Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Cl:15])[C:6]1=NN(C)C.C(OCC)(=[O:24])C>O1CCCC1.P([O-])([O-])([O-])=O.O.O.[Cu](Cl)Cl>[CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Cl:15])[C:6]1=[O:24]
Reactant: COC(CC1CCc2c(Cl)cccc2C1=NN(C)C)OC
Reactant: CCOC(C)=O
Agent: Cl[Cu]Cl
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(CC1CCc2c(Cl)cccc2C1=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Chloro-1-(dimethylhydrazono)-1,2,3,4-tetrahydro-2-naphthaleneacetaldehyde dimethyl acetal (47.5 g) was dissolved under argon in a mixture of 2300 ml of tetrahydrofuran and 780 ml of 0.067M phosphate buffer of pH value 7. The solution was treated with 26.1 g of copper(II) chloride dihydrate and stirred at room temperature for 16 hours. 2000 ml of ethyl acetate were added to the reaction mixture and it was washed three times with 2000 ml of a mixture of 25% ammonia solution and saturated ammonium chloride solution (1:19) each time. The aqueous wash phases were extracted once with 1500 ml of ethyl acetate and once with 1000 ml of ethyl acetate, the organic phases were combined, dried over MgSO4 and freed from solvent. There were obtained 42.2 g of crude 5-chloro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetaldehyde dimethyl acetal which was processed without purification.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[C:8]([NH:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C#CCO)cc1
Reactant: Nc1nccs1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(C#CCO)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-propionic acid (380 mg, 1.4 mmol), in methylene chloride (4 mL) and N,N-dimethylformamide (1 drop) at 0° C. was treated with oxalyl chloride (1.22 mL, 14.0 mmol). The reaction was warmed to 25° C. and stirred at 25° C. for 18 h. At this time, the reaction mixture was concentrated in vacuo. The resulting residue was dissolved in methylene chloride (4 mL) and added to a solution of 2-aminothiazole (280 mg, 2.79 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.87 mmol) in methylene chloride (8 mL) at 25° C. The reaction was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was poured into a 0.5N aqueous hydrochloric acid solution (50 mL) and extracted into ethyl acetate (1×100 mL). The organic extract was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a half-saturated aqueous sodium chloride solution (1×50 mL). The aqueous layer was back extracted with ethyl acetate (1×100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded the 3-cyclopentyl-2-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide (159 mg, 72%) as an off-white solid: mp 220-222° C.; EI-HRMS m/e calcd for C20H22N2O2S (M+) 354.1402, found 354.1388.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][C:13]([CH3:16])([OH:15])[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([I:24])C(=O)C1.CN(C=O)C>>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:12][C:13]([CH3:16])([OH:15])[CH2:14]3)=[N:9][C:10]=2[I:24])[CH:5]=[CH:6][N:7]=1
Reactant: CC1(O)CC(c2ncc3c(Cl)nccn23)C1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: CC1(O)CC(c2nc(I)c3c(Cl)nccn23)C1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol (2.20 g, 9.26 mmol) and NIS (2.71 g, 12.0 mmol) were dissolved in DMF (36.6 mL, 0.472 mol) and stirred at 60° C. for 4 h. The mixture was then concentrated in vacuo and the residue reconstituted in EtOAc (100 mL). This solution was washed with sodium bicarbonate (2×20 mL) and these washes back-extracted with EtOAc (2×20 mL). The organic layers were combined, dried with sodium sulfate, filtered and concentrated in vacuo. The crude solid was purified by chromatography over silica gel eluting with 1:1 EtOAc:hexanes to afford desired product. 1H-NMR (400 MHz, CDCl3) δ ppm 1.53 (s, 3 H), 2.72-2.59 (m, 4 H), 3.37-3.29 (m, 1 H), 7.32 (d, J=4.91 Hz, 1 H) and 7.60 (d, J=4.96 Hz, 1 H). MS (ES+): m/z 363.95 and 365.91 [MH+].
Reaction SMILES: C([Mg]Br)C.CCOCC.[C:10]([CH:12]1[CH2:14][CH2:13]1)#[CH:11].[Si:15]([O:22][CH2:23]/[CH:24]=[N:25]/[S@:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C1COCC1.C(Cl)Cl>[Si:15]([O:22][CH2:23][C@@H:24]([NH:25][S@:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])[C:11]#[C:10][CH:12]1[CH2:14][CH2:13]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[S@](=O)/N=C/CO[Si](C)(C)C(C)(C)C
Reactant: C#CC1CC1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)N[C@@H](C#CC1CC1)CO[Si](C)(C)C(C)(C)C
Temperature: 50 °C

Procedure:
3.0 M ethyl magnesium bromide in Et2O (0.360 mL, 1.081 mmol) was added to a solution of ethynylcyclopropane (71.5 mg, 1.081 mmol) in THF (4 mL). The solution was heated to 50° C. for 1 h, then the resulting Grignard was added to a −78° C. solution of (S,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide (100 mg, 0.360 mmol) in DCM (4.00 mL), and the reaction was allowed to warm to room temperature. After 3h, the reaction was quenched with sat. aq. NH4Cl. The layers were separated and the organics were dried over magnesium sulfate and concentrated to provide (S)—N—((S)-1-((tert-butyldimethylsilyl)oxy)-4-cyclopropylbut-3-yn-2-yl)-2-methylpropane-2-sulfinamide, which was used directly. LCMS (m/z): 344.1 (MH+), 1.23 min.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:71])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56]([C:58]4[N:59]=[C:60]([C:64]5[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=5)[O:61][C:62]=4[CH3:63])=[O:57])=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:70])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:71])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:50]=[CH:51][C:52]([NH:55][C:56]([C:58]4[N:59]=[C:60]([C:64]5[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=5)[O:61][C:62]=4[CH3:63])=[O:57])=[CH:53][CH:54]=3)=[CH:45][CH:46]=2)[C:41]1=[O:70])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: Cc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(-c2ccc3c(c2)C(=O)N([C@H](C(=O)O)C(C)C)C3)cc1
Yield: 89 %

Procedure:
The compound of example 643 was prepared analogous to the compound of example 98 by hydrolysis of compound of example 642.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([N:12]1[CH2:23][CH2:22][CH2:21][C@@H:13]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)(=O)C.[Pd]>[NH2:1][C@H:2]([C:10]([N:12]1[CH2:23][CH2:22][CH2:21][C@@H:13]1[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)[C@@H](N)Cc1ccccc1
Yield: 92.1 %

Procedure:
The dipeptide compound Z-Phe-D-Pro-OtBu (700 mg, 1.45 mmol) obtained in step 1-1 was dissolved in acetic acid (5 ml) and stirred overnight (about 14 hours) under hydrogen atmosphere in the presence of 5% Pd/C (70 mg). After the reaction mixture was filtered and concentrated, an oily residue was dissolved in ethyl acetate and washed with 4% NaHCO3. After being dried over anhydrous sodium carbonate, the product was concentrated to yield H-Phe-D-Pro-OtBu (425 mg, 92%). The concentrate was redissolved in DMF (5 ml), and Z-Phe-OH (434 mg, 1.45 mmol) and HOBt. H2O (245 mg, 1.60 mmol) were added, followed by adding DCC (230 mg, 1.60 mmol) under ice cooling, and as such the mixture was stirred overnight. The reaction mixture was filtered, concentrated, redissolved in ethyl acetate, and washed sequentially with 10% citric acid, 4% NaHCO3 and with saturated aqueous sodium chloride solution. After being dried over MgSO4 and concentrated, the residue was purified by flash silica gel chromatography (CHCl3) to yield 720 mg (90%) of the titled tripeptide compound as a foamy material.
Reaction SMILES: [BrH:1].C1(C)C=CC(S([N:11]2[CH2:16][C@H:15]3[CH2:17][C@@H:12]2[CH2:13][N:14]3[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=O)=O)=CC=1>C(O)(=O)C>[BrH:1].[BrH:1].[C:19]1([CH2:18][N:14]2[CH2:13][C@H:12]3[CH2:17][C@@H:15]2[CH2:16][NH:11]3)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)N2C[C@H]3C[C@@H]2CN3Cc2ccccc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: c1ccc(CN2C[C@H]3C[C@@H]2CN3)cc1
Reaction time: 12 h
Yield: 89 %

Procedure:
To a hot solution of 2.85 L of hydrobromic acid 33% in acetic acid* at 70° C. there was added 1428 g (4.17 moles) of (1R, 4R)-2-(4-toluenesulfonyl)-5-phenylmethyl-2,5-diazabicyclo-[2.2.1]-heptane (8). The solution was stirred for 12 h. The resulting suspension was cooled (18°-20° C.). The precipitate was filtered, washed with diisopropylether and dried at 40° C. under reduced pressure to give 1294 g (89%) of the titled compound. M.P. =276° C. [α]D =-0.38° (c=1, H2O).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])[CH2:27][CH2:26]1.C([O-])(=O)C([O-])=O>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)=[CH:16][CH:15]=2)[CH2:29][CH2:30]1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: COc1ccccc1N1CCN(CCCCN)CC1
Agent: Cl
Agent: O=C([O-])C(=O)[O-]
Product: COc1ccccc1N1CCN(CCCCNC(=O)c2ccc(-c3ccccn3)cc2)CC1
Yield: 53 %

Procedure:
Prepared from 4-pyridin-2-yl-benzoic acid hydrochloride and 4-(4-(2-methoxy-phenyl)-piperazin-1-yl)-butylamine according to the general procedure. Yield: 53%. Mp. (oxalate): foam. 1H NMR (CDCl3): δ1.67-1.74 (m, 4H), 2.49 (t, J 6.84, 2H), 2.67 (s, 2H), 3.07 (s, 2H), 3.51 (q, J 6.0, 2H), 3.84 (s, 3H), 6.83 (m, 5H), 7.26 (m, 1H), 7.73-7.79 (m, 2H), 7.89 (d, J 8.2, 2H), 8.06 (d, J 8.6, 2H), 8.71 (dt, J 4.7, 1.3, 1H). 13C NMR (CDCl3): δ 24.8, 27.9, 40.4, 50.8, 53.9, 55.8, 58.5, 111.6, 118.7, 121.3, 121.4, 128.1, 123.4, 127.4, 127.9, 135.6, 137.3, 142.5, 150.3, 152.7, 156.7, 167.8. Anal. (C27H32N4O2.(COOH)2.0.75H2O) C, H, N.|
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[C:9]([C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)/[CH:10]=[CH:11]/[C@H:12]2[O:17][C:16](=[O:18])[CH2:15][C@H:14]([OH:19])[CH2:13]2)=[CH:4][CH:3]=1.[CH3:33][O:34][C:35](=[O:42])[C@H:36]([CH2:38][CH:39]([CH3:41])[CH3:40])[NH2:37]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[C:9]([C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)[CH:10]=[CH:11][C@@H:12]([OH:17])[CH2:13][C@@H:14]([OH:19])[CH2:15][C:16]([NH:37][C@H:36]([C:35]([O:34][CH3:33])=[O:42])[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:18])=[CH:4][CH:3]=1
Reactant: Cn1nnnc1C(/C=C/[C@@H]1C[C@@H](O)CC(=O)O1)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)C[C@H](O)C[C@H](O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C

Procedure:
When a solution of trans-(4R,6S)-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one in tetrahydrofuran is treated with at least one equivalent of L-leucine methyl ester (prepared in situ from the hydrochloride salt) and heated to reflux temperature, the title compound is thereby produced. EXAMPLE 148
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]([CH3:18])[CH2:12]2)([OH:8])[C:4]([F:7])([F:6])[F:5].Br[CH2:22][CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29].[F:36][C:37]([F:69])([F:68])[C:38]([C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[N:49]([CH2:53][CH2:54][C:55]1[N:56]=[C:57]([CH3:66])[O:58][C:59]=1[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH:48]([CH3:67])[CH2:47]2)([OH:43])[C:39]([F:42])([F:41])[F:40]>>[F:5][C:4]([F:7])([F:6])[C:3]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:22][CH2:23][C:24]1[N:25]=[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:27][C:28]=1[CH3:29])[CH:13]([CH3:18])[CH2:12]2)([OH:8])[C:2]([F:1])([F:19])[F:20].[F:68][C:37]([F:36])([F:69])[C:38]([C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[N:49]([CH2:53][CH2:54][C:55]1[N:56]=[C:57]([CH3:66])[O:58][C:59]=1[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[CH:48]([CH3:67])[CH2:47]2)([OH:43])[C:39]([F:42])([F:41])[F:40]
Reactant: Cc1oc(-c2ccccc2)nc1CCBr
Reactant: CC1Cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2N1
Agent: Cc1nc(CCN2c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3CC2C)c(-c2ccccc2)o1
Product: Cc1oc(-c2ccccc2)nc1CCN1c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2CC1C

Procedure:
In analogy to example 75, from 1,1,1,3,3,3-hexafluoro-2-(2-methyl-2,3-dihydro-1H-indol-5-yl)-propan-2-ol (example 51.1) and 4-(2-bromo-ethyl)-5-methyl-2-phenyl-oxazole was prepared 1,1,1,3,3,3-Hexafluoro-2-{2-methyl-1-[2-(2-methyl-5-phenyl-oxazol-4-yl)-ethyl]-2,3-dihydro-1H-indol-5-yl}-propan-2-ol, MS: 485 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]2[CH2:11][CH:10]2[C:12](OCC)=[O:13])[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2[CH2:12][OH:13])[CH:3]=1
Reactant: CCOC(=O)C1CC1c1cc(Cl)nc(C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc([C@@H]2C[C@H]2CO)n1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
ethyl 2-(6-chloro-2-methylpyrimidin-4-yl)cyclopropanecarboxylate (4-2, 6.8 g, 28.3 mmol, 1.0 eq) was dissolved in THF (141 ml) and cooled to −40° C. with dry ice acetone bath. LAH (32.5 ml, 32.5 mmol, 1.2 eq) (1.0 M solution in THF) was added dropwise over 10 minutes. The reaction appeared complete. To the reaction mixture was added water at 0° C. as to not raise the internal reaction temperature above −10° C., followed by 15% aqueous sodium hydroxide solution (2 mL). The cooling bath was removed and additional water (6 mL) was added. The reaction mixture was stirred for 1 hour. The salts were filtered off through celite and the solid was washed with THF (5×20 mL). The filtrate was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to afford ((1R,2R)-2-(6-chloro-2-methylpyrimidin-4-yl)cyclopropyl)methanol (4-3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]#[N:22])[CH:15]=3)[N:12]=[C:11]([C:23]([O:25]CC)=[O:24])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]#[N:22])[CH:15]=3)[N:12]=[C:11]([C:23]([OH:25])=[O:24])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(C#N)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: N#Cc1cc(-n2nc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)ccc1F
Reaction time: 6 h

Procedure:
The preparation of the title compound takes place starting from the compound of Example 65A in analogy to the synthesis of the compound of Example 71A but with stiffing for 6 hours. 1.88 g of the title compound with 64% purity are obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]([CH3:39])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)[CH:21]=2)[N:16]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[N:15]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>CO.[Ni]>[NH2:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[N:15]=[C:14]3[CH2:13][N:12]([CH3:39])[CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:7])([CH3:8])[CH3:6])=[CH:29][CH:28]=1
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)Cc1nn(C2CCCCO2)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc12
Agent: [Ni]
Solvent: CO
Product: CN(CCN(C)C(=O)OC(C)(C)C)Cc1nn(C2CCCCO2)c2ccc(Oc3ccc(N)cc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
A mixture of (R/S) tert-butyl methyl(2-(methyl((5-(4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methyl)amino)ethyl)carbamate (550 mg, 1.02 mmol, 1.00 equiv) and Raney/Ni (500 mg) in methanol (30 mL) was stirred under hydrogen at room temperature for 30 min. The catalyst was removed by filtration. The filtrate was concentrated under vacuum to give 400 mg (77%) of (R/S) tert-butyl 2-(((5-(4-aminophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methyl)(methyl)amino)ethyl(methyl)carbamate as a colorless oil. 1H-NMR (300 MHz, CDCl3): δ 7.52-7.49 (m, 2H), 7.33-7.26 (m, 2H), 7.18-7.12 (m, 1H), 6.90-6.80 (m, 2H), 6.71-6.61 (m, 2H), 5.70-5.68 (m, 1H), 4.11-4.09 (m, 1H), 4.07-3.91 (m, 1H), 3.79-3.73 (m, 1H), 3.71-3.33 (m, 1H), 2.79 (s, 3H), 2.57-2.52 (m, 2H), 2.49-2.17 (m, 2H), 2.17-2.05 (m, 1H), 1.80-1.68 (m, 4H), 1.42 (s, 9H) ppm.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[N:13][N:14]([C:25]2[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][N:26]=2)[C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)(C(C)(C)C)(C)C.Cl.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C1COCC1.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][O:16][C:15]2[N:14]([C:25]3[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][N:26]=3)[N:13]=[CH:12][C:11]=2[CH2:10][CH2:9][OH:8])=[CH:19][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cnn(-c2cc(C#N)ccn2)c1OCc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccnc(-n2ncc(CCO)c2OCc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a mixture of 2-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-[(4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile (60 mg, 0.13 mmol, PREPARATION 8) in THF (5 mL) was added 3N HCl (1 mL) at 0° C. The reaction mixture was stirred for 2 h at r.t. Cooled to 0° C., added ethyl acetate, water and acidified with NaHCO3 to pH=8, and the mixture was then extracted with ethyl acetate and concentrated to afford the title compound (40 mg, 91%). [M+H] Calc'd for C18H15FN4O2, 339; Found, 339.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([NH:10][C:11]2[N:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)=[C:7]([C:20]([OH:22])=O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].Cl>O>[CH2:1]([C:5]1[S:9][C:8]2[N:10]=[C:11]3[CH:12]=[CH:13][C:14]([C:17]([OH:19])=[O:18])=[CH:15][N:16]3[C:20](=[O:22])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(C(=O)O)c(Nc2ccc(C(=O)O)cn2)s1
Agent: Cl
Solvent: O
Product: CCCCc1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1
Temperature: 142 °C

Procedure:
A mixture of 6-[(5-butyl-3-carboxy-2-thienyl)amino]-3-pyridinecarboxylic acid (Example 39), 1.0 g (0.00312 mol), 25 ml of concentrated hydrochloric acid and 25 ml of water is refluxed in a wax bath under a nitrogen atmosphere at a bath temperature of 142° C. for seventeen and three-quarter hours. The suspension is cooled to room temperature and the precipitate is separated, washed with water and then washed with diethyl ether and dried to give 0.595 g of 2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid; mp 252°-254° C. after recrystallization from ethanol.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[CH:15]=[CH:14][S:13][C:10]2=[CH:11][N:12]=1)(=[O:5])=[O:4].C([O-])(=O)C.[Na+].[Br:23]Br.CC(O)=O.C([O-])([O-])=O.[Na+].[Na+]>>[F:17][C:2]([F:1])([F:16])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[C:15]([Br:23])=[CH:14][S:13][C:10]2=[CH:11][N:12]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(Oc1cc2ccsc2cn1)C(F)(F)F
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=S(=O)(Oc1cc2c(Br)csc2cn1)C(F)(F)F
Temperature: 90 °C
Yield: 55 %

Procedure:
A sealable vial was charged with thieno[2,3-c]pyridin-5-yl trifluoromethanesulfonate (109 mg, 0.300 mmol), sodium acetate (75.3 mg, 0.900 mmol) and 1.0 M bromine in AcOH (0.900 mL, 0.900 mmol). The reaction was heated in a microwave reactor at 90° C. for 2 h. The reaction mixture was treated with aqueous Na2CO3 until the pH was >9, then extracted with EtOAc (3×20 mL). The combined extracts were washed with water (10 mL) and brine (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by ISCO chromatography (0 to 25% EtOAc:heptane) to afford 60 mg (55%) of the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.26 (d, J=0.4 Hz, 1 H), 8.61 (s, 1 H), 7.92 (d, J=1.2 Hz, 1H); MS (ESI): 362.08, 384.04 [M+H]+; HPLC tR=4.39 min (ZQ3: polar—5 min).
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH2:8][CH3:9])[CH2:5][OH:6])[CH2:2][CH3:3].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](O)(=[O:18])=[O:17])=[CH:12][CH:11]=1.N1C=CC=CC=1.Cl>C(Cl)(Cl)Cl>[S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)([O:6][CH2:5][CH:4]([CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH3:3])(=[O:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCC(CO)CCC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCC(CCC)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 19 h
Yield: 96.9 %

Procedure:
To a mixture of 52 g 2-propylpentanol and 86 g of p-toluenesulfonic acid in 175 ml of chloroform was added at 0°-3° C. and under N2 -atmosphere 48 g of pyridine. The mixture was kept at 0° C. for 30 minutes and at room temperature for 19 hrs. After cooling the reaction mixture, 3M HCl (300 ml) was added. The organic phase was separated and washed with water and rine. Drying with Na2SO4 and evaporation gives 110 g of 2-propylpentyl tosylate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([Cl:17])[C:15]=1[OH:16])[C:9](OC)=[O:10].Cl>O>[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([Cl:17])[C:15]=1[OH:16])[C:9]([NH:1][CH2:2][CH2:3][OH:4])=[O:10]
Reactant: NCCO
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1
Agent: Cl
Solvent: O
Product: O=C(NCCO)c1cc(Cl)c(O)c(Cl)c1
Temperature: 80 °C

Procedure:
A 2 L, 3 necked, round bottom flask was charged with 2-aminoethanol (240 gm; 3.93 moles) and heated to 80° C. Methyl 3,5-dichloro-4-hydroxybenzoate (432 gm; 1.96 moles) was added in portions through a powder funnel. The resulting amber solution was heated to 145° C. and the liberated methanol distilled into a Dean Stark trap. The reaction required about 3.5 hrs. Upon completion, the solution was cooled to 90°-100° C. and dissolved in 1.95 L H2O. The aqueous solution was cooled to 25° C., placed in an ice bath and made slightly acidic with concentrated hydrochloric acid (196 ml; 2.35 moles). The product precipitated and filtration afforded a white solid. After drying at 50° C. in a vacuum oven, the product darkened slightly. The crude material (384.4 gm; 78.8%) was ground and passed through a No. 20 mesh screen to produce 3,5-dichloro-4-hydroxy-N-(2-hydroxyethyl)benzamide as a cream colored solid (m.p. 174°-178° C.) which is suitable for use in the next step.