Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25]Br)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8].[N:31]1([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25][N:34]2[CH2:35][CH2:36][N:31]([C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)[CH2:32][CH2:33]2)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8]
Reactant: COc1ccccc1CNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: COc1ccccc1CNC(=O)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-2-methoxy-benzylamide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][CH:39]1[CH2:43][CH2:42][CH2:41][NH:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:40]3[CH2:41][CH2:42][CH2:43][CH:39]3[CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CC1CCCN1
Product: CC1CCCN1c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 2-methylpyrrolidine according to conditions described in general procedure C. Mp: 93-94° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.64 (bs, 2 H), 1.11 (bs, 1 H), 1.58-1.61 (m, 6 H), 1.73-1.84 (m, 4 H), 3.27-3.36 (m, 7 H), 6.24 (s, 1 H), 6.95 (d, J=12.8 Hz, 1 H), 7.14 (d, J=8.4 Hz, 1 H), 7.39 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.53-7.63 (m, 3 H), 7.81 (d, J=6.5 Hz, 1 H), 7.96 (d, J=7.7 Hz, 1 H), 8.22 (d, J=5.5 Hz, 1 H), 10.42 (s, 1 H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:23]N1C(=O)CCC1=O>ClCCl>[Br:23][C:12]1[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:22])[F:21])=[N:17]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(C(F)(F)F)nc12
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c2ccc(C(F)(F)F)nc12
Temperature: 20 °C
Reaction time: 0.42 h
Yield: 98.5 %

Procedure:
A solution of 8-(tert-butyldimethylsilanyloxy)-2-trifluoromethylquinoline (17.5 g) in dichloromethane (100 ml) was treated with N-bromosuccinimide (10.5 g) at 15° C. The mixture was stirred at 20° C. for 25 minutes, washed with 1% sodium sulfite solution (100 ml), and water (50 ml). The organic layer was separated, dried over magnesium sulfate, filtered and the solvent removed in vacuo to give the product (21.4 g) as a dark oil.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:20]3[N:24]=[C:23]([CH3:25])[O:22][N:21]=3)([CH3:19])[C:14]([O:16]CC)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.O>C1COCC1>[CH:1]1([C:4]2[C:5]([O:26][CH2:27][C:28]([F:29])([F:30])[F:31])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:20]3[N:24]=[C:23]([CH3:25])[O:22][N:21]=3)([CH3:19])[C:14]([OH:16])=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)c1noc(C)n1
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(=O)O)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To a solution of ethyl 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoate (example 147b, 0.295 g, 667 μmol) in a mixture of THF (4 ml)/Water (2 ml) was added LiOH monohydrate (83.9 mg, 2.00 mmol). The reaction mixture was sonicated for a few minutes to dissolved solids. The reaction was stirred at room temperature overnight. The reaction was then concentrated in vacuo and the obtained residue was dissolved in ethyl acetate. The organic phase was extracted with a 0.1M aqueous solution hydrochloric acid. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. Combined organic phases were dried over sodium sulfate and evaporated down to dryness to yield the title compound (280 mg, 100%) as a crude yellow oil which was used without any purification. MS (ESI, m/z): 415.5 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:16])[C@@H:4]([OH:15])[CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].O.[OH-].[Li+:19].O>CO>[C:11]([O:10][C:8]([NH:7][CH2:6][CH2:5][C@H:4]([OH:15])[C:3]([O-:16])=[O:2])=[O:9])([CH3:14])([CH3:12])[CH3:13].[Li+:19]
Reactant: COC(=O)[C@@H](O)CCNC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCC[C@H](O)C(=O)[O-]
Yield: 85.8 %

Procedure:
A solution of (S)-4-tert-butoxycarbonylamino-2-hydroxybutyric acid methyl ester (1.52 g, 6.52 mmol) in methanol (20.0 mL) was treated with lithium hydroxide monohydrate (273.8 mg, 6.52 mmol) and water (2.0 mL) for 30 min, concentrated, and dried under vacuum to give a white solid (1.26 g)
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:22](OC)(=[O:27])[CH2:23][C:24]([CH3:26])=[O:25].[H-].[Na+].C([Li])CCC>C1COCC1>[OH:25][C:24]1[CH2:26][C:17]([CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)([CH:18]([CH3:19])[CH3:20])[O:21][C:22](=[O:27])[CH:23]=1
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)C(=O)CCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1(CCc2ccc(O)cc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 6 using 40 g (142 mmol) of 1-(4-benzyloxyphenyl)-4-methyl-pentan-3-one (prepared in Example F), 41.2 g (355 mmol) of methyl acetoacetate, 14.2 g (355 mmol) of 60% NaH dispersion in mineral oil, 216 mL (1.64M, 355 mmol) of n-butyllithium and 700 mL of THF. The reaction mixture was quenched with 0.1N HCl and the product was extracted into EtOAc. The organic layer was dried (MgSO4), and the solvents were evaporated.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:16][C:17]2[CH:24]=[CH:23][C:20]([CH3:21])=[CH:19][CH:18]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(Cn2ccc(OCc3ccccc3)cc2=O)cc1

Procedure:
4-Benzyloxy-2(1H)-pyridone (3.0 g, 0.015 mol), 4-methylbenzyl bromide (3.15 g, 0.17 mol), and potassium carbonate (3.0 g, 0.022 mol) were heated at 80° C. for 2 hours. Contents were allowed to cool, diluted with water and a solid (5.52 g) was filtered. FABHRMS m/z 306.1494 (M+H, C20H20NO2 requires 306.1494). 1H NMR (CDCl3/300 MHz): 7.50-7.40 (m, 5H); 7.20-7.05 (m, 5H); 6.07-6.00 (m, 1H); 5.95-5.90 (m, 1H); 5.05 (s, 2H); 5.00 (s, 2H); 2.32 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@@H:24]3[C@H:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH:27]=[CH:26][CH2:25]3)(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:37](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:37][N:23]([S:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)=[CH:19][CH:18]=1)(=[O:22])=[O:21])[C@@H:24]1[C@H:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH:27]=[CH:26][CH2:25]1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CC=CC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@H]3CC=CC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a stirred solution of 325.5 mg (0.64 mmol) of tert-butyl cis-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohex-3-ene-1-carboxylate in 4 mL of N,N-dimethylformamide was added 353.8 mg of potassium carbonate, followed by 184.9 mg (1.28 mmol) of iodomethane. The suspension was stirred at room temperature overnight. After removal of the volatile material, 80 mL of ethyl acetate was added. The organic phase was washed with water and saturated sodium chloride solution, and dried over magnesium sulfate. The residue was chromatographed on silica gel eluting with ethyl acetate/hexane (3:7) to give 292.1 mg of tert-butyl cis-6-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohex-3-ene-1-carboxylate in 87% yield. MS: 523.1 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12](O)=[O:13])[C:3]1=[O:15].C(Cl)(=O)C([Cl:19])=O.CN(C)C=O>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([Cl:19])=[O:13])[C:3]1=[O:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1c(=O)c(C(=O)O)cc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(=O)c(C(=O)Cl)cc2ccccc21
Temperature: 40 °C
Reaction time: 1 h

Procedure:
0.76 g (3.7 mmol) of 1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid was dissolved in dichloromethane (50 mL), and 1.0 mL (12 mmol) of oxalyl chloride was added to the above solution. Two droplets of N,N-dimethylformamide were added to this mixture, and the resulting mixture was stirred for 1 hour at 40° C. The reaction solution was concentrated under reduced pressure, and thus 1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in acetonitrile (30 mL), and this solution was added to an acetonitrile (50 mL) solution of 0.46 g (4.1 mmol) of 1,3-cyclohexanedione and 0.63 mL (4.5 mmol) of triethylamine under ice cooling. The mixture was stirred overnight at room temperature. This reaction mixture was poured into water and was extracted with ethyl acetate. The organic phase was washed with water, an aqueous solution of sodium hydrogen carbonate, and water in this order, and then was dried and concentrated. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:4 to 1:0), and thus 0.48 g (yield: 43%) of the title compound was obtained as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27]Br)[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].[CH3:30][O:31][P:32]([O:35]C)[O:33][CH3:34]>>[CH3:1][O:2][C:3](=[O:29])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27][P:32]([O:33][CH3:34])([O:31][CH3:30])=[O:35])[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21]
Reactant: COP(OC)OC
Reactant: COC(=O)C(CC=CCBr)CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O
Product: COC(=O)C(CC=CCP(=O)(OC)OC)CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O
Temperature: 25 °C
Yield: 88.2 %

Procedure:
Under a N2 atmosphere, a solution of 2-(4-bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester (490 mg, 1.05 mmol) in trimethylphosphite (2.5 mL, 21.1 mmol) was heated at 120° C. for 1 hour. The reaction was allowed to cool to room temperature. The reaction mixture was worked up by removal of the solvent in vacuo followed by chromatography using EtOAc-hexanes to provide 460 mg (88%) of the product as an oil. 1H NMR (300 MHz, CDCl3) δ 1.77 (s, 3H), 2.081-2.31 (m, 4H), 2.15 (s, 3H), 2.52 (d, 1H, J=22 Hz), 2.54 (d, 1H, J=22 Hz), 2.55-2.63 (m, 1H), 3.36 (d, 2H, J=7 Hz), 3.57 (s, 3H), 3.72 (d, 6H, J=11 Hz), 3.76 (s, 3H), 5.20 (s, 2H), 5.20-5.26 (m, 1H), 5.36-5.56 (m, 2H), 7.69 (s, 1H) ppm; 31p (121.4 MHz, CDCl3) δ 30.1 ppm; MS (m/z) 497.2 [M+H]+, 519.2 [M+Na]+.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[N+:17]([O-:19])=[O:18])[N:5]=[CH:4][C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(Br)(Br)[Br:26]>>[Br:26][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[N+:17]([O-:19])=[O:18])[N:5]=[CH:4][C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1cnn(-c2ccc(C(F)(F)F)cc2[N+](=O)[O-])c1N
Reactant: BrC(Br)Br
Product: CCOC(=O)c1cnn(-c2ccc(C(F)(F)F)cc2[N+](=O)[O-])c1Br

Procedure:
5-Amino-4-ethoxycarbonyl-1-(4-trifluoromethyl-2-nitrophenyl)-1H-pyrazole, was treated with bromoform in a similar manner to Example 11, to give ethyl 5-bromo-1-(4-trifluoromethyl-2-nitrophenyl)-1H-pyrazole-4-carboxylate. This was then reduced with zirconium borohydride to give [5-bromo-1-(4-trifluoromethyl-2nitrophenyl)-1H-pyrazol-4-yl]methanol, which was oxidised in a similar manner to that described in Example 4, to give 5-bromo-1-(4-trifluoromethyl-2-nitrophenyl)-1H-pyrazole-4-carboxaldehyde, which was converted, as described in Example 1, to 5-bromo-1-(4-trifluoromethyl-2-nitrophenyl)-4-[(2-amino-1,2-dicyanoethenylimino)-methyl]-1H-pyrazole, mp 195°-198°, which was cyclised to give 5-bromo-1-(4-trifluoromethyl-2-nitrophenyl)-4-(4,5-dicyano-1H-imidazol-2-yl)-1H-pyrazole, m.p. 86°-90°. (compound 34)
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=O.[CH:17]1([C:20](=[O:25])[CH2:21][C:22](=O)[CH3:23])[CH2:19][CH2:18]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:17]1([C:20]([C:21]2[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)=[C:3]3[C:4]4[CH2:9][CH2:8][CH2:7][C:5]=4[S:6][C:2]3=[N:1][C:22]=2[CH3:23])=[O:25])[CH2:19][CH2:18]1
Reactant: CC(=O)CC(=O)C1CC1
Reactant: Nc1sc2c(c1C(=O)c1ccco1)CCC2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccco2)c1C(=O)C1CC1)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 20.2 %

Procedure:
To a stirred solution of 60 mg (0.26 mmol) (2-amino-5,6-dihydro-4H-cyclopenta [b]thiophen-3-yl)-furan-2-yl-methanone (the preparation of which is described in example 18) in 2 ml acetic acid was added 43 mg (0.34 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 17 mg (21%) cyclopropyl-(4-furan-2-yl-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl)-methanone as a light brown solid. ES-MS m/e (%): 324 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10].N1C=CC=CC=1.[CH2:21]([O:23][C:24](=[O:34])[CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:22]>ClCCl>[CH2:21]([O:23][C:24](=[O:34])[CH2:25][N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[S:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:14])([F:13])[F:1])(=[O:11])=[O:10])[CH3:22]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)CNCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a stirred solution of 2-trifluoromethylbenzenesulfonyl chloride (3.8 g) in dichloromethane (100 mL) under argon was added pyridine (14 mL). A solution of N-benzylglycine ethylester (2 g) in dichloromethane (40 mL) was added slowly. The mixture was stirred at r.t. overnight and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, cyclohexane to cyclohexane/ethyl acetate 1:1) to give [benzyl-(2-trifluoromethyl-benzenesulfonyl)-amino]-acetic acid ethyl ester (2.61 g) as a colorless oil. MS: 402.1 ([M+H]+)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[CH:2]1.CN(C)C=O.Br[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O>[C:13]([CH2:12][N:3]1[CH2:4][CH2:5][N:1]=[CH:2]1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: C1=NCCN1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1C=NCC1)OCc1ccccc1

Procedure:
To a solution of 14.0 g. (0.2 mole) of imidazoline in 150 ml. of dry dimethylformamide is added dropwise with cooling 22.9 g. (0.1 mole) of benzyl bromoacetate. When the addition is complete, the reaction is warmed to 50°-60° C. for several hours, and is then cooled and diluted with water (250 ml.). The product is extracted with diethyl ether, and the extracts are combined and washed several times with a saturated brine solution. The ether phase is dried over sodium sulfate and concentrated to an oil, which is used in the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](O)([CH3:7])[CH3:6].C1(C)C=CC=CC=1.C(O)(=O)C(O)=O>O>[CH3:12][C:3]1[C:4]([C:5]([CH3:7])=[CH2:6])=[CH:9][CH:10]=[CH:11][C:2]=1[Cl:1]
Reactant: Cc1c(Cl)cccc1C(C)(C)O
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)c1cccc(Cl)c1C
Yield: 53.4 %

Procedure:
190 g of 3-chloro-2-methyl-alpha,alpha-dimethylbenzyl alcohol are refluxed with 1.5 l of toluene and 370 g of oxalic acid under a water separator until no more water separates off. The oxalic acid is filtered off under suction and the filtrate is washed with sodium bicarbonate solution, dried over sodium sulfate and evaporated down. Fractional distillation of the residue gives 91.5 g of the desired compound, which is listed in Table 1 as Example 2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[N:9][CH:10]=2)[CH:7]=1.C(=O)(O)[O-].[Na+].[I:18]I>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[N:9][C:10]=2[I:18])[CH:7]=1
Reactant: OCc1ncc2ccc(F)cn12
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1nc(I)c2ccc(F)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
In a round-bottomed flask, (6-fluoro-imidazo[1,5-a]pyridin-3-yl)-methanol (225 mg, 1.15 mmol) was dissolved in ethanol (2 ml) and water (1 ml). Sodium bicarbonate (341 mg, 4.06 mmol) was added followed by iodine (383 mg, 1.51 mmol). The dark brown suspension was stirred at room temperature for 3 h then quenched with 10% Na2S2O3-solution and extracted with EtOAc (2×). The organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient 0-40% EtOAc) to provide 157 mg (50%, 2 steps) of (6-fluoro-1-iodo-imidazo[1,5-a]pyridin-3-yl)-methanol as a light yellow solid.
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([C:15]1[NH:19][C:18]2[S:20][C:21]([Cl:23])=[CH:22][C:17]=2[CH:16]=1)([OH:14])=O.[NH2:24][CH:25]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH2:35][CH2:36][S:37][CH3:38])[C:26]1=[O:39].ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[Cl:23][C:21]1[S:20][C:18]2[NH:19][C:15]([C:12]([NH:24][CH:25]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH2:35][CH2:36][S:37][CH3:38])[C:26]3=[O:39])=[O:14])=[CH:16][C:17]=2[CH:22]=1
Reactant: CSCCN1C(=O)C(N)Cc2ccccc21
Reactant: O=C(O)c1cc2cc(Cl)sc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CSCCN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reaction time: 18 h
Yield: 39.6 %

Procedure:
EDCI (915 mg, 4.77 mmol) was added to a suspension of 5-Carboxy-2-chloro-6H-thieno[2,3-b]pyrrole (801 mg, 3.97 mmol), 3-amino-1-[2-(methylthio)ethyl]-3,4-dihydroquinolin-2(1H)-one (Method 16; 1.40 g, 3.97 mmol) and 1-hydroxybenzotriazole (537 mg, 3.97 mmol) in DCM (60 mL) and the reaction stirred for 18 hours. The reaction was evaporated and the residue was partitioned between DCM (100 mL) and water (25 mL). The organic layer was then separated, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (DCM to DCM:EtOAc (9:1)) to afford the title compound (660 mg, 40%) as a white solid.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([C:18]([OH:20])=O)[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][O:22][CH2:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[NH2:29]>>[CH:1]1([C:6]2[CH:7]=[C:8]([C:18]([NH:29][N:25]3[CH2:26][CH2:27][CH2:28][C@H:24]3[CH2:23][O:22][CH3:21])=[O:20])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC[C@@H]1CCCN1N
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Product: COC[C@@H]1CCCN1NC(=O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 14c) and (2S)-2-(methoxymethyl)-1-pyrrolidinamine (CAN 59983-39-0) as starting materials; MS (EI) 402.3 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35]CC3C=CC=CC=3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[C:30]([OH:35])=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccc(OCc3ccccc3)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc2c(C)ccc(O)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
Prepared in analogous manner to Example 57 from tert.butyl 4'-[(2-n-butyl-4-methyl-7-benzyloxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and hydrogen in the presence of palladium hydroxide on carbon in methanol.
Reaction SMILES: [CH:1]1([C:5]2[C:6]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:20][S:21]([CH2:24][C:25]([NH2:33])([CH3:32])[C:26]1[N:30]=[C:29]([CH3:31])[O:28][N:27]=1)(=[O:23])=[O:22]>>[CH3:20][S:21]([CH2:24][C:25]([NH:33][C:11]([C:8]1[CH:7]=[C:6]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)=[CH:10][N:9]=1)=[O:13])([CH3:32])[C:26]1[N:30]=[C:29]([CH3:31])[O:28][N:27]=1)(=[O:22])=[O:23]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CCC2)cn1
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OCC(F)(F)F)c(C3CCC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 23b, using 5-Cyclobutyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 108f) and 2-Methanesulfonyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 109d) as starting materials and isolated (62 mg, 45%) as colorless oil; MS (ESI, m/z): 477.6 (M+H+).