Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:31](O)=[O:32])[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=2)=[C:11]([F:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][CH2:36][N:37]([CH:41]([CH3:43])C)[CH:38]([CH3:40])C>ClC(Cl)C>[CH2:41]([N:37]1[CH2:36][CH2:35][C:15]([NH:20][C:31]([C:17]2[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]=3[F:34])[CH:16]=2)=[O:32])([C:12]2[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=2)[CH2:40][CH2:38]1)[C:43]1[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)O)c12
Reactant: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)NC3(c4ccccc4)CCN(Cc4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59 %

Procedure:
A mixture of 6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (304 mg), amine (200 (200 mg), DIPEA (340 μL) and BEP (190 mg) in dichloroethane (6.5 mL) was stirred at r.t. for 90 min. The solvent was distilled off in vacuo, the residue was re-dissolved in ethyl acetate (20 mL) and washed twice with water, twice with saturated sodium bicarbonate solution and with brine, then dried over magnesium sulfate. After evaporation of the solvents, the residue was purified by flash chromatography (silica, heptane/ethyl acetate gradient) giving 278 mg (59%) of the title compound.
Reaction SMILES: [OH:1][C:2]1([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:18]=[CH:19][C:20](Cl)=[N:21][C:22]=3[CH:23]=[CH:24][C:25]=2[Cl:26])=[O:15])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([F:11])([F:10])[F:9])[CH2:3]1.CCN(C(C)C)C(C)C.[F:37][C@@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1>>[OH:1][C:2]1([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([N:40]4[CH2:41][CH2:42][C@@H:38]([F:37])[CH2:39]4)=[N:21][C:22]=3[CH:23]=[CH:24][C:25]=2[Cl:26])=[O:15])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([F:11])([F:10])[F:9])[CH2:3]1
Reactant: O=C(NCC1(O)CCCC(C(F)(F)F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: F[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(O)CCCC(C(F)(F)F)C1)c1c(Cl)ccc2nc(N3CC[C@@H](F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3-trifluoromethyl-cyclohexylmethyl)-amide, DIPEA and (R)-3-fluoro-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (d, 1H), 4.72 (s, 1H), 3.80-3.58 (m, 3H), 3.26 (m, 2H), 2.59 (m, 1H), 2.22 (m, 1H), 2.08 (1H), 1.85-1.72 (m, 2H), 1.50 (m, 1H), 1.33-1.20 (m, 3H). m/z: 474 [M+H]
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16]Br)=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)=[CH:4][C:3]=1[NH:23][C:24](=[O:33])[CH:25]=[CH:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:44]3[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]3)=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)=[CH:4][C:3]=1[NH:23][C:24](=[O:33])[CH:25]=[CH:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(NC(=O)c2ccc(CBr)c(C(F)(F)F)c2)cc1NC(=O)C=Cc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1NC(=O)C=Cc1cccnc1

Procedure:
0.4 g of N-(4-methyl-3-(3-(pyridin-3-yl)acrylamido)phenyl)-4-(bromomethyl)-3-(trifluoromethyl)benzamide was added into 20 ml anhydrous tetrahydrofuran, and then 1.0 g of potassium carbonate and 1.0 ml of 4-methyl piperazine. The reaction mixture was heated to reflux for 10 h. The completion of reaction was indicated by TLC. The reaction mixture was filtered, and the filtrate was evaporated to dry. 10 ml of water was added to dissolve the redundant 4-methylpiperazine and corresponding salts. The mixture was filtered, the filter cake was purified on silica gel column using ethyl acetate as an eluent to elute impurities, then using methanol as an eluent to elute the product. Concentration of the eluent under reduced pressure and crystallization gave a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH2:27][CH2:28][N:29]([C:31](OC(C)(C)C)=[O:32])[CH2:30][C:25]=4[O:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Cl.O1CCOCC1.Cl.[CH3:46][N:47]([CH3:54])[CH2:48]/[CH:49]=[CH:50]/C(O)=O>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH2:27][CH2:28][N:29]([C:31](=[O:32])/[CH:50]=[CH:49]/[CH2:48][N:47]([CH3:54])[CH3:46])[CH2:30][C:25]=4[O:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(oc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)C1
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CN(C)C/C=C/C(=O)N1CCc2c(oc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)C1
Temperature: 80 °C
Yield: 38.4 %

Procedure:
tert-Butyl 4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5,8-dihydropyrido[4′,3′:4,5]furo-[2,3-d]pyrimidine-7(6H)-carboxylate from Example 86A (18 mg, 0.034 mmol) was dissolved in 2-propanol (1.0 mL) and treated with 4 M gaseous hydrogen chloride in dioxane (0.25 mL, 1.0 mmol). The mixture was heated to 80° C. for 2 h. Subsequently, the solvent was removed in vacuo. The residue was reacted in analogy to Example 89 with (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (8.0 mg, 0.048 mmol) to yield 7.0 mg (38%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.Cl[C:18]1[N:19]=[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]2[C:26]=1[N+:27]([O-:29])=[O:28].C(N(CC)CC)C>>[CH3:1][C:2]1[N:3]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]4[C:26]=3[N+:27]([O-:29])=[O:28])[CH2:15][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccn12
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Solvent: CCN(CC)CC
Product: Cc1cccc(C#CC=C2CCN(c3nc4ccccn4c3[N+](=O)[O-])CC2)n1
Yield: 55.1 %

Procedure:
A well homogenised mixture of the Compound of Example 3 (150 mg, 0.71 mmol), 2-chloro-3-nitroimidazo[1,2-a]pyridine (154 mg, 0.778 mmol) and triethylamine (0.152 mL, 1.06 mmol) was stirred at 25° C. for 24 h. The reaction crude was purified by flash chromatography (EtOAc—Petroleum Ether 1:1) affording the title product (146 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[S:6](N)([NH2:9])(=[O:8])=[O:7]>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][NH:5][S:6](=[O:8])(=[O:7])[NH2:9]
Reactant: COCCN
Reactant: NS(N)(=O)=O
Solvent: C1CCOC1
Product: COCCNS(N)(=O)=O
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 36.4 %

Procedure:
According to Reference Example 9-26, tetrahydrofuran (3 mL) and 2-methoxyethylamine (0.36 mL, 4.2 mmol) were added to sulfamide (400 mg, 4.2 mmol) and the mixture was stirred by use of a microwave chemical reactor at 300 W at 100° C. for 10 minutes. The solvent was evaporated off under reduced pressure, and purification by silica gel column chromatography (hexane/ethyl acetate=1/0 to 1/4) was performed to give N-(2-methoxyethyl)sulfuric diamide (Compound GF) (236 mg, yield: 37%).
Reaction SMILES: [NH2:1][C@:2]12[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:36])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([CH:24]=[C:25]2[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.P(=O)(O)(O)O.[K].[I-].[K+].Cl[CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][S:57](=[O:61])(=[O:60])[CH2:56][CH2:55]1>C(#N)C>[O:60]=[S:57]1(=[O:61])[CH2:58][CH2:59][N:54]([CH2:53][CH2:52][NH:1][C@:2]23[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:36])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([CH:24]=[C:25]3[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)[CH2:55][CH2:56]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C=C6CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=S1(=O)CCN(CCCl)CC1
Agent: O=P(O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C=C6CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C

Procedure:
To a sealable flask containing ethyl 4-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)methylene)cyclohexanecarboxylate (0.015 g, 0.026 mmol) was added phosphoric acid, potassium salt (0.028 g, 0.130 mmol), potassium iodide (0.013 g, 0.078 mmol) and 4-(2-chloroethyl)thiomorpholine 1,1-dioxide (0.015 g, 0.078 mmol). The mixture was diluted with acetonitrile (1 mL), flushed with nitrogen, sealed, and heated to 100° C. After heating the mixture for 22 h, it was cooled to rt, diluted with water (5 mL), and extracted with dichloromethane (3×5 mL). The organic layers were dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used in the next step with no additional purification. LCMS: m/e: 737.7 (M+H)1, 2.22 min (method 1).
Reaction SMILES: NC1SC=C(C(=O)C(N[C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15](CSC2N4N=C(C(=O)N)N=C4N=C(C)C=2)=[C:16]3[C:20]([OH:22])=[O:21])=O)N=1.O(C(C)(C)C(NNS(C1C=CC(O)=C(O)C=1)(=O)=O)=O)N>>[O:19]=[C:18]1[N:17]2[CH:12]([S:13][CH2:14][CH:15]=[C:16]2[C:20]([OH:22])=[O:21])[CH2:11]1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(C(N)=O)nc2n1
Agent: CC(C)(ON)C(=O)NNS(=O)(=O)c1ccc(O)c(O)c1
Product: O=C(O)C1=CCSC2CC(=O)N12

Procedure:
34 mg of (6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[(2-carbamoyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid were reacted with 28 mg of 2-[2-(aminoxy)-2-methylpropionyl]-1-[(3,4-dihydroxyphenyl)sulphonyl]hydrazine according to the procedure described in Example 7. After purification of the crude product with the chromatographic procedure described in Example 1 and lyophilization of the product, there was obtained (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-[(3,4-dihydroxy-phenyl)sulphonyl]carbazolyl]-1-methylethoxy]imino]aceta-mido]-3-[[(2-carbamoyl)-5-methyl-s-triazolo[1,5-a]-pyrimidin-7-yl)-thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2].[CH2:34]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:35]#[CH:36].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=[C:16]([C:36]#[C:35][CH2:34][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(Oc3ncccc3C(F)(F)F)c2)cc1C
Reactant: C#CCN1CCOCC1
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(Oc3ncccc3C(F)(F)F)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (250 mg; 0.46 mmol) and 4-prop-2-ynyl-morpholine (173.09 mg; 1.38 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 262 mg (97%). HPLC-MS: m/z: 587.5 (M+H)+; Rt: 2.03 min
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:9][C:10]1[CH:19]=[CH:18][C:17]([O:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]>>[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([O:20][C:17]2[CH:18]=[CH:19][C:10]([O:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1O
Product: COC(=O)c1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1OCc1ccccc1

Procedure:
(Bromomethyl)benzene (3.81 g, 22.26 mmol) was added to methyl 2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzoate (may be prepared as described in Description 36; 2.87 g, 8.90 mmol) and the resulting mixture was refluxed overnight. After cooling, the resulting precipitate was filtered and the filtrate was evaporated. The crude product was purified by silica gel chromatography, eluting with a 4:1 mixture of hexane:ethyl acetate to yield the title compound as a colourless oil. 2.7 g.
Reaction SMILES: [C:1]([CH:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[OH:6])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.C1OCCOCCOCCOCCOCCOC1.[N+:34]([C:37]([CH3:39])=[CH2:38])([O-:36])=[O:35]>C(#N)C.O1CCCC1>[N+:34]([CH:37]([CH3:39])[CH2:38][O:6][CH:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:1]([CH3:4])([CH3:3])[CH3:2])([O-:36])=[O:35]
Reactant: C=C(C)[N+](=O)[O-]
Reactant: CC(C)(C)C(O)C(C)(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Li]C(C)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(COC(C(C)(C)C)C(C)(C)C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Di-t-butylmethanol is added to a dry flask under argon at 0+ C. Dry tetrahydrofuran is added with a syringe. Sec-Butyl lithium (1.5M in Hexanes) is added quickly in one portion and the contents of the flask are stirred for one hour at room temperature. A 10 mM solution of 18-crown-6-ether in acetonitrile is added with a syringe and the flask cooled to 0° C. A tetrahydrofuran solution of 2-nitropropene is added with vigorous stirring over a 10 minute period. After completion of the reaction as judged by thin layer chromatography, it is quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer is dried over MgSO4 and evaporated to yield 2-nitro 1-[di-(t-butyl)methoxy]propane.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[CH:16][CH:17]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Reactant: COc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1cc(COc2ccc(-c3ccccc3OC)cc2)c(C)o1
Yield: 21 %

Procedure:
A degassed mixture of 5-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-furan-2-carboxylic acid methyl ester (119) (200 mg, 0.54 mmoles), 1-bromo-2-methoxy-benzene (80 μl, 0.65 mmoles), 2M aqueous cesium carbonate (1.0 ml) and), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (44 mg) in 1,4-dioxan (30 ml), under an argon atmosphere was heated at 95° C. for 18 hours. After cooling, the mixture was concentrated, the residue dissolved in ethyl acetate and washed with brine and dried. After evaporation of the solvent, the residue was purified by flash chromatography using cyclohexane/ethyl acetate 9:1 v/v as eluent to afford compound 125 (40 mg) as an oil. LC/MS System A; Rt=4.14 mins, m/z (ES+)=353 weak (M+H for C21H20O5).
Reaction SMILES: Cl.[CH3:2][C:3]1[N+:4]([O-])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].P(Cl)(Cl)([Cl:22])=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:22][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)[n+]([O-])c1C
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 28.1 %

Procedure:
In to a 5° C. solution of 4,5-dimethyl-2-(4-trifluoromethyl-phenyl)-oxazole N-oxide hydrochloride (113.71 g, 387.5 mmol) in CHCl3 (560 ml), was added phosphorus oxychloride (39.4 ml, 422.4 mmol) in CHCl3, dropwise over 15 min. The reaction was refluxed for 2.5 h, then cooled to 5° C., poured into ice water, and basified with NaOH (1N). The organic layer was dried over MgSO4. Evaporation and recrystallization from ether/hexane, gave a yellow solid (30.0 g, 28% yield, mp 84°-85° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16]S(C)(=O)=O)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1O>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16][C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][C:26]=3[F:28])[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: Oc1ccc(F)cc1F
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(OS(C)(=O)=O)C1
Product: O=C(O)c1cc(Cl)cnc1N1CC(Oc2ccc(F)cc2F)C1
Yield: 86.8 %

Procedure:
The title compound (D108) (84 mg) was prepared according to the experimental procedure described in Description 103A starting from methyl 5-chloro-2-(3-((methylsulfonyl)oxy)azetidin-1-yl)nicotinate (D63) (100 mg, 0.311 mmol) and 2,4-Difluorophenol (0.027 ml, 0.284 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:25]=[CH:26]/[C:27]([O:29]CC)=[O:28])[CH:5]=[N:6][C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:16])[CH2:11][CH2:10]1.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]([OH:29])=[O:28])[CH:5]=[N:6][C:7]=1[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15](=[O:16])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:13][CH2:14]1
Reactant: CCOC(=O)/C=C/c1cnc(NC2CCN(C(=O)Nc3ccc(Cl)cc3)CC2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C=Cc1cnc(NC2CCN(C(=O)Nc3ccc(Cl)cc3)CC2)c(Cl)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl (2E)-3-{5-chloro-6-[(1-{[(4-chlorophenyl)amino]carbonyl}-4-piperidyl)amino]-3-pyridyl}acrylate (363 mg) in THF (3 ml) and MeOH (3 ml) was added 1N NaOH aq (2.35 ml), the mixture was stirred at 80° C. for 1 hour. The pH of the mixture was adjusted to ca.4.5 with 1N HCl aq. The solution was evaporated under reduced pressure to give crude 3-{5-Chloro-6-[1-(4-chlorophenylcarbamoyl)-piperidin-4-ylamino]-pyridin-3-yl}-acrylic acid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH2:7].[CH2:8]([N:10]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=2)=[CH:13][C:12]([C:24]2[CH:25]=[C:26]([C:30]([NH:33][S:34]([CH2:37][C:38]([F:41])([F:40])[F:39])(=[O:36])=[O:35])([CH3:32])[CH3:31])[CH:27]=[CH:28][CH:29]=2)=[N:11]1)[CH3:9]>CN(C=O)C>[CH2:8]([N:10]1[C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][NH:7][CH2:6][CH:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[CH:20][CH:21]=2)=[CH:13][C:12]([C:24]2[CH:25]=[C:26]([C:30]([NH:33][S:34]([CH2:37][C:38]([F:41])([F:39])[F:40])(=[O:35])=[O:36])([CH3:32])[CH3:31])[CH:27]=[CH:28][CH:29]=2)=[N:11]1)[CH3:9]
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C=O)cc1
Reactant: NCC1CCCO1
Solvent: CN(C)C=O
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(CNCC2CCCO2)cc1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
1-(tetrahydrofuran-2-yl)methanamine (12.3 mgs, 0.121 mmol, 1.2 equiv) followed by Si-bound cyanoborohydride (322 mg, 0.303 mmol, 3.0 equiv, 0.94 mmol/g) were added to N-(2-{3-[1-ethyl-5-(4-formylphenoxy)-1H-pyrazol-3-yl]phenyl}propan-2-yl)-2,2,2-trifluoroethanesulfonamide (50.0 mg, 0.101 mmol, 1 equiv) stirring in DMF (with 0.05% acetic acid v:v, 0.5 mL). The resulting mixture was stirred at 22° C. for 16 hours then filtered through a 0.45 micron nylon syringe filter and flushed with methanol. The filtrate was purified by reversed phase HPLC (0-95% acetonitrile:water with 0.025% TFA v:v). Pure fractions were identified, combined, basified with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was filtered away and the filtrate was concentrated in vacuo to give N-(2-{3-[1-ethyl-5-(4-{[(tetrahydrofuran-2-ylmethyl)amino]methyl}phenoxy)-1H-pyrazol-3-yl]phenyl}propan-2-yl)-2,2,2-trifluoroethanesulfonamide. Calc'd (M+1) 581.2. Found: 581.2
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].[CH3:7][N:8]1[CH2:14][CH2:13][C:12]2=[CH:15][C:16](=[O:20])[C:17](=[O:19])[CH:18]=[C:11]2[CH2:10][CH2:9]1>CO>[OH:20][C:16]1[C:17]([OH:19])=[CH:18][C:11]2[CH2:10][CH2:9][N:8]([CH3:7])[CH2:14][CH2:13][C:12]=2[C:15]=1[S:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1cccs1
Reactant: CN1CCC2=CC(=O)C(=O)C=C2CC1
Solvent: CO
Product: CN1CCc2cc(O)c(O)c(Sc3cccs3)c2CC1
Reaction time: 1 h

Procedure:
To a stirred solution of 2-thiophenethiol (0.9 g., 0.0076 mole) in 200 ml. of methanol was added portionwise 2 g. (0.0074 mole) of 3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione, at room temperature under argon. After stirring for 1 hour, the methanol was distilled under vacuum, the residue slurried in 30 ml. of water and filtered. The filtrate was made basic to give the product, 7,8-dihydroxy-3-methyl-6-(2-thienylthio)-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 189°-191° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[CH:10]=[CH2:11].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[N:3]=[CH:4][C:5](/[CH:11]=[CH:10]/[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C=CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Product: Nc1ccc(/C=C/C(=O)OCc2ccccc2)cn1
Yield: 39.3 %

Procedure:
A solution of 2-amino-5-bromopyridine (2.25 g, 13.0 mmole), benzyl acrylate (3.2 g, 19.7 mmole), Pd(OAc)2 (0.31 g, 1.4 mmole), tri-ortho-tolylphosphine (0.73 g. 2.4 mmole), and disopropylethylamine (3.5 mL, 20.0 mmole) in propionitrile (50 mL) was heated at reflux overnight. The dark mixture was filtered through celite®, and the fitrate was concentrated. Flash chromatography on silica Se[(3% MeOH/CH2Cl2) gave the title compound (1.3 g, 39%): MS (ES) m/e 255 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:16][CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:23]([O-])=O)[CH:3]=1>CO.[Pd]>[NH2:23][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N:8]([CH2:16][CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)N(CCCS(C)(=O)=O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCCS(C)(=O)=O)c1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-chloro-2-nitrophenyl(3-(methylsulfonyl)propyl)carbamate (360 mg, 1.45 mmol) in MeOH was added 2% Pd/C 30 mg). The reaction was degassed and refilled with H2. The mixture was stirred at RT under H2 atmosphere for 3 hrs. The catalyst was filtered off and the filtrate was concentrated to afford tert-butyl 2-amino-4-chlorophenyl(3-(methylsulfonyl) propyl)carbamate as crude product (330 mg, yield: 100%). MS obsd. (ESI+) [(M+H)+]: 363.1.