Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH:12]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]3)=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[F:33].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:26][C:27]1[CH:28]=[C:29]([C:2]2[CH:3]=[CH:4][C:5]([O:8][C@H:9]3[CH2:14][CH2:13][C@H:12]([C:15]([N:17]4[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]4)=[O:16])[CH2:11][CH2:10]3)=[N:6][CH:7]=2)[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CC(C)N1CCN(C(=O)C2CCC(Oc3ccc(Br)cn3)CC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(-c4ccc(F)c(F)c4)cn3)CC2)CC1

Procedure:
A mixture of 120 mg (0.29 mmol) of [4-(5-bromo-pyridin-2-yloxy)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone, 69 mg (0.44 mmol) of 3,4-difluorophenylboronic acid, 34 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium, and 93 mg (0.88 mmol) of sodium carbonate, 1.5 ml of toluene and 0.5 ml of water was refluxed for 5 hr under Ar. The mixture was diluted with AcOEt, washed with saturated NaHCO3 solution and brine, dried over MgSO4, and evaporated. The residue was purified by column chromatography on silica eluting with cyclohexane and ethyl acetate=from 100:0 to 4:1. The combined product fractions were evaporated to dryness to yield 22 mg (17%) of the title compound. MS (m/e): 444.2 (MH+).
Reaction SMILES: [CH2:1]([C:8]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[CH2:1]([C:8]1([OH:14])[CH2:13][CH2:12][N:11]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCOc1ccc(OCc2ccccc2)cc1
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: OC1(Cc2ccccc2)CCN(CCOc2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Yield: 98 %

Procedure:
A mixture of 4-benzyl-4-hydroxy-piperidine (0.62 g, 3.3 mmol), 1-(2-bromoethoxy)-4-(phenylmethoxy)-benzene (1.0 g, 3.3 mmol) and potassium carbonate (0.9 g, 6.5 mmol) in 2-butanone (15 ml) was refluxed overnight. It was cooled to room temperature, 30 ml of H2O were added and the organic phase was separated. The water phase was extracted two times with ethyl acetate. The organic phases were then pooled, dried with Na2SO4 and the solvent evaporated to give 4-benzyl-1-[2-(4-benzyloxy-phenoxy)-ethyl]-piperidin-4-ol as a yellowish solid (1.35 g, 99%). MS: m/e=418.4 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1.[CH3:17][C:18]([CH3:50])([CH3:49])[CH2:19][N:20]1[C:24]2[CH:25]=[CH:26][C:27]([O:32]CCCCOC3C=CC(C4NN=NN=4)=CC=3)=[C:28]([CH2:29][CH2:30][CH3:31])[C:23]=2[N:22]=[N:21]1>>[CH3:49][C:18]([CH3:17])([CH3:50])[CH2:19][N:20]1[C:24]2[CH:25]=[CH:26][C:27]([O:32][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=3)=[C:28]([CH2:29][CH2:30][CH3:31])[C:23]=2[NH:22][NH:21]1
Reactant: COC(=O)c1ccc(OCCCCBr)cc1
Reactant: CCCc1c(OCCCCOc2ccc(-c3nnn[nH]3)cc2)ccc2c1nnn2CC(C)(C)C
Product: CCCc1c(OCCCCOc2ccc(C(=O)O)cc2)ccc2c1NNN2CC(C)(C)C

Procedure:
Similar procedures as outlined in examples 1 & 26 were followed using methyl 4-(4-bromobutoxy)benzoate and the mixture of N-alkylated benzotriazoles from example 6. 1H NMR (500 MHz, DMSO) δ 12.58 (bs, 1H), 7.89 (d, 2H), 7.66 (d, 1H), 7.37 (d, 1H), 7.25 (d, 1H), 7.01 (d, 2H), 4.44 (s, 2H), 4.14 (m, 4H), 3.01 (t, 2H), 1.93 (m, 4H), 1.71 (m, 2H), 0.96 (s, 9H), 0.91 (t, 3H). MS (ESI): 440 (M+H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](O)=[O:12])=[CH:5][CH:4]=1.C[N:17](C)C=O.O=S(Cl)Cl.N>C1(C)C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([NH2:17])=[O:12])=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Agent: N
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: NC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Temperature: 47.5 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
(E)-3-(4-(Trifluoromethyl)phenyl)-2-propenoic acid (2400 g, 11.1 mol) and DMF (N,N-dimethylformamide)(82 ml) were added to toluene (12 L). SOCl2 (52.6 mL, 721 mmol) was added dropwise at room temperature and the mixture was stirred at 45-50° C. for 1 hour. The toluene solution cooled to room temperature was added dropwise to 25% aqueous ammonia (12L) at 5-25° C. The mixture was stirred at 45-55° C. for 1 hour. After allowing to cool to room temperature and stirring, the mixture was stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration, washed with water (12 L) and dried under reduced pressure to give (E)-3-(4-(trifluoromethyl)phenyl)-2-propenamide (2293 g, 10.7 mol, yield 96%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:15]([C:17]3[C:18]([O:36][CH2:37][CH3:38])=[C:19]([CH:25]4[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]4)[C:20]([F:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:9]=[C:10]([CH:11]([OH:14])CO)[C:3]=12.C(O)(=O)C.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:15]([C:17]3[C:18]([O:36][CH2:37][CH3:38])=[C:19]([CH:25]4[CH2:26][N:27]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:28]4)[C:20]([F:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:9]=[C:10]([CH:11]=[O:14])[C:3]=12
Reactant: CCOc1c(C(C)n2nc(C(O)CO)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCOc1c(C(C)n2nc(C=O)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-(3-{1-[4-amino-3-(1,2-dihydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-fluorophenyl)azetidine-1-carboxylate (0.754 g, 1.37 mmol) in THF (10 mL) and water (6 mL) was added acetic acid (20 μL, 0.36 mmol) and sodium periodate (0.878 g, 4.10 mmol) at 0° C. After stirring overnight, water was added to the reaction and extracted with dichloromethane (3×). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to yield the crude product. LCMS calculated for C24H29ClFN6O4 (M+H)+: m/z=519.2; Found:519.2.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11].Br[CH2:13][CH2:14][CH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([C@H:22]2[CH2:27][CH2:26][C@H:25]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:23]2)[CH2:18][CH2:17]1>CN(C=O)C.O.CN(C=O)C.C1(C)C=CC=CC=1>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:30][CH2:29][CH2:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([C@H:19]2[CH2:18][CH2:17][C@H:16]([CH2:15][CH2:14][CH3:13])[CH2:21][CH2:20]2)[CH2:23][CH2:24]1
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCCBr)CC2)CC1
Reactant: Oc1cccc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCCOc3cccc(F)c3F)CC2)CC1
Reaction time: 1 h

Procedure:
Under nitrogen gas stream, 29.8 g (683 mmol) of 55% sodium hydride was added to 100 ml of DMF and cooled with water, a solution of 74.0 g (569 mmol) of 2,3-difluorophenol in 700 ml of DMF was added by drops thereto, and they were stirred for 1 hour. To the reaction mixture was added by drops a solution of 156 g (474 mmol) of the crude 1-bromo-3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propane in 400 ml of mixed solvent of DMF/toluene (3/1), and then they were stirred at 80° C. for 3 hours. The reaction mixture was added to 500 ml of water to terminate the reaction, and the organic layer was separated, washed with 500 ml of water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: heptane) and recrystallized from heptane to obtain 101 g of 3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propyl 2,3-difluorophenyl ether.
Reaction SMILES: C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.Cl.CO[C:17]1[CH:40]=[CH:39][C:20]([C:21]([NH:34][CH2:35][CH2:36][N+:37]#[C-:38])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:18]=1.COC1C=CC(C(NCC[N+]#[C-])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1>C(Cl)Cl.CO>[C:21]([NH:34][CH2:35][CH2:36][N+:37]#[C-:38])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:20]1[CH:39]=[CH:40][CH:17]=[CH:18][CH:19]=1
Reactant: [C-]#[N+]CCNC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1
Agent: Cl
Agent: O=C1c2ccccc2C(=O)C1(O)O
Agent: [C-]#[N+]CCNC(c1ccccc1)(c1ccc(OC)cc1)c1ccc(OC)cc1
Solvent: ClCCl
Solvent: CO
Product: [C-]#[N+]CCNC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
C22H20N2 (312.42); RF=0.90 (DCM/MeOH 5:1, v/v); spot stains with ninhydrin spray or with HCl vapour); 2-(4-monomethoxytrityl)aminoethylisocyanide; C23H22N2O (342.44); RF=0.89 (DCM/MeOH 5:1, v/v); spot stains with ninhydrin spray or with HCl vapour); 2-(4,4′-dimethoxytrityl)aminoethylisocyanide; C24H24N2O2 (372.47); RF=0.95 (DCM/MeOH 5:1, v/v); spot stains with ninhydrin spray or with HCl vapour);
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[CH2:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1)([O-])=O.Cl.[OH-].[Na+]>C(O)C.[Fe]>[NH2:1][C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[CH2:6][C:7]1[NH:11][CH:10]=[CH:9][N:8]=1
Reactant: O=[N+]([O-])c1ccccc1Cc1ncc[nH]1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Nc1ccccc1Cc1ncc[nH]1
Reaction time: 1.5 h

Procedure:
50% Aqueous ethanol (5,672 ml) and 2,890 g (14.22 moles) of 2-(2-nitrobenzyl)imidazole are charged into a 22 liter flask. The suspension is stirred under nitrogen atmosphere and 2,400 g (42.97 moles) of iron powder (100 mesh) are added all at once. The mixture is then warmed to 70° and a solution of 1.7 ml of 12N hydrochloric acid in 8.3 ml absolute ethanol are added. A vigorous exotherm results and a strong reflux occurs that persists for 1.5 hours. Then the exotherm subsides, a mixture of 290 ml of 12N HCl and 1400 ml of absolute ethanol are added over 30 minutes. Heat is applied and the mixture is refluxed for 2 hours, diluted with 6,500 ml of absolute ethanol and adjusted to pH 8-9 with 700 ml of 10N sodium hydroxide. The suspension is stirred for 1 hour and filtered. The cake is washed with 1,000 ml of absolute ethanol, the filtrates are combined and the solvent is removed. The remaining solid is then suspended in 10,000 ml of water, stirred under nitrogen atmosphere for two hours, collected, washed with 2,000 ml of water, and dried to yield 2-(2-aminobenzyl)imidazole, m.p. 153°-155°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12](O)=O)=[CH:2]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[OH:36][C:37]1[CH:38]=[CH:39][C:40]2[O:45][CH2:44][C@H:43]([CH2:46][NH2:47])[O:42][C:41]=2[CH:48]=1>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][NH:47][CH2:46][CH:43]2[CH2:44][O:45][C:40]3[CH:39]=[CH:38][C:37]([OH:36])=[CH:48][C:41]=3[O:42]2)=[CH:2]1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: NC[C@H]1COc2ccc(O)cc2O1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)OC(CNCCCc1c[nH]c3ccccc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
3-Indolepropionic acid (1.4 g, 7.4 mmole), 1-hydroxybenzotriazole hydrate (1.2 g, 8.9 mmole) and 1,3-diisopropylcarbodiimide (2.8 ml, 17.8 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise (S)-7-hydroxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.6 g, 7.4 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions containing product were concentrated and washed with a minimum amount of THF to remove a by-product and to give 1.5 g (60%) of the desired product, (S)-(7-hydroxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(1H-indol-3-yl)-propanamide, as a white fluffy solid.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:19](=[O:20])[C:18]4[S:21][C:22]([CH2:24][OH:25])=[CH:23][C:17]=4[N:16]=[CH:15]3)=[CH:10][CH:9]=2)[CH2:4]1.[K].CC(C)([O-])C.[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1.C(OCC)(=O)C>CN(C=O)C.O>[CH:33]1([CH2:36][O:25][CH2:24][C:22]2[S:21][C:18]3[C:19](=[O:20])[N:14]([C:11]4[CH:10]=[CH:9][C:8]([N:5]5[CH2:6][CH2:7][CH:3]([N:2]([CH3:26])[CH3:1])[CH2:4]5)=[CH:13][CH:12]=4)[CH:15]=[N:16][C:17]=3[CH:23]=2)[CH2:35][CH2:34]1
Reactant: BrCC1CC1
Reactant: CN(C)C1CCN(c2ccc(-n3cnc4cc(CO)sc4c3=O)cc2)C1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)C1CCN(c2ccc(-n3cnc4cc(COCC5CC5)sc4c3=O)cc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A mixture of 3-[4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-6-hydroxymethyl-3H-thieno[3,2-d]pyrimidin-4-one (20.0 mg) and potassium-tert.-butoxide (7.65 mg) in DMF (0.3 mL) was stirred at 0° C. for 5 min. Then cyclopropylmethylbromide (11.28 mg) was added. The solution was warmed to room temperature and stirred for 2 h. Then ethyl acetate and water were added. The aqueous phase was extracted several times with ethyl acetate, the combined organic phases dried over sodium sulfate and the solvent removed in vacuo. The crude product was purified by preparative HPLC. The product with the molecular weight of 424.56 (C23H28N4O2S) was obtained in this way; MS (ESI): 425 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:15][CH2:14]1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:31]O>>[CH3:31][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:12]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:17][CH2:18]2)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CO
Reactant: Cc1ccccc1N1CCN(c2ccc(C(=O)O)cc2[N+](=O)[O-])CC1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N2CCN(c3ccccc3C)CC2)c([N+](=O)[O-])c1

Procedure:
3-Nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid (1.0 g, 2.9 mmol) was taken in methanol (100 mL) with sulphuric acid (1.0 mL) and reflux for 16 h. Concentrated and dissolved in ethyl acetate (300 mL) and washed the organic layer with a solution of satd. NaHCO3, dried and concentrated to give 0.37 g of 3-Nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1)=[O:12])=[C:5]2[CH2:20][C:21]([OH:23])=O.[NH2:24][CH2:25][CH2:26][OH:27]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1)=[O:12])=[C:5]2[CH2:20][C:21]([NH:24][CH2:25][CH2:26][OH:27])=[O:23]
Reactant: NCCO
Reactant: Cc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)O)c1
Product: Cc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)NCCO)c1

Procedure:
The title compound was prepared according to the procedure described in Example 43 from [5-chloro-2-(4-methylpyridine)-1H-indol-3-yl]acetic acid (Example 36) and 2-aminoethanol.
Reaction SMILES: C1(S[CH2:8][N:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][CH3:17])[NH:11][S:10]2(=[O:19])=[O:18])C=CC=CC=1.S(Cl)([Cl:23])(=O)=O>C(Cl)Cl>[Cl:23][CH2:8][N:9]1[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][CH3:17])[NH:11][S:10]1(=[O:19])=[O:18]
Reactant: CCCC1NS(=O)(=O)N(CSc2ccccc2)C1=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCCC1NS(=O)(=O)N(CCl)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a solution of 2-phenylthiomethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (5.23 g, 17.43 mmol) in 200 ml of methylene chloride was added sulfuryl chloride (2.15 ml, 26.07 mmol) and the mixture was stirred for 3 hours at room temperature. The mixture was concentrated in vacuo, the residue triturated in hexane (200ml) for 2 hours, and the resulting solid was filtered and dried to afford 3.54 g (90%) of 2-chloromethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula II: R1 =H; R2 =propyl; R3 =H; X=Cl) as a solid.
Reaction SMILES: [OH-:1].[Na+].[CH:3]([N:6]([CH:25]([CH3:27])[CH3:26])[C:7](=[O:24])[CH:8]([CH3:23])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)([CH3:5])[CH3:4]>O1CCCC1>[CH:25]([N:6]([CH:3]([CH3:4])[CH3:5])[C:7](=[O:24])[CH:8]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([OH:1])=[O:22])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)[CH3:23])([CH3:27])[CH3:26]
Reactant: [OH-]
Reactant: CC(C(=O)N(C(C)C)C(C)C)c1ccc(-c2ccc(C=O)cc2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C(=O)N(C(C)C)C(C)C)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
18.04 ml of 1N sodium hydroxide and 3.14 g of Ag2O were added to a solution of 380 mg of the product of Stage A in 8 ml of tetrahydrofuran and the mixture was stirred for 24 hours at ambient temperature. After adding 6N hydrochloric acid, extraction was carried out with ethyl acetate to obtain 380 mg of the expected product which is recrystallized from isopropanol to obtain a Rf=0.11 (ethyl acetate/cyclohexane 1/1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][S:15]([N:18]2[CH2:46][CH2:45][C:21]3([N:25]=[C:24]([C:26]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([O:36]CC5C=CC=CC=5)[CH:27]=4)[NH:23][C:22]3=[O:44])[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[C:9]([CH3:47])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[H][H].ClCCl.CO>C(OCC)(=O)C.C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:48])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][S:15]([N:18]2[CH2:19][CH2:20][C:21]3([N:25]=[C:24]([C:26]4[CH:31]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:29]=[C:28]([OH:36])[CH:27]=4)[NH:23][C:22]3=[O:44])[CH2:45][CH2:46]2)(=[O:16])=[O:17])=[C:9]([CH3:47])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cc(OCc3ccccc3)cc(C(F)(F)F)c1)NC2=O
Agent: [Pd]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cc(O)cc(C(F)(F)F)c1)NC2=O
Yield: 93.8 %

Procedure:
4-{2-[2-(3-Benzyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3-methyl-benzoic acid tert-butyl ester (952.0 mg, 1.39 mmol) was dissolved in ethyl acetate (15.0 ml)-THF (5.0 ml). Pd—C (190.4 mg) was added and the mixture was stirred at room temperature for one hour in a hydrogen atmosphere. After completion of the reaction, the precipitated solid was dissolved by adding dichloromethane and methanol, and the remaining black solid was then filtered off through celite. The filtrate was concentrated under reduced pressure to give 4-{2-[2-(3-hydroxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3-methyl-benzoic acid tert-butyl ester as a white solid (776.2 mg, 93.8%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15]>>[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15]
Reactant: OCCCCCCCl
Reactant: O=C1CCCCN1
Product: O=C1CCCCN1CCCCCCO

Procedure:
In like manner, 6-chloro-1-hexanol is reacted with 2-piperidone to produce 1-(6-hydroxy-1-hexyl)-2-piperidone. The latter is reacted with methanesulfonyl chloride in methylene chloride in the presence of one equivalent of triethylamine to yield 1-(6-methanesulfonyloxy-1-hexyl)-2-piperidone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:16]2[NH:25][C:19]3=[CH:20][N:21]=[CH:22][C:23]([F:24])=[C:18]3[CH:17]=2)=[N:11][C:12](Cl)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:34][C:35]3[CH:45]=[C:44]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])[C:43](B4OC(C)(C)C(C)(C)O4)=[CH:42][C:36]=3[C:37]=2[C:38]([NH:40][CH3:41])=[O:39])=[CH:29][CH:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:43]2[C:44]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])=[CH:45][C:35]3[O:34][C:33]([C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)=[C:37]([C:38]([NH:40][CH3:41])=[O:39])[C:36]=3[CH:42]=2)=[N:11][C:10]=1[C:16]1[NH:25][C:19]2=[CH:20][N:21]=[CH:22][C:23]([F:24])=[C:18]2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cncc2[nH]c(-c3nc(Cl)ccc3OCc3ccccc3)cc12
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(-c4cc5c(F)cncc5[nH]4)n3)cc12
Temperature: 100 °C
Yield: 30.9 %

Procedure:
To a degassed solution of 2-(3-(benzyloxy)-6-chloropyridin-2-yl)-4-fluoro-1H-pyrrolo[2,3-c]pyridine (300 mg, 0.85 mmol) and 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (387 mg, 0.77 mmol) in 1,4-dioxane (5.0 mL) was added Pd2(dba)3 (10 mg), X-Phos (10 mg) and K3PO4 (452 mg, 1.70 mmol) under N2. The mixture was heated at 100° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with H2O, brine, dried over Na2SO4. After it was concentrated, the resulting residue was purified using column (petroleum ether:EtOAc=2:1) to provide 5-(5-(benzyloxy)-6-(4-fluoro-1H-pyrrolo[2,3-c]pyridin-2-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (165 mg, yield: 31%). 1H-NMR (CDCl3, 400 MHz) δ 10.73 (s, 1H), 8.49 (s, 1H), 7.99 (d, J=8.0 Hz, 2H), 7.92 (dd, J=8.0, 8.0 Hz, 2H), 7.50˜7.45 (m, 3H), 7.43˜7.40 (m, 5H), 7.16 (t, J=8.0 Hz, 2H), 6.56 (s, 1H), 5.32 (s, 12H), 3.10 (s, 3H), 2.91 (d, J=4.0 Hz, 3H), 2.80 (s, 3H). MS (M+H)+: 694.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][C@H:38]([CH2:41][CH3:42])[CH2:39][OH:40]>>[OH:40][CH2:39][C@H:38]([NH:37][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:36][CH:35]=1)[CH2:41][CH3:42]
Reactant: CC[C@@H](N)CO
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: CC[C@H](CO)NC(=O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 93 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and (R)-2-amino-1-butanol (45 mg, 0.50 mmol, 1.0M in DMF) were combined to give 53 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 570 [M+H]+.