Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[F:18][C:19]([F:32])([O:23][C:24]1[CH:25]=[C:26]([CH2:30]Br)[CH:27]=[CH:28][CH:29]=1)[CH:20]([F:22])[F:21].O>COCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH:9]([CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:19]([F:18])([F:32])[CH:20]([F:21])[F:22])[CH:25]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1cccc(Cl)c1
Reactant: FC(F)C(F)(F)Oc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (10.2 g, 49.0 mmol) in ethyl acetate (80 ml) were added N-bromosuccinimide (9.6 g, 53.9 mmol) and 2,2′-azobis(isobutyronitrile) (161 mg, 0.98 mmol), and the mixture was heated under reflux for 5 hrs. The reaction solution was concentrated and crystals were filtered with hexane. The filtrate was concentrated to give 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solution of ethyl 3-(3-chlorophenyl)-3-oxopropanoate (10.0 g, 44.1 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% in oil, 1.76 g, 44.1 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene prepared earlier in 1,2-dimethoxyethane (50 ml), and the mixture was stirred overnight at room temperature. The reaction solution was poured into water (300 ml), and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) to give the objective substance (7.5 g, 39%).
Reaction SMILES: [C@@H:1]1([N:9]2[C:13]3[N:14]=[C:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[NH:16][C:17](=[O:18])[C:12]=3[C:11]([I:25])=[CH:10]2)[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.[CH3:26][O:27][C:28]1[CH:49]=[CH:48][C:31]([C:32](Cl)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[CH:30][CH:29]=1.CO.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([C:32]([O:8][CH2:7][C@H:5]2[O:6][C@@H:1]([N:9]3[C:13]4[N:14]=[C:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[NH:16][C:17](=[O:18])[C:12]=4[C:11]([I:25])=[CH:10]3)[CH2:2][C@@H:3]2[OH:4])([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:31]2[CH:48]=[CH:49][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)C(=O)Nc1nc2c(c(I)cn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(I)c4c(=O)[nH]c(NC(=O)C(C)C)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
Compound (59) is repeatedly dried by evaporating off anhydrous pyridine. 400 mg (0.87 mmol) of compound (59) which has been dried in this way are dissolved in 5 ml of anhydrous pyridine. After adding 4,4′-dimethoxytrityl chloride (328 mg, 0.95 mmol) at room temperature, the reaction mixture is stirred overnight. MeOH (3 ml) and 5% aq. NaHCO3 (30 ml) are then added. The aqueous phase is extracted 3 times with CH2Cl2. The organic phase is dried (Na2SO4) and evaporated, and the residue is subjected to flash chromatography (column: 10×5 cm, solvent CH2Cl2/acetone, 9:1). Isolating the material from the main zone affords the colorless, amorphous title compound (61). (600 mg, 91%). 1H-NMR ([D6] DMSO: δ=1.13 (m, 4 CH3), 2.24 (m, H—C(2′)), 2.77 (m, CH), 3.12 (m, H—C(5′)), 3.75 (s, 2 CH3O), 3.93 (m, H—C(4′)), 4.35 (m, H—C(3′)), 5.30 (d, 3′-OH), 6.39 (dd, H—C(1′)), 6.86-7.39 (m, aromatic H+H—C(6)), 11.54, 11.82 (2s, 2 NH). Anal. calculated for C36H37JN4O7 (764.6): C 56.55, H 4.88, N 7.33: found C 56.42, H 4.82, N 7.30.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([Mg]Br)[C:21]([O:24][CH3:25])=[CH:22][CH:23]=1>C1COCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH:1]([OH:2])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH:19]=1
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Reactant: COc1ccc(F)cc1[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(O)c1cnccc1-c1cccc(C#N)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (15 mg, 0.075 mmol) in THF (1 mL) at −78° C. was added 0.5 M 3-fluoro-6-methoxyphenylmagnesium bromide in THF (0.3 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[(5-fluoro-2-methoxy-phenyl)-hydroxy-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2[CH:3]=[CH:2]1)[CH2:7]3.C1(C#C)C=CC=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl>>[CH2:1]1[CH:5]2[C@@H:6]3[CH:10]=[CH:9][C@H:8]([CH:4]2[CH:3]=[CH:2]1)[CH2:7]3
Reactant: C1=CC2C3C=CC(C3)C2C1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Solvent: C#Cc1ccccc1
Product: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Reaction time: 0.1 h

Procedure:
A 10.0 gram (75.6 mmol) amount of dicyclopentadiene was added to a 20 ml scintillation vial. A 5.0 milligram (7.2 μmol) amount of RuClH(H2)(PCy3)2 was added. One equivalent of phenylacetylene per equivalent of RuClH(H2)(PCy3)2 was added via the addition of 0.1 mls of 72 mM solution of phenylacetylene. Ten equivalents of hexachloroethane per equivalent of RuClH(H2)(PCy3)2 were charged via the addition of 1.0 mls of a 72 mM solution. The ring opening polymerization of dicyclopentadiene was observed by a gradual thickening of the solution to a rubbery viscous material after six minutes. After one hour, a solid rubbery material had formed.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][N:6]=1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C>O>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:2]2[S:3][C:4]([C:7]([C:9]3[C:17]4[C:12](=[N:13][CH:14]=[CH:15][CH:16]=4)[NH:11][CH:10]=3)=[O:8])=[CH:5][N:6]=2)=[CH:21][CH:20]=1
Reactant: O=C(c1cnc(Br)s1)c1c[nH]c2ncccc12
Reactant: NCc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(c1cnc(NCc2ccc(Cl)cc2)s1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
A mixture of (2-Bromo-thiazol-5-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (99, 5 mg, 0.02 mmol), p-chlorobenzylamine (61, 10 mg, 0.08 mmol), and N,N-Diisopropylethylamine (10 μL, 0.08 mmol) in tetrahydrfuran (10 mL), in a sealed reaction vessel, was stirred room temperature overnight. The reaction mixture was poured into iced water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a light yellow solid (P-0077, 2 mg, 30%). MS (ESI) [M+H+]=305.90, 307.88.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12](O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:23]=[CH:22][C:19](C=O)=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](/[CH:11]=[CH:12]/[C:19]2[CH:22]=[CH:23][C:16]([CH3:15])=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: O=C(O)CS(=O)(=O)c1ccc(Cl)cc1
Product: Cc1ccc(/C=C/S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 60 %

Procedure:
A solution of 4-chlorophenyl sulfonylacetic acid (0.01 mol) and 4-methylbenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 60-64% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][C:13](=O)O[C:10](=O)[CH2:9]2)=[CH:4][CH:3]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH2:16]([N:23]1[CH2:13][CH2:14][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CC(c2ccc(Br)cc2)CC(=O)O1
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Product: Brc1ccc(C2CCN(Cc3ccccc3)CC2)cc1
Temperature: 100 °C
Yield: 50.2 %

Procedure:
To a 250 mL round-bottomed flask equipped with condenser and N2 inlet were added 4.77 g (17.72 mmol) 3-(4-bromophenyl)glutaric anhydride (prepared as described in J. Org. Chem., 21, 704 (1956)), 1.90 g (17.72 mmol) benzylamine, and 80 mL toluene. The reaction was refluxed 1.5 hours cooled, and concentrated. The residue was taken up in 80 mL acetic anhydride, and heated at 100° C. for 16 hours then cooled and evaporated several times with toluene to remove excess acetic anhydride. The residue was dissolved in 80 mL dry tetrahydrofuran and treated with 40 mL (80 mmol) of a 2 N solution of borane methyl sulfide in tetrahydrofuran. The reaction was refluxed 18 hours cooled, and evaporated, then dissolved in 80 mL ethanol and treated with 3.5 g sodium carbonate and 3.5 g cesium fluoride. The reaction was refluxed 16 hours cooled, and concentrated. The residue was taken up in water and ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using ethyl acetate/hexane as eluant to afford 2.94 g (50%) of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[C:11](Cl)(=[O:15])[C:12]([CH3:14])=[CH2:13]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])=[CH:3][C:4]=1[CH3:10])#[N:7]
Reactant: Cc1cc(N)ccc1C#N
Reactant: C=C(C)C(=O)Cl
Product: C=C(C)C(=O)Nc1ccc(C#N)c(C)c1

Procedure:
N-(4-Cyano-3-methylphenyl)-2-methylacrylamide was prepared as described in Example 1 starting from 4-amino-2-methylbenzonitrile and methacryloyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C@H:22]([O:24][CH3:25])[CH3:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26]N1C(=O)CCC1=O>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C@H:22]([O:24][CH3:25])[CH3:23])=[C:14]([Cl:26])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CO[C@H](C)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Reactant: O=C1CCC(=O)N1Cl
Product: CO[C@H](C)c1nc2c(cc1Cl)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 5, intermediate from (4R,9aR)-6-(1-(R)-methoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and N-chlorosuccinimide.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N=C(N(C)C)N(C)C)(C)(C)C.[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]2[CH2:31][CH2:30][N:29]([C@H:32]3[CH2:36][CH2:35][N:34]([C:37]4[CH:42]=[C:41]([F:43])[C:40]([S:44](Cl)(=[O:46])=[O:45])=[C:39]([F:48])[CH:38]=4)[C:33]3=[O:49])[CH2:28]2)[CH:23]=[C:24]([Cl:26])[CH:25]=1>C(#N)C.CS(C)=O>[Cl:26][C:24]1[CH:23]=[C:22]([CH:27]2[CH2:31][CH2:30][N:29]([C@H:32]3[CH2:36][CH2:35][N:34]([C:37]4[CH:42]=[C:41]([F:43])[C:40]([S:44]([NH:1][C:2]5[S:3][CH:4]=[CH:5][N:6]=5)(=[O:45])=[O:46])=[C:39]([F:48])[CH:38]=4)[C:33]3=[O:49])[CH2:28]2)[CH:21]=[C:20]([Cl:19])[CH:25]=1
Reactant: Nc1nccs1
Reactant: O=C1[C@@H](N2CCC(c3cc(Cl)cc(Cl)c3)C2)CCN1c1cc(F)c(S(=O)(=O)Cl)c(F)c1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CS(C)=O
Solvent: CC#N
Product: O=C1[C@@H](N2CCC(c3cc(Cl)cc(Cl)c3)C2)CCN1c1cc(F)c(S(=O)(=O)Nc2nccs2)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Synthesized according to General Procedure 12, Method B. To a solution of 2-aminothiazole (35 mg, 0.35 mmol) in acetonitrile (0.4 mL) at 0° C. was added 2-tert-butyl-1,1,3,3-tetramethylguanidine (61 mg, 0.35 mmol) dropwise and the reaction mixture stirred at 0° C. for 10 min. 4-[(3′S)-3-(3,5-dichlorophenyl)-2′-oxo-1,3′-bipyrrolidin-1′-yl]-2,6-difluorobenzene-1-sulfonyl chloride (60 mg, 0.12 mmol) was added and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was diluted with DMSO, filtered and purified by reverse phase HPLC using 5%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to afford 4-[(3′S)-3-(3,5-dichlorophenyl)-2′-oxo-1,3′-bipyrrolidin-1′-yl]-2,6-difluoro-N-(thiazol-2-yl)benzenesulfonamide. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=573.3; tR=1.32 min.
Reaction SMILES: [NH2:1][C:2]1[N:20]=[C:5]2[C:6]([O:10][CH2:11][C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14]#[N:15])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([C:24]2[CH:25]=[C:26]([NH:1][C:2]3[N:20]=[C:5]4[C:6]([O:10][CH2:11][C:12]5[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=5[C:14]#[N:15])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:27]=[CH:22][CH:23]=2)[CH2:29][CH2:30]1
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Reactant: N#Cc1ccccc1COc1cccn2nc(N)nc12
Product: CN1CCN(c2cccc(Nc3nc4c(OCc5ccccc5C#N)cccn4n3)c2)CC1

Procedure:
2-{2-[3-(4-Methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yloxymethyl}benzonitrile was prepared from 2-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yloxymethyl)-benzonitrile (115.0 mg, 0.434 mmol) and 1-(3-bromo-phenyl)-4-methyl-piperazine (128 mg, 0.500 mmol in a manner analogous to Example 2d. Product was isolated as a pale orange solid (0.111 g, 58%). MP=68-70° C. (foam). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.46 (s, 1H), 8.43 (d, J=6.4 Hz, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.81-7.79 (m, 2H), 7.64-7.62 (m, 1H), 7.33 (s, 1H), 7.20 (d, J=7.2 Hz, 1H), 7.09 (d, J=4.8 Hz, 2H), 6.96-6.92 (m, 1H), 6.47-6.44 (m, 1H), 5.50 (s, 2H), 3.12-3.09 (m, 4H), 2.44-2.42 (m, 4H), 2.22 (s, 3H). MS=440 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10](O)(=O)[CH:11]([CH3:13])[CH3:12]>>[CH:11]([C:13]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][C:6]=2[CH3:9])([CH3:12])[CH3:10]
Reactant: Cc1ccnc(N)c1N
Reactant: CC(C)C(=O)O
Product: Cc1ccnc2nc(C(C)C)[nH]c12

Procedure:
The title compound was prepared from 2,3-diamino-4-picoline (0.246 g, 2 mmol) and isobutyric acid (0.19 ml, 2 mmol) according to the procedure described in Step 1 of Example 9. The crude product was purified by flash chromatography on silica-gel using EtOAc-MeOH (20:1) to give the pure product (0.25 g, 72%) as a tan colored solid. 1H NMR (300 MHz, CDCl3): 8.21 (d, 1H, J=5 Hz), 7.05 (d, 1H, J=5 Hz), 3.40 (m, 1H), 2.71 (s, 3H), 1.55 (d, 6H, J=7 Hz). FAB-MS: m/e 176 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:32][CH2:31][CH2:30][C@@:7]2([CH2:11][C@H:10]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]1O)=[O:4].CS(Cl)(=O)=O.O>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH2:32][CH2:31][CH2:30][C@@:7]2([CH2:11][C@H:10]([O:12][Si:13]([C:26]([CH3:29])([CH3:27])[CH3:28])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:9][CH2:8]2)[CH:6]=1)=[O:4]
Reactant: COC(=O)C1CCC[C@]2(CC[C@@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)C1O
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)C1=C[C@]2(CCC1)CC[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 36.3 %

Procedure:
To a solution of the crude (2R,5R)-2-(tert-butyldiphenylsilanyloxy)-6-hydroxy-spiro[4.5]decane-7-carboxylic acid methyl ester (1.76 g) obtained in Step 5 in pyridine (5 mL) was added methanesulfonyl chloride (0.25 mL) under ice-cooling, followed by stirring the mixture at room temperature for 15 hours. Then, to the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was dissolved in tetrahydrofuran (10 mL). To this solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.88 mL), followed by stirring the mixture at 70° C. for 3.5 hours. After cooling down to room temperature and adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N aqueous hydrochloric acid solution and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:30 to 1:25) to give (2R,5R)-2-(tert-butyldiphenylsilanyloxy)-spiro[4.5]dec-6-en e-7-carboxylic acid methyl ester (0.615 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1F.[ClH:18].Cl.[NH:20]1[C:24]2=[N:25][CH:26]=[CH:27][C:28]([O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36]C4N=CC=CC=4C(NC4C=CC=CC=4C)=O)=[CH:32][C:31]=3[F:53])=[C:23]2[CH:22]=[CH:21]1>>[ClH:1].[ClH:18].[NH:20]1[C:24]2=[N:25][CH:26]=[CH:27][C:28]([O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:11]4[N:12]=[CH:13][CH:14]=[CH:15][C:10]=4[C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[O:17])=[CH:32][C:31]=3[F:53])=[C:23]2[CH:22]=[CH:21]1
Reactant: O=C(Nc1ccccc1Cl)c1cccnc1F
Reactant: Cc1ccccc1NC(=O)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: Cl
Product: O=C(Nc1ccccc1Cl)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Yield: 36 %

Procedure:
N-(2-Chlorophenyl)-2-fluoronicotinamide (0.050 g, 0.20 mmol) was converted to the title compound (0.037 g, 36%) in a manner similar to the preparation of 2-(4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-o-tolylnicotinamide (Step B of Example 8). 1H NMR (DMSO-d6) δ 12.75 (s, 1H), 10.80 (s, 1H), 10.49 (s, 1H), 8.10-8.44 (m, 4H), 7.24-7.60 (m, 7H), 6.96-7.10 (m, 1H), 6.70 (m, 1H), 6.45-6.50 (m, 1H); HRMS(ESI+), 474.1133 (M+H)+ calc, 474.1129 (M+H)+ found.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][N:8](C)[S:9]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[CH:32]=[CH:31][C:20]3=[N:21][CH:22]=[C:23]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[CH:24]=[C:19]3[C:18](=[O:33])[C:17]=2[CH:34]=1)(=[O:11])=[O:10].N[C:37]1[CH:42]=[CH:41]C=[CH:39][CH:38]=1>O1CCOCC1.O>[CH3:30][N:28]1[CH:29]=[C:25]([C:23]2[CH:24]=[C:19]3[C:18](=[O:33])[C:17]4[CH:34]=[C:13]([CH2:12][S:9]([NH:8][C:7]5[CH:41]=[CH:42][CH:37]=[CH:38][CH:39]=5)(=[O:10])=[O:11])[CH:14]=[CH:15][C:16]=4[CH:32]=[CH:31][C:20]3=[N:21][CH:22]=2)[CH:26]=[N:27]1
Reactant: CN(C)S(=O)(=O)Cc1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cnc3ccc4ccc(CS(=O)(=O)Nc5ccccc5)cc4c(=O)c3c2)cn1
Temperature: 180 °C

Procedure:
Cesium carbonate (80 mg, 0.245 mmol) was added to a solution of N,N-dimethyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide (50 mg, 0.122 mmol) and aniline (559 μL, 6.12 mmol) in dioxane (1113 μl) and water (111 μl) in a 0.5 ml to 2 ml microwave vial. The vial was then sealed and the mixture was heated to 180° C. for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.1% TFA, to afford the title compound as a yellow solid. 1H NMR (600 MHz, DMSO-D6) δ 9.84 (br s, 1H); 9.22 (d, 1H); 8.51 (d, 1H); 8.48 (s, 1H); 8.15 (s, 1H); 8.04 (d, 1H); 7.76 (d, 1H); 7.63 (dd, 1H); 7.38 (d, 1H); 7.32 (d, 1H); 7.27 (m, 2H); 7.16 (dd, 2H); 7.00 (m, 1H); 4.68 (s, 2H); 3.89 (s, 3H). LRMS (APCI) calculated for C25H21N4O3S [M+H]+, 457.1; found 457.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([C@H:12]([NH:22][C:23](=[O:38])CN2C3CCCCC=3C(C(F)(F)F)=N2)[CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[N:6][CH:7]=1.BrC1C([C@@H](NC(=O)[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])CC2C=C(F)C=C(F)C=2)=NC(SC)=NC=1.C(OC(C)(C)C)=O>>[Br:1][C:2]1[C:3]([C@@H:12]([NH:22][C:23](=[O:38])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[CH2:13][C:14]2[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=2)=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: CSc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)n1
Reactant: CS(=O)(=O)c1ncc(Br)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Agent: CC(C)(C)OC=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(S(C)(=O)=O)ncc1Br

Procedure:
The title compound (23B) was prepared according to the method presented for the synthesis of compound 11H of Example 11 utilizing 23A. MS (m/z) 394.03 [M+H-Boc]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][OH:12])[N:8]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[S:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[O:16][N:15]=2)[N:7]=1)=[O:5])[CH3:2].Br[CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][O:12][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[N:8]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[S:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[O:16][N:15]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(CO)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Reactant: COCCOCCBr
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(COCCOCCOC)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Reaction time: 0.17 h

Procedure:
To a solution of 100 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-hydroxymethyl-1H-pyrazole-3-carboxylic acid ethyl ester in 2 ml DMF 11 mg NaH (60% in mineral oil) were added at RT and stirred for 10 min. Then 100 mg 1-Bromo-2-(2-methoxy-ethoxy)-ethane were added and the mixture was stirred for 16 h. After addition of 5 ml of water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The crude residue was directly subjected to the next reaction step. Yield: 130 mg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1F.[CH:16]([N:29]1[CH2:32][CH:31]([C:33]#[N:34])[CH2:30]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH:16]([N:29]1[CH2:32][C:31]([C:3]2[CH:4]=[CH:5][C:6]([CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])=[CH:7][C:2]=2[Br:1])([C:33]#[N:34])[CH2:30]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(OCC)c1ccc(F)c(Br)c1
Reactant: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccc(C2(C#N)CN(C(c3ccccc3)c3ccccc3)C2)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a solution of 2-bromo-4-(diethoxymethyl)-1-fluorobenzene (Preparation 15, 10.0 g, 36.0 mmol) in THF (125 mL) was added 1-benzhydrylazetidine-3-carbonitrile (13.4 g, 54.1 mmol) and KHMDS (10.8 g, 54.1 mmol). The reaction mixture is left stirring at room temperature for 1 hour. Next, the reaction mixture is concentrated to an oil under vacuum, diluted with EtOAc, and washed 2× with water. The organic phase was dried (Na2SO4) and concentrated under vacuum. The crude material was chromatographed (220 g Redi-Sep column) eluting from 100% heptane to 20:80 EtOAc:heptane to afford the intermediate (13.7 g, 75%) as a solid. 1HNMR (CDCl3) δ ppm: 7.73 (1H), 7.48-7.44 (5H), 7.37-23 (6H), 7.13 (1H), 5.47 (1H), 4.33 (1H), 4.14 (2H), 3.65-3.52 (4H), 3.41 (2H), 1.29-1.25 (6H).