd, J=6.9, 6.9, 1.1 Hz, 1H), 6.62 (d, J=16.0 Hz, 1H), 3.79 (s, 2H), 3.75 (s, 3H), 2.91-2.78 (m, 4H), 2.18 (bs, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:10]([O:12]CC)=[O:11])[S:9][C:5]=2[N:4]=[C:3]1[CH2:15][O:16][CH3:17].[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[S:9][C:5]=2[N:4]=[C:3]1[CH2:15][O:16][CH3:17]
Reactant: CCOC(=O)c1cc2c(nc(COC)n2C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCc1nc2sc(C(=O)O)cc2n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.90 g (3.54 mmol) of ethyl 1-methyl-2-methoxymethylthieno[2,3-d]imidazol-5-yl-carboxylate in 30 mL of ethanol were added dropwise 5 mL of 2 N sodium hydroxide solution and the mixture was stirred for 2 hours at ambient temperature. Then the solvent was distilled off in vacuo, the residue was taken up in 5 mL of water and washed with 10 mL of diethylether. The aqueous phase was acidified with 6 mL of 2N hydrochloric acid, cooled to 0° C. and the precipitated crystals are filtered off. Yield: 0.50 g (63% of theory), C9H10N2O3S (226.26); Rf value: 0.21 (silica gel; methylene chloride/ethanol=9:1+a few drops of acetic acid); mass spectrum: (M)+=226.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].CC(C)=O.O.[Cl:15][C:16]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:22]([C:28]([F:31])([F:30])[F:29])=[CH:21][C:17]=1[C:18](Cl)=[O:19].O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:23]=[C:24]([N+:25]([O-:27])=[O:26])[C:16]=2[Cl:15])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reaction time: 18 h
Yield: 93.9 %

Procedure:
To a solution of 3,4-dichloroaniline (2.6 g; 2 eq.) in a 1/1 acetone/water mixture (30 ml) is added dropwise at 0° C. a solution of 2-chloro-3-nitro-5-trifluoromethylbenzoyl chloride (2.3 g; 1 eq.) in acetone (10 ml). After 18 hours at room temperature, 20 ml of water are added. The resulting solid is filtered off by suction, washed with water and dried. 3.1 g of N-(3,4-dichlorophenyl)-2-chloro-3-nitro-5-trifluoromethylbenzamide are obtained (m.p.=202° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([OH:23])([C:19]([F:22])([F:21])[F:20])[CH2:6][C:7]([C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[O:17]C)([CH3:9])[CH3:8])[CH3:2].B(Br)(Br)Br.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([O:3][C:4](=[O:24])[C:5]([OH:23])([C:19]([F:20])([F:21])[F:22])[CH2:6][C:7]([C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[OH:17])([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cc(F)ccc1OC)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(O)(CC(C)(C)c1cc(F)ccc1O)C(F)(F)F
Temperature: 3 °C
Reaction time: 3 h
Yield: 51.5 %

Procedure:
A solution of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester (WO 00/32584) (10.83 g, 30.74 mmol) in dichloromethane (200 ml) is mixed with 1 M boron tribromide-chloroform solution (60 ml) while being cooled in an ice bath, and it is stirred for 3 hours at 2-4° C. The batch is poured onto ice and saturated NaHCO3 solution, and it is stirred for 30 minutes while being cooled with ice. The organic phase is separated, and the aqueous phase is extracted twice more with dichloromethane. The combined, organic extracts are washed with saturated NaCl solution, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography of the residue (silica gel) with hexane-ethyl acetate yields 5.36 g of product. Extraction of the aqueous phase with ethyl acetate yields 4.0 g of product again.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]([CH:21]2[CH2:23][CH2:22]2)[CH2:19][CH3:20])[C:12]=1[N+:24]([O-])=O.Cl[Sn]Cl>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]([CH:21]2[CH2:22][CH2:23]2)[CH2:19][CH3:20])[C:12]=1[NH2:24]
Reactant: CCC(Nc1nccc(-c2cc(C)c(OC)cc2Cl)c1[N+](=O)[O-])C1CC1
Agent: Cl[Sn]Cl
Product: CCC(Nc1nccc(-c2cc(C)c(OC)cc2Cl)c1N)C1CC1
Yield: 96.4 %

Procedure:
[4-(2-Chloro-4-methoxy-5-methyl-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine (90 mg, 0.24 mmol) and SnCl2 (0.13 g, 0.72 mmol) were treated substantially as described in Part D of Example 74a to yield 80 mg (98%) of 4-(2-chloro-4-methoxy-5-methyl-phenyl)-N2-(1-cyclopropyl-propyl)-pyridine-2,3-diamine: MS (EI) m/z 346.22 [(M+H)+, 100].
Reaction SMILES: C(OC([N:6]1[C:14]([NH2:15])=[C:13]2[C:8]([C:9]([NH2:20])=[CH:10][C:11]([C:16]([F:19])([F:18])[F:17])=[CH:12]2)=[N:7]1)=O)C>C(OC(OC(OCC)=O)=O)C>[NH2:15][C:14]1[C:13]2[C:8](=[C:9]([NH2:20])[CH:10]=[C:11]([C:16]([F:18])([F:17])[F:19])[CH:12]=2)[NH:7][N:6]=1
Reactant: CCOC(=O)n1nc2c(N)cc(C(F)(F)F)cc2c1N
Agent: CCOC(=O)OC(=O)OCC
Product: Nc1n[nH]c2c(N)cc(C(F)(F)F)cc12

Procedure:
Analogously to Example 1, 0.1 mol of 3.7-diamino-5-trifluoromethylindazole in 70 ml of pyrocarbonic acid diethyl ester gives 3,7-diamino-5-trifluoromethylindazole-2-carboxylic acid ethyl ester (melting point: 193°-194° C; 90% of theory) in 1 hour at 20°-30° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([OH:23])=O)=[CH:12][CH:11]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:39]1([S:42]([NH2:45])(=[O:44])=[O:43])[CH2:41][CH2:40]1.C1CCN2C(=NCCC2)CC1.Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([NH:45][S:42]([CH:39]2[CH2:41][CH2:40]2)(=[O:44])=[O:43])=[O:23])=[CH:14][CH:15]=1
Reactant: O=C(O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Reactant: NS(=O)(=O)C1CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NS(=O)(=O)C1CC1)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 40.1 %

Procedure:
A solution of 3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-benzoic acid (5.0 g, 13.96 mmol) in THF (100 mL) was treated with CDI (3.37 g, 20.78 mmol), heated at 50° C. for 30 min, cooled to room temperature, added cyclopropanesulfonamide (1.86 g, 15.35 mmol) and DBU (4.2 mL, 28.08 mmol) and heated at 60° C. for 17 h. The reaction mixture was cooled to room temperature, treated with aqueous 2N HCl (50 mL), stirred for 10 min, added water (50 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with conc. HCl (20 mL), water (50 mL), 1/1 water/brine (50 mL), brine (50 mL), dried (MgSO4), filtered, concentrated and recrystallized from methanol to give cyclopropanesulfonic acid 3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-benzoylamide (2.58 g, 40.1%) as a white solid. LC-MS (ES) calculated for C23F18F3NO4S, 461.46; found m/z 460 [M−H]−.
Reaction SMILES: [CH2:1]([S:4]([C:7]1[C:12]2[N:13]([CH2:16][C:17](O)=[O:18])[CH:14]=[N:15][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5])CC.ClC1C(SC)=CC=CC=1[N+]([O-])=O>>[CH3:1][S:4]([C:7]1[C:12]2[N:13]([CH2:16][CH2:17][OH:18])[CH:14]=[N:15][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:5])=[O:6]
Reactant: CCCS(=O)(=O)c1cccc2ncn(CC(=O)O)c12
Agent: CSc1cccc([N+](=O)[O-])c1Cl
Product: CS(=O)(=O)c1cccc2ncn(CCO)c12

Procedure:
This compound was synthesized according to the procedure described for the synthesis of [7-(propylsulfonyl)-1H-benzimidazol-1-yl]acetic acid starting from 2-chloro-1-nitro-3-(methylthio)benzene. MS (ESI) m/z 241 [M+H]. 1H NMR (400 MHz, DMSO-D6) δ 8.39 (s, 1H), 8.05 (dd, J=8.1, 1.0 Hz, 1H), 7.86 (dd, J=7.8, 1.0 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 5.01 (t, J=5.1 Hz, 1H), 4.71 (t, J=5.2 Hz, 2H), 3.79-3.76 (m, 2H), 3.46 (s, 3H).