Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[C:21]([F:29])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O>[F:29][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[C:25]([F:28])([F:27])[F:26])[CH2:18][C@H:10]1[CH2:9][C@@H:8]([C:6]2[O:7][NH:33][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(C(F)(F)F)c(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(C(F)(F)F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (2.033 g, 4.69 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. Sodium hydroxide (0.188 g, 4.69 mmol) dissolved in water (2.4 mL) was added over 1 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.3 mL, 4.90 mmol) was added over 1 min and stirring continued at −40° C. for 2 h 20 min. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (40 mL, 240.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. Product was pale yellow oil. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-35% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (1.32 g, 70%) was isolated as a colorless foam. 1H NMR (600 MHz, cdcl3) δ 1.84-1.99 (m, 3H), 1.99-2.10 (m, 1H), 2.62 (dd, 1H), 2.82 (dd, 1H), 2.92-3.06 (m, 1H), 3.10-3.19 (m, 1H), 3.59 (s, 3H), 3.93-4.03 (m, 1H), 4.19-4.34 (m, 1H), 5.73 (s, 1H), 6.91-6.99 (m, 2H), 7.46 (t, 1H). MS m/z 403 (M+H)+
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.O[CH2:28][CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>>[N:30]1([CH2:29][CH2:28][O:24][C:21]2[CH:22]=[CH:23][C:18]([N:15]3[CH2:14][CH2:13][N:12]([C:9]4[CH:10]=[CH:11][C:6]5[N:7]([C:3]([C:2]([F:1])([F:25])[F:26])=[N:4][N:5]=5)[N:8]=4)[CH2:17][CH2:16]3)=[CH:19][CH:20]=2)[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: Oc1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: OCCn1ccnc1
Product: FC(F)(F)c1nnc2ccc(N3CCN(c4ccc(OCCn5ccnc5)cc4)CC3)nn12
Yield: 6 %

Procedure:
Obtained in 6% yield by an analogous method to Example 514, starting from 4-[4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]phenol and 1-(2-hydroxyethyl)imidazole.
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]([O:20][CH2:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[CH2:24]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH2:34])=[CH:28][CH:27]=1)[CH3:25].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]([O:20][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]([C:17](=[O:19])[NH:34][CH2:33][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([CH2:24][CH3:25])=[CH:27][CH:28]=2)([CH3:15])[CH3:16])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23])[CH3:22]
Reactant: CCc1ccc(CCN)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OCC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2ccc(CC)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 2) and 2-(4-ethyl-phenyl) ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C25H33NO5 [M+H]+: 428.
Reaction SMILES: [P:1]([O-:6])([O:4]C)[O:2]C.O.[CH2:8]([NH2:14])[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1>CO>[CH3:8][P:1](=[O:6])([O-:4])[O-:2].[CH2:8]([NH3+:14])[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1.[CH2:8]([NH3+:14])[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccco1
Reactant: COP([O-])OC
Solvent: CO
Solvent: O
Product: CP(=O)([O-])[O-]
Product: [NH3+]Cc1ccco1
Yield: 98.5 %

Procedure:
A mixture of 11 g. (0.1 moles) of dimethyl phosphite, 20 ml. of water and 20 ml. of methanol is reacted with a mixture of 9.71 g. (0.1 moles) of furfuryl amine and 30 ml. of methanol as described in example 1. 17.3 g. of furfuryl-ammoniummethyl phosphonate are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.N12CCCN=[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[C:34]([O:42][CH2:43][C@@H:44]1[C@@:48]([O:50][C:51](=[O:53])C)([CH3:49])[C@:47]([F:55])([CH3:54])[CH:46](OC(=O)C)[O:45]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(#N)C>[C:34]([O:42][CH2:43][C@@H:44]1[C@@:48]([O:50][C:51](=[O:53])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH3:49])[C@:47]([F:55])([CH3:54])[CH:46]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[Cl:1])[O:45]1)(=[O:41])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)[C@](C)(OC(C)=O)[C@@]1(C)F
Reactant: Clc1ncnc2nc[nH]c12
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: C[C@]1(F)C(n2cnc3c(Cl)ncnc32)O[C@H](COC(=O)c2ccccc2)[C@]1(C)OC(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 40 %

Procedure:
To a stirred solution of 6-chloropurine (about 0.26 g, 1.74 mmol) in Acetonitrile (about 8 ml) was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (about 0.52 ml, 3.48 mmol) and Trimethylsilyl trifluoromethanesulfonate (about 0.84 ml, 4.65 mmol) at about 0° C., stirred for about 15 minutes then ((2R,3S,4R)-3,5-diacetoxy-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.5 g, 1.16 mmol) in Acetonitrile (about 7 ml) was added and reaction continued stirring at about 65° C. for about 8 hours. Completion of reaction monitored by thin-layer chromatography and quenched with saturated sodium bicarbonate. Aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with sodium bicarbonate solution, brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 20% ethyl acetate: hexane as eluent furnished title compounds Isomer A and B (0.24 g) as a colorless liquid. Yield: 40%
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15]O)[O:12][C@@H:11]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:50]I>C(#N)C.CCOCC>[I:50][CH2:15][CH2:14][C@H:13]1[O:12][C@@H:11]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:10][C@@H:9]1[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: II
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CCO)O2)c(=O)[nH]c1=O
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CCI)O2)c(=O)[nH]c1=O
Reaction time: 0.75 h
Yield: 90 %

Procedure:
To a solution of 3'-O-t-butyldimethylsilyl-5'-deoxy-5'-hydroxymethyl thymidine prepared according to the method of Example 5 (0.3 g, 0.9 mmol) in dry acetonitrile (5 ml) and ether (3.4 ml) were added 3 eq of triphenyl phosphine (0.7 g, 2.8 mmol), 4 eq of imidazole (0.3 g, 3.7 mmol) and 2.2 eq of iodine (0.5 g, 2.8 mmol). The reaction mixture was stirred for 45 min and the solvent was evaporated. Ethyl acetate was added to the residue and the residue washed with water, saturated sodium chloride and dried with sodium sulfate. The title compound was purified by flash chromatography using a 30-50% gradient of ethyl acetate in hexane. The yield was 90%.
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O:9][C:10](=[O:43])[N:11]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[C:25]([NH2:30])[CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][C:21]2=[O:31])[CH2:14][CH2:13]1)([CH3:8])([CH3:7])[CH3:6].[CH2:44]([N:46]=[C:47]=[O:48])[CH3:45]>C(N(CC)CC)C>[C:5]([O:9][C:10](=[O:43])[N:11]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[C:25]([NH:30][C:47]([NH:46][CH2:44][CH3:45])=[O:48])[CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][C:21]2=[O:31])[CH2:16][CH2:17]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(N)cccc32)CC1
Reactant: CCN=C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.2 %

Procedure:
To 2 mL of a chloroform solution containing 80 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-amino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 45 mg of triethylamine and 31 mg of ethyl isocyanate were added, and stirred at room temperature for 3 days. The reaction mixture was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate:methanol=10:1], to give 60 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-(3-ethylureido)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:34][CH2:35][CH3:36])=[C:8]([N:10]=[C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14](=[O:23])[C:13](=[C:24]3[N:28]([CH3:29])[C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[S:25]3)[S:12]2)[CH:9]=1)(=O)[CH3:2].Cl.[NH2:38][OH:39]>N1C=CC=CC=1>[CH2:16]([N:15]1[C:14](=[O:23])[C:13](=[C:24]2[N:28]([CH3:29])[C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[S:25]2)[S:12][C:11]1=[N:10][C:8]1[CH:9]=[C:4]([C:1](=[N:38][OH:39])[CH3:2])[CH:5]=[CH:6][C:7]=1[NH:34][CH2:35][CH3:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NO
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CCNc1ccc(C(C)=NO)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Temperature: 80 °C

Procedure:
To the product of Example 38 was added hydroxylamine hydrochloride (2 equiv) and pyridine. The resulting mixture was heated at 80° C. for 24 h, cooled, concentrated and chromatographed (TEA-washed silica gel, 0–50% EtOAc/Hex) to give the title compound. 1H-NMR (DMSO-d6): δ 11.07 (1H, s), 7.88 (1H, s), 7.67 (2H, m), 7.53 (1H, d), 7.39 (2H, m), 7.21–7.33 (5H, m), 7.09–7.14 (1H, m), 5.05 (2H, s). 3.92 (2H, q), 3.27 (3H, s), 2.23 (3H, s), 1.03 (3H, t); MS(ESI): 530 (MH+).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Si:13]([O:20][CH2:21][C@@H:22]([CH3:27])[CH2:23][CH2:24][CH2:25][OH:26])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>ClCCl.C(OCC)C>[CH3:8][S:9]([O:26][CH2:25][CH2:24][CH2:23][C@H:22]([CH3:27])[CH2:21][O:20][Si:13]([C:16]([CH3:18])([CH3:19])[CH3:17])([CH3:15])[CH3:14])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H](CCCOS(C)(=O)=O)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
Triethyl amine (413 μl, 3.09 mmol, 1.53 equiv) and methanesulfonyl chloride (212 μl, 2.73 mmol, 1.35 equiv) is added to a solution of (S)-5-(tert-butyldimethylsilyloxy)-4-methyl-pentan-1-ol 6 (471 mg, 2.03 mmol) in 6.5 ml of dichloromethane. The mixture is stirred for 15 min at 0° C., diluted with diethyl ether (30 ml), washed with water (5 ml), 1.0 M hydrochloric acid (5 ml), saturated aqueous sodium bicarbonate solution (5 ml), and brine (5 ml). The organic phase is separated, dried over magnesium sulfate and concentrated in vacuo. (S)-1-methanesudonyloxy-5-(tert-butyldimethylsilyloxy)-4-methyl-pentane 7 (472 mg, 99%) is obtained as a colourless oil. 13C-NMR (100 MHz, CDCl3): δ=70.44; 67.98; 37.41; 35.31; 28.99; 26.80; 25.95; 18.34; 16.56; −5.37, −5.38 (—SiMe2tBu).
Reaction SMILES: Br[C:2]1[C:3]([CH3:32])=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:5]2[N:6]([N:8]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:38]1[N:42]([C:43]2[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=2)[N:41]=[CH:40][CH:39]=1)CCC>>[CH3:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:9]2[N:10]=[C:5]3[C:4]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=4)=[C:3]([CH3:32])[C:2]([C:38]4[N:42]([C:43]5[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=5)[N:41]=[CH:40][CH:39]=4)=[CH:7][N:6]3[N:8]=2)=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(C#N)cc1
Reactant: Cc1c(Br)cn2nc(Cc3ccc(S(C)(=O)=O)cc3)nc2c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(Cc3ccc(S(C)(=O)=O)cc3)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 6-bromo-2-(4-methanesulfonyl-benzyl)-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (Int. 13, 50 mg, 0.095 mmol) and 4-(5-tributylstannanyl-pyrazol-1-yl)-benzonitrile (Int. 3, 100 mg, 0.218 mmol) using a similar method to that used in Example 1 (Step 4) (29 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1.[CH:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:19]([CH:18]([C:5]1[N:4]([CH2:3][CH:2]([CH3:17])[CH3:1])[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=1)[OH:23])[CH2:20][CH2:21][CH3:22]
Reactant: CC(C)Cn1cnc2cnc3ccccc3c21
Reactant: CCCCC=O
Product: CCCCC(O)c1nc2cnc3ccccc3c2n1CC(C)C

Procedure:
Using the method of Example 45, 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (20 g; 89 mmol) was reacted with valeraldehyde to provide 11.6 g of the desired product as a solid.
Reaction SMILES: [C:1](O)(=[O:5])[C:2]#[C:3][CH3:4].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)C(C)C)(C)C.[O:31]([C:38]1[CH:60]=[CH:59][C:41]([O:42][C:43]2[CH:48]=[CH:47][N:46]=[C:45]3[CH:49]=[C:50]([C:52]4[CH:53]=[C:54]([CH:56]=[CH:57][CH:58]=4)[NH2:55])[O:51][C:44]=23)=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCOCC1>[O:31]([C:38]1[CH:60]=[CH:59][C:41]([O:42][C:43]2[CH:48]=[CH:47][N:46]=[C:45]3[CH:49]=[C:50]([C:52]4[CH:53]=[C:54]([NH:55][C:1](=[O:5])[C:2]#[C:3][CH3:4])[CH:56]=[CH:57][CH:58]=4)[O:51][C:44]=23)=[CH:40][CH:39]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Nc1cccc(-c2cc3nccc(Oc4ccc(Oc5ccccc5)cc4)c3o2)c1
Reactant: CC#CC(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC#CC(=O)Nc1cccc(-c2cc3nccc(Oc4ccc(Oc5ccccc5)cc4)c3o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a 20-mL glass vial was added but-2-ynoic acid (7.57 mg; 0.09 mmol), and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (28.66 mg; 0.11 mmol), and N,N-diisopropylethylamine (0.05 ml; 0.30 mmol) suspended in dioxane (3.00 ml). The reaction mixture was stirred at room temperature for 1 hour. 3-[7-(4-phenoxyphenoxy)furo[3,2-b]pyridin-2-yl]aniline (29.60 mg; 0.08 mmol.) was added. The reaction mixture was then stirred at room temperature overnight. The mixture was purified using preparative HPLC to afford the title compound as a white solid (30.00 mg, 87%). HPLC (method F): 100%, RT=4.400 min. 1H NMR (DMSO-d6) δ [ppm] 10.79 (s, 1H), 8.40 (d, 1H), 8.24 (s, 1H), 7.70 (d, 1H), 7.66 (d, 1H), 7.62 (s, 1H), 7.47 (t, 1H), 7.41 (t, 2H), 7.38 (d, 2H), 7.16 (m, 3H), 7.08 (d, 2H), 6.77 (d, 1H), 2.05 (s, 3H). MS: m/z=461 [M+H]+, RT=4.52 min.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[C:6]2[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][C:17]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[O:19][N:18]=3)=[CH:10][C:7]=2[S:8][CH:9]=1.[OH-].[K+].OP(O)(O)=O>O1CCCC1>[CH3:14][C:12]1[C:11]([O:15][CH2:16][C:17]2[CH:21]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[O:19][N:18]=2)=[CH:10][C:7]2[S:8][CH:9]=[C:5]([CH2:4][C:3]([OH:29])=[O:2])[C:6]=2[CH:13]=1
Reactant: COC(=O)Cc1csc2cc(OCc3cc(-c4ccc(Cl)cc4)on3)c(C)cc12
Agent: O=P(O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc2c(CC(=O)O)csc2cc1OCc1cc(-c2ccc(Cl)cc2)on1
Temperature: 25 °C
Yield: 34.5 %

Procedure:
Compound 79A (0.03 g, 0.07 mmol) from the preceding step was dissolved in 2–3 mL of tetrahydrofuran, an equal volume of 2N KOH was added, and the mixture stirred at room temp. After 18 hours 75 mL of icewater was added and the mixture was acidified with H3PO4. After ˜30 min the precipitate was filtered off, rinsed 3× with water, and dried. The product was triturated in 4N HCl, allowed to stand for an hour, then filtered off, rinsed with water then ethanol, and dried to afford 0.01 g (99%) of the title compound as a white powder; mp 198–200° C. (dec). MS m/z 413 (M).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11](F)=[N:12][CH:13]=1.[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.CCOCC>[CH2:15]([S:22][C:11]1[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][N:12]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Fc1ccc(Cl)cn1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Clc1ccc(SCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.8 %

Procedure:
To a suspension of cesium carbonate (3.76 g, 11.5 mmol) in DMF (20 mL) at room temperature was added 5-chloro-2-fluoropyridine (1.00 mL, 9.96 mmol) and benzylmercaptan (1.15 mL, 9.80 mmol). The reaction mixture was stirred at room temperature for 16 h and heated to 60° C. for 6 h. The reaction mixture was diluted with Et2O. The organic phase was washed with water (2×), brine and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (5% to 10% EtOAc in heptane) to give the title compound (2.33 g, 9.88 mmol, 101% yield) as a colorless oil that was used without further purification in the next step. MS) m/z=236.1 [M+H]+. Calculated for C12H10ClNS 235.0.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[C:21]([CH3:31])[CH:20]=1>>[ClH:1].[CH2:16]([C:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][N:25]([C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][C:21]=3[CH3:31])[CH2:30][CH2:29]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15])[CH3:17]
Reactant: Cc1cc(F)ccc1N1CCNCC1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Product: CCC1(CCCCN2CCN(c3ccc(F)cc3C)CC2)C(=O)Nc2ccccc21
Product: Cl

Procedure:
The title compound is prepared according to process H by applying processing method 2 from the starting compounds 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(4-fluoro-2-methylphenyl)-piperazine.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([OH:14])[C:5]2[CH:6]=[C:7]([C:9](=[O:11])[CH3:10])[O:8][C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]1([C:40]2[S:41][CH:42]=[C:43]([CH2:45]O)[N:44]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.ClCCl.C1C=CC=CC=1>[F:1][C:2]1[CH:13]=[C:12]([O:14][CH2:45][C:43]2[N:44]=[C:40]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[S:41][CH:42]=2)[C:5]2[CH:6]=[C:7]([C:9](=[O:11])[CH3:10])[O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1cc2c(O)cc(F)cc2o1
Reactant: OCc1csc(-c2ccccc2)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: ClCCl
Product: CC(=O)c1cc2c(OCc3csc(-c4ccccc4)n3)cc(F)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
Benzene was added to 1-(6-fluoro-4-hydroxybenzofuran-2-yl)ethanone (Example 36C, 178 mgs, 0.917 mmol) and the mixture was sonicated for 30 sec. and concentrated in vacuo to remove traces of water in the starting material. Triphenylphosphine (373 mgs, 1.421 mmol) was added and the mixture was dried on high vacuum for 10 min. (2-Phenylthiazol-4-yl)methanol (Example 3B, 175 mgs, 0.917 mmol) and THF (15 mL) were added and the mixture was sonicated/heated for 5 min. Diisopropyl azodicarboxylate (275 L, 1.412 mmol) in THF (2 mL) was added dropwise over 1 h and the resulting yellow solution was sonicated for 15 min. and stirred overnight at r.t. The mixture was diluted in dichloromethane, washed with saturated. NaHCO3, brine, dried over MgSO4 and concentrated. The residue was purified on silica gel chromatography (ISCO 24 g gold column, using 5% ethyl acetate in hexanes to 40% (10% increments)) to give the title material (132 mgs, 32%) as a white solid. LC (Method B): 2.613 min. LCMS (APCI) calcd for C20H15FNO3S [M+H]+ m/z 368.07, found 368.2. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.94-8.02 (m, 2H), 7.62-7.67 (m, 1H), 7.44-7.51 (m, 3H), 7.38 (s, 1H), 6.91-6.96 (m, 1H), 6.64-6.72 (m, 1H), 5.39 (d, J=0.78 Hz, 2H), 2.58 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:41]=[CH:40][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]3[CH:25]=[CH:24][C:23]4[NH:22][C:21]5[CH2:26][CH2:27][N:28](C(OCC6C=CC=CC=6)=O)[CH2:29][C:20]=5[C:19]=4[CH:18]=3)=[O:16])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[N:2].Br.CC(O)=O.C(N(CC)CC)C.[F:54][C:55]([F:67])([F:66])[C:56]1[CH:61]=[CH:60][C:59]([S:62](Cl)(=[O:64])=[O:63])=[CH:58][CH:57]=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]3[CH:25]=[CH:24][C:23]4[NH:22][C:21]5[CH2:26][CH2:27][N:28]([S:62]([C:59]6[CH:58]=[CH:57][C:56]([C:55]([F:54])([F:66])[F:67])=[CH:61][CH:60]=6)(=[O:64])=[O:63])[CH2:29][C:20]=5[C:19]=4[CH:18]=3)=[O:16])[CH2:10][CH2:9]2)=[CH:40][CH:41]=1)#[N:2]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1ccc(CN2CCC(NC(=O)c3ccc4[nH]c5c(c4c3)CN(C(=O)OCc3ccccc3)CC5)CC2)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CN2CCC(NC(=O)c3ccc4[nH]c5c(c4c3)CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)CC5)CC2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of benzyl 8-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (4a, 50 mg, 91 μmol) in DCM (dichloromethane) (1.0 mL) was added dropwise a solution of HBr/AcOH (48% w/v, 1.0 mL). After the resulting brown reaction mixture was stirred for 30 min, the volatiles were evaporated, MeOH (2 mL) was added and the volatiles evaporated again. The resulting brown residue was dissolved in DMF (1.0 mL) and triethylamine (0.5 mL, 0.36 g, 3.6 mmol) and 4-(trifluoromethyl)benzenesulfonyl chloride (45 mg, 0.2 mmol) were added. The resulting reaction mixture was allowed to stir at room temperature overnight, then poured into saturated sodium bicarbonate solution (20 mL) to give a brown precipitate which was filtered and purified by reverse phase HPLC to provide Compound 24 upon trituration with ethyl ether (18 mg, 31%). 1H NMR (DMSO-d6, 300 MHZ) 11.21 (br s, 1H), 11.18 (br s, 1H), 9.75 (br s, 1H), 8.26 (d, J=7.2 Hz, 1H), 8.07 (d, J=8.3 Hz, 2H), 7.98 (d, J=7.7 Hz, 4H), 7.71 (d, J=8.3 Hz, 2H), 7.57 (d, J=8.5 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 4.40 (d, J=8.3 Hz, 4H), 3.55-3.06 (m, 7H), 2.92-2.82 (m, 2H), 2.07 (d, J=10.5 Hz, 2H), 1.78 (q, J=11.3 Hz, 2H) ppm; MS (ES) 622 (M+H).