Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:37])[C:19]([OH:36])([C:24]3[CH:25]=[CH:26][C:27]4[O:32][CH2:31][C:30](=[O:33])[N:29]([CH3:34])[C:28]=4[CH:35]=3)[C:20]([F:23])([F:22])[F:21])=[C:14]([Cl:38])[CH:13]=2)[CH:8]=[CH:7][C:6]=1[F:39])C.[Li+].[OH-].Cl>O1CCCC1.CO>[Cl:38][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[CH:18]([CH3:37])[C:19]([OH:36])([C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[N:29]([CH3:34])[C:28]=2[CH:35]=1)[C:20]([F:22])([F:21])[F:23])[O:11][C:9]1[CH:8]=[CH:7][C:6]([F:39])=[C:5]([CH:10]=1)[C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)c1cc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)ccc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(c1ccc(Oc2ccc(F)c(C(=O)O)c2)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 81.2 %

Procedure:
To a solution of 5-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-propyl]-phenoxy}-2-fluoro-benzoic acid ethyl ester (23 mg, 0.04 mmol) in tetrahydrofuran (0.085 ml) and methanol (0.085 ml) was added a 1 M aqueous LiOH solution (0.08 ml, 0.08 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min and at room temperature for 2.5 h. The mixture was cooled in an ice bath and acidified using 1 M aqueous HCl. The mixture was concentrated. To the residue, water was added, extracted twice with AcOEt, the organic phases were washed with water, dried (MgSO4) and concentrated to give the title compound (18 mg) as a white solid. MS (m/e, ISP neg. ion)=552.2 [M−H+].
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:31]([CH3:32])=[CH:30][C:18]2[N:19]=[C:20]([O:22]CC3C=CC=CC=3)[S:21][C:17]=2[C:16]=1[Br:33])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>CCOC(C)=O.CCO.[Pd]>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:31]([CH3:32])=[CH:30][C:18]2[N:19]=[C:20]([OH:22])[S:21][C:17]=2[C:16]=1[Br:33])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: Cc1cc2nc(OCc3ccccc3)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc2nc(O)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of (S)-2-(2-(benzyloxy)-7-bromo-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (67A), Pd/C (800 mg) in EtOAc/EtOH (10 ml, 1:1) was charged into a flask with H2 balloon, and stirred at rt for 1 h. The reaction mixture was filtered over celite, concentrated down, purified by silica gel column, eluting by 0-50% EtOAc in hexanes to give 67B (850 mg).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH2:28](O)[CH3:29]>>[CH2:28]([O:9][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[C:13]([C:19]([F:22])([F:20])[F:21])[CH:12]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:29]
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(CC1CCCC1)c1ccc(SC)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionic acid (1.29 g, 3.89 mmol) in ethanol (25 mL) was treated slowly with concentrated sulfuric acid (0.01 mL). The resulting reaction mixture was heated under reflux for 48 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The residue was dissolved in ethyl acetate (35 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×15 mL), water (1×15 mL), and a saturated aqueous sodium chloride solution (3×20 mL). The organic layer was then dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionic acid ethyl ester (1.39 g, 94.8%) as yellow oil: EI-HRMS m/e calcd for C18H23F3O2S (M+) 360.1370, found 360.1370.
Reaction SMILES: [CH3:1][O:2][C:3]([C@:5]1([CH3:18])[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:4].[OH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C:30](O)=[O:31]>>[CH3:1][O:2][C:3]([C@:5]1([CH3:18])[CH2:9][C@H:8]([NH:10][C:30]([C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]=2[OH:19])=[O:31])[CH2:7][N:6]1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:4]
Reactant: COC(=O)[C@]1(C)C[C@H](N)CN1CC1CCCCC1
Reactant: O=C(O)c1ccc2ccccc2c1O
Product: COC(=O)[C@]1(C)C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1

Procedure:
(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-pyrrolidine-2-carboxylic acid methyl ester was prepared from (2S,4S)-4-amino-1-cyclohexylmethyl-2-methyl-pyrrolidine-2-carboxylic acid methyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C25H33N2O4 [(M+H)+] 425, obsd. 425.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[N:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(Oc2ccc(F)cc2)nc1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
A mixture of 4-fluorophenol (96.8 g), methyl 6-chloropyridine-3-carboxylate (30 g) and cesium carbonate (285.3 g) in DMSO (875 mL) was stirred and heated to 130° C. over a period of 1.75 h then cooled overnight. The reaction mixture was reheated to ˜150° C. over a period of 1.5 h, kept at this temperature for ˜1 h, then cooled to ˜40° C. and poured into water (4 L). The aqueous solution was extracted with ether (1.0 L) then adjusted to pH7-8 by addition of 2M HCl. The solution was extracted with further ether (2×1.0 L), then adjusted to pH 2 by addition of 2M HCl causing precipitation of a solid. The precipitate was collected by filtration, washed with water and dried overnight at 40° C. in vacuo to give the title compound as a beige/pink solid (36.7 g).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=[C:30]([CH3:38])[C:29]4=[O:39])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=[C:30]([CH3:38])[C:29]4=[O:39])[CH2:24][CH2:25]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Cc1cc2ccccc2n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c1=O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2ccccc2n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To 2 mL of a chloroform solution containing 97 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(3-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2 mL of trifluoroacetic acid was added and stirred at room temperature for 4 hours. After the solvent was removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 78 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-3-methylquinolin-2(1H)-one as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=3)[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccc(F)cc2)CC1
Reaction time: 2 h
Yield: 85 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with 4-fluorobenzoyl chloride, (0.018 mL, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (35 mg, 82%). LCMS calculated for C22H20ClFN3O2 (M+H)+: m/z=412.1; Found: 412.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[S:5][C:4]=1[C:11]([OH:13])=O.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([N:21]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([C:4]1[S:5][C:6]([C:8]([OH:10])=[O:9])=[CH:7][C:3]=1[O:2][CH3:1])=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc(C(=O)O)sc1C(=O)O
Reactant: NCc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)sc1C(=O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 3-methoxy-thiophene-2,5-dicarboxylic acid (0.382 g), benzylamine (0.41 mL), N,N′-carboxyl≈diimidazole (0.66 g), and DMF was heated at 60° C. to yield 0.39 g of 3-methoxy-thiophene-2,5-dicarboxylic acid bis benzylamide; MI-APCI+ 381.1; Elem. Anal. (C21H20N2O3S); Calc'd: C, 66.30; H, 5.30; N, 7.36. Found: C, 66.52; H, 5.06; N, 7.41.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20].Cl>O.C(=S)=S>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:19](=[O:21])[CH3:20])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: COc1ccc(-c2ccc(C(C)=O)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The 4′-methoxybiphenyl (0.05 mol) and AlCl3 (0.06 mol) were dissolved in boiling CS2 (60 mL) with stirring. Acetyl chloride (0.1 mol) was added dropwise and reflux continued for 1 hour. The mixture was poured onto crushed ice (150 mL) containing water (50 mL) and HCl (50 mL). The organic phase was separated and the CS2 removed by distillation. The residue was recrystallised from aqueous isopropanol to give the title compound. δC (CDCl3, 62.9 MHz): 26.6, 55.4, 114.4, 126.6, 128.4, 129.0, 132.2, 135.3, 145.4, 159.9 and 198.0
Reaction SMILES: COC([C:5]1[C:6]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[N:13]=2)[CH:8]=[CH:9][N:10]=1)=O.CO.Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:12]1[N:13]=[C:6]2[CH:5]=[N:10][CH:9]=[CH:8][N:7]2[CH:11]=1
Reactant: COC(=O)c1nccn2cc(-c3ccc(F)cc3F)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Fc1ccc(-c2cn3ccncc3n2)c(F)c1
Temperature: 105 °C
Yield: 70.2 %

Procedure:
2-(2,4-Difluorophenyl)-imidazo[1,2-a]pyrazine-8-carboxylic acid methyl ester (prepared from general procedure B using 3-aminopyrazine-2-carboxylic acid methyl ester and 2-bromo-1-(2,4-difluorophenyl)-ethanone; 5.0 g, 17 mmol) was dissolved in DCM (30 mL) and MeOH (30 mL) and was treated with 1.0 M aqueous HCl (160 mL). The mixture was heated at about 105° C. for about 13 h, allowed to cool to ambient temperature, and neutralized with NaHCO3. The solid was filtered and dried overnight to yield the title compound (2.76 g, 70%): LC/MS (Table 1, Method b) Rt=1.9 min; MS m/z: 232.0 (M+H)+.
Reaction SMILES: [CH:1](O)=[O:2].CC(OC(C)=O)=O.[NH2:11][CH:12]([C:18]#[N:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1>[C:18]([CH:12]([NH:11][CH:1]=[O:2])[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:19]
Reactant: O=CO
Reactant: CCOC(=O)C(N)C#N
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(C#N)NC=O
Temperature: 25 °C
Yield: 70.4 %

Procedure:
Under N2, HCOOH (2.44 g, 53 mmol) was added to Ac2O (6.48 g, 63.6 mmol) at 0° C. After it was allowed to warm to ambient temperature the reaction was heated at 50° C. for 15 hr. It was allowed to cool to ambient temperature. This mixed acid anhydride was then added dropwise to a solution of ethyl 2-amino-2-cyanoacetate (128 mg, 1 mmol) in dry THF (5 mL) at 0° C. After the cooling bath was removed, the reaction was maintained at ambient temperature for additional 1 hr. The reaction mixture was concentrated and purified by silica gel column chromatography (5:1 PE/EtOAc) to afford ethyl 2-cyano-2-formamidoacetate (110 mg, 70%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[C:9]([C:11](=[O:24])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH:8]=[N:7][C:6]=1[N:25]1[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]1)C.[Li+].[OH-].O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCO>[OH:30][C@@H:27]1[CH2:28][CH2:29][N:25]([C:6]2[N:7]=[CH:8][C:9]([C:11](=[O:24])[NH:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20]([F:22])([F:21])[F:23])=[CH:17][CH:18]=3)=[CH:10][C:5]=2[C:4]([OH:31])=[O:3])[CH2:26]1
Reactant: CCOC(=O)c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(C(=O)O)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-2-(3-hydroxypyrrolidin-1-yl)-5-((4-(trifluoromethoxy)phenyl)carbamoyl)nicotinic acid ethyl ester (Stage 72.4, 3.20 g, 7.28 mmol) and LiOH in EtOH (18 mL)/water (6 mL) was stirred at 50° C. for 8 h. The solution was cooled to RT, acidified with citric acid monohydrate and resulting crystalline title compound was filtered and dried. m.p. 242-245° C., HPLC (Condition 4) tR=4.45 min, UPLC-MS (Condition 8) tR=0.80 min, m/z=412 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.92 (br. s, 2H), 3.10 (d, J=12.12 Hz, 1H), 3.39 (br. s, 1H), 3.50-3.75 (m, 2H), 4.31 (br. s, 1H), 4.80-5.01 (m, 1H), 7.30 (d, J=8.60 Hz, 2H), 7.74-7.88 (m, 2H), 8.39 (d, J=2.35 Hz, 1H), 8.76 (d, J=2.35 Hz, 1H), 10.23 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:11]=1[C:12](Cl)=[O:13]>O1CCOCC1>[NH2:8][C:4]1[N:3]=[C:2]([NH:1][C:12](=[O:13])[C:11]2[C:15]([Cl:20])=[CH:16][C:17]([Cl:19])=[CH:18][C:10]=2[Cl:9])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: C1COCCO1
Product: Nc1cccc(NC(=O)c2c(Cl)cc(Cl)cc2Cl)n1
Yield: 39.5 %

Procedure:
Using a method similar to Preparation 48, using 2,6-diaminopyridine (2.6 g, 12 mmol), dioxane (80 mL), and 2,4,6-trichlorobenzoyl chloride (1.95 g, 8 mmol) (stir at 0-25° C. for 16 hr.) gives the title intermediate (1.0 g, 39% yield): mass spectrum (ion spray): m/z=316.0 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=1.CC1(C)C(C)(C)OB([C:47]2[S:48][C:49]([CH3:52])=[CH:50][CH:51]=2)O1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].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>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:9]1[CH2:10][C:6]2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]3[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]3[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=[C:2]([C:47]3[S:48][C:49]([CH3:52])=[CH:50][CH:51]=3)[C:7]=2[C:8]1=[O:22]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4ccc(C)s4)c3C2=O)c(OC)c1
Yield: 54.4 %

Procedure:
A solution of tert-butyl (3R,4R)-4-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (51 mg, 0.093 mmol), 4,4,5,5-tetramethyl-2-(5-methylthiophen-2-yl)-1,3,2-dioxaborolane (104 mg, 0.463 mmol), and bis(triphenylphosphine)palladium chloride (65.0 mg, 0.093 mmol) in dioxane (1 mL) and saturated Na2CO3 aq (1 mL) was heated to 140° C. for 40 min. After filtering out the solids, the solvent was removed from the filtrate. The resulting residue was dissolved in MeOH and DCM (10 mL) and was purified via preparative HPLC eluting with water (0.05% TFA) and ACN (80%, 0.035% TFA). The collected fractions were combined and solvent was stripped to dryness via rotary evaporation to give the title compound (31 mg, 55%). [M+H] calc'd for C31H37FN4O6S, 613. found, 613.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]1[CH:10]([CH2:11][C:12]#[C:13][CH2:14][CH3:15])[C:9](=[O:16])[CH:8]=[CH:7]1)=[O:4].[BH4-].[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3]([CH2:5][CH:6]1[CH2:7][CH2:8][CH:9]([OH:16])[CH:10]1[CH2:11][C:12]#[C:13][CH2:14][CH3:15])=[O:4]
Reactant: CCC#CCC1C(=O)C=CC1CC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCC#CCC1C(O)CCC1CC(=O)OC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
4-Methoxycarbonylmethyl-5-(2-pentynyl)-2-cyclopentenone (890 mg) and 350 mg of sodium borohydride are dissolved in 20 ml of methanol, and the mixture is refluxed at 80° C. for one hour. On completion of the reaction, the mixture is cooled to room temperature. With addition of 60 ml of acetic acid, the mixture is stirred for 30 minutes and thereafter concentrated in a vacuum. The residue is purified with a silica gel column and distilled in a vacuum, affording 3-methoxycarbonylmethyl-2-(2-pentynyl)cyclopentanol (compound (1), R2 =CH3) in a yield of 94%, b.p. 65°-69° C./0.15 mm Hg.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[C:8]([Cl:15])[C:9]=1[O:10][CH2:11][CH:12]1[CH2:14][CH2:13]1.Cl>CN(C=O)C.O>[Br:3][C:4]1[CH:5]=[C:6]([CH:16]([CH2:4][CH2:9][O:10][CH3:11])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[C:8]([Cl:15])[C:9]=1[O:10][CH2:11][CH:12]1[CH2:13][CH2:14]1
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC2CC2)c(Br)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCOC)c1cc(Cl)c(OCC2CC2)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
To a stirred solution of NaH (0.3 g, 12.5 mmol) in DMF (10 mL) was added ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate (2.0 g, 5.70 mmol) at 0° C. The reaction mixture was stirred at 0° C. over a period of 30 min. To the reaction mixture was added 2-bromo ethyl methyl ether (0.87 g, 6.25 mmol) and stirred at 0 oC for 30 min. After completion of starting material (by TLC), the reaction mixture was diluted with water (20 mL), acidified with 1N HCl (pH=5) and extracted with EtOAc (3×50 mL). Combined organic layers were washed with water (3×25 mL), brine and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude material was purified by column chromatography to afford ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methoxybutanoate (560 mg) as an off white solid.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH3:21])[C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)(=O)C.[ClH:22]>CO>[ClH:22].[NH:4]1[CH2:5][CH2:6][CH:7]([N:10]([CH3:21])[C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:9]1
Reactant: CC(=O)N1CCC(N(C)C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: CO
Product: CN(C(=O)OCc1ccccc1)C1CCNCC1

Procedure:
14.5 g of the compound obtained in Stage B are refluxed with 50 ml of methanol and 30 ml of 6N hydrochloride acid for 20 hours. After evaporation the hydrochloride of the desired product is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22].[NH2:27][C@H:28]1[C@@H:32]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)[CH2:31][NH:30][CH2:29]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:30]2[CH2:31][C@H:32]([N:33]3[CH:37]=[CH:36][N:35]=[N:34]3)[C@H:28]([NH2:27])[CH2:29]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22]
Reactant: N[C@@H]1CNC[C@@H]1n1ccnn1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Product: Nc1c(F)c(N2C[C@@H](N)[C@@H](n3ccnn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Yield: 66 %

Procedure:
Prepared by following the same procedure as described for Example 17 by using 5-amino-1-(2,4-difluorophenyl) -6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and cis-3-amino-4-(1,2,3-triazol-1-yl)-pyrrolidine. Yield: 66%, m.p. 279°-281° C. 1H NMR (TFA) δ: 4.48-4.82 (m, 4H), 5.02 (m, 1H), 6.26 (m, 1H), 7.17 (m, 2H), 7.62 (m, 1H), 8.6 (s, 1H), 8.82 (d, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[H-].[Na+].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]>C(O)C>[Cl:5][CH2:4][CH2:3][CH2:2][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: N#Cc1cccc(O)c1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cccc(OCCCCl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
A suspension of 1-bromo-3-chloropropane (13.9 g, 88.1 mmol) and 60% sodium hydride (oil dispersion, 3.02 g, 126 mmol) in ethanol (50 mL) was stirred at room temperature for 30 min. 3-Hydroxybenzonitrile (10.0 g, 83.9 mmol) was added to the reaction mixture at 0° C., and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The obtained oil was purified by silica gel column chromatography (5%-15% ethyl acetate/hexane) to give the title compound as a colorless oil (14.2 g, 86%).
Reaction SMILES: C(OC1C=CC([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=CC=1)C1C=CC=CC=1>[Pd].C(O)C>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][CH:14]([OH:13])[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCc3ccccc3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 144.8 %

Procedure:
To 10% palladium on carbon (0.75 g), under a stream of argon, was added a solution of tert-butyl 4-[4-(benzyloxy)phenoxy]piperidine-1-carboxylate (7.5 g) in ethanol (250 mL). The vessel was purged with argon three times, before hydrogen was introduced to the system via a balloon. The reaction was stirred vigorously at ambient temperature for 3 hours. Hydrogen was removed from the system and purged three times with argon before filtering through a celite pad. The pad was washed thoroughly. The filtrate and washings were combined and evaporated, the solid triturated with 20% diethyl ether/iso-hexane to yield tert-butyl-4-hydroxy-1-piperidinecarboxylate (5.7 g) NMR Spectrum: (CDCl3) 1.5 (s, 9H), 1.7 (m, 2H), 1.9 (m, 2H), 3.3 (m, 2H), 3.7 (m, 2H), 4.3 (m, 1H), 4.8 (s, 1H), 6.7 (m, 4H).