Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C([Mg]Cl)CCC.[F:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][C:19](I)=[CH:18]2.[C:24]([C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=[O:31])([CH3:27])([CH3:26])[CH3:25].Cl>O1CCCC1>[C:24]([C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]([C:19]1[CH:20]=[N:21][C:22]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[F:12])[OH:31])([CH3:27])([CH3:25])[CH3:26]
Reactant: Fc1cccc2cc(I)cnc12
Reactant: CC(C)(C)c1ccccc1C=O
Agent: CCCC[Mg]Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1C(O)c1cnc2c(F)cccc2c1
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
After 3 ml of tetrahydrofuran was cooled to −10° C., 0.91 ml of n-butyllithium (2.6 M hexane solution) and 1.35 ml of n-butylmagnesium chloride (0.91 M tetrahydrofuran solution) were added. After 30 minutes of stirring, 0.98 g of 8-fluoro-3-iodoquinoline was added and the mixture was stirred for 15 minutes. 0.49 g of 2-t-butylbenzaldehyde was added to the reaction solution and the mixture was stirred for 3 hours. After dilute hydrochloric acid was added to the reaction mixture, the liquid was separated with ethyl acetate. After the organic layer was concentrated and purified by silica gel column chromatography, 0.55 g of (2-t-butyl-phenyl)-(8-fluoro-quinolin-3-yl)-methanol (Compound Number 54) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[CH:7][C:6]=1[CH3:13].Cl[C:15]1[CH:16]=[CH:17][C:18]([N+:30]([O-:32])=[O:31])=[C:19]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:20]=1.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:15]2[CH:16]=[CH:17][C:18]([N+:30]([O-:32])=[O:31])=[C:19]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:20]=2)=[CH:7][C:6]=1[CH3:13]
Reactant: COCOc1c(C)cc(O)cc1C
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1c(C)cc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)cc1C
Yield: 90.9 %

Procedure:
By using 1.46 g of 4-methoxymethoxy-3,5-dimethylphenol, 2.29 g of t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate, 0.35 g of sodium hydride (55% by weight) and 30 ml of anhydrous N,N-dimethylformamide, reaction and purification were carried out in a similar manner to that described in Reference Example 6, whereby 3.14 g of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2>CO.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:2]=2[CH3:1])=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccc([N+](=O)[O-])cc2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)Cn1c(C)c(Cc2ccc(N)cc2)c2ccccc21
Yield: 92.3 %

Procedure:
Into a dry reaction vessel, ethyl 2-[2-methyl-3-(4-nitrobenzyl)-1H-indol-1-yl]acetate (2.7 g, 7.66 mmol) was added, and dissolved in 30 mL methanol. 10% Pd/C 300 mg was added, purged with hydrogen, and reacted overnight. After completion of the reaction, it was filtered, and the filter cake was washed with methanol. The filtrate was rotate evaporated to dryness to obtain a white solid 2.28 g, at a yield of 92.3%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)[CH3:2].Cl[CH2:21][C:22]1[S:26][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH3:37]>>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[S:26][C:25]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[N:24][C:23]=1[CH3:37])[CH:11]=[CH:10]2)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Product: CCOC(=O)C(Cc1ccc2c(ccn2Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)c1)OCC

Procedure:
In analogy to the procedures described in examples 36a) and 36b), rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester [preparation 1] was reacted with 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole [PCT Int. Appl. (2001), WO 01/00603 A1] to give rac-2-ethoxy-3-{1-[4-methyl-2-(4-trifluoromethyl-phenyl )-thiazol-5-ylmethyl]-1H-indol-5-yl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[S:33][C:32]([C:34]3([OH:38])[CH2:37][CH2:36][CH2:35]3)=[N:31][CH:30]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=3)[N:8]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[NH:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([C:29]2[S:33][C:32]([C:34]3([OH:38])[CH2:37][CH2:36][CH2:35]3)=[N:31][CH:30]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH2:15][N:50]4[CH2:54][CH2:53][CH2:52][CH2:51]4)=[CH:17][CH:18]=3)[N:8]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3ccc(C=O)cc3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)n2c(-c3ccc(CN4CCCC4)cc3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(5-chloro-4-(2-(1-hydroxycyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)benzaldehyde (Example 8B) (2.10 g, 3.72 mmol) in tetrahydrofuran (33.8 mL) was added sequentially acetic acid (0.426 mL, 7.45 mmol), sodium sulfate (1.058 g, 7.45 mmol), and pyrrolidine (0.466 ml, 5.58 mmol). The reaction was stirred for 0.5 hours at ambient temperature, and sodium triacetoxyborohydride (1.578 g, 7.45 mmol) was added in a single portion. The reaction was stirred for 1 hour and was then quenched by the addition of saturated aqueous sodium bicarbonate solution (20 mL), ethyl acetate (20 mL), and solid sodium bicarbonate. The layers were separated, and the aqueous layer was extracted with addition ethyl acetate (2×). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 10% methanol in dichloromethane with 1% v/v aqueous ammonium hydroxide solution, to give the title compound. MS ESI(+) m/z 619.3 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][C:22]#[CH:23])[CH:18]=3)[N:13]([CH2:24][C:25]3[CH:26]=[C:27]([NH:31][C:32](=[O:44])[CH2:33][N:34]4[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][CH3:43])[CH2:36][CH2:35]4)[CH:28]=[CH:29][CH:30]=3)[C:12](=[O:45])[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Li+].[CH3:47]C([N-]C(C)C)C.CN(P(N(C)C)(N(C)C)=O)C.CI>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][C:22]#[CH:23])[CH:18]=3)[N:13]([CH2:24][C:25]3[CH:26]=[C:27]([N:31]([CH3:47])[C:32](=[O:44])[CH2:33][N:34]4[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][CH3:43])[CH2:36][CH2:35]4)[CH:28]=[CH:29][CH:30]=3)[C:12](=[O:45])[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(NC(=O)CN2CCN(CCOC)CC2)c1
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CI
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(N(C)C(=O)CN2CCN(CCOC)CC2)c1
Temperature: -78 °C

Procedure:
A solution of 1.20 g (2 mmol) of N-{3-[4-(4-isopropyl-phenyl)-2-oxo-6-propargyloxy-2H-quinazolin-1-ylmethyl]-phenyl}-2-[4-(2-methoxy-ethyl)-piperazin-1-yl]-acetamide is treated with 4.1 ml 0.5 M LDA-solution (in THF) and 0.35 ml (2.0 mmol) HMPT at −78° C. The cooling bath is removed and stirring continued for half an hour while the solution turns slowly red. The reaction mixture is cooled down again to −78° C., 284 μl methyl iodide (2 mmol; diluted with 5 ml THF) is added. After stirring overnight at rt, the orange solution is concentrated in vacuo The yellow foamy residue is purified by chromatography (CH2Cl2/MeOH 9:1). Yield: 480 mg (13%) yellow foam.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[NH:14][CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1.I[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1.CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN1CCCC1=O.[Cu](I)I>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([CH:12]3[C:17]([CH3:18])=[CH:16][CH2:15][N:14]([C:21]4[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)[C:13]3=[O:19])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Cc1cccc(I)c1
Reactant: Cc1cc[nH]c(=O)c1N1CCc2nc(N)ncc2C1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN1CCCC1=O
Product: CC1=CCN(c2cccc(C)c2)C(=O)C1N1CCc2nc(N)ncc2C1
Temperature: 70 °C
Reaction time: 17 h
Yield: 47.7 %

Procedure:
A degassed solution of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylpyridin-2(1H)-one (24 mg, 0.096 mmol), 1-iodo-3-methylbenzene (20 mg, 0.097 mmol), N1,N2-dimethylethane-1,2-diamine (5 mg, 0.049 mmol), copper iodide (5 mg, 0.022 mmol), and potassium phosphate (44 mg, 0.199 mmol) in 2 mL of N-methylpyrrolidone was heated to 70° C. After allowing the reaction to stir overnight (17 h) at 70° C., the reaction was complete and allowed to cool to room temperature. The reaction was extracted with EtOAc (3×5 mL) and with NaHCO3 (2×10 mL). The crude organic layers were combined, dried over anhydrous Na2SO4 (s), filtered and then concentrated in vacuo. The crude mixture was then purified using the ISCO flash chromatography system using a CHCl3/EtOAc gradient. Upon reaching a 1:1 mixture of EtOAc and CHCl3, 3% MeOH was added and increased to 6% MeOH which, after concentrating the appropriate fractions, afforded the title compound as a pale yellow solid (16 mg, 47%). 1H NMR (DMSO) δ: 7.99 (s, 1H), 7.80 (d, J=6.0, 1H), 6.56 (d, J=6.0, 1H), 6.28 (m, 1H), 6.20 (d, J=7.0 Hz, 2H), 3.99 (br. S, 2H), 3.31 (s, 2H), 2.66(t, j=5.3 Hz, 2H), 2.15 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([N:21]=[CH:22][N:23]([CH3:25])[CH3:24])(=[O:20])=[O:19])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:26][C:27]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:29][C:28]=1[CH:38]=[O:39].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC>[Cl:26][C:27]1[N:31]=[C:30]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:29]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([N:21]=[CH:22][N:23]([CH3:25])[CH3:24])(=[O:20])=[O:19])(=[O:11])=[O:10])=[CH:5][CH:4]=2)[C:28]=1[CH:38]=[O:39]
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1S(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C=NS(=O)(=O)c1ccccc1S(=O)(=O)c1ccc(Cn2c(-c3ccccc3)nc(Cl)c2C=O)cc1
Yield: 12.8 %

Procedure:
1.6 g of 2-(4-bromomethylbenzenesulfonyl)-N-dimethylaminomethylenebenzenesulfonamide, 680 mg of 5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde and 1.4 g of K2CO3 are stirred at RT for 3 days in 15 ml of anhydrous DMF. The reaction mixture is then diluted with 200 ml of EA and washed three times with 50 ml of a saturated aqueous Na2CO3 solution each time. It is dried over MgSO4 and the solvent is removed in vacuo. Chromatography on silica gel using MTB yields 240 mg of a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C([O:23][C:24](=O)[C:25]1[CH:30]=[C:29]([C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[CH:32]=2)[C:28]([O:39][CH2:40][CH2:41][OH:42])=[C:27]([C:43]2[CH:48]=[C:47]([CH3:49])[CH:46]=[C:45]([CH3:50])[CH:44]=2)[CH:26]=1)C.CCOC(C)=O>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:24](=[O:23])[C:25]2[CH:30]=[C:29]([C:31]3[CH:32]=[C:33]([CH3:38])[CH:34]=[C:35]([CH3:37])[CH:36]=3)[C:28]([O:39][CH2:40][CH2:41][OH:42])=[C:27]([C:43]3[CH:44]=[C:45]([CH3:50])[CH:46]=[C:47]([CH3:49])[CH:48]=3)[CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cc(-c2cc(C)cc(C)c2)c(OCCO)c(-c2cc(C)cc(C)c2)c1
Reactant: NCCCCCCCCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(-c2cc(C(=O)NCCCCCCCCc3ccccc3)cc(-c3cc(C)cc(C)c3)c2OCCO)c1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a cooled solution (0° C.) of 8-phenyloctyl amine (1.56 g, 7.58 mmol, 1.51 ml) in 10 mL anhydrous THF was added n-BuLi (5.1 mL, 7.96 mmol) as a solution in hexanes dropwise. After the addition, the reaction was warmed up to room temperature and was stirred for one-half hour at room temperature. Then the lithiated amine was cooled back down to 0° C. and was added to a cooled (0 ° C. ) solution of 3,5-bis-(3,5-dimethylphenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester (1.04 g, 2.49 mmol) in 10 mL anhydrous THF. The resulting reaction mixture was stirred for 5 min at 0° C. then allowed to warm up to room temperature. At that point, additional n-BuLi was added (2.04 mL, 3.18 mmol). When the reaction appeared to be practically complete (by TLC), it was worked up as in Step 2 of Example 135. After flash chromatography (25% EtOAc:75% Hexanes), there yielded 850 mg, 59.4% of the amide as a yellow oil. 1H NMR (CDCl3) δ 1.25-1.40 (m, 8H); 1.40-1.64 (m, 5H); 2.37 (s, 12H); 2.57 (t, J=8.18 Hz, 2H); 3.25 (t, J=4.09 Hz, 2H); 3.36-3.47 (m, 4H); 6.06 (t, J=6.54 Hz, 1H); 7.02 (s, 2H); 7.11-7.19 (m, 4H); 7.20-7.48 (m, 5H); 7.69 (s, 2H).
Reaction SMILES: [N:1]1[N:2]([C:6]2[C:7]([C:12]([N:14]3[CH2:18][CH:17]4[CH2:19][N:20](C(OC(C)(C)C)=O)[CH2:21][CH:16]4[CH2:15]3)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[N:2]([C:6]2[C:7]([C:12]([N:14]3[CH2:18][CH:17]4[CH:16]([CH2:21][NH:20][CH2:19]4)[CH2:15]3)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ncccc3-n3nccn3)CC2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ncccc1-n1nccn1)N1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
tert-Butyl 5-(3-(2H-1,2,3-triazol-2-yl)picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (491 mg, 1.28 mmol) in DCM (6 mL) was added TFA (3 mL). After stirring for 2 h at room temperature the reaction was complete and concentrated in vacuo. The TFA salt was purified on a Prep Agilent system with a XBridge C18 OBD 50×100 mm column eluting with 5 to 99% 0.05% NH4OH in H2O/ACN over 17 min to afford (3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone as a white solid (306 mg, 84%). MS (ESI) mass calculated for C14H16N6O, 284.14; m/z found, 285.0.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][C@H:11]1[CH2:15][C:14](=[O:16])[O:13][C@@H:12]1[O:17][CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[CH2:1]([O:8][C:9](=[O:20])[NH:10][C@H:11]1[CH2:15][C:14](=[O:16])[O:13][C@H:12]1[O:17][CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO[C@H]1OC(=O)C[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCO[C@@H]1OC(=O)C[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
To a suspension of (2S,3S) (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid benzyl ester (0.43 g, 1.54 mmol) in Ethyl acetate (50 mL) at room temperature was added 10 mol % Pd/C (˜0.05 g). The reaction flask was purged between H2 (1 atm) and vacuum three times before stirring under H2 (1 atm) at room temperature. After stirring at room temperature for 3 hrs, the reaction mixture was filtered through celite and then evaporated to dryness to give the title compound (0.21 g, 94%) as a clear oil. 1HNMR (CDCl3) δ 5.17 (d, J=1.2 Hz, 1H), 3.93-3.82 (dq, J=9.6, 7.2 Hz, 1H), 3.67-3.57 (dq, J=9.3, 6.9 Hz, 1H), 2.95-287 (dd, J=17.7, 6.9 Hz, 1H), 2.56-2.19 (dd, J=17.4, 2.7 Hz, 1H), 1.26-1.21 (t, J=7.2 Hz, 31H). MS(ES) for C6H11NO3 (MW=145.16): positive 146 ([M+]). Part C: (4S,5R)-4-Amino-5-ethoxy-dihydro-furan-2-one
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:25]([C:26]5[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=5)=[CH:24][N:23]([CH3:32])[N:22]=4)=[CH:17][CH:16]=3)=[N:10]2)=[CH:5][CH:4]=1.ClCC1C=CC2C(=CC=C([F:45])C=2)N=1>>[ClH:2].[F:45][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:3]=1)[N:10]=[C:9]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]3[C:25]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[CH:24][N:23]([CH3:32])[N:22]=3)=[CH:17][CH:16]=1)[CH:8]=[CH:7]2
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccc(Cl)cc4n3)cc2)n1
Reactant: Fc1ccc2nc(CCl)ccc2c1
Agent: Cl
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4cc(F)ccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 7-Chloro-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline hydrogen chloride but substituting 2-chloromethyl-6-fluoro-quinoline provided the title compound. 1H NMR (400 MHz, DMSO) δ 8.67 (d, J=6.6 Hz, 2H), 8.55 (s, 1 H), 8.42 (d, J=8.3, 1H), 8.04 (m, 1H), 7.82 (m, 1H), 7.71 (m, 4H), 7.36 (d, J=8.7 Hz, 2H), 7.12 (d, J=8.7, 2H), 5.37 (s, 2H), 3.91 (s, 3 H); MS: (M+H m/z=411.2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11](O)=[O:12])=[C:4]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])(=[O:17])=[O:16])[CH:3]=1.[CH3:26][CH2:27][N:28]=[C:29]=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O.CNCC>CN(C=O)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([N:28]([CH2:27][CH3:26])[CH3:29])=[O:12])=[C:4]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])(=[O:17])=[O:16])[CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Agent: CCNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C)C(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
To a solution of 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoic acid (297 mg, 0.70 mmol) in DMF (2 ml) was added EDC.HCl (148 mg, 0.77 mmol), HOBT.H2O (104 mg, 0.77 mmol), and N-methylethanamine (0.30 ml, 3.5 mmol). The reaction was stirred at room temperature for 16 hours, diluted with 1M HCl, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10-40% EtOAc in hexane) to yield the title compound (269 mg, 83%) as a mixture of amide bond cis-trans isomers.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([F:12])([F:11])[F:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])O.[Na+].[C:18]([C:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27])([CH3:22])[CH3:21])#[N:19]>O1CCCC1>[C:18]([C:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([F:10])([F:11])[F:12])=[C:6]([OH:8])[CH:7]=1)=[O:27])([CH3:22])[CH3:21])#[N:19]
Reactant: Nc1ccc(C(F)(F)F)c(O)c1
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C(F)(F)F)c(O)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
To a two-layer solution of 5-amino-2-(trifluoromethyl)phenol (1.50 g, 8.46 mmol) in tetrahydrofuran (25 mL)/1N aqueous sodium hydrogen carbonate solution (25 mL) was added a solution of 3-(1-cyano-1-methylethyl)benzoyl chloride synthesized above in tetrahydrofuran (15 mL), and the mixture was stirred at room temperature for 4 hr. The aqueous layer was separated, and extracted with ethyl acetate (200 mL). The combined organic layer was washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with ethyl acetate/hexane to give the title compound (2.03 g, 69%) as a colorless powder.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=3[N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[N:6]2[N:5]=1)=O.[OH-:26].[Na+].Cl>>[OH:26][C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=3[N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[N:6]2[N:5]=1
Reactant: [OH-]
Reactant: Cc1ccc(-c2ccc3cnc(S(C)=O)nn23)c(N(C)S(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Product: Cc1ccc(-c2ccc3cnc(O)nn23)c(N(C)S(C)(=O)=O)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-methyl-phenyl]-N-methyl-methanesulfonamide (315 mg, 0.832 mmol) in 5M NaOH (10 mL, 10 mmol) was stirred at 80° C. After 3 h, HPLC and MS showed product formation with no SM. The mixture was cooled to RT and pH of the solution was adjusted to 4 by adding HCl. The mixture was repeatedly extracted from EtOAc. Combined organic was washed with brine and was dried over magnesium sulfate. After solvent evaporation, N-[2-(2-Hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-methyl-phenyl]-N-methyl-methanesulfonamide was isolated as a solid (153 mg, 55%). LCMS (E/I+) 333 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[NH:6][C:7](=[O:19])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([N:6]1[C:7](=[O:19])[C:8]2[CH:18]=[CH:17][CH:16]=[N:15][C:9]=2[N:10]([CH2:13][CH3:14])[C:11]2[N:12]=[C:2]([Cl:1])[CH:3]=[C:4]([CH3:20])[C:5]1=2)(=[O:23])[CH3:22]
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(Cl)nc21
Reactant: CC(=O)OC(C)=O
Product: CCN1c2ncccc2C(=O)N(C(C)=O)c2c(C)cc(Cl)nc21
Temperature: 140 °C

Procedure:
A suspension of 2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (5.1 g) in acetic anhydride (25 mL) was heated at 140° C. for 5 hours. The solvent was evaporated and the residue fractionated over silica gel to give 4.48 g of 5-acetyl-2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one, suitable for use in the next reaction.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20]1[N:21]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:22]=[C:23]([CH3:25])[CH:24]=1)=[O:4].[OH-].[Li+]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([C@H:8]1[CH2:7][N:6]([C:20]2[N:21]([CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:22]=[C:23]([CH3:25])[CH:24]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]1)(=[O:12])=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1CCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)O)n(CCc2ccccc2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(5-methyl-2-phenethyl-2H-pyrazol-3-yl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as brown oil which was used in the next step without further purification. MS (ESI): m/z=472.2 [M−H]−.