Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:7]2.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]1([O:12][C:8]2[CH:9]=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[N:22]2[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cccc2cc(Oc3ccccc3)cnc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3cc(Oc4ccccc4)cnc23)CC1
Temperature: 150 °C
Yield: 48.9 %

Procedure:
A stirred suspension of 8-chloro-3-(phenyloxy)quinoline (D7)(0.115 g, 0.45 mmol), 1,1-dimethylethyl 1-piperazinecarboxylate (0.084 g, 0.45 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.012 g, 0.014 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.016 g, 0.041 mmol) and sodium tert-butoxide (0.043 g, 0.45 mmol) in degassed toluene (2.5 ml) was heated in a sealed tube at 150° C. for 10 mins in a microwave oven. The cooled reaction mixture was washed with water (20 ml), dried (MgSO4) and concentrated in vacuo to an oil. The oil was purified by chromatography over silica gel eluting with a gradient of ethyl acetate/hexane to afford the title compound (D8) as a yellow oil (0.09 g, 0.22 mmol, 49%).
Reaction SMILES: C[O:2][C:3]([C:5]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.O>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]1
Reactant: COC(=O)C1(Oc2ccc(F)cc2F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(Oc2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.4 %

Procedure:
To a solution of 1-(2,4-Difluoro-phenoxy)-cyclopropanecarboxylic acid methyl ester (1.89 g, 8.28 mmol) in THF (20 ml) added a solution of LiOH (0.86 g, 20.7 mmol) in water (5 ml) was added, and mixture is stirred at r.t. for 18 h. Solvent was evaporated at reduced pressure acidified with 1N HCl (pH˜2) and extracted in ethyl acetate (70 ml) and washed with brine (2×10 ml), dried over Na2SO4 and concentrated under reduced pressure to obtain 1-(2,4-Difluoro-phenoxy)-cyclopropanecarboxylic acid (1.16 g, 66%). 1H NMR (400 MHz, CDCl3): δ 1.46 (dd, J=5.6 and 9.2 Hz, 1H), 1.71 (dd, J=5.6 and 9.2 Hz, 1H), 2.27-2.31 (m, 1H), 3.97-4.0 (m, 1H), 4.85 (t, J=5.6 Hz, 1H), 6.77-83 (m, 1H), 6.85-6.92 (m, 1H), 7.0-7.06 (m, 1H).
Reaction SMILES: [CH:1]1([N:6]([C@H:20]2[CH2:25][CH2:24][C@H:23]([CH2:26][CH3:27])[CH2:22][CH2:21]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14]CC(O)=O)=[CH:12][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N[C@H]2CC[C@H](CC)CC2)CCCC1.C([O:44][C:45](=[O:55])[CH2:46][CH2:47]SC1SC(N)=NC=1)C>>[CH:1]1([N:6]([C@H:20]2[CH2:25][CH2:24][C@H:23]([CH2:26][CH3:27])[CH2:22][CH2:21]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:47][CH2:46][C:45]([OH:55])=[O:44])=[CH:12][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Reactant: CCOC(=O)CCSc1cnc(N)s1
Agent: CC[C@H]1CC[C@H](NC2CCCC2)CC1
Product: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCC(=O)O)s2)C2CCCC2)CC1

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cyclopentyl-(trans-4-ethyl-cyclohexyl)-amine and 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester to give the title compound.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3/[C:23](=[CH:28]\[O:29][CH3:30])/[C:24]([O:26][CH3:27])=[O:25])[CH:11]=2)=CC=1)([O-])=O.[H][H].C(OCC)(=O)C.CCCCCC>C(O)C.[Pd]>[OH:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[C:23](=[CH:28]\[O:29][CH3:30])/[C:24]([O:26][CH3:27])=[O:25])[CH:11]=1
Reactant: [H][H]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(OCc2ccc([N+](=O)[O-])cc2)ncn1
Agent: [Pd]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(O)ncn1
Reaction time: 1.5 h
Yield: 51.7 %

Procedure:
(E)-Methyl 2-[2-(6-(4-nitrobenzyloxy)pyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (1.4 g) in ethanol (30 ml) in the presence of 5% Pd/C catalyst (300 mg) was treated with hydrogen at 1 atmosphere pressure. After 90 minutes, the reaction mixture was filtered and evaporated to give a yellow oil. Chromatography (eluent ethyl acetate-hexane, 95:5) afforded (E)-methyl 2-[2-(6-hydroxypyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (500 mg) as a pale yellow solid; m.p. 168-170° C.; 1H NMR: δ 3.80 (3H, s), 5.65 (1H, s), 7.15 (1H, d), 7.3 (3H, m), 7.50 (1H, s), 7.95 (1H, s) ppm; IR maximum: 1680cm−1; mass spectrum m/e 302 (M+).
Reaction SMILES: [C:1](=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[C:9]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH:35]([CH3:38])[CH2:34][CH2:33]3)=[CH:25][CH:24]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:13]=1.COB(O)O>O1CCOCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:13]=[C:8]([CH3:1])[C:9]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH:35]([CH3:38])[CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[N:10][CH:11]=2)=[CH:15][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: CC1CCN(CCOc2ccc(C#Cc3ncc(-c4ccc(Cl)cc4)cc3Br)cc2)CC1
Agent: COB(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(Cl)cc2)cnc1C#Cc1ccc(OCCN2CCC(C)CC2)cc1

Procedure:
2.5 n-L of 2M aqueous sodium carbonate solution and 15 mg (0.013 mmol) of tetrakis(triphenylphosphane)palladium were added under argon to a suspension of 130 mg (0.255 mmol) of 3-bromo-5-(4-chlorophenyl)-2-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyridine and 18.9 mg (0.306 mmol) of methylboric acid in 5 mL of 1,4-dioxane and the mixture was refluxed for 5 hours. A further 18.9 mg (0.306 mmol) of methylboric acid was added and again the mixture was refluxed for 2 hours. The reaction mixture was exhaustively extracted with EtOAc, the combined organic phases were washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and evaporated down in vacuo. The residue was purified by HPLC-MS (Symmetry C18, gradient 0.15% formic acid in water/acetonitrile 10/90→50/50 v/v) and the product fractions were lyophilized. Product fraction 1: Yield: 12 mg (11% of theoretical); C28H29ClN2O (M=444.995); calc.: molpeak (M+H)+: 445/447 (Cl); found: molpeak (M+H)+: 445/447 (Cl); HPLC-MS: 4.00 minutes (method E).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1.CC(C)([O-])C.[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]>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:10][CH:9]=1
Reactant: Brc1ccc(Br)cc1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Brc1ccc(N2CCOCC2)cc1

Procedure:
To a solution of of morpholine (0.85 mmol, 739 mg) in dioxane (12 mL) was added 1,4-dibromobenzene (21.2 mmol, 5 g), 2-(di-t-butylphosphine)biphenyl (1.02 mmol, 304 mg), potassium t-butoxide (25.5 mmol, 2.47 g) and Pd2(dba)3 (0.254 mmol, 233 mg) The mixture was degassed under a stream of nitrogen and then heated to reflux for 20 h. The mixture was diluted with EtOAc and washed with water and brine. The organic extract was concentrated under reduced pressure and the residue was chromatographed to give the desired product.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:15]([N:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][NH2:21])[CH3:16]>C(Cl)(Cl)Cl>[CH2:15]([N:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][NH:21][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:16]
Reactant: CCN(CC)CCCN
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCC(=O)NCCCN(CC)CC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 500 ml RB flask containing a solution of lauroyl chloride (19.03 g., 87 mM) in dry chloroform (200 ml) was cooled to 0° C. on an ice bath. A solution of N,N-diethyl-1,3-propanediamine (15.00 g., 115 mM) in dry chloroform (25 ml) was added dropwise to the cold solution then allowed to warm to room temperature and stirred for 2 hours. The chloroform was removed under reduced pressure and the residue redissolved in an ethanol/water mixture (1:1) and neutralized with sodium bicarbonate, followed by extraction with chloroform (4×50 ml). The combined extracts were dried (MgSO4), concentrated, and the residue distilled under reduced pressure (bp 176° C., 20μ) to give 21.47 g. (79%) of the subject compound as an amber oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH:14]=O)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[Br-].[CH2:19]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.O1CCCC1.C(O)C.[C].[Pd]>[C:20]1([CH2:19][CH2:14][C:12]2[NH:11][N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=3)[CH:13]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cc(-c2ccc(C(F)(F)F)cc2)n[nH]1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(CCc3ccccc3)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 55.6 %

Procedure:
3-[4-(Trifluoromethyl)phenyl]-1H-pyrazole-5-carbaldehyde (1.20 g, 5.0 mmol) was dissolved in N,N-dimethylformamide (10 mL), and benzyltriphenylphosphonium bromide (3.25 g, 7.5 mmol) and potassium carbonate (2.76 g, 20.0 mmol) were added. The mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (10%-65% ethyl acetate/hexane) to give colorless crystals. The colorless crystals were dissolved in tetrahydrofuran (30 mL) and ethanol (30 mL), and 10% palladium-carbon (50% water-containing product, 500 mg) was added. Under an atmospheric hydrogen atmosphere, the mixture was stirred at room temperature for 2 hr. The catalyst was filtered off, and the filtrate was concentrated to give the title compound (880 mg, yield 56%, 2 steps) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][C:9]3([NH:17][C:16](=[O:18])[C:15]4[CH:19]=[C:20](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28]C5CCCCO5)=[O:26])[CH:21]=[CH:22][C:14]=4[O:13]3)[CH2:8]2)=[CH:4][CH:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][C:9]3([NH:17][C:16](=[O:18])[C:15]4[CH:19]=[C:20](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])[CH:21]=[CH:22][C:14]=4[O:13]3)[CH2:8]2)=[CH:35][CH:36]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3ccc(F)cc3)C1)O2)NOC1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3ccc(F)cc3)C1)O2)NO
Yield: 66.8 %

Procedure:
A solution of (±)-(E)-3-{1′-(4-fluoro-benzyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (45 mg, 0.091 mmol) in DCM (5 ml) was treated with 4 M HCl in dioxane (0.5 ml) as described in Example 30, STEP C to give (±)-(E)-3-{1′-(4-fluoro-benzyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-hydroxy-acrylamide (25 mg, hydrochloride salt) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH:11]2[CH2:13][O:12]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[OH:14][CH2:15][C@@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>CCO>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([CH:11]([OH:12])[CH2:13][N:21]2[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17][C@@H:16]2[CH2:15][OH:14])=[CH:10][C:3]=1[O:2][CH3:1])#[N:6]
Reactant: COc1cc(C2CO2)ccc1C#N
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Solvent: CCO
Product: COc1cc(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@@H]2CO)ccc1C#N
Temperature: 25 °C

Procedure:
A Pyrex vessel was charged with magnetic stirring bar, (2.0 g, 11.42 mmol) of 2-methoxy-4-(oxiran-2-yl)benzonitrile, (3.70 g, 17.12 mmol) of tert-butyl (3R)-3-(hydroxymethyl)piperazine-1-carboxylate, and 6 mL of EtOH. Then it was introduced in the microwave reactor and irradiated at 150° C. for 3 h. The mixture was cooled to room temperature and the solvent was evaporated and the resulting residue was purified by column chromatography (silica gel, 1-20% dichloromethane/MeOH) which afforded the product as a mixture of two diastereomers (1:1) LC/MS: (IE, m/z) [(M+1)-t-Bu]+=336.41
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:25])[N:18]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:12]2[N:11]=1)[CH3:2].[S:26](Cl)([Cl:29])(=[O:28])=[O:27]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:26]([Cl:29])(=[O:28])=[O:27])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:25])[N:18]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:12]2[N:11]=1)[CH3:2]
Reactant: CCCCCc1nc(C)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Reactant: O=S(=O)(Cl)Cl
Product: CCCCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 0.3 g (0.88 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-pentyl-3H-imidazo[5,1-f][1,2,4]triazin4-one (Example 21A). This gives 0.3 g (77.6%) of sulphonyl chloride as a white foam which is directly reacted further.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][S:11]([CH2:14][CH2:15][CH2:16][N:17]([CH3:50])[CH2:18][CH2:19][O:20][C@H:21]1[CH2:28][N:27]2[C:29]3[CH:30]=[C:31]([C:42]([O:44]C)=[O:43])[CH:32]=[CH:33][C:34]=3[C:35]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[C:26]2[C:25]2[CH:46]=[CH:47][CH:48]=[CH:49][C:24]=2[O:23][CH2:22]1)(=[O:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([NH:10][S:11]([CH2:14][CH2:15][CH2:16][N:17]([CH3:50])[CH2:18][CH2:19][O:20][C@H:21]1[CH2:28][N:27]2[C:29]3[CH:30]=[C:31]([C:42]([OH:44])=[O:43])[CH:32]=[CH:33][C:34]=3[C:35]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[C:26]2[C:25]2[CH:46]=[CH:47][CH:48]=[CH:49][C:24]=2[O:23][CH2:22]1)(=[O:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCCN(C)CCCS(=O)(=O)NCc1ccccc1)COc1ccccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CCCS(=O)(=O)NCc1ccccc1)CCO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Temperature: 60 °C

Procedure:
Sodium hydroxide (2 N, 6 eq.) was added to a solution of methyl(7S)-7-{2-[{3-[(benzylamino)sulfonyl]propyl}(methyl)amino]ethoxy}-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.025 M) in MeOH. The reaction was heated at 60° C. for 1 h prior to introducing further sodium hydroxide (2 N, 10 eq.) and continuing heating for 2 h. The mixture was then partitioned between H2O and EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The product was used in the next step without further purification. (ES+) m/z 660 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:28][C:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][CH:35]=[CH:34]3)=[O:30])[B:15]2[O:23]C3C(C)(C4CC(C3)C4(C)C)[O:16]2)[C:8]=1OC)(C)(C)C.B(Cl)(Cl)Cl>>[OH:23][B:15]1[CH:14]([NH:28][C:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][CH:35]=[CH:34]3)=[O:30])[CH2:13][C:9]2[C:8](=[C:7]([C:6]([OH:5])=[O:42])[CH:12]=[CH:11][CH:10]=2)[O:16]1
Reactant: COc1c(CC(NC(=O)c2ccc3[nH]ccc3c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: O=C(NC1Cc2cccc(C(=O)O)c2OB1O)c1ccc2[nH]ccc2c1

Procedure:
Prepared from 3-[2-[(1H-Indole-5-carbonyl)-amino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester and BCl3 following the procedure described in Step 2 of Example 3. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 351.0 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:37]([NH:39][NH2:40])=[O:38])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[C:41](N1C=CN=C1)(N1C=CN=C1)=[O:42].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:31][CH2:32][C@H:33]([CH3:36])[CH2:34][CH2:35]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:37]3[O:38][C:41](=[O:42])[NH:40][N:39]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(C(=O)NN)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(-c4n[nH]c(=O)o4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbohydrazide (4.5 g, 8.03 mmol) and 1,1′-carbonyldiimidazole (1.43 g, 8.84 mmol) dissolved in acetonitrile (53.6 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.8 mL, 32.1 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was washed with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% methanol/dichloromethane, and then 0-100% ethyl acetate/hexanes, linear gradient) to afford 5-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,3,4-oxadiazol-2(3H)-one. MS ESI calc'd. for C31H32ClN7O3 [M+H]+ 586. found 586. 1H NMR (500 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.79 (d, J=8.3, 2H), 8.27 (s, 1H), 7.87 (s, 1H), 7.42 (t, J=10.0, 2H), 7.25 (t, J=7.2, 2H), 7.22-7.17 (m, 1H), 4.76 (s, 1H), 4.05-3.81 (m, 4H), 3.80-3.69 (m, 1H), 3.67-3.47 (m, 2H), 3.27 (s, 1H), 1.37 (t, J=13.0, 2H), 1.03 (broad, 1H), 0.83 (broad, 1H), 0.68 (d, J=6.2, 4H), 0.64-0.52 (m, 2H), 0.51-0.27 (m, 3H).
Reaction SMILES: N[C:2]1[C:3]([C:20]#[N:21])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:6]=2[N:13]=1.N(OCCC(C)C)=O.[ClH:30].O>CS(C)=O.[Cu](Cl)Cl>[Cl:30][C:2]1[C:3]([C:20]#[N:21])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:6]=2[N:13]=1
Reactant: Cl
Reactant: N#Cc1c(N)nc2[nH]c(=O)[nH]c(=O)c2c1-c1ccccc1
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1c(Cl)nc2[nH]c(=O)[nH]c(=O)c2c1-c1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1.0 g (3.04 mmol) of 7-amino-2,4-dioxo-5-phenyl-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile [Assy, M. G. et al., J. Indian Chem. Soc. 1996, 73 (11), 623-624] was dissolved in 8 ml of DMSO, 0.82 ml (713 mg, 6.09 mmol) of isopentyl nitrite and 818 mg (6.09 mmol) of copper(II) chloride were added and the mixture was stirred at 80° C. overnight. The reaction mixture was cooled, and 6 ml of 1 N hydrochloric acid solution followed by 100 ml of water were then added. The precipitate formed was filtered off and dried under high vacuum. The product was not purified any further (purity according to LC-MS: about 82%).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([O:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH2:17]O)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.CN(C1C=CC=CN=1)C.CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([CH3:1])[CH:20]=[CH:19][C:5]=3[N:6]=2)=[CH:11][CH:12]=1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2nc(Oc3ccc(CCO)cc3)sc2c1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2nc(Oc3ccc(CCS(C)(=O)=O)cc3)sc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.3 %

Procedure:
To a solution of 2-[4-(6-methyl-benzothiazol-2-yloxy)-phenyl]-ethanol (6.8 g, 23.8 mmol) and dimethylaminopyridine (290 mg, 2.4 mmol) in CH2Cl2 (80 mL) was added (i-Pr)2NEt (4.9 g, 28.6 mmol) followed by the addition of methanesulfonyl chloride (2.2 mL, 28.6 mmol) at 0° C. The reaction was warmed to rt and stirred for 15 min. The reaction was washed with satd. aq. Na2CO3 (75 mL), 5% aq. H2SO4 (75 mL) and brine. The organic layer was dried (Na2SO4), filtered and concentrated to afford the title compound (7.3 g, 85%). 1H NMR (500 MHz, CDCl3): 7.61 (d, J=8.3 Hz, 1H), 7.47 (s, 1H), 7.36-7.29 (m, 4H), 7.20 (dd, J=8.3, 1.2 Hz, 1H), 4.45 (t, J=6.8 Hz, 2H), 3.10 (t, J=6.8 Hz, 2H), 2.91 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([CH2:9]Cl)[CH:3]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[O:18]=[C:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(O)C.O.C(OC)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:19]1([CH2:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22]1)[O:18][CH2:9]2
Reactant: ClCc1cc(Br)ccc1I
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(C)[Mg]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(Br)ccc12
Temperature: -20 °C
Reaction time: 8 h

Procedure:
4-bromo-2-(chloromethyl)-1-iodobenzene (500 g, 1.509 moles) was dissolved in tetrahydrofuran (3750 mL) and cooled to −20° C. i-PrMgCl—LiCl (1.3M solution in THF) (1275 ml, 1.66 moles) was added at less than −15° C. The reaction mixture was cooled to −20° C. 3-oxo-azetidine-1-carboxylic acid, tert-butyl ester (310 g, 1.81 moles), as a solution in tetrahydrofuran (750 mL), was added. The reaction was warmed to room temperature over 90 minutes, and then stirred overnight. 1M Aqueous citric acid solution (2 L) was added, followed by tert-butylmethylether (2 L). The mixture was shaken. The organic phase was separated, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness to give an orange oil. The oil was dissolved in ethanol (2.5 L) and the solution diluted with water (1 L). The mixture stood at room temperature, overnight. The resulting crystals of tert-butyl 5′-bromo-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate were filtered under reduced pressure and dried under vacuum at 50° C., giving 290 g. 1H NMR (CDCl3) δ ppm: 1.49 (9H, s), 4.15 (2H, d), 4.34 (2H, d), 5.11 (2H, s), 7.38 (2H, m), 7.56 (1H, d).
Reaction SMILES: Cl[C:2]1[C:6]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[NH3:14]>>[NH2:14][C:2]1[C:6]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1
Reactant: N
Reactant: O=S1(=O)N=C(Cl)c2c(Cl)cccc21
Product: NC1=NS(=O)(=O)c2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.72 g of 3,4-dichlorobenzo[d]isothiazole-1,1-dioxide were added to 15 ml of 25% ammonia in 15 ml of ice water. After stirring at room temperature for two hours, the desired product was sucked off and dried; yield 4.20 g; melting-point 260° C.