Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:12][NH:13][C:14](=[O:15])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-:16].[Na+]>Cl>[OH:16][C:2]1[C:11]2[CH2:12][NH:13][C:14](=[O:15])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: [OH-]
Reactant: O=C1NCc2c(Cl)nc3ccccc3c21
Agent: Cl
Agent: [Na+]
Product: O=C1NCc2c(O)nc3ccccc3c21
Temperature: 80 °C
Yield: 88 %

Procedure:
8 g (24.9 mmoles) of Compound 3 was dissolved in 1 litre of 1N HCl and heated to 80° C. for 4 h with stirring. The reaction mixture was then cooled to 0° C., brought to pH 9 with 5N NaOH and extracted with chloroform. The organic extracts were dehydrated with anhydrous sodium sulphate, filtered and evaporated at reduced pressure to give 7 g of Compound 5 (yield 88%). Crystallization from ethyl acetate, gave a pure compound which melted at 245-246° C. 1H NMR (CDCl3): 1.46-1.61 (m, 4H), 2.16-2.23 (m, 5H), 2.43-2.58 (m, 2H), 3.27 (m, 2H), 4.35 (s, 2H), 4.61 (m, 1H), 7.28-7.36 (m, 2H), 7.55 (m, 1H), 8.84 (d, j=8.2, 1H), 10.63 (br s, 1H), MS: m/z 323 (M+, 28).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:46])[NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([NH:33][C:34]4[N:39]=[C:38]([C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)[CH:37]=[CH:36][N:35]=4)[CH:27]=3)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>CN(C=O)C>[CH3:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:24]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][N:14]3[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][P:4](=[O:3])([OH:5])[OH:8])[CH2:16][CH2:15]3)=[CH:23][CH:22]=2)=[O:46])=[CH:27][C:28]=1[NH:33][C:34]1[N:39]=[C:38]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH:37]=[CH:36][N:35]=1
Reactant: CCOP(=O)(CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc2)CC1)OCC
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(CCP(=O)(O)O)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 110 °C
Reaction time: 14 h
Yield: 59.6 %

Procedure:
To a solution of [2-(4-{4-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenylcarbamoyl]-benzyl}-piperazin-1-yl)-ethyl]-phosphonic acid diethyl ester (8 mg, 0.012 mmol) in DMF (1 mL) was added TMSBr (15 μL, 0.12 mmol) at room temperature. The reaction was allowed to proceed at room temperature for 14 hours. Another portion of TMSBr (20 μL) was added and heated at 110° C. for 12 hours when completion of the reaction was detected by LCMS. The reaction was cooled down to room temperature and quenched with addition of MeOH. The reaction mixture was dried under reduced pressure and the residue was purified by RP HPLC using a C18 column with a gradient of H2O— Acetonitrile (5-100%) over 20 minutes to provide 4.2 mg (50%) of the product as mono-TFA salt. 1H NMR (300 MHz, CD3OD) δ 1.80-1.84 (m, 2H), 2.08-2.02 (m, 2H), 2.23 (s, 3H), 3.07 (bs, 4H), 3.30-3.32 (2H, possible overlap with solvent), 3.89 (m, 2H), 4.01 (s, 2H), 6.87 (s, 1H), 7.23-7.3 (m, 3H), 7.52-7.60 (m, 3H), 8.01 (d, 2H, J=8 Hz), 8.08 (dd, 1H, J=2, 5 Hz), 8.30 (s, 1H), 8.58 (d, 1H, J=5 Hz), 8.89 (d, 1H, J=2 Hz), 9.22 (dd, 1H, J=2, 5 Hz), 9.63 (s, 1H); 31P (121.4 MHz, CD3OD) δ 21.9; MS (m/z) 588 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][Br:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOC(CBr)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.3 %

Procedure:
To a cooled (0° C.) solution of 2-hydroxymethylmorpholine-4-carboxylic acid tert-butyl ester (1.04 g, 4.79 mmol, see Step 1) in dichloromethane (20 mL) was added CBr4 (1.98 g, 5.98 mmol). After stirring the mixture for 10 minutes, triphenylphosphine (2.20 g, 8.38 mmol) was added portion-wise. The reaction mixture was stirred at 0° C. for 6 hours and then allowed to warm to room temperature and stirred for 60 hours. The mixture was concentrated under reduced pressure and then diluted with ether. The crude mixture was filtered and the filtrate was concentrated to afford the crude product, which was chromatographed on Biotage eluting with dichloromethane. The desired fractions were combined and concentrated to yield 0.50 g of product (37% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Cl)[CH:6]=[CH:7][CH:8]=1.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])[CH3:11].P>C1(C)C=CC=CC=1.C(Cl)C=CC1C=CC=CC=1.[Pd]>[O:2]([C:3]1[CH:4]=[C:5]([CH2:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:6]=[CH:7][CH:8]=1)[CH3:1]
Reactant: CC(=O)c1ccccc1
Reactant: COc1cccc(Cl)c1
Agent: [Pd]
Agent: ClCC=Cc1ccccc1
Agent: P
Solvent: Cc1ccccc1
Product: COc1cccc(CC(=O)c2ccccc2)c1
Yield: 83.5 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 3. The difference is that, the reactants are m-methoxyphenyl chloride (142.7 mg, 1.0 mmol), acetophenone (299.9 mg, 2.5 mmol), palladium cinnamyl chloride (7.8 mg, 0.015 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino)phenyldicyclohexyl)phosphine (18.3 mg, 0.045 mmol), K3PO43H2O (663.9 mg, 2.5 mmol) in 3 mL dry toluene at 110° C. for 12 h. 2-(3′-Methoxylphenyl)-1-phenyl-1-ethanone (189.0 mg) was obtained with a yield of 84% as liquids. 1H NMR (300 MHz, CDCl3) δ 8.02-7.96 (m, 2H, ArH), 7.55-7.47 (m, 1H, ArH), 7.46-7.38 (m, 2H, ArH), 7.21 (t, J=7.8 Hz, 1H, ArH), 6.87-6.73 (m, 3H, ArH), 4.22 (s, 2H, CH2), 3.73 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3) δ 197.3, 159.6, 136.3, 135.9, 133.0, 129.5, 128.47, 128.45, 121.6, 115.0, 112.2, 55.0, 45.4; IR (neat) v (cm−1) 3058, 3002, 2938, 2835, 1682, 1597, 1490, 1448, 1317, 1263, 1211, 1153, 1050, 1020, 1001; MS (70 eV, EI) m/z (%): 227 (M++1, 2.28), 226 (M+, 12.78), 105 (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CC[O-].[Na+].[C:14]1(=[O:19])[O:18][CH2:17][CH2:16][CH2:15]1>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:17][CH2:16][CH2:15][C:14]([OH:19])=[O:18])=[CH:5][CH:4]=1
Reactant: O=C1CCCO1
Reactant: COc1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(OCCCC(=O)O)cc1
Temperature: 155 °C
Reaction time: 0.08 h

Procedure:
4-Methoxyphenol was added to a solution of NaOC2H5 made by dissolving 2.3 g of Na in 50 ml ethanol. After 5 minutes, gamma-butyrolactone was added and the mixture heated at reflux overnight. Ethanol was distilled off and the residue heated at 155° C. overnight, then cooled, diluted with water and acidified to pH 3 with dilute hydrochloric acid. The product was collected by filtration, 19.5 g, m.p. 103-104° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([S:11][C:12]#[N:13])=O)=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:15]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:15])[S:11][CH:9]=2)=[CH:4][CH:3]=1
Reactant: N#CSC(=O)Cc1ccc(Cl)cc1
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(Cl)cc2)cs1
Temperature: 0 °C
Yield: 91 %

Procedure:
The compound (40)(10.9 mg, 52.2 mmol) was suspended in acetic acid (50 ml) and 50% sulfuric acid (15 ml) was added dropwise at 60° C. The mixture was heated under reflux for 2 hrs. After cooling, the reaction mixture added to ice (200 g). The precipitated crystals were collected by filtration, washed twice with water (200 ml) and dried under reduced pressure to give the title compound (10.1 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[C:10]([CH:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)O)[CH:9]=2)=[CH:4][CH:3]=1.CC(C)=[O:24]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[C:10]([CH:15]3[C:17](=[O:24])[CH:21]=[CH:20][CH:19]3[OH:18])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: CCc1sc(-c2ccc(Cl)cc2)cc1C(O)c1ccco1
Solvent: O
Product: CCc1sc(-c2ccc(Cl)cc2)cc1C1C(=O)C=CC1O
Temperature: 60 °C

Procedure:
To a solution of [5-(4-chloro-phenyl)-2-ethyl-thiophen-3-yl]-furan-2-yl-methanol (2.52 g, 7.9 mmol) in acetone (30 ml) and water (5 ml) is added polyphosphoric acid (0.5 ml) and the resulting solution heated at 60° C. for 5 hours. The resulting black solution is concentrated in vacuo and purified by flash chromatography on silica gel to give 5-[5-(4-chloro-phenyl)-2-ethyl-thiophen-3-yl]-4-hydroxy-cyclopent-2-enone as a clear gum (320 mg)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH2:27]([S:30](Cl)(=[O:32])=[O:31])[CH2:28][CH3:29]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][S:30]([CH2:27][CH2:28][CH3:29])(=[O:32])=[O:31])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: CCCS(=O)(=O)Nc1cccc(CCN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Yield: 62 %

Procedure:
The title compound was prepared in 62% yield using a similar procedure to example E43 starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and propanesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[F:32][C@@H:33]1[CH2:37][NH:36][C@H:35]([C:38]([OH:40])=[O:39])[CH2:34]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:36]5[CH2:37][C@@H:33]([F:32])[CH2:34][C@H:35]5[C:38]([OH:40])=[O:39])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:30])([F:31])[F:29])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: O=C(O)[C@@H]1C[C@H](F)CN1
Product: O=C1N=C(N2C[C@@H](F)C[C@H]2C(=O)O)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-4-(S)-fluoro-L-proline was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 4-(S)-Fluoro-pyrrolidine-2-(S)-carboxylic acid following General Procedure C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:12].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:24]1[N:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27]>C1COCC1>[Cl:33][C:31]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([NH:12][C:3]2[CH:4]=[CH:5][C:6]([Si:8]([CH3:9])([CH3:11])[CH3:10])=[CH:7][C:2]=2[F:1])[N:32]=1
Reactant: C[Si](C)(C)c1ccc(N)c(F)c1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(Nc2nc(Cl)ccc2C(=O)O)c(F)c1
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 77.9 %

Procedure:
To a cold (−78° C.) solution of 2-fluoro-4-trimethylsilanyl-phenylamine (64.7 g, 353 mmol) in anhydrous THF (170 mL) was added a solution of LHMDS (555 mL, 1 M in hexanes, 555 mmol) dropwise over 45 minutes under a nitrogen atmosphere. After 2.5 hours at 78° C., a solution of 2,6-dichloro-nicotinic acid (33.8 g, 177 mmol) in anhydrous THF (100 mL) was added. The reaction mixture was stirred at −78° C. for 30 minutes then allowed to warm to room temperature. After 18 hours stirring at room temperature the reaction was quenched with crushed ice and the pH adjusted to pH 1 by the addition of concentrated HCl (ca. 90 mL). The resultant solution was extracted with ethyl acetate and the organic layer washed with water followed by brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was triturated three times successively with methanol and filtered to afford the title compound as a yellow solid (46.7 g, 78%). LCMS (method B): RT=4.83 min, M+H+=339.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH2:24][OH:25])[CH2:4][CH3:5])[CH3:2].C=O.[CH3:28]C1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[C:8]=1[CH2:24][O:25][CH2:28][N:14]2[C:15]1[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=1[CH3:21])[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1CO
Agent: C=O
Solvent: Cc1ccccc1
Product: CCC(CC)Oc1cc(C)nc2c1COCN2c1c(C)cc(C)cc1C
Yield: 97.3 %

Procedure:
A mixture of [4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanol (79 mg, 0.231 mmol), 37% aqueous formaldehyde (0.1 ml) and p-TsOH (22 mg, 0.116 mmol) in 10 ml of toluene was heated at reflux using a Dean-Stark apparatus for 3 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give 100 mg of the crude material. The crude material was purified through silica gel column chromatography using 2% methanol in chloroform as eluent to give 40 mg (50%) of the title compound as a clear oil. 1H NMR (CDCl3) δ 6.90(s,2H), 6.04(s,1H), 4.87(2 sets of s, 4H), 4.16(m,1H), 2.28(s,3H), 2.19(s,3H), 2.14(s,6H), 1.67(m,4H), 0.94(t,6H) ppm.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.C1([Si](C2C=CC=CC=2)(C2C=CC=CC=2)[SH:23])C=CC=CC=1.C(N(CC)CC)C>CO>[OH:1][C:3]1([CH2:2][SH:23])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: S[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O)(CS)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 808.6 %

Procedure:
To a mixture of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (35.3 g, 16.55 mmol) and triphenylsilanethiol (48.4 g, 16.55 mmol) in anhydrous methanol (1.0 L) was added triethylamine (23.1 ml, 16.55 mmol) drop-wise over the course of 30 minutes. The reaction was stirred for 1 hour at room temperature and the methanol was evaporated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 5% EtOAc in hexanes to 40% EtOAc in hexanes) to afford 81% (33.1 g) pure final product. M.p.=54-55° C.; 400 MHz 1H NMR (CDCl3) δ: 3.97-3.78 (m, 2H), 3.19-3.08 (m, 2H), 2.61 (d, J=4.4 Hz, 2H), 1.70-1.55 (m, 2H), 1.50-1.38 (m, 11H); LCMS: 248 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1>Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc(N3CCNCC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.6 %

Procedure:
A mixture of 101i (3.6 g, 7.8 mmol) and 4.0 M HCl/dioxane (10 mL) was stirred for 5 h at room temperature. It was then concentrated at reduced pressure. The residue was basified with aqueous 1.0M NaOH and extracted with methylene chloride. The combined organic layers were washed with water and concentrated under reduced pressure to give 101j (2.46 g, 87%). MS: [M+H]+ 364.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][CH:11]=1.Cl[C:17]1[N:22]=[C:21]([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([CH3:30])[CH2:25][CH2:24]2)[CH:20]=[N:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([N:23]3[CH2:29][CH2:28][CH2:27][N:26]([CH3:30])[CH2:25][CH2:24]3)[N:22]=2)[CH:7]=1
Reactant: COC(=O)/C=C/c1cccc(B(O)O)c1
Reactant: CN1CCCN(c2cncc(Cl)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1cccc(-c2cncc(N3CCCN(C)CC3)n2)c1
Temperature: 120 °C
Yield: 61.7 %

Procedure:
[3-(E-3-methoxy-3-oxo-1-propen-1-yl)phenyl]boronic acid (125 mg, 0.61 mmol) and bistriphenylphosphinepalladium(II)chloride (30 mg, 0.057 mmol) were combined in a microwave reaction tube. Subsequently 1-(6-chloro-pyrazin-2-yl)-4-methyl-[1,4]diazepane (130 mg, 0.57 mmol) was added as a solution in DMF (8 mL) followed by an aqueous solution of Na2CO3 (2M, 3 mL, 6 mmol). The tube was sealed and the reaction mixture was heated in the microwave at 120° C. for 20 min. The reaction mixture was then filtered through a plug of celite, and purified by flash chromatography to provide the title compound (124 mg 61%); MS analysis electrospray, 353 (M+H).
Reaction SMILES: Cl.[CH3:2][C@H:3]1[N:8]([CH2:9][C:10]([F:13])([F:12])[F:11])[C:7](=[O:14])[C@@H:6]([NH:15][S:16]([C:19]2[CH:20]=[C:21]3[CH2:44][C@@:26]4([C:34]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[N:28](COCC[Si](C)(C)C)[C:27]4=[O:43])[CH2:25][C:22]3=[N:23][CH:24]=2)(=[O:18])=[O:17])[CH2:5][C@H:4]1[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O1CCOCC1>[CH3:2][C@H:3]1[N:8]([CH2:9][C:10]([F:13])([F:12])[F:11])[C:7](=[O:14])[C@@H:6]([NH:15][S:16]([C:19]2[CH:20]=[C:21]3[CH2:44][C@@:26]4([C:34]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[NH:28][C:27]4=[O:43])[CH2:25][C:22]3=[N:23][CH:24]=2)(=[O:18])=[O:17])[CH2:5][C@H:4]1[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: C[C@@H]1[C@H](c2ccccc2)C[C@H](NS(=O)(=O)c2cnc3c(c2)C[C@@]2(C3)C(=O)N(COCC[Si](C)(C)C)c3ncccc32)C(=O)N1CC(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](NS(=O)(=O)c2cnc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C(=O)N1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of HCl in dioxane (4 M, 0.7 mL, 2.8 mmol) was added to a solution of (S)—N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2′-oxo-1′-((2-(trimethylsilyl)ethoxy)methyl)-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-sulfonamide (0.027 g, 0.038 mmol) in dioxane (0.5 mL) pre-cooled to 0° C. The mixture was gradually warmed to ambient temperature, then heated at 60° C. for 22 h. The reaction mixture was concentrated in vacuo, and the residue was purified by reverse-phase HPLC (C18 column), eluting with 30% MeOH in water (0.1% TFA used as a modifier) initially, grading to 100% MeOH over 30 min with a flow rate of 15 mL/min to furnish the title compound. MS: m/z=586.2 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.92 (s, 1H), 8.22 (s, 1H), 8.11 (d, 1H, J=4.3 Hz), 7.42-7.34 (m, 3H), 7.32-7.23 (m, 3H), 6.93 (dd, 1H, J=7.4, 5.4 Hz), 4.88 (obscured m, 1H), 4.62 (dq, 1H, J=15.2, 9.4 Hz), 4.30 (dd, 1H, J=11.7, 7.2 Hz), 3.84 (quintet, 1H, J=6.0 Hz), 3.68-3.57 (m, 3H), 3.36-3.29 (obscured m, 2H), 2.65-2.52 (m, 1H), 2.45-2.36 (m, 1H), 0.98 (d, 3H, J=6.5 Hz).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[CH3:7].C(N(CC)CC)C>ClCCl>[CH2:6]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:16][CH2:17][CH:18]([C:21]3[CH:22]=[CH:23][C:24]([C@@H:27]([NH:29][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:28])=[CH:25][CH:26]=3)[CH2:19][CH2:20]2)=[CH:13][CH:14]=1)[CH3:7]
Reactant: CCOc1ccc(N2CCC(c3ccc([C@H](C)N)cc3)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(N2CCC(c3ccc([C@H](C)NS(C)(=O)=O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 17 mg (0.15 mmol) methanesulfonyl chloride is added a solution of 32 mg (0.1 mmol) (S)-1-{4-[1-(4-ethoxy-phenyl)-piperidin-4-yl]-phenyl}-ethylamine (XIII.1) and 42 μL triethyl amine in 2 mL dichloromethane. The mixture is stirred for 2 d at rt. The solvent is removed under reduced pressure and the residue is purified using reversed phase column chromatography (water/MeOH, 0.1% TFA) and the corresponding fractions are concentrated to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([CH3:14])[N:3]=1.[NH2:15][C:16]1[CH:35]=[CH:34][C:19]([CH2:20][N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:18][CH:17]=1>CN1C(=O)CCC1>[C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][N:21]([CH2:20][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:6]3[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([CH3:14])[N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:35][CH:34]=2)[CH2:26][CH2:25]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N)cc2)CC1
Reactant: CCOC(=O)c1c(C)nc(Cl)nc1Cl
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1c(C)nc(Cl)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
Ethyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate (0.5 g, 2.1 mmol) and tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate (0.6 g, 2.06 mmol) were dissolved in NMP and stirred at 0° C. for 2 hour. The reaction mixture was poured onto water and extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4 and evaporated under vacuum to get the desired compound (0.62 g). 1H NMR (400 MHz, CDCl3): δ 10.58 (s, 1H), 7.58 (d, J=6.4 Hz, 2H), 7.31 (d, J=6.4 Hz, 2H), 4.45 (q, J=6.8 Hz, 2H), 3.56 (s, 2H), 3.41 (m, 4H), 2.69 (s, 3H), 2.47 (m, 4H), 1.45 (s, 9H), 1.43 (t, J=6.8 Hz, 3H); MS m/z 490.0 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:19]1[N:20]=[CH:21][N:22]=[C:23]2[C:30]=1[C:29]1[C@H:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:27][CH2:26][C:25]=1[S:24]2>O1CCCC1>[C:11]([O:10][C:9]([NH:8][CH:5]1[CH2:6][CH2:7][CH:2]([O:1][C:19]2[N:20]=[CH:21][N:22]=[C:23]3[C:30]=2[C:29]2[C@H:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:27][CH2:26][C:25]=2[S:24]3)[CH2:3][CH2:4]1)=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: CCOC(=O)C[C@@H]1CCc2sc3ncnc(Cl)c3c21
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2sc3ncnc(OC4CCC(NC(=O)OC(C)(C)C)CC4)c3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
A solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate (412 mg, 1.91 mmol, 1.10 equiv) in freshly distilled tetrahydrofuran (10 mL) was treated with sodium hydride (60% dispersion in mineral oil, 280 mg, 4.00 equiv) for 1 h at room temperature under nitrogen. To this mixture was then added a solution of 16.3 (510 mg, 1.72 mmol, 1.00 equiv) in dry tetrahydrofuran (5 mL) via syringe. After stirring overnight at room temperature, the reaction was then quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:2) and purified to afford ethyl 2-[(3S)-12-[(4-[[(tert-butoxy)carbonyl]amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetate (16.4, 400 mg, 49%) as a yellow oil.