Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15]([OH:17])=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:24][CH:25]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[CH2:26][CH2:27][OH:28]>>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15]([NH:24][CH:25]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH2:26][CH2:27][OH:28])=[O:17])(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: O=C(O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Reactant: NC(CCO)c1ccc(F)cc1
Product: O=C(NC(CCO)c1ccc(F)cc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general strategies and protocols outlined in Example 1, starting from 3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid (Intermediate 8) and 3-amino-3-(4-fluorophenyl)-1-propanol (Intermediate 2), the title compound was obtained in 92% purity by HPLC.
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].C1N=CN(C(N2C=NC=C2)=O)C=1.O[NH:40][C:41](=[NH:43])[CH3:42]>CN(C=O)C.O>[CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[C:20]([C:21]4[O:23][N:43]=[C:41]([CH3:42])[N:40]=4)[CH:19]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:6])[CH3:7])(=[O:4])=[O:3]
Reactant: CC(=N)NO
Reactant: CC(C)(c1cc(-c2cccc(C(=O)O)c2)c2ncccc2c1)S(C)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-benzoic acid from Step 2 (1.0 eq.) in DMF (0.1M) was added CDI (2.0 eq.) and N-hydroxy-acetamidine (2.0 eq.). The mixture was stirred for 1 h at rt then 12 h at 120° C. The mixture was cooled, poured in water and extracted with EtOAc. The organic extract was washed with water (2×), brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9:1 to 1:9 in 20 min) afforded the title compound as a white solid. 1H NMR (500 MHz, acetone-d6): δ 8.91 (dd, 1H), 8.52 (m, 3H), 8.38 (d, 1H), 8.25 (d, 1H), 8.04 (d, 1H), 7.78 (t, 1H), 7.64 (dd, 1H), 2.77 (s, 3H), 2.43 (s, 3H), 2.05 (s, 6H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:8][C:7]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1.[C:14]([NH:16][C:17](SC)=[N:18][CH3:19])#[N:15]>>[C:14]([NH:16][C:17]([NH:13][CH2:12][CH2:11][S:10][CH2:9][C:7]1[O:8][C:4]([CH2:3][NH:2][CH3:1])=[CH:5][CH:6]=1)=[N:18][CH3:19])#[N:15]
Reactant: CNCc1ccc(CSCCN)o1
Reactant: CN=C(NC#N)SC
Product: CN=C(NC#N)NCCSCc1ccc(CNC)o1
Yield: 38.6 %

Procedure:
A mixture of 2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.0 g) and N-cyano-N'-methylcarbamimido-thioic acid, methyl ester (1.25 g) was heated on a steam bath for 6.5 hr. Vacuum was applied at regular intervals to remove methanethiol. The crude product was purified by column chromatography Rf 0.65 (silica/methanol:ammonia 79:1) to give N-cyano-N'-[2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio]ethyl]-N"-methylguanidine (1.05 g) m.p. 81°-85°.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:53]([C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([NH2:72])[CH:67]=2)=[CH:62][CH:61]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CN(C=O)C>[O:53]([C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([NH:72][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:67]=2)=[CH:62][CH:61]=1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: Nc1cccc(-c2ccc(Oc3ccccc3)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc(Oc3ccccc3)cc2)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 78 %

Procedure:
DIEA (0.011 mL, 0.063 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.016 g, 0.057 mmol) and HATU (0.024 g, 0.063 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-phenoxy-biphenyl-3-ylamine (0.015 g, 0.057 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.023 g of product in 78% yield: LCMS (ESI) m/z 518 (MH+).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.C[O:10][C:11]([C:13]1[S:17][C:16](/[CH:18]=[CH:19]/[C:20]2[C:21]([CH2:26][CH2:27][CH2:28][CH3:29])=[N:22][O:23][C:24]=2[CH3:25])=[N:15][C:14]=1[CH3:30])=O>O1CCOCC1.C1(C)C=CC=CC=1>[CH:1]([NH:4][C:11]([C:13]1[S:17][C:16](/[CH:18]=[CH:19]/[C:20]2[C:21]([CH2:26][CH2:27][CH2:28][CH3:29])=[N:22][O:23][C:24]=2[CH3:25])=[N:15][C:14]=1[CH3:30])=[O:10])([CH3:3])[CH3:2]
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)OC)s1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NC(C)C)s1
Temperature: 90 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a stirred solution of isopropylamine (59 mg, 1.0 mmol) in dioxane (2 mL) under argon and at room temperature was added trimethylaluminium (0.50 mL of a 2M solution in toluene, 1.0 mmol). After 1 h, a solution of 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (80 mg, 0.25 mmol) in dioxane (2 mL) was added and the reaction mixture warmed to 90° C. After 48 h, the reaction mixture was cooled, quenched with Seignettes's salt solution (2 mL) and water (2 mL), then extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated. Purification by chromatography (silica, 10 to 80% ethyl acetate in heptane) gave the title compound (59 mg, 68%) as pale yellow solid. MS: m/e=348.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[NH2:27][C:28]1[S:29][CH2:30][CH2:31][N:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C:28]2[S:29][CH2:30][CH2:31][N:32]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: NC1=NCCS1
Product: O=C(NC1=NCCS1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2-amino-4,5-dihydrothiazole via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(4,5-dihydrothiazol-2-yl)terephthalamide. MS (Q1) 471 (M)+.
Reaction SMILES: [CH3:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4](Cl)[N:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH3:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[N:3]=1
Reactant: Cc1nc(Cl)cc(N)[n+]1[O-]
Reactant: C1CCNCC1
Product: Cc1nc(N2CCCCC2)cc(N)[n+]1[O-]
Yield: 69.6 %

Procedure:
A solution of 44 g (0.261 mol) of 2-methyl4-amino-6-chloropyrimidine 3-oxide in 352 ml of piperidine is refluxed gently for 4 hours 30 minutes, with stirring and under nitrogen. A yellow suspension is obtained. The suspension is cooled in a salt ice bath and the precipitate is drained and washed on the filter with 30 ml of piperidine and then with ethyl ether. It is then taken up, with stirring, twice ill 150 ml of ice-water. The solid is drained and dried under vacuum at ambient temperature. 42 g of product in the form of the monohydrate are obtained. The product is recrystallized from acetonitrile with 3% of water, After drying at 80° C., 37.8 g (0.181 mol) of anhydrous pure product having a melting point of 200°-200.5° C. are recovered. The yield is 69.6%.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28](Cl)[N:27]=[C:26]([Cl:32])[N:25]=2)=[O:21])[CH2:8][N:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[CH2:38][N:39]1[C:43]2[N:44]=[CH:45][N:46]=[CH:47][C:42]=2[N:41]=[N:40]1.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:32][C:26]1[N:25]=[C:24]([NH:23][NH:22][C:20](=[O:21])[C@H:7]([CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:8][N:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[O:11])[C:29]([F:30])=[C:28]([N:33]2[CH2:37][CH2:36][CH2:35][C@H:34]2[CH2:38][N:39]2[C:43]3[N:44]=[CH:45][N:46]=[CH:47][C:42]=3[N:41]=[N:40]2)[N:27]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(Cl)c1F)OCc1ccccc1
Reactant: c1ncc2nnn(C[C@@H]3CCCN3)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(N2CCC[C@H]2Cn2nnc3cncnc32)c1F)OCc1ccccc1
Temperature: 65 °C
Yield: 23.7 %

Procedure:
{(2R)-2-(Cyclopentylmethyl)-3-[2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)hydrazino]-3-oxopropyl}[(phenylmethyl)oxy]formamide (136 mg, 0.278 mmol) and 3-[(2S)-2-pyrrolidinylmethyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidine (63 mg, 0.308 mmol) were dissolved in DMSO (5 mL), then DIEA (59 μL, 0.308 mmol) was added, and the solution was heated at 65° C. overnight. When the reaction was complete as determined by LCMS, the solution was concentrated in vacuo, and the resulting crude product was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(2S)-2-(3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-1-pyrrolidinyl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (43 mg, 21%). LCMS: (M+H)+: 651.6.
Reaction SMILES: F[C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[C:4](/[N:6]=[C:7]1/[N:8]([CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][O:19]2)[N:9]([CH3:16])[C:10]([C:12]2([CH3:15])[CH2:14][CH2:13]2)=[CH:11]/1)=[O:5].[CH3:31][C:32]([OH:37])([CH3:36])[CH2:33][CH2:34][OH:35].CC([O-])(C)C.[Na+]>C1COCC1.O>[OH:37][C:32]([CH3:36])([CH3:31])[CH2:33][CH2:34][O:35][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:3]=1[C:4](/[N:6]=[C:7]1/[N:8]([CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][O:19]2)[N:9]([CH3:16])[C:10]([C:12]2([CH3:15])[CH2:13][CH2:14]2)=[CH:11]/1)=[O:5]
Reactant: CC(C)(O)CCO
Reactant: Cn1c(C2(C)CC2)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2F)n1C[C@H]1CCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C2(C)CC2)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OCCC(C)(C)O)n1C[C@H]1CCCO1
Yield: 54.4 %

Procedure:
A mixture of Example 68D (600 mg, 1.41 mmol), 3-methylbutane-1,3-diol (294 mg, 2.82 mmol) and sodium 2-methylpropan-2-olate (271 mg, 2.82 mmol) in THF (30 mL) was heated at 40° C. for 12 hours. The reaction mixture was diluted with H2O and extracted with EtOAc (2×). The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 50% hexanes/EtOAc to 100% EtOAc to 9:1:0.1 EtOAc:MeOH:Et3N) to afford 391 mg (54%) of the title compound. 1H NMR (500 MHz, chloroform-d) δ ppm 0.76-0.83 (m, 2H) 0.89-0.98 (m, 2H) 1.31 (s, 6H) 1.34 (s, 3H) 1.69-1.82 (m, 2H) 1.81-1.90 (m, 1H) 1.96-2.11 (m, 3H) 3.66-3.80 (m, 2H) 3.83 (s, 3H) 4.15-4.32 (m, 4H) 4.52 (dd, J=14.49, 2.59 Hz, 1H) 5.62 (s, 1H) 6.98 (d, J=8.54 Hz, 1H) 7.03 (s, 1H) 7.53 (dd, J=8.54, 2.14 Hz, 1H) 8.30 (d, J=2.14 Hz, 1H); MS (DCI/NH3) m/z 510 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[F:10][C:11]([F:27])([F:26])[CH:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=2)[CH:15]=1)[OH:13].[H-].[Na+]>O1CCOCC1>[Cl:9][C:4]1[CH:5]=[C:6]([O:13][CH:12]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=3)[CH:15]=2)[C:11]([F:26])([F:27])[F:10])[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: COc1ccc2cc(C(O)C(F)(F)F)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc2cc(C(Oc3cc(Cl)nc(N)n3)C(F)(F)F)ccc2c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 104.2 %

Procedure:
2-Amino 4,6-dichloro pyrimidine (0.096 g, 0.6 mmol), 2,2,2-trifluoro-1-(6-methoxy-naphthalen-2-yl)-ethanol (0.140 g, 0.55 mmol), and NaH (96 mg, 0.60 mmol) were added to anhydrous dioxane (20 ml) under a nitrogen atmosphere. The reaction was stirred at 80° C. for 12 hours, cooled to room temperature, and quenched with water (0.2 ml). The reaction mixture was concentrated, and the residue dissolved in CH2Cl2 (50 ml), washed with water (20 ml), brine (20 ml) dried (Na2SO4) and concentrated to afford the crude intermediate, 4-chloro-6-[2,2,2-trifluoro-1-(6-methoxy-naphthalene-2-yl)-ethoxy]-pyrimidin-2-ylamine (0.22 g) which was directly used in the following step.
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][CH2:10][CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][P:12](=[O:19])([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18]
Reactant: CCOP(=O)(CCCN1C(=O)c2ccccc2C1=O)OCC
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOP(=O)(CCCN)OCC
Reaction time: 12 h
Yield: 51.1 %

Procedure:
To this end, 23.08 g (46.1 mmol) of hydrazine monohydrate are added dropwise to 15 g (46.1 mmol) of diethyl phthalimidopropylphosphonate in about 500 ml of absolute ethanol. The reaction medium is stirred for 12 hours. The salts formed are filtered off and washed with ethanol. After evaporating off the ethanol, salts are again formed. These salts are washed with CH2Cl2 and filtered on a Millipore membrane (0.45 μm). The filtrate is recovered and the CH2Cl2 is evaporated off. A yellow oil is obtained. The crude product is purified by chromatography on a column of silica gel with a 90/10 CHCl3/MeOH mixture as eluent. 4.6 g of diethyl 3-aminopropylphosphonate (APPE) are obtained in a yield of 51.8%.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]1([O:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH:17]=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1>O1CCCC1>[C:1]1([CH:17]([OH:18])[C:16]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:14]([O:13][CH:8]3[CH2:9][CH2:10][CH2:11][CH2:12]3)[CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1ccccc1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccccc2)cc1OC1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
Phenyllithium (1.8M solution in cyclohexane/diethyl ether, 25.5 milliliters, 46 mmol) was added dropwise over 15 minutes to a stirred solution of 3-cyclopentyloxy-4-methoxybenz-aldehyde (6 grams, 27 mmol) in dry tetrahydrofuran (20 milliliters) at -78° C. The resulting solution was stirred at -78° C. for 30 minutes and quenched at -78° C. by the rapid addition of aqueous saturated NH4Cl (70 milliliters). After warming to room temperature, water was added to dissolve the solids and volatiles were removed in vacuo. The residue was partitioned between water (250 milliliters) and ethyl acetate (250 milliliters), the aqueous phase was extracted with ethyl acetate (3×250 milliliters) and the combined organic layers washed with water (200 milliliters). The organics were dried over Na2SO4 and concentrated in vacuo to give a light yellow oil. The oil was purified by flash chromatography (SiO2 :hexane/ethyl acetate (4:1)) to afford the title compound as a pale yellow oil (7.4 grams) .
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].Cl[S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9]>ClC1C=CC=CC=1>[CH3:6][S:3]([N:2]([CH3:1])[S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])(=[O:5])=[O:4]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CNS(C)(=O)=O
Solvent: Clc1ccccc1
Product: CN(S(C)(=O)=O)S(=O)(=O)N=C=O

Procedure:
151 g (1.38 moles) of methanesulfonic acid methyl amide are dissolved in 500 ml of chlorobenzene, a solution of 215 g (1.52 moles) of chlorosulfonyl-isocyanate in 200 ml of chlorobenzene is added within 10 minutes at room temperature, the whole is subsequently heated at 120° - 125°C for 4 hours with agitation, and finally, the methanesulfonyl-methylamino-sulfonylisocyanate is isolated by distillation. The yield is 173 g (59 %), boiling point 94° - 98°C/0.1 torr.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2.Br[C:24]1[C:33]2[CH2:32][CH2:31][CH2:30][CH:29]([NH:34][S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[C:28]=2[CH:27]=[N:26][CH:25]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:24]2[C:33]3[CH2:32][CH2:31][CH2:30][CH:29]([NH:34][S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[C:28]=3[CH:27]=[N:26][CH:25]=2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)cc(F)c21
Reactant: CCS(=O)(=O)NC1CCCc2c(Br)cncc21
Product: CCS(=O)(=O)NC1CCCc2c(-c3cc(F)c4c(c3)CCC(=O)N4C)cncc21
Yield: 25 %

Procedure:
In analogy to the procedure described for the preparation of example 28, 8-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-7) and (rac)-ethanesulfonic acid (4-bromo-5,6,7,8-tetrahydro-isoquinolin-8-yl)-amide (intermediate B-4) were used to give the title compound (10.3 mg, 25%) as a white solid. MS: 418.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Si:24]([CH3:36])([CH3:35])[CH2:25][CH2:26][O:27][CH2:28][N:29]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)(Cl)Cl.O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:34][C:31]3[CH:32]=[CH:33][N:29]([CH2:28][O:27][CH2:26][CH2:25][Si:24]([CH3:36])([CH3:35])[CH3:23])[N:30]=3)[N:17]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(Cc2cccc(Br)n2)CCN(Cc2ccccc2)CC1
Reactant: C[Si](C)(C)CCOCn1ccc(N)n1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: C[Si](C)(C)CCOCn1ccc(Nc2cccc(CC3(O)CCN(Cc4ccccc4)CC3)n2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 469 mg of 1-benzyl-4-((6-bromopyridin-2-yl)methyl)piperidin-4-ol, 332 mg of 1((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (WO2006/046734, page 132, Reference 2), 150 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, 134 mg of tris(dibenzylideneacetone)dipalladium(0)-chloroform complex, 827 mg of potassium phosphate and 10 ml of 1,4-dioxane was stirred at 100° C. overnight, followed by cooling to room temperature. The reaction mixture was diluted with chloroform. An insoluble matter was filtered off using Celite, washed with chloroform, and the filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=10/1) to give the title compound as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[OH:9]O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N+:3]=1[O-:9]
Reactant: Brc1cccc(Br)n1
Reactant: OO
Solvent: O=C(O)C(F)(F)F
Product: [O-][n+]1c(Br)cccc1Br
Temperature: 100 °C
Yield: 90 %

Procedure:
To an ice-cold solution of 2,6-dibromopyridine (50 g, 0.21 mol) in trifluoroacetic acid (250 mL) was added 30% H2O2 solution (70 mL) drop wise over 1 h. The reaction mixture was washed, heated to 100° C. for 16 h then cooled to rt, poured into 1.50 L of water and the precipitate filtered. The solid thus obtained (10 g) was the starting material (2,6-dibromopyridine). The filtrate was extracted with dichloromethane (3×1 L) and the combined organic layer was washed with 0.50 M K2CO3 solution (3×500 mL). The organic layer was then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was treated with hexane then filtered to obtain the desired product as an off white solid (38.50 g, 72% and 90% yield based on the recovery of the starting material).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])O[C:8](=[O:9])[C:7]=12.[N:14]1C=CC=C[CH:15]=1>C(O)(=O)C>[CH3:1][C:2]1[C:7]2[C:8](=[O:9])[NH:14][CH2:15][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: Cc1cccc2[nH]c(=O)oc(=O)c12
Solvent: CC(=O)O
Product: Cc1cccc2c1C(=O)NCC(=O)N2

Procedure:
6-Methylisatoic anhydride (10.0 g, 56 mmol) ethyl glycinate hydrochloride (9.77g, 1.25 equiv.) and anhydrous pyridine (200 mL) were combined and heated under reflux 3.5 h in a nitrogen atmosphere. The pyridine was removed by evaporation under reduced pressure to give an oil. The oil was dissolved in acetic acid (15 mL) and heated under reflux for 6 h. The volatiles were removed under reduced pressure to give a residue which was triturated methanol and filtered to recover 3.63 g of 6-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione as a yellow solid. The methanol filtrate was evaporated and acetic acid (200 mL) was added to the residue. The brown solution was heated under reflux overnight. The reaction mixture was cooled and the volume of acetic acid was reduced to half its volume under reduced pressure. Upon cooling, a solid precipitated which was collected. A second crop of 6-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (4.7 g) was obtained as a beige solid.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: FC(F)(F)c1ccccc1CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2C(F)(F)F)CCCC1=O
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
40% Methanolic Triton B (2.18 mL, 4.8 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (973 mg, 4.0 mM) in 10 mL of DMF at −10° C. After 30 minutes, 2-(trifluoromethyl)benzyl bromide (1.3 g, 5.2 mM) was added and the resultant mixture stirred at room temperature for 23 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and dried in vacuo to afford 1.34 g (83%) of the 9-[(2-trifluoromethylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan solid. 1H NMR (CDCl3) δ7.7 (d, 1H, J=8 Hz), 7.4-7.1 (m, 5H), 6.4 (d, 1H, J=8 Hz), 5.5 (s, 2H), 4.05 (s, 3H), 2.8 (t, 2H, J=6 Hz), 2.6 (t, 2H, J=6 Hz), and 2.2 (m, 2H). IR (KBr, cm−1) 1729 and 1656. MS (ES) m/e 402.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]#[N:11])[CH2:5][CH2:4]1>[Ni].CCO>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][NH2:11])[CH2:5][CH2:4]1
Reactant: COC1CCN(CC#N)CC1
Agent: [Ni]
Solvent: CCO
Product: COC1CCN(CCN)CC1
Reaction time: 16 h

Procedure:
A mixture of nitrile 287 (10.25 g, 66.5 mmol) and Raney Nickel (50% w/w in water, ca. 10 mL) in EtOH (150 mL) and cNH3 (10 mL) was stirred under H2 (60 psi) for 16 h. The mixture was filtered through Celite, washed with EtOH (3×10 mL) and the solvent evaporated to give crude diamine 288 as an oil which was used directly.