Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([CH:15](Br)[C:16]([O-:18])=[O:17])C1C=CC=CC=1.C(N(CC)CC)C>ClCCl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:15][C:16]([OH:18])=[O:17])[CH2:4][CH2:3]1
Reactant: O=C([O-])C(Br)Cc1ccccc1
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1-methylpiperazine (10.7 g), benzylbromoacetate (24 g), triethylamine (28 ml) and dichloromethane (100 ml) was stirred at ambient temperature for 4 hours. The reaction was concentrated to dryness, taken up in tetrahydrofuran (100 ml), filtered, and the filtrate evaporated to dryness. The residue was taken up in methanol (100 ml), treated with aqueous sodium hydroxide solution (100 ml, 1M) and stirred at reflux for 24 hours. The reaction was concentrated to dryness, diluted with water (100 ml) and then acidified to pH6.0 by addition of concentrated hydrochloric acid. The mixture was evaporated.. A portion of the resulting brown oil (2.0 g) was taken up in water (100 ml), treated with Dowex 50WX8 resin (80 g) and stirred at ambient temperature for 10 minutes. The mixture was filtered and the resin washed with water until the washings were neutral. The resin was then stirred with 2.0M aqueous ammonia (3×100 ml) for 5 minutes and filtered. The combined ammonia washings were concentrated to leave the title compound as a white waxy solid (0.8 g).
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[CH:46][C:45]=2[S:52]([C:54]2[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][C:55]=2[C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[C:64]([N+:69]([O-])=O)[CH:63]=2)=[O:53])=[CH:40][C:39]=1[N+:72]([O-])=O>>[NH2:69][C:64]1[CH:63]=[C:62]([C:55]2[CH:56]=[C:57]([O:60][CH3:61])[CH:58]=[CH:59][C:54]=2[S:52]([C:45]2[CH:46]=[CH:47][C:48]([O:50][CH3:51])=[CH:49][C:44]=2[C:41]2[CH:42]=[CH:43][C:38]([Cl:37])=[C:39]([NH2:72])[CH:40]=2)=[O:53])[CH:67]=[CH:66][C:65]=1[Cl:68]
Reactant: COc1ccc(S(=O)c2ccc(OC)cc2-c2ccc(Cl)c([N+](=O)[O-])c2)c(-c2ccc(Cl)c([N+](=O)[O-])c2)c1
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: COc1ccc(S(=O)c2ccc(OC)cc2-c2ccc(Cl)c(N)c2)c(-c2ccc(Cl)c(N)c2)c1
Yield: 86 %

Procedure:
Following the procedure described in Example 40 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of (4-chloro-3-nitrophenyl)-4-methoxyphenyl sulfoxide, the title compound is obtained.
Reaction SMILES: [CH2:1]([N:5]=[C:6]([OH:20])[C:7]1[C:8](=[C:12](Cl)[C:13](Cl)=[C:14](Cl)[C:15]=1Cl)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH2:1]([N:5]=[C:6]([OH:20])[C:7]1[C:8](=[C:12]([S:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([S:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:14]([S:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]=1[S:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCCN=C(O)c1c(Sc2ccccc2)c(Sc2ccccc2)c(Sc2ccccc2)c(Sc2ccccc2)c1C(=O)O

Procedure:
20 g (58.65 millimols) of tetrachlorophthalic acid N-n-butylimide, 26.49 g (240.5 millimols) of thiophenol, 49.04 g (355 millimols) of potassium carbonate and 200 ml of ethyl acetate are stirred at 25° C. for 18 hours and worked up as described in the preceding examples. After recrystallisation from toluene/cyclohexane, 35.99 g (97% of theory) of tetrakis-(phenylthio)-phthalic acid N-n-butylimide are obtained: melting point 159°-60° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:16](=[O:18])[CH3:17])[CH:7]=[C:8]([S:10]([F:15])([F:14])([F:13])([F:12])[F:11])[CH:9]=1)[CH3:2].[Br-:19].[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>C1COCC1.C(Cl)Cl>[Br:19][CH2:17][C:16]([C:6]1[CH:7]=[C:8]([S:10]([F:11])([F:12])([F:13])([F:15])[F:14])[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)=[O:18]
Reactant: [Br-]
Reactant: CCOc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1
Agent: C[N+](C)(C)c1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)CBr)cc(S(F)(F)(F)(F)F)c1
Yield: 125.4 %

Procedure:
1-[3-Ethoxy-5-(pentafluorosulfanyl)phenyl]ethanone (2.07 g) was dissolved in THF (80 ml) and phenyltrimethylammonium tribromide (2.90 g) was added while stirring. After stirring at RT for 3 h, the mixture was diluted with DCM and washed once with 5% sodium thiosulfate solution. The DCM phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel (120 g cartridge, n-heptane/MtB ether gradient of 0-20% within 60 min). 2.07 g of the title compound were obtained.
Reaction SMILES: [CH2:1]([C:3](Cl)=[O:4])[CH3:2].C(Cl)Cl.[N:9]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:26]=4[CH3:32])[C:23]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH:13]=[CH:12][N:11]=[CH:10]1>N1C=CC=CC=1>[N:9]1([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([NH:31][C:3](=[O:4])[CH2:1][CH3:2])=[CH:27][C:26]=4[CH3:32])[C:23]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: Cc1cc(N)ccc1-n1c(CCC(=O)O)ccc1-c1ccc(-n2ccnc2)cc1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)Nc1ccc(-n2c(CCC(=O)O)ccc2-c2ccc(-n3ccnc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of pyridine (1 mL) and C2H5COCl/DCM (v/v=1/100, 4.2 mL) was added a solution of 20B (see scheme 20) (150 mg, 0.389 mmol) in pyridine (1 mL) at 0° C. The mixture was stirred at room temperature overnight. The solvents were removed under reduced pressure and the resulting solid was acidified with 10% hydrochloric acid to pH=5.0. The resulting precipitate was isolated by centrifuge, rinsed with water, dried under reduced pressure to afford the crude product as a brown powder, After purification by prep-HPLC, 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(2-methyl-4-propionamidophenyl)-1H-pyrrol-2-yl)propanoic acid (32 mg, 19%) was obtained as a brown oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[C@H:4]([CH2:16][OH:17])[CH2:3]1.[H-].[Na+].S(OCC)(O[CH2:24][CH3:25])(=O)=O.O>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[C@H:4]([CH2:16][O:17][CH2:24][CH3:25])[CH2:3]1
Reactant: CN1CC[C@H](c2ccc(Cl)c(Cl)c2)[C@H](CO)C1
Reactant: CCOS(=O)(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC[C@@H]1CN(C)CC[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
A solution of (3) (2.4 g, 8.6 mmol) in tetrahydrofuran (40 ml) was added 60% NaH (0.69 g, 17 mmol) and stirred at room temperature for one hour. Diethyl sulfate (1.4 ml, 11 mmol) was added and the reaction mixture stirred over night. Water was added and the reaction mixture was extracted with diethyl ether (3×40 ml). The combined organic phases was dried with magnesium sulfate and evaporated to dryness. Column chromatography, using a mixture of dichloromethane, methanol and ammonia (aq) (9:1:1%) yielded 1.5 g (56%) of product (9) (oil).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Cl[CH2:32][C:33]#[C:34][CH2:35][OH:36].Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:32][C:33]#[C:34][CH2:35][OH:36])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1O2
Reactant: OCC#CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Product: OCC#CCN1CCN(C2Cc3cc(Cl)ccc3Oc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6 G. of 1-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine are dissolved in 65 ml. of ethanol. Subsequently, there are added successively 2.7 g. of sodium carbonate, 0.27 g. of sodium iodide. Then, a solution of 2.4 g. of 4-chloro-2-butyn-1-ol in 15 ml. of ethanol is added dropwise. The mixture is stirred for 16 hours at room temperature and thereafter for 3.5 hours at 40° C. The ethanol is then evaporated under reduced pressure and the residue partitioned between water and chloroform. The phases are separated, the aqueous solution is extracted with water and the chloroform extracts are washed with water. The solvent is evaporated, the residue dissolved in benzene and chromatographed over 140 g. of silica gel. Elution is carried out first with benzene. The 4-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-2-butyn-1-ol is eluted with benzene/methanol (99:1), which is obtained as an oil and is converted to the hydrochloride using the calculated amount of hydrogen chloride in ethanol. The hydrochloride crystallizes by the addition of ether; melting point 194°-195° C. (with decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:8][C:5]2=[N:6][CH:7]=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([NH:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:8][C:5]2=[N:6][CH:7]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc2cc(N)cnc2[nH]1
Reactant: O=C(Cl)c1ccccc1
Product: COC(=O)c1cc2cc(NC(=O)c3ccccc3)cnc2[nH]1
Yield: 55.4 %

Procedure:
The compound is prepared according to the protocol described in example A (stage 2) using 200 mg (1.04 mmol) of methyl 5-amino-1H-pyrrolo[2,3-b]pyridine-2-carboxylate and 121 μL (1.04 mmol) of benzoyl chloride instead of cyclopropanecarbonyl chloride. After treatment, 170 mg of beige solid is obtained (55%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C@@H:7]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=1)[C@H:6]2[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:23][CH:22]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C@@H:7]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1)[C@H:6]2[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]2[CH2:31][CH2:32][CH2:33][CH2:34]2)=[CH:23][CH:22]=1
Reactant: COc1cccc([C@@H]2COc3ccc(OC)cc3[C@@H]2c2ccc(OCCN3CCCC3)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cccc([C@@H]2COc3ccc(O)cc3[C@@H]2c2ccc(OCCN3CCCC3)cc2)c1

Procedure:
Thus, (±)-cis-6-methoxy-3-(3-methoxyphenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)-chromane (0.24 g, 0.52 mmol) was de-methylated by heating with pyridine hydrochloride (0.60 g, 5.20 mmol) to give the title compound, after purification and drying, as a colourless gum.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].II.N#N.[Cl:11][C:12]1[CH:13]=[C:14]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=[CH:16][C:17]=1[C:18]#[N:19]>C1COCC1>[NH2:19][CH2:18][C:17]1[CH:16]=[CH:15][C:14]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:13][C:12]=1[Cl:11]
Reactant: CS(=O)(=O)Nc1ccc(C#N)c(Cl)c1
Agent: II
Agent: N#N
Agent: [Al+3]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(CN)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.2 %

Procedure:
In a three-neck round-bottom flask containing a 0° C. solution of LiAlH4 (2M in THF) (26.0 mL, 52.0 mmol) was added iodine (6.60 g, 26.0 mmol) in THF (20 mL) dropwise under N2. After addition, the mixture was stirred for 30 min at 0° C. N-(3-chloro-4-cyanophenyl)methanesulfonamide (4 g, 17.34 mmol) in THF (20 mL) was then added dropwise. After addition, the reaction mixture was warmed to room temperature and stirred for 1 h, during which time precipitate crashed out of the solution. The reaction mixture was filtered, and the cake washed with cold THF. The cake was carefully transferred to a beaker which contained 60 mL of THF. The mixture was acidified to pH=2 with 6N HCl with constant stirring at 0° C. The layers were separated and the aqueous layer was washed with DCM (30 mL). The aqueous layer was concentrated by rotary evaporation. The resulting solids were washed with cold MeOH to give a yellow solid. The mother liquid was subjected to the same workup (2×). The combined crops were collected and dried to give the title compound as the HCl salt (4.2 g, 89%). MS (ES+): m/e 234.7 [M+H]+.
Reaction SMILES: F[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[C:3]=1[F:14].[CH3:15][C@H:16]1[CH2:21][C@@H:20]([CH3:22])[CH2:19][NH:18][CH2:17]1>>[CH3:15][C@H:16]1[CH2:21][C@@H:20]([CH3:22])[CH2:19][N:18]([C:2]2[C:11]([CH:12]=[O:13])=[CH:10][C:5]3[C:6]([CH3:9])=[N:7][O:8][C:4]=3[C:3]=2[F:14])[CH2:17]1
Reactant: Cc1noc2c(F)c(F)c(C=O)cc12
Reactant: C[C@@H]1CNC[C@H](C)C1
Product: Cc1noc2c(F)c(N3C[C@H](C)C[C@H](C)C3)c(C=O)cc12

Procedure:
Starting materials: 6,7-difluoro-3-methylbenzo[d]isoxazole-5-carbaldehyde (Intermediate 374) and (3S,5R)-3,5-dimethylpiperidine (HCl Salt).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:16](=[O:18])[CH3:17])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1.[CH:19](OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:15][C:11]1[CH:10]=[C:9]([N:8]2[C:7]3[CH:6]=[CH:5][C:4]([C:16](=[O:18])[CH3:17])=[CH:3][C:2]=3[N:1]=[CH:19]2)[CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccc(Nc2cccc(Br)c2)c(N)c1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)ncn2-c1cccc(Br)c1

Procedure:
This was prepared from 1-[3-amino-4-(3-bromo-phenylamino)-phenyl]-ethanone (86.5 g, 0.28 mol) by treatment with triethyl orthoformate in THF in the presence of p-toluenesulfonic acid as described in Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][CH:13]([CH2:16]OS(C4C=CC(C)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[C@H:38]1[CH2:43][CH2:42][C@H:41]([NH2:44])[CH2:40][CH2:39]1>>[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[C@H:38]1[CH2:43][CH2:42][C@H:41]([NH:44][CH2:16][C@@H:13]2[O:12][C:8]3=[C:9]4[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14]2)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]4)[CH2:40][CH2:39]1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc4nc(C)ccc4c3O2)cc1
Reactant: N[C@H]1CC[C@H](c2c[nH]c3ccc(F)cc32)CC1
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN[C@H]1CC[C@H](c2c[nH]c4ccc(F)cc42)CC1)O3

Procedure:
This compound was prepared in a manner similar to Example 1, using toluene-4-sulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.5 g, 1.29 mmol) and trans-4-(5-fluoro-1H-indol-3-yl)-cyclohexylamine (0.4 g, 1.72 mmol) to give 0.09 g (18%) product as the fumarate salt: MS (ESI) m/z 446 [M+H]+.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1([C:10](OCC)=[O:11])[CH2:9][CH2:8]1)=[O:6])[CH2:2][CH3:3].[BH4-].[Na+]>CCO>[OH:11][CH2:10][C:7]1([C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:6])[CH2:8][CH2:9]1
Reactant: CCCNC(=O)C1(C(=O)OCC)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCNC(=O)C1(CO)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.7 %

Procedure:
To a solution of ethyl 1-(propylcarbamoyl)cyclopropanecarboxylate (Example 183d) (1.65 g, 8.27 mmol) in EtOH (70 mL) was added NaBH4 (0.97 g, 25.64 mmol) at rt. The obtained mixture was stirred at rt over 2 days, quenched with 1.5M HCl and concentrated under reduced pressure. The concentrated mixture was extracted with EtOAc (4×70 mL), the combined extract was washed with saturated NaHCO3 and brine, and was dried over MgSO4. The filtrate was evaporated and the residue was purified by chromatography on silica gel using the solvent gradient hexanes→hexanes/EtOAc (1:9), to furnish 1.14 g (88%) of the product as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 7.49 (broad s, 1H), 5.09 (broad s, 1H), 3.49 (s, 2H), 3.05 (q, J=6.4 Hz, 2H), 1.41 (hex, J=7.6 Hz, 2H), 0.86-0.91 (m, 2H), 0.83 (t, J=7.2 Hz, 3H), 0.55-0.60 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[C:18]([F:30])[CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6]C=CC=1.CN(C)[C@@H]1CCN(C2C=CC(NC(=O)C3C=CC(O)=CC=3)=CC=2F)C1.C1(CBr)CC1>>[CH:2]1([CH2:1][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]4)=[C:18]([F:30])[CH:17]=3)=[O:14])=[CH:31][CH:32]=2)[CH2:7][CH2:6]1
Reactant: CN(C)[C@@H]1CCN(c2ccc(NC(=O)c3ccc(OCc4ccccc4)cc3)cc2F)C1
Agent: BrCC1CC1
Agent: CN(C)[C@@H]1CCN(c2ccc(NC(=O)c3ccc(O)cc3)cc2F)C1
Product: CN(C)[C@@H]1CCN(c2ccc(NC(=O)c3ccc(OCC4CC4)cc3)cc2F)C1

Procedure:
(R)-4-Benzyloxy-N-[4-(3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]benzamide underwent debenzylating hydrogenation by method B. The resulting (R)-N-[4-(3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-4-hydroxybenzamide was alkylated with cyclopropylmethyl bromide by method H. This resulted in the product with the molecular weight of 397.50 (C23H28N3O2); MS (ESI): 398 (M+H+). The following examples were likewise obtained by method H:
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[K+].CC[O:17]CC.Cl>CS(C)=O.O>[Br:1][C:2]1[C:3]([OH:17])=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOCC
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(Br)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A solution of 3-bromo-2,4-difluoro-1-nitrobenzene (10.5 g, 44 mmol) in dimethyl sulfoxide (85 ml) was stirred at ambient temperature. A solution of potassium hydroxide (14.1 g, 251 mmol) in water (21 ml) was added dropwise over 15 minutes. The black reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was then poured onto water (200 ml) and three ether extractions (100 ml) were performed. The aqueous layer was acidified with concentrated hydrochloric acid and extracted three times with ether (100 ml). The combined organic layers were dried over magnesium sulfate and filtered. Solvent was removed in vacuo to give a yellow solid (9.7 g, 93% yield). Recrystallization from isopropyl ether afforded an analytical sample: m.p. 65°-66° C. NMR (CDCl3, 60 MHz): 8.1 (dd, 1H, J=10, 5 Hz), 6.8 (dd, 1H, J=10, 8 Hz)
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([OH:30])[C@H:11]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33].O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:31][S:32]([O:30][C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C@H:11]([NH:22][C:23]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29])[C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=1)(=[O:34])=[O:33]
Reactant: CC(C)(C)OC(=O)N[C@H](c1ccc(C(F)(F)F)cc1)[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](c1ccc(C(F)(F)F)cc1)[C@H](CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of tert-butyl (1R,2R)-3-(tert-butyldimethylsilyloxy)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)-propylcarbamate (14.50 g, 32.3 mmol) in 50 mL DCM at −15° C. were added TEA (4.57 g, 45.2 mmol), N,N-dimethylpyridin-4-amine (0.197 g, 1.61 mmol), and methanesulfonyl chloride (3.26 mL, 41.9 mmol). The mixture was allowed to warm to room temperature. Distilled water (200 mL) was added, and the aqueous phase was extracted into DCM (2×200 mL). The combined organic layers were washed with cold 5% HCl, saturated sodium bicarbonate, and water. The resulting product was then chromatographed eluting with 15% EtOAc in hexane. After removing the solvent, the product was obtained as a colorless oil (15 g, yield=88%). 1H NMR (400 MHz, CD3OD) δ ppm 0.11 (d, J=3.91 Hz, 6 H) 0.93-0.98 (m, 9 H) 1.44 (s, 9 H) 2.84 (s, 3H) 3.80-3.87 (m, 2H) 4.84-4.86 (m, 1H) 5.13 (d, J=5.28 Hz, 1H) 7.58 (d, J=8.02 Hz, 2H) 7.69 (d, J=8.22 Hz, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][CH:11](C2C=CC(OC)=C(OC)C=2)[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].NC1C=C(C=CC=1)C(N)=O.[CH2:35]([O:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][C:43]=1[O:44][CH:45]([CH3:47])[CH3:46])[CH3:36].O.C(O)(=O)C=O>>[C:1]([C:4]1[CH:5]=[C:6]([NH:10][CH:11]([C:40]2[CH:41]=[CH:42][C:43]([O:44][CH:45]([CH3:47])[CH3:46])=[C:38]([O:37][CH2:35][CH3:36])[CH:39]=2)[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: COc1ccc(C(Nc2cccc(C(N)=O)c2)C(=O)O)cc1OC
Reactant: CCOc1cc(B(O)O)ccc1OC(C)C
Agent: NC(=O)c1cccc(N)c1
Agent: O=CC(=O)O
Solvent: O
Product: CCOc1cc(C(Nc2cccc(C(N)=O)c2)C(=O)O)ccc1OC(C)C
Yield: 80 %

Procedure:
11A was prepared in a procedure similar to that of 1A using 3-aminobenzamide, 3-ethoxy-4-isopropoxyphenylboronic acid and glyoxylic acid monohydrate. Yield: 80%. 1H NMR (400 MHz, CDCl3) δ ppm 1.16 (d, J=6.15 Hz, 6 H) 1.25 (t, J=7.03 Hz, 3H) 3.88-3.97 (m, 2H) 4.32-4.45 (m, 1H) 4.93 (s, 1H) 6.64-6.69 (m, 1H) 6.80 (d, J=8.35 Hz, 1H) 6.92 (dd, J=8.35, 2.20 Hz, 1H) 6.95-7.07 (m, 4H). LCMS: 373 (M+1).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+]([O-])=O)[C:5]=1[CH3:13])([O-])=O.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CN(C=O)C>[CH3:16][N:17]([CH:19]=[CH:13][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:4]=1)[CH3:18]
Reactant: Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1ccccc1
Yield: 139.3 %

Procedure:
A mixture solution of 2,6-dinitrotoluene (18.2 g, 0.1 mol) and N,N-dimethylformamide dimethylacetal (28 mL, d=0.89, 0.2 mol) in anhydrous DMF (80 mL) was refluxed for 5 h. The mixture was then evaporated to concentrate to a reddish-black oil. After run flash column using CH2Cl2:MeOH (10:1) as eluent to give a red crystalline solid intermediate, 2,6-dinitro-trans-{circumflex over (α)}-dimethylaminostyrene (20.5 g, yield 86%).