Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([N+:11]([O-])=O)[C:3]=1[NH2:4].Cl[Sn]Cl.C([O-])(O)=O.[Na+].FC1C(F)=CC(N)=C(N)C=1>C(OCC)(=O)C.O.C(O)C>[Cl:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:11])[CH:6]=[C:7]([F:10])[C:8]=1[F:9]
Reactant: Nc1c([N+](=O)[O-])cc(F)c(F)c1Cl
Agent: Cl[Sn]Cl
Agent: Nc1cc(F)c(F)cc1N
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Nc1cc(F)c(F)c(Cl)c1N
Temperature: 25 °C

Procedure:
3-Chloro-4,5-difluoro-1,2-diaminobenzene was prepared using an adaptation of the method of Bellamy et al. (Bellamy, F. D. et al., Tetrahedron Lett. 25: 839 (1984)) A mixture of 2-chloro-3,4-difluoro-6-nitroaniline (160 mg, 0.767 mmol) and SnCl2 2H2O (0.863 g, 3.84 mmol) was dissolved in 5 mL ethyl acetate and 2 mL absolute ethanol under N2 and heated at 75 ° C. for 5 h. The reaction was allowed to cool to room temperature and poured into 50 mL H2O. Sufficient sat'd NaHCO3 solution was added (foaming!) to bring the pH to 7. The resulting mixture was extracted with 3×20 mL ethyl acetate and the combined organic extracts washed with 20 mL sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a brown solid, 124 mg (91%). 1H NMR (CDCl3) δ 3.52 (br s, 4H, 2(NH2)); 6.49 (dd, 1H, JHF =7.5, 10.8 Hz, H-6). There was 13% 4,5-difluoro-1,2-diaminobenzene present by NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5](O)=[O:6].[CH3:29][NH2:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[NH:30][CH3:29])[CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: CN
Reactant: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)O)cc1Cl
Product: CNC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1

Procedure:
3-Chloro-4-(N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and methylamine were reacted by a procedure similar to Example 47 to give 250. MS: (ESI+) 427.2
Reaction SMILES: [Na].Br[C:3]1[N:4]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([O:13][CH:14]([CH3:18])[CH2:15][O:16][CH3:17])[N:6]=2.[CH3:25][OH:26]>>[CH3:18][CH:14]([O:13][C:7]1[N:6]=[C:5]2[C:10]([N:11]=[C:3]([O:26][CH3:25])[N:4]2[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[C:9]([NH2:12])[N:8]=1)[CH2:15][O:16][CH3:17]
Reactant: CO
Reactant: COCC(C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Agent: [Na]
Product: COCC(C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1

Procedure:
Sodium (1.16 g, 50.5 mmol) was dissolved in methanol (40 ml) and 8-bromo-2-{[1-methyl-2-(methoxy)ethyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (6.5 g, 16.8 mmol) added with stirring. The mixture was heated to reflux for 2 h. The solvent was removed by evaporation. The residue was purified on a silica column using DCM: MeOH 150:1 as eluent. This gave product (4.7 g, 82.9%).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH3:34][C:35]1[C:43]2[CH:42]=[C:41]([C:44](=[O:47])[CH2:45][CH3:46])[S:40][C:39]=2[CH:38]=[CH:37][CH:36]=1>O1CCCC1>[Br:1][CH:45]([CH3:46])[C:44]([C:41]1[S:40][C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:34])[C:43]=2[CH:42]=1)=[O:47]
Reactant: [Br-]
Reactant: CCC(=O)c1cc2c(C)cccc2s1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc2sc(C(=O)C(C)Br)cc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 46.7 %

Procedure:
Phenyltrimethylammonium tribromide (1.47 g) was added in portions under nitrogen at 0° C. over 10 minutes to a stirred solution of 1-(4-methylbenzo[b]thiophen-2-yl)propan-1-one (0.53 g) in tetrahydrofuran (15 ml), then the mixture was stirred at 0° C. for 3 hours and at ambient temperature for 16 hours. Further phenyltrimethylammonium tribromide (0.49 g) was added, then the mixture was stirred at ambient temperature for 26 hours and filtered. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica using a 4:1 mixture of petroleum ether (b.p. 60-80° C.) and dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 2-bromo-1-(4-methylbenzo[b]thiophen-2-yl)propan-1-one (0.3 g) as a yellow solid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH2:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][NH:37]2)=[O:33])=[CH:4][N:3]=1.[C:42](O)(=[O:44])[CH3:43]>>[C:42]([N:37]1[CH2:38][CH2:39][CH2:40][CH2:41][CH:36]1[CH2:35][NH:34][C:32]([C:5]1[C:6]2[S:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:7]=2[C:2]([NH2:1])=[N:3][CH:4]=1)=[O:33])(=[O:44])[CH3:43]
Reactant: COc1cc(-c2csc3c(C(=O)NCC4CCCCN4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CC(=O)O
Product: COc1cc(-c2csc3c(C(=O)NCC4CCCCN4C(C)=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
4-Amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)-N-(piperidin-2-ylmethyl)thieno[3,2-c]pyridine-7-carboxamide (0.090 g, 0.16 mmol) and acetic acid (0.012 g, 0.17 mmol) were treated according to General Procedure D to provide the title compound. LCMS Conditions a: 3.11 minute, 611.1 (MH+).
Reaction SMILES: [CH3:1][C:2]([NH2:6])([CH3:5])[C:3]#[CH:4].[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([F:21])[C:16]=1[O:17][CH2:18][C:19]#[CH:20])[C:11](Cl)=[O:12]>>[CH3:1][C:2]([NH:6][C:11](=[O:12])[C:10]1[CH:14]=[C:15]([F:21])[C:16]([O:17][CH2:18][C:19]#[CH:20])=[C:8]([F:7])[CH:9]=1)([CH3:5])[C:3]#[CH:4]
Reactant: C#CCOc1c(F)cc(C(=O)Cl)cc1F
Reactant: C#CC(C)(C)N
Product: C#CCOc1c(F)cc(C(=O)NC(C)(C)C#C)cc1F

Procedure:
According to the same method as that of Production Example 1, 1,1-dimethyl-2-propynylamine was used in place of 2,2-dimethylpropylamine, 3,5-difluoro-4-(2-propynyloxy)benzoyl chloride was used in place of 4-(2-propynyloxy)-3-methoxybenzoyl chloride to obtain N-(1,1-dimethyl-2-propynyl)-3,5-difluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 51 of the present invention) represented by the formula:
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH:7]([CH:9]=[CH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.[CH3:26][O+](C)C>C(Cl)Cl>[CH3:26][O:1][C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH:9]=[CH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[N:8]=1
Reactant: C[O+](C)C
Reactant: COC(=O)c1ccccc1C=CC1CCCCC(=O)N1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccccc1C=CC1CCCCC(OC)=N1

Procedure:
The product of Example 79 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([O:28][CH2:29][C:30]([O:32]C)=[O:31])[C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][C:20]=2[C:34](=[O:36])[NH2:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([O:28][CH2:29][C:30]([OH:32])=[O:31])[C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][C:20]=2[C:34](=[O:36])[NH2:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1ccccc1Cc1ccccc1
Yield: 45.2 %

Procedure:
A solution of the {9-[(2-benzylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (16.2 mg, 0.034 mM) and 0.034 mL (0.034 mM) of 1 N NaOH in 3 mL of ethanol was stirred for 16 hours at 25° C. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH, then dried in vacuo to afford 7.1 mg (70%) of the {9-[(2-benzylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (DMSO-d6) δ7.5-6.8 (m, 14H), 6.65 (d, 1H, J=8 Hz), 6.55 (d, 1H, J=8 Hz), 6.05 (d, 1H, J=8 Hz), 5.55 (s, 2H), 4.35 (s, 2H), and 4.3 (s, 2H). IR (CDCl3, cm−1) 1666, 1616, 1495, 1452, and 1422. MS (ES) m/e 463, 465.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([O:11][CH2:12][CH2:13][CH3:14])[N:3]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]#[N:8])=[C:4]([O:11][CH2:12][CH2:13][CH3:14])[N:3]=1
Reactant: CCCOc1nc(Cl)ccc1C(N)=O
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCOc1nc(Cl)ccc1C#N
Temperature: 55 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of 6-chloro-2-propoxy-nicotinamide (3.80 g, 17.71 mmol) and pyridine (8.50 mL, 106.21 mmol) in acetonitrile (25 mL) was added phosphorus oxychloride (4.81 mL, 53.13 mmol) over a period of 5 min. The reaction was stirred at 55° C. for 1 h. Acetonitrile was evaporated in vacuo and the resulting residue was neutralized with 1N NaOH at 0° C. until pH reached to ˜7. The reaction mixture was extracted with EtOAc (100 mL). The organic layer was collected and the aqueous layer was further extracted with EtOAc (3×50 mL). All organics were combined washed with brine (2×25 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give yellow oil. Purification was accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes gradient elution to yield the title compound (3.4 g, 98%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.29 (d, J=7.9 Hz, 1H), 7.29 (d, J=7.9 Hz, 1H), 4.31 (t, J=6.5 Hz, 2H), 1.79-1.66 (m, 2H), 0.96 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH:1]1([N:5]([CH3:28])[C:6](=[O:27])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=3[CH3:24])[CH:10]=[CH:9][C:8]=2[O:25]C)[CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>O>[CH:1]1([N:5]([CH3:28])[C:6](=[O:27])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=3[CH3:24])[CH:10]=[CH:9][C:8]=2[OH:25])[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)N(C)C1CCC1
Agent: BrB(Br)Br
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(C(=O)N(C)C2CCC2)c1

Procedure:
N-Cyclobutyl-5-(2,6-dimethyl-4-nitro-phenoxy)-2-hydroxy-N-methyl-benzamide was prepared from N-cyclobutyl-5-(2,6-dimethyl-4-nitro-phenoxy)-2-methoxy-N-methyl-benzamide according to a procedure analogous to that described in EXAMPLE 2, Step B. Boron tribromide (1M in dichloromethane, 2.0 equiv) was used. After water addition, the mixture was extracted with dichloromethane (3×10 ml). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated. The title product of Step E was used in the next step without purification. MS (APCI+) Calc.: 370.4, Found: 371.1 (M+1).
Reaction SMILES: [BH4-].[Na+].Br[C:4]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:5]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>CN(C)C(=O)C.O.O.O.O.O.O.[Co](Cl)Cl>[CH:5]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH:4]1[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)C1CC1(Br)C(=O)OC(C)(C)C
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)C1CC1C(=O)OC(C)(C)C
Yield: 100 %

Procedure:
Sodium borohydride (35.7 mg, 0.944 mmol) was added to and dissolved in N,N-dimethylacetamide (1.5 mL) at room temperature, followed by addition of an N,N-dimethylacetamide solution (1.0 mL) of di-tert-butyl 1-bromocyclopropane-1,2-dicarboxylate (cis/trans=11/89) (hereinafter the compound will be referred to as “compound (4c)”) (202 mg, 0.629 mmol) at 10° C. Without manipulating the temperature of the reaction, cobalt chloride hexahydrate (0.7 mg, 0.003 mmol) was added to the resultant solution. After completion of addition, the resultant mixture was stirred at 10° C. for 15 minutes. After completion of reaction, the entirety of the reaction mixture was diluted with an HPLC mobile phase to 20 mL, to thereby yield a solution containing 152.4 mg (yield: 100%) of the title compound. Yield was determined by means of high performance liquid chromatography (HPLC) (the same shall apply hereinafter).
Reaction SMILES: [CH2:1]([I:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].C(O)C.[CH2:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH3:17].C(OCC)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:1]([I:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[CH2:16]([NH+:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH3:17]
Reactant: CCN(CC)CC
Agent: C=CCCCCCCCCCI
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC[NH+](CC)CC

Procedure:
Undecylenyl iodide (15 grams), ethanol (120 milliliters), and triethylamine (55 grams) were added to a 500 milliliter round bottom flask equipped with a reflux condenser and a mechanical stirrer. The mixture was boiled at reflux for 46 hours. Solvent was then removed using a rotary evaporator and the residue was treated with diethyl ether and hexane to yield a brown-yellow solid. The solid dissolved in toluene was treated with diethyl ether and hexane to yield a light yellow powder. After isolation by filtration and washing with diethyl ether, the powder was dried in vacuum to yield the product, triethylammonium undecylenyl iodide (12.5 grams), which was identified by 13C NMR spectrometry.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Cl.Cl[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH2:12][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=Cc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2ccc3ccccc3n2)c1
Yield: 87.3 %

Procedure:
With stirring, a mixture of 3-hydroxybenzaldehyde (8.5 g), 2-chloromethylquinoline hydrochloride (17 g), and anhydrous potassium carbonate (100 g) in dimethylformamide (200 ml) was heated for 6 hours. After filtration, the solvent was removed with reduced pressure and the residue was partitioned between chloroform and water. The organic layer was dried and concentrated to an oil which upon cooling and treatment withhexane, gave the product as an off-white colored solid (16 g), m.p. 48°-53° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[C:18]([CH3:24])[N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([CH:32]2[CH2:36][CH2:35][CH2:34][NH:33]2)[CH2:28][CH2:27]1.CC([O-])(C)C.[Na+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1(C)C=CC=CC=1>[CH:21]([N:20]1[C:16]([C:10]2[N:11]=[C:12]3[C:13]4[CH:14]=[N:15][C:2]([N:33]5[CH2:34][CH2:35][CH2:36][CH:32]5[CH:29]5[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]5)=[CH:3][C:4]=4[O:5][CH2:6][CH2:7][N:8]3[CH:9]=2)=[N:17][C:18]([CH3:24])=[N:19]1)([CH3:23])[CH3:22]
Reactant: CN1CCC(C2CCCN2)CC1
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(Cl)cc2OCC3)n(C(C)C)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cn3c(n2)-c2cnc(N4CCCC4C4CCN(C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A 10 mL microwave vial was charged with 12-chloro-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca1(14), 2,4,10,12-Pentaene (160 mg, 0.470 mmol), toluene (4 mL), 1-methyl-4-(pyrrolidin-2-yl)piperidine (156 mg, 0.94 mmol), Pd(PtBu3)2(27 mg, 0.047 mmol), NaOtBu (135 mg, 1.40 mmol). The vial was sealed and degassed with N2 for three times. The resulting mixture was stirred at 110° C. for 1 h. After concentration, the residue was purified by reverse phase Combiflash eluting with a 0-50% gradient of CH3CN in 0.3% NH4HCO3 to give 249, which was separated by chiral HPLC (AD column, 30% EtOH (0.1% DEA) in n-hexane isocratic) to give: 9 mg of one enantiomer and 6 mg of the other (7% total yield)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[N:12]=[C:11]([C:21](O)=[O:22])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[N:12]=[C:11]([C:21]([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=[O:22])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1cc(-c2ccc(F)c(Cl)c2)n(-c2cccc(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Product: O=C1CN(C(=O)c2cc(-c3ccc(F)c(Cl)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 79A in analogy to the synthesis of the compound of Example 1. 52 mg (87% of theory) of the title compound are obtained.
Reaction SMILES: [O:1]([CH2:8][C:9]#[N:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[NH2:18][OH:19]>CCO.O>[OH:19][N:18]=[C:9]([NH2:10])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCOc1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(COc1ccccc1)=NO

Procedure:
A mixture of 1 g of phenoxyacetonitrile, 2.4 g of K2CO3 and 1.2 g of hydroxylamine hydrochloride in 60 ml of EtOH and 10 ml of water is heated at reflux for 3 hours. The reaction mixture is concentrated under vacuum and the residue is taken up in water and extracted with AcOEt. The organic phase is extracted with 1N HCl solution, the aqueous phase is alkalified by adding 1N NaOH solution, extracted with AcOEt and dried over MgSO4, and the solvent is evaporated under vacuum. This gives 0.9 g of the expected compound in the form of a colourless oil which crystallizes.
Reaction SMILES: [CH2:1]([O:8][N:9]([C:16](=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](Cl)=[O:37].C(ON(CCCCC#N)C(=O)CCCCCl)C1C=CC=CC=1>C(Cl)Cl.[OH-].[Na+]>[Cl:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](=[O:37])[N:21]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:20][CH2:19][CH2:18][CH2:17][C:16](=[O:30])[N:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15]
Reactant: N#CCCCCN(OCc1ccccc1)C(=O)CCCCNOCc1ccccc1
Reactant: O=C(Cl)CCCCCl
Agent: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#CCCCCN(OCc1ccccc1)C(=O)CCCCN(OCc1ccccc1)C(=O)CCCCCl

Procedure:
Compound (5) (2.44 g, 5.96 mmol) was reacted with 5-chlorovaleryl chloride (1.13 g, 7.29 mmol) in CH2Cl2 (150 mL) and 1N NaOH (200 mL) by the procedure used for (3). Silica gel column chromatography, eluting with 3% EtOH/CHCl3, gave (6) in quantitative yield as an oil: NMR δ 1.50-1.87 (m, 12H), 2.23-2.53 (m, 6H), 3.47 (t, 2H, J=6), 3.60 (t, 4H, J=6), 4.77 (s, 4H) , 7.33 (s, 10H) . Anal. (C29H38ClN3O4) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[K+].[Br-].O.[C:14]([OH:17])(=[O:16])[CH3:15]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:1]([C:4]1[CH:9]=[CH:8][C:15]([C:14]([OH:17])=[O:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)O
Agent: Cc1ccc([N+](=O)[O-])cc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1

Procedure:
600 of p-nitrotoluene was oxidized in 2700 ml of glacial acetic acid after the addition of 8 g KBr and 30 g Co(OAc)2 . 4H2O. The reaction product was suction filtered, washed and dried. The mother liquor was combined with the glacial acetic acid used for washing, and after the addition of 500 ml of benzene, the water was separated azeotropically. Benzene and excess acetic acid were removed by distillation down to a remainder of 2500 ml. After the addition of 600 g of p-nitrotoluene, the oxidation was performed again and the product was processed as before. The same procedure was repeated three more times. At reaction temperatures of 180° C, the oxidation of the total input amount of 3000 g of p-nitrotoluene gave a yield of 3313 g of p-nitrobenzoic acid (90.5% of the theory), 689 g of water having been removed (170% of the theory).
Reaction SMILES: C[O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].C([O-])(O)=O.[Na+]>Br.CCCCCC>[CH3:19][CH:18]([CH3:20])[CH2:17][CH2:16][N:11]1[C@@H:12]2[C@@H:8]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([OH:2])[C:15]=3[CH2:14][CH2:13]2)[CH2:9][CH2:10]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC(C)C
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Product: CC(C)CCN1CC[C@@H]2c3cccc(O)c3CC[C@@H]21
Temperature: 0 °C
Yield: 83.2 %

Procedure:
3.19 g (0.01167 mol) of rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-(3-methyl-butyl)-1H-benzo[e]indole were dissolved in 0.13 l of 48% aqueous HBr and boiled under reflux for 5 hours. The mixture was poured into an ice-cold aqueous solution of 46.3 g (1.16 mol) of NaOH. Solid NaHCO3 was added thereto and the mixture was extracted three times with CH2Cl2. The organic phase was washed with saturated aqueous NaHCO3 and NaCl solutions, dried with Na2SO4, filtered and concentrated. The product obtained by chromatography of the residue over silica gel with cyclohexane/ethyl acetate 2:1 was dissolved in hot n-hexane and crystallized at room temperature. There were obtained 2.52 g (75%) of rac-cis-2,3,3a,4,5,9b-hexahydro-3-(3-methyl-butyl)-1H-benzo[e]indol-6-ol as white crystals with m.p. 70°-72° and 0.59 g (16%) of oily material from the mother liquors.
Reaction SMILES: [F:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:8]2(O)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[O:13][CH3:14])[CH2:9][CH2:10][CH2:11]1
Reactant: COc1c(F)cccc1C1(O)CCC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(F)cccc1C1CCC1
Yield: 78.9 %

Procedure:
To a 500 mL round-bottomed flask were added a stir bar, 1-(3-fluoro-2-methoxyphenyl)cyclobutanol (5.21 g, 26.6 mmol), dry DCM (250 mL), Et3SiH (39.0 mL, 244 mmol) and TFA (20 mL, 260 mmol). The resultant mixture was stirred at rt for 22 h before concentrating to dryness and subjecting the residue to FCC to give 1-cyclobutyl-3-fluoro-2-methoxybenzene as a pale-yellow oil (3.78 g, 79%). 1H NMR (600 MHz, CDCl3) δ 7.03-6.99 (m, 1H), 6.99-6.95 (m, 1H), 6.91 (m, 1H), 3.86 (d, J=1.6, 3H), 3.83-3.72 (m, 1H), 2.39-2.28 (m, 2H), 2.19-2.07 (m, 2H), 2.07-1.98 (m, 1H), 1.89-1.80 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C1C=CC=CC=1>[N:17]1([C:2]2[N:3]=[C:4]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:5]3[S:11][CH2:10][CH2:9][CH2:8][C:6]=3[N:7]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: Clc1nc2c(c(N3CCCC3)n1)SCCC2
Solvent: c1ccccc1
Product: C1CSc2c(nc(N3CCNCC3)nc2N2CCCC2)C1
Yield: 61.1 %

Procedure:
10 g of 2-chloro-4-pyrrolidino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine, 10 g of piperazine and 50 ml of benzene were heated at a bath temperature of 70°-80° C. for 4 hours. The solvent was then distilled off and the resulting residue was dissolved in dichloromethane. The solution was washed with water and dried. The solvent was distilled off and the resulting crystals were washed thoroughly with diethyl ether to obtain 7.3 g (61% yield) of 2-piperazino-4-pyrrolidino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine.