Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][C:18]=1[CH2:19][OH:20])=[C:14]([C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[F:28])[C:13](=[O:29])[CH:12]=[CH:11]2.CC(C)=[O:32].OS(O)(=O)=O.O=[Cr](=O)=O>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][C:18]=1[C:19]([OH:32])=[O:20])=[C:14]([C:21]1[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=1[F:27])[C:13](=[O:29])[CH:12]=[CH:11]2
Reactant: O=c1ccn2c(-c3ccc(F)cc3F)c(CO)ccc2c1-c1c(F)cccc1F
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc2c(-c3c(F)cccc3F)c(=O)ccn2c1-c1ccc(F)cc1F
Temperature: 0 °C

Procedure:
To a solution of 6-(2,4-difluorophenyl)-1-(2,6-difluorophenyl)-7-(hydroxymethyl)-2H-quinolizin-2-one (Example 50, 100 mg) was added Jones reagent (0.5 mL, 4 N in sulfuric acid; prepared using procedure similar to that disclosed in Bowers, Halsall, Jones, and Lemin, J. Chem. Soc., (1953), 2548-2560) at 0° C. The mixture was stirred for a couple of hours at 0° C. until reaction complete and then quenched with isopropanol (1 mL). After stirring for 10 min (green solution), the mixture was filtered through celite and concentrated. The residue was diluted with ethyl acetate and washed with water, brine, dried over MgSO4 and concentrated to give title compound (87 mg).
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9]([O:13][C:14]([NH:16][CH:17]([NH2:19])[CH3:18])=[O:15])([CH3:12])([CH3:11])[CH3:10]>C1(C)C=CC=CC=1>[N:5]1[CH:6]=[CH:1][CH:2]=[C:3]([CH2:7][NH:19][CH:17]([NH:16][C:14]([O:13][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:15])[CH3:18])[CH:4]=1
Reactant: CC(N)NC(=O)OC(C)(C)C
Reactant: O=Cc1cccnc1
Solvent: Cc1ccccc1
Product: CC(NCc1cccnc1)NC(=O)OC(C)(C)C

Procedure:
2.92 g of 3-pyridyl carboxaldehyde are added to a solution of 4.82 g of N-(tert.butoxycarbonyl)ethanediamine in 50 ml of toluene in the presence of a dehydrating agent (4 Å molecular sieves) at about 5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][CH2:18][C:19]1[C:27]2[C:22](=[N:23][C:24]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)=[C:25]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[C:26]=2[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[NH:21][N:20]=1>>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]2[C:25]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)=[C:24]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)[N:23]=[C:22]3[NH:21][N:20]=[C:19]([CH2:18][NH:17][C:14]([CH:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]4)=[O:16])[C:27]=23)=[CH:29][CH:30]=1
Reactant: NCc1n[nH]c2nc(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)c12
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCc2n[nH]c3nc(-c4ccc(F)cc4)c(-c4ccncc4)c(-c4ccc(F)cc4)c23)CC1
Yield: 26 %

Procedure:
Following a similar procedure to that described in example 48, but using 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid instead of 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]acetic acid and 3-aminomethyl-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (obtained in example 68) instead of morpholine, the title compound was obtained (yield: 26%).
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([C:21](O)=[O:22])[CH:20]=1)[NH:17][CH:16]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[CH:25]=1)[C:15]([CH3:38])([CH3:37])[CH2:14]2.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:20]=1)[NH:17][CH:16]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]3)[CH:25]=1)[C:15]([CH3:38])([CH3:37])[CH2:14]2
Reactant: NS(=O)(=O)C1CC1
Reactant: CN1CCN(c2cccc(C3Nc4c(cc(Cl)cc4C(=O)O)CC3(C)C)c2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc(C3Nc4c(cc(Cl)cc4C(=O)NS(=O)(=O)C4CC4)CC3(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a suspension of 60% sodium hydride (114 mg, 2.8 mmol) in N,N-dimethylformamide (1.5 mL) was added cyclopropanesulfonamide (350 mg, 2.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 6-chloro-3,3-dimethyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (120 mg, 0.3 mmol) and 1,1′-carbonyldiimidazole (118 mg, 0.8 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {6-chloro-3,3-dimethyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carbonyl}-amide (62 mg, 40%) as a white solid: LC/MS m/e calcd for C26H33ClN4O3S (M+H)+: 517.0, observed: 517.1.
Reaction SMILES: [C-]#N.[Na+].O.[N:5]12CCN(CC1)C[CH2:6]2.[N:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23](SC)[N:22]([CH3:27])[C:21](=[O:28])[C:20]=2[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[CH:15][CH:14]=1>CN1CCCC1=O>[CH3:27][N:22]1[C:21](=[O:28])[C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[C:19]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)[N:24]=[C:23]1[C:6]#[N:5]
Reactant: C1CN2CCN1CC2
Reactant: CSc1nc(-c2ccncc2)c(-c2cccc(C(F)(F)F)c2)c(=O)n1C
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cn1c(C#N)nc(-c2ccncc2)c(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of NaCN (55 mg), water (0.1 ml) in 1-methyl-2-pyrrolidone (50 mL) was added 1,4-diazabicyclo[2,2,2]octane (220 mg, 2 mmole) and a solution of 365 mg of 6-(4-pyridyl)-3-methyl-2-methylthio-5-(3-(trifluoromethyl)phenyl)-(3H)-pyrimidin-4-one in 1-methyl-2-pyrrolidone (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 5 minutes. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4 and then concentrated. The residue was purified by flash chromatography (20% EtOAc:Hexanes) to provide the product as a colorless oil; MS (m/z) 357 (M+H)+; C18H11F3N4O requir. 356.3.
Reaction SMILES: [ClH:1].[CH:2]([N:5]([CH:27]([CH3:29])[CH3:28])[CH2:6][CH2:7][C@@H:8]([C:15]1[CH:20]=[C:19]([CH2:21][CH2:22]C(=O)N)[CH:18]=[CH:17][C:16]=1[OH:26])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])[CH3:3].[OH-:30].[K+].[CH3:32][OH:33]>C(O)C.O>[ClH:1].[CH:27]([N:5]([CH:2]([CH3:3])[CH3:4])[CH2:6][CH2:7][C@@H:8]([C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:32]([OH:33])=[O:30])[CH:18]=[CH:17][C:16]=1[OH:26])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:29])[CH3:28]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCC(N)=O)ccc1O)C(C)C
Reactant: CO
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCC(=O)O)ccc1O)C(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-N,N-diisopropyl-3-[5-(2-carbamoylethyl)-2-hydroxyphenyl]-3-phenylpropanamine (obtained in Example 25), (0.50 g, 1.31 mmol) in ethanol (15 mL) and H2O (10 mL) was added KOH (3.75 g, 66.8 mmol). The mixture was stirred overnight at 100° C. The solvent was evaporated and the residue redissolved in H2O and washed with diethyl ether. The aqueous layer was acidified with conc. HCl and the precipitate was collected by filtration and washed with 2 M HCl. The product was fractionated on a reversed-phase PEP RPC HR 30/26 (Pharmacia Biotech AB, Sweden) column using a gradient of 20-60% acetonitrile with 0.1% TFA. Fractions were pooled and hydrochloric acid (2 mL, conc.) was added and the solvent was evaporated. The residue was crystallised from methanol-diethyl ether to give 0.37 g (0.96 mmol, 74%); 1H NMR (CD3OD) δ1.28 (m, 12H), 2.48 (m, 4H), 2.76 (t, 2H), 3.04 (t, 2H), 3.67 (m, 2H), 4.39 (t, 1H), 6.72 (d, 1H), 6.92 (d, 1H), 7.00 (s, 1H), 7.19 (t, 1H), 7.32 (m, 4H); mp. 205-207° C.; [α]D +3.7° (c=1.0, methanol). Anal. (C24H33NO3*1.0HCl) C, H, N.
Reaction SMILES: [CH:1]1CCCCCCCCCC[CH:2]=1.[C:13]1(=[O:23])[O:18][C:16](=O)[CH:15]2[CH2:19][CH2:20][CH:21]=[CH:22][CH:14]12.[C:24]([OH:27])(=[O:26])[CH3:25]>>[C:24]([CH2:25][CH2:1][CH2:2][CH2:16][CH2:15][CH2:19][CH2:20][CH2:21][CH2:22][CH2:14][C:13]([OH:18])=[O:23])([OH:27])=[O:26]
Reactant: O=C1OC(=O)C2CCC=CC12
Reactant: CC(=O)O
Reactant: C1=CCCCCCCCCCC1
Product: O=C(O)CCCCCCCCCCC(=O)O
Yield: 94 %

Procedure:
The co-oxidation reaction was carried out in a manner as described in Example 1, except that cyclododecene was used in lieu of cis-Δ4 -tetrahydrophthalic anhydride. Acetic acid was obtained at a yield of 95% and 1,10-dicarboxy decane was obtained at a yield of 94%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[S:15][C@@H:16]([F:20])[C@H:17](O)[N:18]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C(N(CC)CC)C.C(OC(=O)C)(=O)C>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[S:15][C:16]([F:20])=[CH:17][N:18]=2)(=[O:11])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(S(=O)(=O)NC2=N[C@@H](O)[C@H](F)S2)ccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cc(S(=O)(=O)Nc2ncc(F)s2)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
To a suspension of 3-cyano-4-fluoro-N-[(4S,5R)-5-fluoro-4-hydroxy-4,5-dihydro-1,3-thiazol-2-yl]benzenesulfonamide (Preparation 33, 1.42 g, 4.45 mmol) in dichloromethane (150 mL) was added triethylamine (6.20 mL, 44.5 mmol) and acetic anhydride (1.30 mL, 13.8 mL). The reaction mixture was stirred at room temperature under an atmosphere of nitrogen for 18 hours. The mixture was washed with a 2M aqueous solution of hydrogen chloride. The organics were separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was triturated with dichloromethane to afford the title compound as a pale yellow solid (825 mg, 62%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:31])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[N:9]=3)[CH2:2]1.[O:32]1[CH2:36][CH2:35][C:34](=O)[CH2:33]1>>[CH3:31][N:7]1[C:6]([CH2:5][CH:3]2[CH2:2][N:1]([C@@H:34]3[CH2:35][CH2:36][O:32][CH2:33]3)[CH2:4]2)=[N:14][C:13]2[C:8]1=[N:9][C:10]([N:21]1[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]1[CH3:30])=[N:11][C:12]=2[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: O=C1CCOC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN([C@@H]4CCOC4)C3)n(C)c2n1

Procedure:
Following General Procedure L, 4-(8-(azetidin-3-ylmethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and dihydrofuran-3(2 H)-one were reacted to give the racemic mixture. The enantiomers were separated by SFC to give 573. LCMS m/z: 245.2 (2M+H+)
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10](=O)([O-])[O-].[Cs+].[Cs+].[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[C:19](Cl)[N:18]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([O:25][CH3:10])=[O:24])[CH:20]=[C:19]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:18]=1
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)nc(-c2ccccc2)c1

Procedure:
Phenylboronic acid (326 mg), PdCl2(PPh3)2 (84 mg) and cesium carbonate (3.9 g) were added in that order to a THF (10 mL) solution of 2,6-dichloropyridine-4-carboxylic acid (500 mg), and stirred under heat with refluxing for 1.5 hours. The reaction liquid was filtered through Celite, concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain a crude product of the title compound as a yellow oil. Not purified, this was used in the next step.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13](COCC[Si](C)(C)C)[CH:12]=1)=[O:10])[CH3:7].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[NH:13][CH:12]=1)=[O:10])[CH3:7]
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ncco1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ncco1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.8 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-oxazol-2-yl-ethyl)-amide (64 mg, 0.12 mmol) was dissolved in dichloromethane (0.6 ml) and trifluoroacetic acid (0.4 ml, 5.0 mmol) was added. The reaction mixture was stirred at room temperature for 2.5 h then concentrated. The residue was dissolved in dichloromethane (0.6 ml) and ethylenediamine (0.5 ml, 7.3 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 33 mg (65%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-oxazol-2-yl-ethyl)-amide as a light yellow powder. MS: (M+H)+=406; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.93 (br. s., 1H), 9.13 (s, 1H), 8.66 (d, J=8.7 Hz, 1H), 8.51 (s, 1H), 8.47 (dd, J=8.9, 5.5 Hz, 1H), 8.11 (s, 1H), 7.69 (dd, J=9.8, 2.3 Hz, 1H), 7.25 (s, 1H), 7.07 (td, J=9.2, 2.1 Hz, 1H), 5.48-5.61 (m, 1H), 4.15 (s, 3H), 1.67 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.O[CH2:71][C@@H:72]1[CH2:74][C@H:73]1[C:75]([O:77][CH2:78][CH3:79])=[O:76].C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:71][C@@H:72]3[CH2:74][C@H:73]3[C:75]([O:77][CH2:78][CH3:79])=[O:76])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)[C@@H]1C[C@H]1CO
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1COc1cc(CCCOC)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl(3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from the previous step in toluene (0.1 M) was added 1,1′-(azodicarbonyl)dipiperidine (1.2 eq.), ethyl (1R,2R)-2-(hydroxyl-methyl)cyclopropanecarboxylate (appendage 1) (2 eq.), and tri-n-butylphosphine (1.2 eq.). The reaction was heated to 80° C. and stirred for 18 h. While hot, the reaction was diluted with EtOAc/water. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 40% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[NH:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:30]4[CH:31]=[N:27][NH:28][CH:29]=4)=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3cn[nH]c3)cc1OCC2)c1ccccc1Cl

Procedure:
Following Examples 44 and 60, 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 and pyrazole-4-boronic acid pinacol ester were reacted to give 132. MS: (ESI+) 436.1
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Na]>ClCCl.C(O)(=O)C.FC(F)(F)C(O)=O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:18][CH:17]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: ClCCl
Product: Clc1ccc(NC2CCNCC2)cc1

Procedure:
Was synthesised in the same way as (A) from 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.59 g, 18.0 mmol), 4-chloro-phenylamine (1.15 g, 9.0 mmol) and sodium triacetoxyborhydride (5.34 g, 25.2 mmol) in dichloromethane (40 ml) and acetic acid (3.1 ml). The deprotection was run in dichloromethane (37 ml) and trifluoro acetic acid (18 ml). Yield 1.5 g, 79%
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:4][CH:3]=1.[SH:18][CH2:19][CH2:20][OH:21].C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O>[OH:21][CH2:20][CH2:19][S:18][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: OCCS
Reactant: Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(C(=O)c2ccc(SCCO)cc2)cc1C
Reaction time: 6 h

Procedure:
12.2 g (0.05 mol) of 4'-chloro-3,4-dimethylbenzophenone and 4.3 g (0.055 mol) of 2-mercaptoethanol in 50 ml of dimethylacetamide are heated to 95° under nitrogen. 13.8 g (0.1 mol) of calcined K2CO3 are then added. The suspension is kept at 90°-100° C. for 6 hours. 100 ml of water are poured over the resulting reaction mixture and the mixture is extracted with ether. The ether layer is washed with water, dried over Na2SO4 and concentrated. The crystals obtained are recrystallised from methanol and dried in vacuo at 60° C. Yield: 10.1 g (71%). Melting point 92°-93° C.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[F:15][C:16]1[CH:17]=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=1[F:22]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:23][C:18]2[CH:19]=[CH:20][C:21]([F:22])=[C:16]([F:15])[CH:17]=2)=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Reactant: Oc1ccc(F)c(F)c1
Product: COC(=O)c1cc(Cl)ccc1COc1ccc(F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 3,4-difluorophenol:
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([NH2:17])(=[O:16])=[O:15])[CH2:5][CH2:4][O:3]1.[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([NH:28][C:29](=O)[O:30]C2C=CC=CC=2)[N:21]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C.O>[CH3:27][O:26][C:24]1[CH:25]=[C:20]([O:19][CH3:18])[N:21]=[C:22]([NH:28][C:29]([NH:17][S:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[C:6]2[CH2:5][CH2:4][O:3][C:2]2=[O:1])(=[O:15])=[O:16])=[O:30])[N:23]=1
Reactant: NS(=O)(=O)c1ccccc1C=C1CCOC1=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C=C2CCOC2=O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
To a stirred suspension of 0.09 g (0.0004 mol) of the product of Example 3 and 0.15 g (0.0005 mol) of (4,6-dimethoxy-2-pyrimidinyl)carbamic acid, phenyl ester in 1 mL dry acetonitrile under nitrogen was added dropwise 0.08 mL (0.08 g, 0.0005 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture was stirred at room temperature for 30 min and was then diluted with water and acidified with 1N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and washed well with water and ether to yield 0.1 g (64%) of the title compound: m.p. 185°-190° (gas evolution); IR (nujol) 3180 (br), 1755, 1740, 1710, 1700, 1610, 1560, 1355, 1165 cm-1 ; NMR (CDCl3, 200 MHz) δ 3.05 (2H, m), 4.29 (2H, t, J=7 Hz), 3.99 (6H, s), 5.83 (1H, s), 7.2 (NH, s), 7.4-7.8 (3H, m), 8.1 (1H, m), 8.12 (NH, s), 8.14 (1H, m).
Reaction SMILES: Cl[C:2]1[N:28]=[CH:27][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[N:16]=[CH:17][N:18]=1)[N:7]=3.[NH:29]1[CH2:36][CH2:35][CH2:34][C@H:30]1[C:31]([NH2:33])=[O:32].C(N(CC)CC)C.[NH4+].[Cl-]>CN1CCCC1=O.ClCCl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:15]1[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:27]=[N:28][C:2]([N:29]5[CH2:36][CH2:35][CH2:34][C@H:30]5[C:31]([NH2:33])=[O:32])=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)=[N:18][CH:17]=[N:16]1
Reactant: Fc1ccc(-n2ncnc2-c2cn3c(n2)-c2cnc(Cl)cc2OCC3)c(F)c1
Reactant: NC(=O)[C@@H]1CCCN1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: NC(=O)[C@@H]1CCCN1c1cc2c(cn1)-c1nc(-c3ncnn3-c3ccc(F)cc3F)cn1CCO2
Yield: 39.4 %

Procedure:
A solution of 8-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene (0.200 g, 0.499 mmol), L-prolinamide (0.171 g, 0.00150 mol) and Triethylamine (0.417 mL, 0.00299 mol) in N-Methylpyrrolidinone (5 mL) under N2 was heated to 150° C. overnight. The mixture was diluted with dichloromethane. Saturated NH4Cl was added and the mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried with Na2SO4 and concentrated. The crude was purified by reverse-phase HPLC to obtain 94 mg (39% yield) of 378 as a light pink solid. MS (ESI+) 479.2. 1H NMR (400 MHz, DMSO) δ 8.35 (s, 1H), 8.18 (s, 1H), 7.86 (s, 1H), 7.69 (td, J=8.7, 6.0 Hz, 1H), 7.62-7.53 (m, 1H), 7.35-7.26 (m, 2H), 6.92 (br, 1H), 5.84 (s, 1H), 4.47-4.36 (m, 4H), 4.24 (d, J=7.4 Hz, 1H), 3.62-3.53 (m, 1H), 3.42-3.32 (m, 1H), 2.24-2.08 (m, 1H), 2.02-1.83 (m, 3H)