Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:27])=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:28][CH2:29][O:30][C:5]2=[CH:4][CH:3]=1.[F:31][CH2:32][CH2:33]O>>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH2:33][CH2:32][F:31])=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:28][CH2:29][O:30][C:5]2=[CH:4][CH:3]=1
Reactant: OCCF
Reactant: CN1CCC(Oc2cc(O)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Product: CN1CCC(Oc2cc(OCCF)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1

Procedure:
Using an analogous procedure to that described in Example 51, 4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-(N-methylpiperidin-4-yloxy)quinazoline was reacted with 2-fluoroethanol to give the title compound; NMR Spectrum: (CDCl3) 2.0-2.1 (m, 2H), 2.15-2.3 (m, 2H), 2.35 (s, 3H), 2.3-2.4 (m, 2H), 2.8 (br s, 2H), 4.32 (m, 1H), 4.4 (m, 1H), 4.65 (m, 1H), 4.8 (m, 1H), 4.9 (m, 1H), 6.05 (s, 2H), 6.6 (s, 1H), 6.75 (d, 1H), 6.85 (s, 1H), 7.0 (d, 1H), 8.55 (s, 1H), 9.3 (s, 1H); Mass Spectrum: M+H+ 475 and 477.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C@@H:10]1[CH2:14][C@H:13]([S:15]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:12][N:11]1[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:36])(=[O:3])[NH2:2].SCCO>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[C:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C@@H:10]1[CH2:14][C@H:13]([SH:15])[CH2:12][N:11]1[C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=1)=[O:36])(=[O:3])[NH2:2]
Reactant: NC(=O)[C@@H]1CCCN1C[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: OCCS
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: NC(=O)[C@@H]1CCCN1C[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
To a solution of (2S,4S)-2-[(2S)-2-carbamoylpyrrolidin-1-yl]methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (1.76 g) in trifluoroacetic acid (10 ml) was added 2-mercaptoethanol (0.38 ml) under ice-cooling and the mixture was stirred at ambient temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure to give a residue The residue was dissolved in toluene (10 ml) and the solution was evaporated in vacuo. The resulting residue was dissolved in ethyl acetate (50 ml), washed successively with saturated aqueous sodium hydrogen carbonate (20 ml) and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-[(2S)-2-carbamoylpyrrolidin-1-yl]methyl-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.58 g).
Reaction SMILES: [F:1][C:2]([F:23])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([CH3:6])(O)[CH3:4].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[F:1][C:2]([F:23])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([CH3:6])=[CH2:4]
Reactant: CCCCCCCCCCCCCCCCC(F)(F)C(C)(C)O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: C=C(C)C(F)(F)CCCCCCCCCCCCCCCC
Temperature: 50 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
A solution of 160 mg of 3,3-difluoro-2-methyl-2-nonadecanol in 2 ml of pyridine containing 50 ul of phosphorous oxychloride is heated at 90° C. then allowed to cool to 50° C. An additional 250 ul of phosphorous oxychloride is added followed by heating at 90° C. for 2 hours. After allowing to stand at ambient temperature for 18 hours, the volatiles are removed and the concentrate partitioned between hexanes and 10% hydrochloric acid. The organic layer is washed with water and 10% sodium bicarbonate then dried and evaporated to a residue which is purified by chromatography on silica gel using hexane to give 140 mg of the desired product as an oil.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]([CH:14]1[CH2:16][CH2:15]1)#[CH:13]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:14]1([C:12]#[C:13][C:2]2[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH2:16][CH2:15]1
Reactant: Nc1ccc([N+](=O)[O-])cc1Br
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Nc1ccc([N+](=O)[O-])cc1C#CC1CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 23243.2 %

Procedure:
To a deoxygenated solution of 2-bromo-4-nitroaniline (2.17 g, 0.01 mmol), ethynyl-cyclopropane (1 g, 15 mmol) and CuI (10 mg, 0.05 mmol) in triethylamine (20 mL) was added Pd(PPh3)2Cl2 (210 mg, 0.3 mmol) under N2. The mixture was heated at 70° C. and stirred for 24 hours. The solid was filtered off and washed with EtOAc (50 mL×3). The filtrate was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to give 2-(cyclopropylethynyl)-4-nitroaniline (470 mg, 23%). 1H NMR (300 MHz, CDCl3) δ 8.14 (d, J=2.7 Hz, 1H), 7.97 (dd, J=2.7, 9.0 Hz, 1H), 6.63 (d, J=9.0 Hz, 1H), 4.81 (brs, 2H), 1.55-1.46 (m, 1H), 0.98-0.90 (m, 2H), 0.89-0.84 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH:3]=1.[Li]CCCC.[CH3:26][CH2:27][C:28](=[O:31])[CH2:29][CH3:30]>C1COCC1>[F:8][C:6]1[CH:7]=[C:2]([C:28]([OH:31])([CH2:29][CH3:30])[CH2:27][CH3:26])[CH:3]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH:5]=1
Reactant: COc1ccc(COc2cc(F)cc(Br)c2)cc1OC
Reactant: CCC(=O)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(O)(CC)c1cc(F)cc(OCc2ccc(OC)c(OC)c2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 1-bromo-3-(3,4-dimethoxybenzyloxy)-5-fluorobenzene (Step 1) (1.02 g) in THF (10 mL) at -78° C. was added n-BuLi (1.5 mL of a 2.2M solution) dropwise. After 30 min. 3-pentanone (0.33 mL) was added and after 30 min. the bath was removed and the mixture stirred for 10 min. The reaction mixture was quenched with NH4OAc buffer and extracted with EtOAc. The organics were dried (MgSO4) and concentrated. Chromatography of the residue (silica gel; hexane/EtOAc (3:1) provided the title compound as a colorless oil.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[C:6]([C:25]2[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][CH:26]=2)=[CH:7][C:8](=[O:24])[N:9]([CH2:11][CH2:12][C@@:13]([CH3:23])([S:19]([CH3:22])(=[O:21])=[O:20])[C:14]([O:16]CC)=[O:15])[CH:10]=1.Cl>C1COCC1.O>[F:4][C:5]1[C:6]([C:25]2[CH:26]=[CH:27][C:28]([S:31][CH3:32])=[CH:29][CH:30]=2)=[CH:7][C:8](=[O:24])[N:9]([CH2:11][CH2:12][C@@:13]([CH3:23])([S:19]([CH3:22])(=[O:21])=[O:20])[C:14]([OH:16])=[O:15])[CH:10]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(-c2ccc(SC)cc2)cc1=O)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(-c2cc(=O)n(CC[C@](C)(C(=O)O)S(C)(=O)=O)cc2F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
Lithium hydroxide monohydrate (165 mg, 6.68 mmol) was added to a solution of ethyl (2R)-4-{5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoate (0.492 g, 1.12 mmol) in THF:water (1:1, 14 mL) and the reaction was allowed to stir at rt for 18 h. The reaction mixture was acidified using 4 M aq HCl to afford a precipitate. The solid was collected via filtration and dried under vacuum to afford the title compound as a solid (339 mg, 73%). MS (LCMS) m/z 414.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (s, 3H) 2.17 (ddd, J=13.42, 10.00, 5.07 Hz, 1H) 2.41-2.45 (m, 1H) 2.49 (s, 3H), 3.14 (s, 3H) 3.78-4.15 (m, 2H) 6.46 (d, J=7.81 Hz, 1H) 7.28-7.39 (m, 2H) 7.43-7.55 (m, 2H) 8.01 (d, J=6.83 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)=[C:5]2[Cl:21].[CH3:22][O:23]C1C=CC(CC(C(O)=O)C(O)=O)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:23][CH3:22])=[CH:16][CH:15]=1)=[C:5]2[Cl:21]
Reactant: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Reactant: COc1ccc(CC(C(=O)O)C(=O)O)cc1
Product: COc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1

Procedure:
The title compound was prepared by substituting 2-(4-chlorobenzyl)malonic acid (Intermediate 3: step b) with 2-(4-methoxybenzyl)malonic acid (Intermediate 7: step b) then following the procedure described for the preparation of 6-bromo-2,4-dichloro-3-(4-chlorobenzyl)quinoline (Intermediate 3: step c).
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:4])[CH2:2][CH3:3].[CH:10](OC)(OC)OC.OS(O)(=O)=O>>[CH3:9][O:8][C:6](=[O:7])[CH:5]=[C:1]([O:4][CH3:10])[CH2:2][CH3:3]
Reactant: CCC(=O)CC(=O)OC
Reactant: COC(OC)OC
Agent: O=S(=O)(O)O
Product: CCC(=CC(=O)OC)OC
Reaction time: 8 h

Procedure:
To a mixture of methyl propionylacetate (104 g. 0.8 mole) and trimethyl orthoformate 98% (95.3 g, 0.88 mole) was added dropwise 1 ml of concentrated H2SO4 at room temperature and it was allowed to stir overnight. After neutralization with excess anhydrous K2CO3, the solution was filtered and distilled to yield the title ester, b.p. 55° C. (0.55 mm).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[F:22][C:23](=[CH2:27])[C:24](O)=[O:25].C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:22][C:23](=[CH2:27])[C:24]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:25]
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Reactant: C=C(F)C(=O)O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: C=C(F)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Temperature: 50 °C

Procedure:
Ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (0.028 g, 0.10 mmol), 2-fluoroacrylic acid (0.013 g, 0.15 mmol), 3-[(diethoxyphosphoryl)oxy]-1,2,3-benzotriazin-4(3H)-one (0.060 g, 0.20 mmol), and DIPEA (0.070 mL, 0.40 mmol) were suspended in DMA (1.0 mL) in a sealed tube. The reaction mixture was purged with argon and the reaction flask was capped and heated to 50° C. for 12 hours. The completed reaction was passed through a syringe filter, and was directly purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% NH4OH modifier to afford ethyl 4-{3-[(2-fluoroacryloyl)amino]phenyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C18H16FN4O3 [M+H]+: 355, found 355. 1H NMR (600 MHz, DMSO-D6) δ 12.99 (s, 1H), 10.44 (s, 1H), 8.91 (s, 1H), 8.32 (s, 1H), 8.09 (t, J=1.8 Hz, 1H), 7.87 (ddd, J=1.1, 2.1, 8.0 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.40 (dt, J=1.3, 7.7 Hz, 1H), 5.72 (dd, J=3.6, 47.6 Hz, 1H), 5.44 (dd, J=3.7, 15.6 Hz, 1H), 3.85 (q, J=7.1 Hz, 2H), 0.84 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:21]1([N:27]=[C:28]=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([NH:27][C:28]([NH:20][S:17]([C:15]2[CH:14]=[CH:13][C:10]3[CH2:11][CH2:12][N:6]([C:4](=[O:5])[NH:3][CH2:1][CH3:2])[CH2:7][CH2:8][C:9]=3[CH:16]=2)(=[O:18])=[O:19])=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCNC(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1
Reactant: O=C=NC1CCCCC1
Product: CCNC(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2CC1

Procedure:
By the reaction of 3-ethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide with cyclohexylisocyanate in a manner analogous to that described in Example 1, there is obtained 1-cyclohexyl-3-[(3-ethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]urea, m.p. 158°-160° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[C:9]2[C:4](=[C:5]([C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br-:29].[K+]>CS(C)=O.C1COCC1>[Br:29][C:10]1[C:9]2[C:4](=[C:5]([C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1
Reactant: [Br-]
Reactant: Cc1cc(C)c(-c2cccc3c(OS(=O)(=O)C(F)(F)F)cc(C)nc23)c(C)c1
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C)c(-c2cccc3c(Br)cc(C)nc23)c(C)c1
Temperature: 120 °C
Yield: 105.2 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 2-methyl-8-(2,4,6-trimethyl-phenyl)-quinolin-4-yl ester (426 mg, 1 mmol) and potassium bromide (KBr) (809 mg, 1.1 mmol) in a mixture of 1 ml of dry DMSO and 3 ml of dry THF was heated in 120° C. oil bath for 3 hours. The mixture was quenched with water, extracted with ethyl acetate. The organic layer was dried and concentrated to give 358 mg of the title compound as an off-white solid. 1H NMR (CDCl3) δ 8.16 (m,1H), 7.59 (m,1H), 7.56(s,1H), 7.48(m,1H), 6.97(s,1H), 2.53(s,3H), 2.37(s,3H), 1.87(,6H) ppm.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[F:9][C:10]([F:21])([F:22])[O:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:2]2[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][CH2:3]2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Br)o1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: OC[C@H]1CC[C@@H](c2ccc(OC(F)(F)F)cc2)O1

Procedure:
{cis-5-[4-(Trifluoromethoxy)phenyl]tetrahydrofuran-2-yl}methanol was prepared from 5-bromofuran-2-carbaldehyde and [4-(trifluoromethoxy)phenyl]boronic acid using a method analogous to that described in footnote 21.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=O)[CH:11]([C:15](=O)[CH2:16][CH3:17])[C:10](=[O:19])[CH2:9]1.O.[NH2:21][NH2:22].O.NN>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12]2[NH:22][N:21]=[C:15]([CH2:16][CH3:17])[C:11]=2[C:10](=[O:19])[CH2:9]1
Reactant: NN
Reactant: CCC(=O)C1C(=O)CC(c2ccccc2Cl)CC1=O
Solvent: O
Solvent: CCO
Product: CCc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Yield: 142.7 %

Procedure:
A solution of 5-(2-chlorophenyl)-2-propionylcyclohexane-1,3-dione (0.6 g) and hydrazine hydrate hydrazine hydrate (0.12 g) in ethanol (20 ml) was refluxed for 2 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give colorless crystals of 6-(2-chlorophenyl)-3-ethyl-4,5,6,7-tetrahydroindazol-4-one (0.47 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH2:3]1.CCN(C(C)C)C(C)C.[Cl:23][C:24]1[C:25]([C:31]#[N:32])=[N:26][CH:27]=[C:28](Cl)[N:29]=1>C1COCC1>[Cl:23][C:24]1[N:29]=[C:28]([NH:1][C@@H:2]2[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH2:3]2)[CH:27]=[N:26][C:25]=1[C:31]#[N:32]
Reactant: CN(C)C(=O)N1CCCC[C@@H](N)C1
Reactant: N#Cc1ncc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)N1CCCC[C@@H](Nc2cnc(C#N)c(Cl)n2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 28.1 %

Procedure:
(R)-3-Amino-N,N-dimethylazepane-1-carboxamide (508) (˜200 mg crude) was dissolved in THF (7 mL), and DIEA (0.30 mL, 1.7 mmol) was added, followed by 3,5-dichloropyrazine-2-carbonitrile (100 mg, 0.57 mmol). The reaction was stirred at RT for 12 hours. The solvents were removed under reduced pressure, and the residue was purified by silica column chromatography (MeOH, DCM) to give (R)-3-(6-chloro-5-cyanopyrazin-2-ylamino)-N,N-dimethylazepane-1-carboxamide (509) (53 mg, 0.16 mmol, 14% yield over 3 steps).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Br.[Br:12][CH2:13][CH2:14][NH2:15].[OH-].[Na+]>>[Br:12][CH2:13][CH2:14][NH:15][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: NCCBr
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCBr)c1ccc(F)cc1
Yield: 68.9 %

Procedure:
4-fluoro-benzoyl chloride (3 ml; 0.026 mol) was added dropwise to a cold (~0° C.). Stirring mixture of 2-bromo-ethyl-amine hydrobromide (5 g; 0.0236 mol) and 10% aqueous sodium hydroxide (21 ml; 0.052 mol). Crystalline product started to precipitate out of the reaction mixture almost immediately. After 15 minutes of stirring, the product was collected by filtration, triturated with diethyl ether and dried under vacuum giving the desired compound as a white solid (4 g).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNC1
Reactant: N#Cc1ccc(Cl)cc1
Product: N#Cc1ccc(N2CCCC2)cc1
Temperature: 100 °C
Yield: 33 %

Procedure:
To commercially available 4-chlorobenzonitrile 17 (5 g, 36 mmol) 12 ml of pyrrolidine were added and the reaction was heated at 100° C. for 24 hours in closed vessel. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The purification of the crude residue by chromatographic column using AcOEt 1/Petroleum ether 9 as eluant gave 1.68 g of a pale yellow solid. Yield=33% 1HNMR (DMSO, 200 MHz) δ 1.96 (4H, m), 3.28 (4H, m), 6.58 (2H, d, J=9 Hz), 7.51 (2H, d, J=9 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH2:6]1)=[O:4].[CH3:19]I.[H-].[Na+].Cl>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:19])[CH2:9][CH2:10]1)=[O:4]
Reactant: CI
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1

Procedure:
16.2 g (62.95 mmol) of trans-4-tert-butoxy carbonylamino-cyclohexanecarboxylic acid methyl ester and 5.87 mL (94.43 mmol, 1.5 eq) of methyl iodide in 100 ml DMF were treated under stirring and ice-cooling with 3.57 g (81.84 mmol, 1.3 eq) of NaH (55% in oil). The solution was stirred at RT for 20 h and then treated under ice-cooling with 1M HCl. The reaction mixture was dissolved in ether and washed 4 times with water. The ether-phases were concentrated under reduced pressure to yield 17.5 g (quantitative) of trans-4-(tert-butoxycarbonyl-methyl-amino)-cyclohexanecarboxylic acid methyl ester, MS: 201 (M−OC4H9).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14]>O1CCOCC1>[CH3:17][O:16][C:12](=[O:15])[CH2:13][CH2:14][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[N+:9]([O-:11])=[O:10]
Reactant: C=CC(=O)OC
Reactant: O=[N+]([O-])Cc1cccc(Cl)c1
Solvent: C1COCCO1
Product: COC(=O)CCC(c1cccc(Cl)c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a solution of 1 g (5.828 mmol) 1-chloro-3-nitromethyl-benzene (CAS: 38362-91-3) at 0° C. in 2 ml dioxane was added 0.512 g (5.828 mmol) methyl acrylate followed by 3.3 g Amberlyst A-21. The reaction mixture was stirred overnight at room temperature, filtered and the filtrate was dried over sodium sulfate and concentrated in vacuo. The crude product was purified with flash column chromatography on silica gel (Eluent: Heptane/ethyl acetate 0 to 10%) to provide 980 mg (65%) of the title compound as a colorless oil.
Reaction SMILES: Cl.[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.CCN(C(C)C)C(C)C.Br[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(#N)C>[CH2:31]([N:3]1[CH2:4][CH2:5][C:6]2[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:2]1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cn1c2c(c3ccccc31)CN(CCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
Step a): To a stirred solution of Intermediate 1 (50 mg, 0.17 mmol) and DIEA (73 μl, 0.42 mmol) in acetonitrile (1 ml) is added (2-bromo-ethyl)-benzene (26 μl, 0.19 mmol). The reaction mixture is stirred at rt overnight. The solvent is removed under reduced pressure and the crude product is purified by silica gel column chromatography (hexane/EtOAc 3:1, 1% NEt3), affording pure ethyl (2-phenethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-acetate (37 mg) in 60% yield: tR (LC-2) 1.69 min; ESI-MS (pos. ion): m/z 363.26 [M+H]+ (calcd 362.46 for C23H26N2O2).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][O:5][CH2:6][CH:7]=1.CN1CCOCC1.[N+:15]([C:18]1[CH:27]=[CH:26][C:21]([O:22][C:23](Cl)=[O:24])=[CH:20][CH:19]=1)([O-:17])=[O:16]>C(Cl)Cl>[N+:15]([C:18]1[CH:27]=[CH:26][C:21]([O:22][C:23]([O:1][CH2:2][C:3]2[CH2:4][O:5][CH2:6][CH:7]=2)=[O:24])=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCC1=CCOC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(OCC1=CCOC1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To 65 mg (0.65 mmol) of the compound from Example 336D in methylene chloride was added 0.079 mL of 4-methylmorpholine and 144 mg (0.715 mmol) of p-nitrophenoxycarbonylchloride. The mixture was stirred for 2 hours, diluted with solvent, washed with saturated brine, and the solvent removed. The residue was chromatographed on a silica gel column, eluting with 20% and 30% ethyl acetate in hexane. The solvent was removed and the product dried to afford 0.115 g of the title product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[Br:10][CH2:11][CH2:12][CH2:13]Br>>[Br:10][CH2:11][CH2:12][CH2:13][O:9][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8]
Reactant: Oc1c(F)cccc1F
Reactant: BrCCCBr
Product: Fc1cccc(F)c1OCCCBr

Procedure:
Analogously to Example 91b, 2.00 g of 2,6-difluorophenol and 30.7 g of 1,3-dibromopropane are reacted. The title compound is obtained as a colourless oil. Rf=0.70 (1:6 EtOAc-heptane); Rt=4.97.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:51])([CH3:50])[C:29]([F:49])([F:48])[C@:30]([C:33]3[CH:38]=[C:37](B4OCC(C)(C)CO4)[CH:36]=[CH:35][C:34]=3[F:47])([CH3:32])[N:31]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Br[C:53]1[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=1>>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:9]([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:50])([CH3:51])[C:29]([F:48])([F:49])[C@:30]([C:33]3[CH:38]=[C:37]([C:53]4[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=4)[CH:36]=[CH:35][C:34]=3[F:47])([CH3:32])[N:31]=2)([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:21][CH:20]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(B4OCC(C)(C)CO4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4ccc(C#N)cc4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 78.2 %

Procedure:
Reaction of [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-5-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (intermediate B10.1) (199 mg, 254 μmol) with 4-bromobenzonitrile (61.3 mg, 330 μmol) yielded the 3′-((R)-3-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-5-yl)-4′-fluoro-biphenyl-4-carbonitrile (137 mg, 78% yield) as a white foam. MS (ISP): m/z=690.4 [M+H]+.