Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([NH:10][CH2:11][CH2:12][OH:13])[CH:7]=[C:6]([NH:14][C:15]2[N:20]=[C:19]([O:21][CH2:22][C:23]#[CH:24])[C:18]([Br:25])=[CH:17][N:16]=2)[CH:5]=1>O1CCCC1.[OH-].[Na+]>[Br:25][C:18]1[C:19]([O:21][CH2:22][C:23]#[CH:24])=[N:20][C:15]([NH:14][C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([NH:10][CH2:11][CH2:12][OH:13])[CH:7]=2)[C:3]([OH:26])=[O:2])=[N:16][CH:17]=1
Reactant: C#CCOc1nc(Nc2cc(NCCO)cc(C(=O)OC)c2)ncc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C#CCOc1nc(Nc2cc(NCCO)cc(C(=O)O)c2)ncc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.5 %

Procedure:
Methyl3-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]-5-[(2-hydroxyethyl)amino]benzoate (350 mg) in a mixture of tetrahydrofuran (6 ml) and sodium hydroxide solution (2 n; 6 ml) was stirred for 48 h at room temperature. After evaporation the residue was diluted with water and acidified until the product precipitated Filtration and drying yielded the title compound (340 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[C:4](=[O:13])[N:3]=1.N1C=CC=CC=1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[CH:10]1([CH2:9][N:5]2[CH:6]=[C:7]([F:8])[C:2]([NH:1][C:21](=[O:22])[O:23][CH2:24][CH3:25])=[N:3][C:4]2=[O:13])[CH2:12][CH2:11]1
Reactant: Nc1nc(=O)n(CC2CC2)cc1F
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1nc(=O)n(CC2CC2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.2 %

Procedure:
4-Amino-1-(cyclopropylmethyl)-5-fluoropyrimidin-2(1H)-one (200 mg, 1.09 mmol) was dissolved in CH2Cl2 (0.90 mL) and pyridine (172.4 mg, 2.18 mmol) at room temperature and then was cooled to −20° C. Ethyl chloroformate (166 mg, 1.53 mmol) was then added to the reaction mixture dropwise, keeping the reaction temperature between −20 and −5° C. After the addition was complete, the reaction was allowed to warm slowly to room temperature and stirred for 2 h. The reaction mixture was filtered, and the solids were rinsed with EtOAc (15 mL×3). The filtrate was concentrated in vacuo, and purified by preparative thin layer chromatography, to afford ethyl 1-(cyclopropylmethyl)-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-ylcarbamate (70 mg, 30%) as a pale yellow solid: mp 90-92° C.; 1H NMR (400 MHz, methanol-d4) δ 8.20 (s, 1H), 4.26 (q, J=7.1 Hz, 2H), 3.70 (d, J=7.2 Hz, 2H), 1.24-1.36 (m, 4H), 0.65-0.57 (m, 2H), 0.46-0.39 (m, 2H); ESIMS m/z 256 ([M+H]+).
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:9](=[O:25])[C:10]3[N:11]=[CH:12][N:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([OH:21])=O)[C:14]=3[N:15]=2)=[CH:3][CH:2]=1.[NH4+:39].[OH-]>O=S(Cl)Cl.O>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:9](=[O:25])[C:10]3[N:11]=[CH:12][N:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([NH2:39])=[O:21])[C:14]=3[N:15]=2)=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccccc5)cc4)nc32)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccccc5)cc4)nc32)c1
Temperature: 25 °C

Procedure:
A solution of 3-[2-biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzoic acid (40 mg, 0.077 mmol) in SOCl2 (1 mL) was heated at 70° C. for 1 h. The reaction mixture was allowed to cool to room temperature and poured into a 50% aqueous solution of NH4OH (15 mL). The resulting mixture was diluted with H2O and extracted with CH2Cl2. The combined organics were dried (MgSO4), filtered, and concentrated. The crude material was purified by flash column chromatography (silica gel, 5% MeOH/CH2Cl2) to give the title compound 3-[2-biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzamide as a white solid. 1H NMR (CDCl3) δ (ppm) 8.67 (s, 1H), 8.29 (t, 1H), 8.15 (br s, 1H), 8.02 (d, 1H), 7.98 (d, 1H), 7.71 (t, 1H), 7.64 (d, 2H), 7.58 (d, 3H), 7.46 (br s, 2H), 7.44 (m, 6H), 7.37 (m, 1H); HPLC-MS calculated for C30H20ClN5O2 (M+H+): 518.1. Found 518.1.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([NH:15][N:16]=[C:17]([C:19]2[C:23]([OH:24])=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)[S:21][CH:20]=2)[CH3:18])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.Cl>CN1CCCC1=O>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:22]2[S:21][CH:20]=[C:19]([C:17](=[N:16][NH:15][C:13](=[O:14])[C:11]3[CH:10]=[CH:9][C:5]([C:6]([N:54]4[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]4)=[O:7])=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH3:18])[C:23]=2[OH:24])=[CH:30][CH:29]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(=NNC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: CN1CCNCC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(=NNC(=O)c1ccc(C(=O)N2CCN(C)CC2)c([N+](=O)[O-])c1)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Reaction time: 2 h
Yield: 10 %

Procedure:
To a N-methyl-2-pyrrolidinone (1.0 mL) solution of 2-nitro-4-[(2-{1-[5-(4-t-butylphenyl)-4-hydroxy-3-thienyl]-ethylidene}hydrazino)carbonyl]benzoic acid (50 mg, 0.10 mmol, see the synthetic example 47) and triethylamine (16 μL, 0.11 mmol) was added isobutyl chloroformate (26 μL, 0.20 mmol) at 0° C. The reaction mixture was stirred for 2 hours at this temperature, and then N-methyl piperazine (45 μL, 0.40 mmol) was added. After stirring for 1 hour at room temperature, the reaction mixture was acidified with 1M aqueous HCl solution (1.0 mL) and concentrated under the reduced pressure. To the residue was added water, then the precipitate was collected by filtration, washed with water, isopropanol and methanol, then dried by means of a vacuum pump to give the desired product as a pale yellow solid (yield 10%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li+].CC([N-]C(C)C)C.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH:29]=[O:30])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH:29]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[Br:1])[OH:30])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Brc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccncc2Br)CC1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 70.2 %

Procedure:
To a cold (−90° C.) solution of 3-bromo pyridine (741 mg, 4.7 mmol) in freshly distilled THF (18 ml) was added LDA (2.0M, 2.6 mL, 5.2 mmol). The mixture was stirred under N2 for 20 min. A solution of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.34 mmol) was added slowly to maintain the bath temperature below −80° C. The reaction was continued at below −80° C. for 30 min, warmed to −20° C. within 30 min and quenched with saturated aqueous NH4Cl (10 mL). Work-up and purification gave 4-[(3-bromo-pyridin-4-yl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester (610 mg, 70%) as colourless oil.
Reaction SMILES: [OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][CH:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:37]4[CH2:38][CH2:39][CH:35]([F:34])[CH2:36]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1
Reactant: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: FC1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(F)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.16 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H). m/z: 420 [M+H]
Reaction SMILES: [C:1]([O:4][CH2:5]/[CH:6]=[C:7](\[CH3:16])/[CH2:8]OC1CCCCO1)(=[O:3])[CH3:2].C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]([O:4][CH2:5]/[CH:6]=[C:7](\[CH3:16])/[CH2:8][Br:18])(=[O:3])[CH3:2]
Reactant: CC(=O)OC/C=C(\C)COC1CCCCO1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)OC/C=C(\C)CBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 460 mg (2.0 mmol) of (E)-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)but-2-enyl acetate in 20 ml of CH2Cl2 was added a solution of 1.33 g (4 mmol) of CBr4 in 10 ml of CH2Cl2. The solution was cooled to 0° C. and a solution of 1.05 g (4 mmol) of triphenylphosphine was added dropwise. The solution was allowed to warm up to room temperature for 6 hours and stirred at the same temperature for further 1 hour. The precipitate was filtered and the filtrate was evaporated. The residue was purified by chromatography on silica gel using Heptane/EtOAc (8/2) as eluent. 314 mg (1.52 mmol, 76%) of (E)-4-bromo-3-methylbut-2-enyl acetate were isolated as colourless oil.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:15]=[CH:14][C:13]([C:3]#[C:2][CH2:1][OH:4])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(Br)ccc1Br
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#CCO)ccc1C#CCO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.3 %

Procedure:
Pd(Ph3P)4 (1.95 g), CuBrSMe2 (0.75 g) and propargyl alcohol (5.35 ml, 70.0 mmol) are added successively to a solution of methyl 2,5-dibromobenzoate (10.0 g, 34.0 mmol) in triethylamine (235 ml), and the mixture is stirred at RT for 10 min and then under reflux at 80° C. for 3 h. After cooling, the reaction mixture is filtered off with suction through kieselguhr, and the filter cake is washed with ethyl acetate (50 ml). The organic phase is concentrated under reduced pressure. Further purification is carried out by chromatography [toluene/acetone (8:2)] on a silica gel column. This gives the title compound (6.0 g) as a colorless solid. TLC, silica gel (glass plates), [toluene/acetone (8:2)], Rf=0.16.
Reaction SMILES: [C:1](=[O:15])(OC(Cl)C(Cl)(Cl)Cl)[O:2][CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[F-].[K+].[F:18]C([O-])=O>C(#N)C1C=CC=CC=1>[F:18][C:1]([O:2][CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:15]
Reactant: CC(C)(C)COC(=O)OC(Cl)C(Cl)(Cl)Cl
Reactant: O=C([O-])F
Agent: [F-]
Agent: [K+]
Solvent: N#Cc1ccccc1
Product: CC(C)(C)COC(=O)F
Temperature: 65 °C
Yield: 76 %

Procedure:
In this experiment, neopentyl 1,2,2,2-tetrachloroethyl carbonate is used as the starting material. A mixture of 3.3 g (0.011 mole) of neopentyl 1,2,2,2-tetrachloroethyl carbonate, 1 g (0.017 mole) of anhydrous KF, 5 g (0.001 mole) of polyethyleneglycol monomethylether (average molecular weight 5000 Aldrich) and 10 cc of benzonitrile is heated under stirring at 65° C. (oil bath). The reaction is stopped at the end of 34 hours. By infrared and NMR analysis it is determined that the fluoroformate is obtained in a 76% yield.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1>>[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:7]([C:3]4[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=4)=[O:9])[CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: Cn1cccc1C(=O)O
Product: Cn1cccc1C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 9, making variations only as required to use 1-methyl-1H-pyrrole-2-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)-amide, the title compound was obtained as a white powder (51.8% yield). 1H NMR (500 MHz, CDCl3) δ 8.07, 8.01, 7.00, 6.75, 6.40, 6.12, 4.00-3.80, 3.58, 1.52, 0.76, 0.48, 0.10. MS (ES+) m/z 383 (M+1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[NH:49][C:50]([C:52]1[C:53]2[CH:54]=[CH:55][N:56]=[CH:57][C:58]=2[CH:59]=[CH:60][CH:61]=1)=[NH:51]>CN(C=O)C>[F:13][C:2]([F:1])([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[O:10][N:51]=[C:50]([C:52]3[CH:61]=[CH:60][CH:59]=[C:58]4[C:53]=3[CH:54]=[CH:55][N:56]=[CH:57]4)[N:49]=2)=[CH:11][CH:12]=1
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Reactant: N=C(NO)c1cccc2cnccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)Oc1ccc(-c2nc(-c3cccc4cnccc34)no2)cc1
Temperature: 120 °C
Yield: 46 %

Procedure:
4-[(Trifluoromethyl)oxy]benzoic acid (Aldrich; 132 mg, 0.642 mmol) was stirred in DMF (1 ml) with HATU (244 mg, 0.642 mmol) and DIPEA (0.28 ml, 1.605 mmol) at room temperature for 30 mins before adding a solution of N-hydroxy-5-isoquinolinecarboximidamide (D1, 100 mg, 0.535 mmol) in DMF (1 ml). The resulting mixture was heated to 120° C. for 30 mins in a Biotage Initiator microwave. The solvent was removed under vacuum and the residue was purified by column chromatography on silica, eluting with 0-80% ethyl acetate in cyclohexane. The relevant fractions were combined and concentrated under vacuum to give the title compound as a white solid (88 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]([O:12]C(C)(C)C)=[O:11])[CH2:9][CH2:8]2)[CH:6]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]([OH:12])=[O:11])[CH2:8][CH2:9]2)[CH:6]=1
Reactant: Cc1cnn(C2(C(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnn(C2(C(=O)O)CC2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 220.8 %

Procedure:
Into a 100 mL pear shaped flask containing tert-butyl 1-(4-methyl-1H-pyrazol-1-yl)cyclopropanecarboxylate (218 mg, 0.981 mmol) were added dichloromethane (5 mL) and trifluoroacetic acid (0.2 mL, 3 mmol). The clear solution was stirred at room temperature for 30 minutes after which another 0.3 mL of trifluoroacetic acid were added. The mixture was stirred at room temperature for 45 minutes and another 0.3 mL of trifluoroacetic acid were added. The mixture was stirred at room temperature for 18 h. The solvent and excess of trifluoroacetic acid were removed under reduced pressure to afford the title compound (360 mg). The material was used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.78 (m, 2H), 2.02 (m, 2H), 2.17 (s, 3H), 7.54 (s, 1H), 7.74 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][N:14](C(=O)C4C(Cl)=CC=CC=4Cl)[C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C1COCC1.N>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Yield: 74 %

Procedure:
Crude compound 9 and THF (6 L) were added to a 12 L round-bottom flask and stirred until the clear solution was obtained. A solution of ammonia in methanol (1.24 L; 7M) was added and stirred for 24 h at 28-35° C. The reaction mixture was concentrated to near dryness after with methanol was added and concentrated at 45-50° C. The separated solid was filtered and dried at 45-50° C. under vacuum to obtain crude compound 10 (601.7 g; Purity=≧95%; Yield=85.4%). Recrystallization of the crude in acetone/methanol (2:1) provided compound 10 in 74% yield with a purity of 98.5%. 1H NMR (DMSO-d6): δ (ppm) 9.78 (s, 1H), 8.72-8.73 (d, J=2.2 Hz, 1H), 8.65 (brs, 1H), 8.26 (s, 1H), 7.79-7.82 (d, J=8.5 Hz, 2H), 7.57-7.61 (m, 3H), 7.28-7.32 (t, J=8.3 Hz, 1H), 2.50-2.52 (m, 2H), 1.73-1.78 (m, 2H), and 0.96-0.98 (t, 3H). MS (ESI) [M+H+]+=490.1 and 492.1.
Reaction SMILES: [CH2:1]1[S:3][CH:2]1[CH2:4]Cl.[C:6]([O:10][C:11](=[O:19])[NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:6]([O:10][C:11](=[O:19])[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:4][CH:2]2[CH2:1][S:3]2)[CH2:15][CH2:14]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: ClCC1CS1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(CC2CS2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 114 %

Procedure:
Epithiochlorohydrine (268 mg, 2.40 mmol, 1.0 eq) is added at room temperature to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (500 mg, 2.40 mmol, 1.0 eq) in N,N-dimethylformamide (15 mL), followed by potassium carbonate (335 mg, 2.40 mmol, 1.0 eq). After 24 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×20 mL) and water (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford (1-thiiranylmethyl-piperidin-4-yl)-carbamic acid tert-butyl ester as a white solid (745 mg, 57% yield).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[N:18]=[N:19][N:20](C3CCCCO3)[N:21]=2)=[CH:7][CH:6]=1)C.C(O)C.Cl>O>[NH:21]1[C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:8]2[CH:9]=[CH:10][C:5]([CH:4]=[O:3])=[CH:6][CH:7]=2)=[N:18][N:19]=[N:20]1
Reactant: CCOC(OCC)c1ccc(-c2ccccc2-c2nnn(C3CCCCO3)n2)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
To 5-(4′-diethoxymethyl-biphenyl-2-yl)-2-(tetrahydropyran-2-yl)-2H-tetrazole (0.408 g; 1.00 mmol) are added 94% ethanol (2.5 mL) and a 2N aqueous solution of hydrochloric acid (0.5 mL; 1.0 mmol). The resulting solution is heated to 45° C. for 3 hours. After the addition of water (about 2 mL) the mixture is allowed to cool down to room temperature and then stirred at 0 to 5° C. for 30 minutes. The resulting suspension is filtered and the solids are washed with a small amount of water, dried in vacuo at 40° C. to afford 2′-(1H-tetrazol-5-yl)biphenyl-4-carbaldehyde as white, crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:5]=[C:4]([CH2:20][C:21]([O:23]CC)=[O:22])[C:3]=1[C:26]([O:28]CC)=[O:27]>O>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:5]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[C:3]=1[C:26]([OH:28])=[O:27]
Reactant: CCOC(=O)Cc1nc2cccc(CCC3CCCCC3)c2c(N)c1C(=O)OCC
Solvent: O
Product: Nc1c(C(=O)O)c(CC(=O)O)nc2cccc(CCC3CCCCC3)c12

Procedure:
Prepared as in Example 1 from ethyl 4-amino-5-(2-cyclohexylethyl)-2-(2-ethoxy-2-oxoethyl)quinoline-3-carboxylate (Example 113a) as an orange solid (69%). 1H NR (400 MHz, DMSO-d6) δ 0.89-0.92 (m, 2H), 1.14-1.29 (m, 4H), 1.44-1.49 (m, 2H), 1.56-1.66 (m, 4H), 1.73-1.76 (m, 1H), 3.15 (t, J=8.0 Hz, 2H), 3.70 (s, 2H), 7.09-7.11 (m, 1H), 7.38-7.42 (m, 1H), 7.46-7.51 (m, 2H). MS 338 (MH+—H2O).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][NH:9][C:10]=2[CH:11]=[C:12](Br)[CH:13]=1)=[O:4].[CH3:15]N(C=O)C.CB1OB(C)OB(C)O1.C([O-])([O-])=O.[Na+].[Na+]>O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][NH:9][C:10]=2[CH:11]=[C:12]([CH3:15])[CH:13]=1)=[O:4]
Reactant: COC(=O)c1cc(Br)cc2[nH]ccc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)cc2[nH]ccc12
Temperature: 120 °C
Yield: 50 %

Procedure:
A reaction tube was charged with 6-bromo-1H-indole-4-carboxylic acid methyl ester (635 mg, 2.5 mmol) and Pd(PPh3)4 (15.7 mg, 0.06 mmol) followed by DMF (8 mL), trimethylboroxine (1.3 mL, 9.5 mmol), and an aqueous solution of Na2CO3 (2.75 mL, 4M, 11 mmol). The tube was sealed and the reaction mixture was heated in the microwave at 120° C. for 80 m. The reaction mixture was diluted with water (25 mL) and ethyl acetate (25 mL), filtered, and the mother liquors were isolated and washed with water (2×25 mL) and brine (1×25 mL), dried and concentrated. The residue was purified by flash chromatography using a gradient of ethyl acetate and hexane. The intermediate, 6-methyl-1H-indole-4-carboxylic acid methyl ester (238 mg, 50% yield) was isolated by evaporation of the solvent. A solution of this intermediate (238 mg, 1.26 mmol) in THF (10 mL) was cooled to 0° C. and LAH (77 mg, 2.0 mmol) was added in portions under an atmosphere of N2. The reaction mixture was stirred at 0° C. for 2 h, then at ambient temperature for 18 h. An additional portion of LAH (40 mg, 1.05 mmol) was added and the reaction mixture was stirred an additional 3 h then added to a saturated solution of NaHCO3 in portions. After stirring for 15 m, the mixture was extracted with ethyl acetate (3×15 mL) and the combined extracts were washed with brine, dried and concentrated to 174 mg of crude 6-methyl-1H-indol-4-yl)-methanol which was used directly. This intermediate was converted to the title compound using methods similar to those described in Example 31. LCMS (ESMS): m/z 392 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:28])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:16][N:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4].[OH-].[Na+]>C(O)C>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:11]([NH:10][C:9]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][S:7][CH:8]=2)=[O:28])=[N:15][CH:16]=1
Reactant: COC(=O)c1cscc1NC(=O)COc1ccc(-c2ccccc2OC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1-c1ccc(OCC(=O)Nc2cscc2C(=O)O)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.2 %

Procedure:
To 4-{2-[5-(2-methoxy-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carboxylic acid methyl ester (93 mg, 0.233 mmol) in ethanol (10 mL) was added a solution of sodium hydroxide (1N, 0.47 mL, 0.47 mmol) and the reaction was stirred at room temperature for 2 days. After such time the reaction mixture was filtered through glass wool and the filtrate was then neutralized by addition of a solution of hydrochloric acid (1N, 0.46 mL). Additional water was added to the solution (in excess of 10 mL) before the precipitate was isolated by filtration, washed with water and dried in vacuo to yield the title compound as a white solid (79 mg, 88%).